Myeloma cells suppress osteoblasts through sclerostin secretion

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Colucci, S; Brunetti, G; Oranger, A [Department of Human Anatomy and Histology, University of Bari Medical School, Bari (Italy); Mori, G [Department of Biomedical Science, University of Foggia, Foggia (Italy); Sardone, F [Department of Human Anatomy and Histology, University of Bari Medical School, Bari (Italy); Specchia, G; Rinaldi, E; Curci, P; Liso, V [Department of Emergency and Organ Transplantation, Hematology Section, Bari University Medical School, Bari (Italy); Passeri, G [Department of Internal Medicine and Biomedical Sciences, Center for Metabolic Bone Diseases, University of Parma, Parma (Italy); Zallone, A [Department of Human Anatomy and Histology, University of Bari Medical School, Bari (Italy); Rizzi, R [Department of Emergency and Organ Transplantation, Hematology Section, Bari University Medical School, Bari (Italy); Grano, M [Department of Human Anatomy and Histology, University of Bari Medical School, Bari (Italy)

2011-06-01

Wingless-type (Wnt) signaling through the secretion of Wnt inhibitors Dickkopf1, soluble frizzled-related protein-2 and -3 has a key role in the decreased osteoblast (OB) activity associated with multiple myeloma (MM) bone disease. We provide evidence that another Wnt antagonist, sclerostin, an osteocyte-expressed negative regulator of bone formation, is expressed by myeloma cells, that is, human myeloma cell lines (HMCLs) and plasma cells (CD138+ cells) obtained from the bone marrow (BM) of a large number of MM patients with bone disease. We demonstrated that BM stromal cells (BMSCs), differentiated into OBs and co-cultured with HMCLs showed, compared with BMSCs alone, reduced expression of major osteoblastic-specific proteins, decreased mineralized nodule formation and attenuated the expression of members of the activator protein 1 transcription factor family (Fra-1, Fra-2 and Jun-D). Moreover, in the same co-culture system, the addition of neutralizing anti-sclerostin antibodies restored OB functions by inducing nuclear accumulation of β-catenin. We further demonstrated that the upregulation of receptor activator of nuclear factor κ-B ligand and the downregulation of osteoprotegerin in OBs were also sclerostin mediated. Our data indicated that sclerostin secretion by myeloma cells contribute to the suppression of bone formation in the osteolytic bone disease associated to MM.

Consensus guidelines on plasma cell myeloma minimal residual disease analysis and reporting.

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Arroz, Maria; Came, Neil; Lin, Pei; Chen, Weina; Yuan, Constance; Lagoo, Anand; Monreal, Mariela; de Tute, Ruth; Vergilio, Jo-Anne; Rawstron, Andy C; Paiva, Bruno

2016-01-01

Major heterogeneity between laboratories in flow cytometry (FC) minimal residual disease (MRD) testing in multiple myeloma (MM) must be overcome. Cytometry societies such as the International Clinical Cytometry Society and the European Society for Clinical Cell Analysis recognize a strong need to establish minimally acceptable requirements and recommendations to perform such complex testing. A group of 11 flow cytometrists currently performing FC testing in MM using different instrumentation, panel designs (≥ 6-color) and analysis software compared the procedures between their respective laboratories and reviewed the literature to propose a consensus guideline on flow-MRD analysis and reporting in MM. Consensus guidelines support i) the use of minimum of five initial gating parameters (CD38, CD138, CD45, forward, and sideward light scatter) within the same aliquot for accurate identification of the total plasma cell compartment; ii) the analysis of potentially aberrant phenotypic markers and to report the antigen expression pattern on neoplastic plasma cells as being reduced, normal or increased, when compared to a normal reference plasma cell immunophenotype (obtained using the same instrument and parameters); and iii) the percentage of total bone marrow plasma cells plus the percentages of both normal and neoplastic plasma cells within the total bone marrow plasma cell compartment, and over total bone marrow cells. Consensus guidelines on minimal current and future MRD analyses should target a lower limit of detection of 0.001%, and ideally a limit of quantification of 0.001%, which requires at least 3 × 10(6) and 5 × 10(6) bone marrow cells to be measured, respectively. © 2015 International Clinical Cytometry Society.

Molecular purging of multiple myeloma cells by ex-vivo culture and retroviral transduction of mobilized-blood CD34+ cells

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Corneo Gianmarco

2007-07-01

Full Text Available Abstract Background Tumor cell contamination of the apheresis in multiple myeloma is likely to affect disease-free and overall survival after autografting. Objective To purge myeloma aphereses from tumor contaminants with a novel culture-based purging method. Methods We cultured myeloma-positive CD34+ PB samples in conditions that retained multipotency of hematopoietic stem cells, but were unfavourable to survival of plasma cells. Moreover, we exploited the resistance of myeloma plasma cells to retroviral transduction by targeting the hematopoietic CD34+ cell population with a retroviral vector carrying a selectable marker (the truncated form of the human receptor for nerve growth factor, ΔNGFR. We performed therefore a further myeloma purging step by selecting the transduced cells at the end of the culture. Results Overall recovery of CD34+ cells after culture was 128.5%; ΔNGFR transduction rate was 28.8% for CD34+ cells and 0% for CD138-selected primary myeloma cells, respectively. Recovery of CD34+ cells after ΔNGFR selection was 22.3%. By patient-specific Ig-gene rearrangements, we assessed a decrease of 0.7–1.4 logs in tumor load after the CD34+ cell selection, and up to 2.3 logs after culture and ΔNGFR selection. Conclusion We conclude that ex-vivo culture and retroviral-mediated transduction of myeloma leukaphereses provide an efficient tumor cell purging.

Inhibition of fatty acid metabolism reduces human myeloma cells proliferation.

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José Manuel Tirado-Vélez

Full Text Available Multiple myeloma is a haematological malignancy characterized by the clonal proliferation of plasma cells. It has been proposed that targeting cancer cell metabolism would provide a new selective anticancer therapeutic strategy. In this work, we tested the hypothesis that inhibition of β-oxidation and de novo fatty acid synthesis would reduce cell proliferation in human myeloma cells. We evaluated the effect of etomoxir and orlistat on fatty acid metabolism, glucose metabolism, cell cycle distribution, proliferation, cell death and expression of G1/S phase regulatory proteins in myeloma cells. Etomoxir and orlistat inhibited β-oxidation and de novo fatty acid synthesis respectively in myeloma cells, without altering significantly glucose metabolism. These effects were associated with reduced cell viability and cell cycle arrest in G0/G1. Specifically, etomoxir and orlistat reduced by 40-70% myeloma cells proliferation. The combination of etomoxir and orlistat resulted in an additive inhibitory effect on cell proliferation. Orlistat induced apoptosis and sensitized RPMI-8226 cells to apoptosis induction by bortezomib, whereas apoptosis was not altered by etomoxir. Finally, the inhibitory effect of both drugs on cell proliferation was associated with reduced p21 protein levels and phosphorylation levels of retinoblastoma protein. In conclusion, inhibition of fatty acid metabolism represents a potential therapeutic approach to treat human multiple myeloma.

Decorin is down-regulated in multiple myeloma and MGUS bone marrow plasma and inhibits HGF-induced myeloma plasma cell viability and migration

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Kristensen, Ida Bruun; Pedersen, Lise Mariager; Rø, Torstein Baade

2013-01-01

pathway in multiple myeloma (MM). METHODS: Decorin levels in paired peripheral blood and bone marrow plasma samples from healthy volunteers (HV) (n=23), and patients with monoclonal gammopathy of undetermined significance (MGUS) (n=41) and MM (n=19) were determined by ELISA. Further, the ability...

Osteoprotegerin is bound, internalized, and degraded by multiple myeloma cells

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Standal, Therese; Seidel, Carina; Hjertner, Øyvind

2002-01-01

Multiple myeloma (MM) is a hematologic malignancy characterized by accumulation of plasma cells in the bone marrow (BM). Bone destruction is a complication of the disease and is usually associated with severe morbidity. The balance between receptor activator of nuclear factor-kappaB (NF-kappaB......) ligand and osteoprotegerin (OPG) is of major importance in bone homeostasis. We have recently shown that serum OPG levels are lower in patients with myeloma than in healthy individuals. Here we show that myeloma cells can bind, internalize, and degrade OPG, thereby providing a possible explanation...... for the lower levels of OPG in the BM of patients with MM. This process is dependent on interaction of OPG with heparan sulfates on the myeloma cells. The results suggest a novel biologic mechanism for the bone disease associated with MM and that treatment of the bone disease with OPG lacking the heparin...

Production of simplex RNS and ROS by nanosecond pulse N2/O2 plasma jets with homogeneous shielding gas for inducing myeloma cell apoptosis

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Liu, Zhijie; Xu, Dehui; Liu, Dingxin; Cui, Qingjie; Cai, Haifeng; Li, Qiaosong; Chen, Hailan; Kong, Michael G.

2017-05-01

In this paper, atmospheric pressure N2/O2 plasma jets with homogeneous shielding gas excited by nanosecond pulse are obtained to generate simplex reactive nitrogen species (RNS) and reactive oxygen species (ROS), respectively, for the purpose of studying the simplex RNS and ROS to induce the myeloma cell apoptosis with the same discharge power. The results reveal that the cell death rate by the N2 plasma jet with N2 shielding gas is about two times that of the O2 plasma jet with O2 shielding gas for the equivalent treatment time. By diagnosing the reactive species of ONOO-, H2O2, OH and \\text{O}2- in medium, our findings suggest the cell death rate after plasma jets treatment has a positive correlation with the concentration of ONOO-. Therefore, the ONOO- in medium is thought to play an important role in the process of inducing myeloma cell apoptosis.

Hypermethylation Is A Key Feature of the Transition of Multiple Myeloma to Plasma Cell Leukemia

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Walker, Brian A.; Wardell, Christopher P.; Boyd, Kevin D.

2010-01-01

in the transition of MM to PCL can be classified as either tumor suppressor genes, genes involved in cell-cell signaling, or as cell adhesion molecules. The further analysis of these genes will allow us to identify genes which are down-regulated through methylation and mediate the progression of MM to PCL allowing...... to malignant plasma cells and little is known about the genetic mechanisms mediating the final stages of this pathway. The methylation status of genes in myeloma can change as the malignancy progresses and as such identifying genes deregulated by methylation that mediate the progression of MM to PCL may offer...... the various cytogenetic subgroups of MM and in mediating the transition to PCL. Hypermethylation affects genes and pathways important in retaining plasma cells in the bone marrow as well as in their growth factor independent growth in the absence of stromal cell support. DisclosuresNo relevant conflicts...

Plasma cell leukemia

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Fernández de Larrea, C; Kyle, R A; Durie, B G M

2013-01-01

Plasma cell leukemia (PCL) is a rare and aggressive variant of myeloma characterized by the presence of circulating plasma cells. It is classified as either primary PCL occurring at diagnosis or as secondary PCL in patients with relapsed/refractory myeloma. Primary PCL is a distinct clinic......-pathological entity with different cytogenetic and molecular findings. The clinical course is aggressive with short remissions and survival duration. The diagnosis is based upon the percentage (≥ 20%) and absolute number (≥ 2 × 10(9)/l) of plasma cells in the peripheral blood. It is proposed that the thresholds...... regimens and bortezomib-based regimens are recommended followed by high-dose therapy with autologous stem cell transplantation if feasible. Allogeneic transplantation can be considered in younger patients. Prospective multicenter studies are required to provide revised definitions and better understanding...

MMSET deregulation affects cell cycle progression and adhesion regulons in t(4;14) myeloma plasma cells

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Brito, Jose L.R.; Walker, Brian; Jenner, Matthew; Dickens, Nicholas J.; Brown, Nicola J.M.; Ross, Fiona M.; Avramidou, Athanasia; Irving, Julie A.E.; Gonzalez, David; Davies, Faith E.; Morgan, Gareth J.

2009-01-01

Background The recurrent immunoglobulin translocation, t(4;14)(p16;q32) occurs in 15% of multiple myeloma patients and is associated with poor prognosis, through an unknown mechanism. The t(4;14) up-regulates fibroblast growth factor receptor 3 (FGFR3) and multiple myeloma SET domain (MMSET) genes. The involvement of MMSET in the pathogenesis of t(4;14) multiple myeloma and the mechanism or genes deregulated by MMSET upregulation are still unclear. Design and Methods The expression of MMSET was analyzed using a novel antibody. The involvement of MMSET in t(4;14) myelomagenesis was assessed by small interfering RNA mediated knockdown combined with several biological assays. In addition, the differential gene expression of MMSET-induced knockdown was analyzed with expression microarrays. MMSET gene targets in primary patient material was analyzed by expression microarrays. Results We found that MMSET isoforms are expressed in multiple myeloma cell lines, being exclusively up-regulated in t(4;14)-positive cells. Suppression of MMSET expression affected cell proliferation by both decreasing cell viability and cell cycle progression of cells with the t(4;14) translocation. These findings were associated with reduced expression of genes involved in the regulation of cell cycle progression (e.g. CCND2, CCNG1, BRCA1, AURKA and CHEK1), apoptosis (CASP1, CASP4 and FOXO3A) and cell adhesion (ADAM9 and DSG2). Furthermore, we identified genes involved in the latter processes that were differentially expressed in t(4;14) multiple myeloma patient samples. Conclusions In conclusion, dysregulation of MMSET affects the expression of several genes involved in the regulation of cell cycle progression, cell adhesion and survival. PMID:19059936

Tug of war in the haematopoietic stem cell niche: do myeloma plasma cells compete for the HSC niche?

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Noll, J E; Williams, S A; Purton, L E; Zannettino, A C W

2012-09-14

In the adult mammal, normal haematopoiesis occurs predominantly in the bone marrow, where primitive haematopoietic stem cells (HSC) and their progeny reside in specialised microenvironments. The bone marrow microenvironment contains specific anatomical areas (termed niches) that are highly specialised for the development of certain blood cell types, for example HSCs. The HSC niche provides important cell-cell interactions and signalling molecules that regulate HSC self-renewal and differentiation processes. These same signals and interactions are also important in the progression of haematological malignancies, such as multiple myeloma (MM). This review provides an overview of the bone marrow microenvironment and its involvement in normal, physiological HSC maintenance and plasma cell growth throughout MM disease progression.

Validation of interphase fluorescence in situ hybridization (iFISH for multiple myeloma using CD138 positive cells

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Renata Kiyomi Kishimoto

2016-06-01

Full Text Available ABSTRACT BACKGROUND: Multiple myeloma is a plasma cell neoplasm with acquired genetic abnormalities of clinical and prognostic importance. Multiple myeloma differs from other hematologic malignancies due to a high fraction of low proliferating malignant plasma cells and the paucity of plasma cells in bone marrow aspiration samples, making cytogenetic analysis a challenge. An abnormal karyotype is found in only one-third of patients with multiple myeloma and interphase fluorescence in situ hybridization is the most useful test for studying the chromosomal abnormalities present in almost 90% of cases. However, it is necessary to study the genetic abnormalities in plasma cells after their identification or selection by morphology, immunophenotyping or sorting. Other challenges are the selection of the most informative FISH panel and determining cut-off levels for FISH probes. This study reports the validation of interphase fluorescence in situ hybridization using CD138 positive cells, according to proposed guidelines published by the European Myeloma Network (EMN in 2012. METHOD: Bone marrow samples from patients with multiple myeloma were used to standardize a panel of five probes [1q amplification, 13q14 deletion, 17p deletion, t(4;14, and t(14;16] in CD138+ cells purified by magnetic cell sorting. RESULTS: This test was validated with a low turnaround time and good reproducibility. Five of six samples showed genetic abnormalities. Monosomy/deletion 13 plus t(4;14 were found in two cases. CONCLUSION: This technique together with magnetic cell sorting is effective and can be used in the routine laboratory practice. In addition, magnetic cell sorting provides a pure plasma cell population that allows other molecular and genomic studies.

HIF-1α inhibition blocks the cross talk between multiple myeloma plasma cells and tumor microenvironment

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Borsi, Enrica, E-mail: enrica.borsi2@unibo.it [Department of Experimental Diagnostic and Specialty Medicine (DIMES), “L. and A. Seràgnoli”, Bologna University School of Medicine, S. Orsola' s University Hospital (Italy); Perrone, Giulia [Fondazione IRCCS Istituto Nazionale dei Tumori, Hematology Department, Via Venezian 1, 20133 Milano (Italy); Terragna, Carolina; Martello, Marina; Zamagni, Elena; Tacchetti, Paola; Pantani, Lucia; Brioli, Annamaria; Dico, Angela Flores; Zannetti, Beatrice Anna; Rocchi, Serena; Cavo, Michele [Department of Experimental Diagnostic and Specialty Medicine (DIMES), “L. and A. Seràgnoli”, Bologna University School of Medicine, S. Orsola' s University Hospital (Italy)

2014-11-01

Multiple myeloma (MM) is a malignant disorder of post-germinal center B cells, characterized by the clonal proliferation of malignant plasma cells (PCs) within the bone marrow (BM). The reciprocal and complex interactions that take place between the different compartments of BM and the MM cells result in tumor growth, angiogenesis, bone disease, and drug resistance. Given the importance of the BM microenvironment in MM pathogenesis, we investigated the possible involvement of Hypoxia-Inducible transcription Factor-1 alpha (HIF-1α) in the PCs-bone marrow stromal cells interplay. To test this hypothesis, we used EZN-2968, a 3rd generation antisense oligonucleotide against HIF-1α, to inhibit HIF-1α functions. Herein, we provide evidence that the interaction between MM cells and BM stromal cells is drastically reduced upon HIF-1α down-modulation. Notably, we showed that upon exposure to HIF-1α inhibitor, neither the incubation with IL-6 nor the co-culture with BM stromal cells were able to revert the anti-proliferative effect induced by EZN-2968. Moreover, we observed a down-modulation of cytokine-induced signaling cascades and a reduction of MM cells adhesion capability to the extracellular matrix proteins in EZN-2968-treated samples. Taken together, these results strongly support the concept that HIF-1α plays a critical role in the interactions between bone BM cells and PCs in Multiple Myeloma. - Highlights: • HIF-1α inhibition induces a mild apoptotic cell death. • Down-modulation of cytokine-induced signaling cascades upon HIF-1α inhibition. • Reduced interaction between MM cells and BMSCs upon HIF-1α down-modulation. • Reduced PCs adhesion to the extracellular matrix protein induced by EZN-2968. • HIF-1α inhibition may be an attractive therapeutic strategy for Multiple Myeloma.

radiochemical studies on the growth of myeloma cells

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Elshershaby, H.M.M.

2008-01-01

cancer is a disease of unregulated cell growth. humans of all ages develop cancer, and a wide variety of organs are affected. multiple myeloma is a cancer in which antibody-producing plasma cells grow in an uncontrolled and invasive (malignant) manner. melphalan (DNA cross-linker), is one of the most widely used and effective drugs in the treatment of multiple myeloma. thalidomide as an immunomodulatory agent is clinically useful in a number of cancers. antitumor activity may be related to a number of known properties, including antitumor necrosis factor (TNF)-α and T-cell costimulatory and antiangiogenic effect. however, it may also involve direct antitumor effects. radiotherapy is an important modality in the treatment of cancer. the aim of radiotherapy is to deliver radiation doses and schedules that kill cancer cells, while preserving normal tissue function. the aim of these studies was to evaluate the therapeutic effects of some chemical substances (chemotherapy)such as melphalan and thalidomide and γ-radiation (radiotherapy)on the growth of myeloma cells. also some confirmatory tests such as β2-microglobulin, caspases enzymes 8 and 9 and flow cytometric analyses were performed for the obtained optimum doses.

Aurora A kinase RNAi and small molecule inhibition of Aurora kinases with VE-465 induce apoptotic death in multiple myeloma cells.

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Evans, Robert; Naber, Claudia; Steffler, Tara; Checkland, Tamara; Keats, Jonathan; Maxwell, Christopher; Perry, Troy; Chau, Heidi; Belch, Andrew; Pilarski, Linda; Reiman, Tony

2008-03-01

The expression of RHAMM and other centrosome-associated genes are known to correlate with the extent of centrosome amplification in multiple myeloma, and with poor prognosis. RHAMM has a significant interaction with TPX2, a protein which regulates the localization and action of Aurora A kinase (AURKA) at the spindle poles. AURKA is known to be a central determinant of centrosome and spindle function and is a target for cancer therapy. Given these observations, we investigated the role of Aurora kinases as therapeutic targets in myeloma. Here we report that AURKA is expressed ubiquitously in myeloma, to varying degrees, in both cell lines and patients' bone marrow plasma cells. siRNA targeting AURKA induces apoptotic cell death in myeloma cell lines. The Aurora kinase inhibitor VE-465 also induces apoptosis and death in myeloma cell lines and primary myeloma plasma cells. The combination of VE-465 and dexamethasone improves cell killing compared with the use of either agent alone, even in cells resistant to the single agents. The phenotype of myeloma cells treated with VE-465 is consistent with published reports on the effects of Aurora kinase inhibition. Aurora kinase inhibitors should be pursued as potential treatments for myeloma.

Daratumumab depletes CD38sup>+> immune-regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma

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Krejcik, Jakub; Casneuf, Tineke; Nijhof, Inger S

2016-01-01

target non-plasma cells that express CD38, which prompted evaluation of daratumumab's effects on CD38-positive immune subpopulations. Peripheral blood (PB) and bone marrow (BM) from patients with relapsed/refractory myeloma from two daratumumab monotherapy studies were analyzed before and during therapy......Daratumumab targets CD38-expressing myeloma cells through a variety of immune-mediated mechanisms (complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and antibody-dependent cellular phagocytosis) and direct apoptosis with cross-linking. These mechanisms may also...... and at relapse. Regulatory B cells (Bregs) and myeloid-derived suppressor cells (MDSCs), previously shown to express CD38, were evaluated for immunosuppressive activity and daratumumab sensitivity in the myeloma setting. A novel subpopulation of regulatory T cells (Tregs) expressing CD38 was identified...

The novel immunotoxin HM1.24-ETA′ induces apoptosis in multiple myeloma cells

International Nuclear Information System (INIS)

Staudinger, M; Glorius, P; Burger, R; Kellner, C; Klausz, K; Günther, A; Repp, R; Klapper, W; Gramatzki, M; Peipp, M

2014-01-01

Despite new treatment modalities, the clinical outcome in a substantial number of patients with multiple myeloma (MM) has yet to be improved. Antibody-based targeted therapies for myeloma patients could make use of the HM1.24 antigen (CD317), a surface molecule overexpressed on malignant plasma cells and efficiently internalized. Here, a novel immunotoxin, HM1.24-ETA′, is described. HM1.24-ETA′ was generated by genetic fusion of a CD317-specific single-chain Fv (scFv) antibody and a truncated variant of Pseudomonas aeruginosa exotoxin A (ETA′). HM1.24-ETA′ inhibited growth of interleukin 6 (IL-6)-dependent and -independent myeloma cell lines. Half-maximal growth inhibition was observed at concentrations as low as 0.3 nM. Target cell killing occurred via induction of apoptosis and was unaffected in co-culture experiments with bone marrow stromal cells. HM1.24-ETA′ efficiently triggered apoptosis of freshly isolated/cryopreserved cells of patients with plasma cell leukemia and MM and was active in a preclinical severe combined immunodeficiency (SCID) mouse xenograft model. Importantly, HM1.24-ETA′ was not cytotoxic against CD317-positive cells from healthy tissue (monocytes, human umbilical vein endothelial cells). These results indicate that CD317 may represent a promising target structure for specific and efficient immunotoxin therapy for patients with plasma cell tumors

Identify multiple myeloma stem cells: Utopia?

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Saltarella, Ilaria; Lamanuzzi, Aurelia; Reale, Antonia; Vacca, Angelo; Ria, Roberto

2015-01-26

Multiple myeloma (MM) is a hematologic malignancy of monoclonal plasma cells which remains incurable despite recent advances in therapies. The presence of cancer stem cells (CSCs) has been demonstrated in many solid and hematologic tumors, so the idea of CSCs has been proposed for MM, even if MM CSCs have not been define yet. The existence of myeloma CSCs with clonotypic B and clonotypic non B cells was postulated by many groups. This review aims to focus on these distinct clonotypic subpopulations and on their ability to develop and sustain MM. The bone marrow microenvironment provides to MM CSCs self-renewal, survival and drug resistance thanks to the presence of normal and cancer stem cell niches. The niches and CSCs interact each other through adhesion molecules and the interplay between ligands and receptors activates stemness signaling (Hedgehog, Wnt and Notch pathways). MM CSCs are also supposed to be responsible for drug resistance that happens in three steps from the initial cancer cell homing microenvironment-mediated to development of microenvironment-independent drug resistance. In this review, we will underline all these aspects of MM CSCs.

Multiple myeloma

International Nuclear Information System (INIS)

Sohn, Jeong Ick; Ha, Choon Ho; Choi, Karp Shik

1994-01-01

Multiple myeloma is a malignant plasma cell tumor that is thought to originate proliferation of a single clone of abnormal plasma cell resulting production of a whole monoclonal paraprotein. The authors experienced a case of multiple myeloma with severe mandibular osteolytic lesions in 46-year-old female. As a result of careful analysis of clinical, radiological, histopathological features, and laboratory findings, we diagnosed it as multiple myeloma, and the following results were obtained. 1. Main clinical symptoms were intermittent dull pain on the mandibular body area, abnormal sensation of lip and pain due to the fracture on the right clavicle. 2. Laboratory findings revealed M-spike, reversed serum albumin-globulin ratio, markedly elevated ESR and hypercalcemia. 3. Radiographically, multiple osteolytic punched-out radiolucencies were evident on the skull, zygoma, jaw bones, ribs, clavicle and upper extremities. Enlarged liver and increased uptakes on the lesional sites in RN scan were also observed. 4. Histopathologically, markedly hypercellular marrow with sheets of plasmoblasts and megakaryocytes were also observed.

Different aspects of thalidomide treatment and stem cell transplantation in multiple myeloma patients

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Marion, A.M.W. van

2006-01-01

Multiple myeloma (MM) is an haematological malignancy caused by an unrestrained proliferation of plasma cells (monoclonally differentiated B-cells), and part of the white blood cell count. This proliferation infiltrates the blood forming skeletal bone marrow, producing osteoclastic factors, causing

Coexisting multiple myeloma, lymphoma, and non-small cell lung cancer: a case report and review of the literature

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Khade P

2017-11-01

Full Text Available Parth Khade, Srinivas Devarakonda Department of Internal Medicine, Louisiana State University Health, Shreveport, LA, USA Abstract: Multiple myeloma is a plasma cell dyscrasia characterized by neoplastic proliferation of plasma cells, producing a monoclonal immunoglobulin. Small lymphocytic lymphoma (SLL is a neoplasm consisting of monoclonal B-cell lymphocyte proliferation. We present an extremely rare case of coexisting multiple myeloma, SLL, and squamous cell carcinoma of the lung in a 74-year-old female patient. She initially presented with a midline mass with pain in the lumbar area. Debulking surgery was performed, and pathology showed plasmacytoma. Further evaluation revealed coexistent IgG kappa myeloma. Imaging revealed extensive abdominal lymphadenopathy, and mesenteric lymph node biopsy confirmed the presence of SLL. The patient was also found to have a mass in the left lower lobe of the lung; biopsy showed squamous cell carcinoma. This patient was treated with lenalidomide and dexamethasone for multiple myeloma, and stereotactic body radiotherapy for limited stage lung cancer. Due to the more indolent course of SLL, watchful waiting was applied. Keywords: coexisting, multiple myeloma, lung cancer, non-Hodgkin’s lymphoma

Evaluation of anticancer effects of a novel proteasome inhibitor (Velcade), interferon (alpha-interferon) and anti myeloma antibodies on the growth of myeloma cells

International Nuclear Information System (INIS)

El shershaby, H.M.M.

2013-01-01

Cancer is an abnormal growth of cells caused by multiple changes in gene expression leading to deregulated balance of cell proliferation and cell death and ultimately evolving into a population of cells that can invade tissues and metastasize to distant sites, causing significant morbidity. Multiple myeloma (MM) is characterized by the accumulation of malignant plasma cells in the bone marrow leading to impaired hematopoiesis and bone diseases, which includes mainly lytic lesions, pathological fractures, hypercalcaemia and osteoporosis. Chemotherapy is the systemic treatment of cancer with anticancer drugs. Chemotherapy uses powerful drugs that work by slowing or stopping the cancer cells from growing, spreading or multiplying to other parts of the body. Extensive studies were run all over the world during the last years to discovery some new drugs which possess anticancer effect with less toxicity and have the ability to increase the survival time. In the current study Bortezomib was employed as chemotherapeutic drug for the treatment of myeloma cells where a variable dose of Bortezomib (5, 10,20,30,50 and 100 nM/ml) were used for treatment of myeloma cells in vitro. The results obtained indicated that the T.C/ml was decreased by increasing the drug conc. compared to that of control group. These results illustrated the effect of Bortezomib on the growth of myeloma cells, where the myeloma cell division was decreased while the older cells were deteriorated so that the T.C/ml were decreased. Also the viability of myeloma cells were significantly decreased after 72 hours of addition at drug concentration 20, 30, 50 and 100 nM/ml).

Genetic variations in multiple myeloma I

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Vangsted, A.; Klausen, T.W.; Vogel, Ulla Birgitte

2012-01-01

Few risk factors have been established for the plasma cell disorder multiple myeloma, but some of these like African American ethnicity and a family history of B-cell lymphoproliferative diseases suggest a genetic component for the disease. Genetic variation represents the genetic basis of variab......Few risk factors have been established for the plasma cell disorder multiple myeloma, but some of these like African American ethnicity and a family history of B-cell lymphoproliferative diseases suggest a genetic component for the disease. Genetic variation represents the genetic basis...

Multiple myeloma in a captive lion (Panthera leo

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Adrian S.W. Tordiffe

2013-09-01

Full Text Available Multiple myeloma is a rare, systemic proliferation of neoplastic plasma cells. A case was reported in an 11-year-old male captive lion (Panthera leo at the National Zoological Gardens of South Africa, Pretoria. The classic features of symptomatic multiple myeloma were all evident in this case; namely osteolytic lesions, monoclonal gammopathy in the serum with excretion of monoclonal proteins in the urine, neoplastic plasma cells in the bone marrow and associated renal failure and anaemia. In addition, similar to the common pattern of this disease in domestic felids, at least three extramedullary tumours were found and several organs were infiltrated by neoplastic plasma cells. The cytoplasm of approximately 50%of the neoplastic round cells, including a few giant myeloma cells, stained weakly to strongly using immunohistochemical stains for B-lymphocytes (CD79a. The normal haematological parameters and lack of any osteolytic lesions in the lion at the time of the first evaluation suggest that the primary neoplastic cells could have originated from one of the extramedullary tumour sites. Only two cases of multiple myeloma have previously been reported in captive wild felids. To the authors’ knowledge, there are no case reports of multiple myeloma in lions.

Natural killer cell lines preferentially kill clonogenic multiple myeloma cells and decrease myeloma engraftment in a bioluminescent xenograft mouse model.

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Swift, Brenna E; Williams, Brent A; Kosaka, Yoko; Wang, Xing-Hua; Medin, Jeffrey A; Viswanathan, Sowmya; Martinez-Lopez, Joaquin; Keating, Armand

2012-07-01

Novel therapies capable of targeting drug resistant clonogenic MM cells are required for more effective treatment of multiple myeloma. This study investigates the cytotoxicity of natural killer cell lines against bulk and clonogenic multiple myeloma and evaluates the tumor burden after NK cell therapy in a bioluminescent xenograft mouse model. The cytotoxicity of natural killer cell lines was evaluated against bulk multiple myeloma cell lines using chromium release and flow cytometry cytotoxicity assays. Selected activating receptors on natural killer cells were blocked to determine their role in multiple myeloma recognition. Growth inhibition of clonogenic multiple myeloma cells was assessed in a methylcellulose clonogenic assay in combination with secondary replating to evaluate the self-renewal of residual progenitors after natural killer cell treatment. A bioluminescent mouse model was developed using the human U266 cell line transduced to express green fluorescent protein and luciferase (U266eGFPluc) to monitor disease progression in vivo and assess bone marrow engraftment after intravenous NK-92 cell therapy. Three multiple myeloma cell lines were sensitive to NK-92 and KHYG-1 cytotoxicity mediated by NKp30, NKp46, NKG2D and DNAM-1 activating receptors. NK-92 and KHYG-1 demonstrated 2- to 3-fold greater inhibition of clonogenic multiple myeloma growth, compared with killing of the bulk tumor population. In addition, the residual colonies after treatment formed significantly fewer colonies compared to the control in a secondary replating for a cumulative clonogenic inhibition of 89-99% at the 20:1 effector to target ratio. Multiple myeloma tumor burden was reduced by NK-92 in a xenograft mouse model as measured by bioluminescence imaging and reduction in bone marrow engraftment of U266eGFPluc cells by flow cytometry. This study demonstrates that NK-92 and KHYG-1 are capable of killing clonogenic and bulk multiple myeloma cells. In addition, multiple myeloma

Predicting the impact of combined therapies on myeloma cell growth using a hybrid multi-scale agent-based model.

Science.gov (United States)

Ji, Zhiwei; Su, Jing; Wu, Dan; Peng, Huiming; Zhao, Weiling; Nlong Zhao, Brian; Zhou, Xiaobo

2017-01-31

Multiple myeloma is a malignant still incurable plasma cell disorder. This is due to refractory disease relapse, immune impairment, and development of multi-drug resistance. The growth of malignant plasma cells is dependent on the bone marrow (BM) microenvironment and evasion of the host's anti-tumor immune response. Hence, we hypothesized that targeting tumor-stromal cell interaction and endogenous immune system in BM will potentially improve the response of multiple myeloma (MM). Therefore, we proposed a computational simulation of the myeloma development in the complicated microenvironment which includes immune cell components and bone marrow stromal cells and predicted the effects of combined treatment with multi-drugs on myeloma cell growth. We constructed a hybrid multi-scale agent-based model (HABM) that combines an ODE system and Agent-based model (ABM). The ODEs was used for modeling the dynamic changes of intracellular signal transductions and ABM for modeling the cell-cell interactions between stromal cells, tumor, and immune components in the BM. This model simulated myeloma growth in the bone marrow microenvironment and revealed the important role of immune system in this process. The predicted outcomes were consistent with the experimental observations from previous studies. Moreover, we applied this model to predict the treatment effects of three key therapeutic drugs used for MM, and found that the combination of these three drugs potentially suppress the growth of myeloma cells and reactivate the immune response. In summary, the proposed model may serve as a novel computational platform for simulating the formation of MM and evaluating the treatment response of MM to multiple drugs.

The Danish National Multiple Myeloma Registry

DEFF Research Database (Denmark)

Gimsing, Peter; Holmström, Morten Orebo; Klausen, Tobias Wirenfelt

2016-01-01

AIM: The Danish National Multiple Myeloma Registry (DMMR) is a population-based clinical quality database established in January 2005. The primary aim of the database is to ensure that diagnosis and treatment of plasma cell dyscrasia are of uniform quality throughout the country. Another aim...... diagnosed patients with multiple myeloma (MM), smoldering MM, solitary plasmacytomas, and plasma cell leukemia in Denmark are registered annually; ~350 patients. Amyloid light-chain amyloidosis, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome......), monoclonal gammopathy of undetermined significance and monoclonal gammopathy of undetermined significance with polyneuropathy have been registered since 2014. MAIN VARIABLES: The main registered variables at diagnosis are patient demographics, baseline disease characteristics, myeloma-defining events...

N-cadherin-mediated interaction with multiple myeloma cells inhibits osteoblast differentiation

NARCIS (Netherlands)

Groen, Richard W. J.; de Rooij, Martin F. M.; Kocemba, Kinga A.; Reijmers, Rogier M.; de Haan-Kramer, Anneke; Overdijk, Marije B.; Aalders, Linda; Rozemuller, Henk; Martens, Anton C. M.; Bergsagel, P. Leif; Kersten, Marie José; Pals, Steven T.; Spaargaren, Marcel

2011-01-01

Multiple myeloma is a hematologic malignancy characterized by a clonal expansion of malignant plasma cells in the bone marrow, which is accompanied by the development of osteolytic lesions and/or diffuse osteopenia. The intricate bi-directional interaction with the bone marrow microenvironment plays

N-cadherin-mediated interaction with multiple myeloma cells inhibits osteoblast differentiation

NARCIS (Netherlands)

Groen, R.W.J.; de Rooij, M.F.M.; Kocemba, K.A.; Reijmers, R.M.; de Haan-Kramer, A.; Overdijk, M.B.; Aalders, L.; Rozemuller, H.; Martens, A.C.M.; Bergsagel, P.L.; Kersten, M.J.; Pals, S.T.; Spaargaren, M.

2011-01-01

Background Multiple myeloma is a hematologic malignancy characterized by a clonal expansion of malignant plasma cells in the bone marrow, which is accompanied by the development of osteolytic lesions and/or diffuse osteopenia. The intricate bi-directional interaction with the bone marrow

Bone morphogenetic protein-9 suppresses growth of myeloma cells by signaling through ALK2 but is inhibited by endoglin

International Nuclear Information System (INIS)

Olsen, O E; Wader, K F; Misund, K; Våtsveen, T K; Rø, T B; Mylin, A K; Turesson, I; Størdal, B F; Moen, S H; Standal, T; Waage, A; Sundan, A; Holien, T

2014-01-01

Multiple myeloma is a malignancy of plasma cells predominantly located in the bone marrow. A number of bone morphogenetic proteins (BMPs) induce apoptosis in myeloma cells in vitro, and with this study we add BMP-9 to the list. BMP-9 has been found in human serum at concentrations that inhibit cancer cell growth in vitro. We here show that the level of BMP-9 in serum was elevated in myeloma patients (median 176 pg/ml, range 8–809) compared with healthy controls (median 110 pg/ml, range 8–359). BMP-9 was also present in the bone marrow and was able to induce apoptosis in 4 out of 11 primary myeloma cell samples by signaling through ALK2. BMP-9-induced apoptosis in myeloma cells was associated with c-MYC downregulation. The effects of BMP-9 were counteracted by membrane-bound (CD105) or soluble endoglin present in the bone marrow microenvironment, suggesting a mechanism for how myeloma cells can evade the tumor suppressing activity of BMP-9 in multiple myeloma

Cyclic AMP induces apoptosis in multiple myeloma cells and inhibits tumor development in a mouse myeloma model

International Nuclear Information System (INIS)

Follin-Arbelet, Virginie; Hofgaard, Peter O; Hauglin, Harald; Naderi, Soheil; Sundan, Anders; Blomhoff, Rune; Bogen, Bjarne; Blomhoff, Heidi K

2011-01-01

Multiple myeloma is an incurable disease requiring the development of effective therapies which can be used clinically. We have elucidated the potential for manipulating the cAMP signaling pathway as a target for inhibiting the growth of multiple myeloma cells. As a model system, we primarily used the murine multiple myeloma cell line MOPC315 which can be grown both in vivo and in vitro. Human multiple myeloma cell lines U266, INA-6 and the B-cell precursor acute lymphoblastic leukemia cell line Reh were used only for in vitro studies. Cell death was assessed by flow cytometry and western blot analysis after treatment with cAMP elevating agents (forskolin, prostaglandin E2 and rolipram) and cAMP analogs. We followed tumor growth in vivo after forskolin treatment by imaging DsRed-labelled MOPC315 cells transplanted subcutaneously in BALB/c nude mice. In contrast to the effect on Reh cells, 50 μM forskolin more than tripled the death of MOPC315 cells after 24 h in vitro. Forskolin induced cell death to a similar extent in the human myeloma cell lines U266 and INA-6. cAMP-mediated cell death had all the typical hallmarks of apoptosis, including changes in the mitochondrial membrane potential and cleavage of caspase 3, caspase 9 and PARP. Forskolin also inhibited the growth of multiple myeloma cells in a mouse model in vivo. Elevation of intracellular levels of cAMP kills multiple myeloma cells in vitro and inhibits development of multiple myeloma in vivo. This strongly suggests that compounds activating the cAMP signaling pathway may be useful in the field of multiple myeloma

EEN regulates the proliferation and survival of multiple myeloma cells by potentiating IGF-1 secretion

International Nuclear Information System (INIS)

Huang, Er-Wen; Xue, Sheng-Jiang; Li, Xiao-Yan; Xu, Suo-Wen; Cheng, Jian-Ding; Zheng, Jin-Xiang; Shi, He; Lv, Guo-Li; Li, Zhi-Gang; Li, Yue; Liu, Chang-Hui; Chen, Xiao-Hui; Liu, Hong; Li, Jie; Liu, Chao

2014-01-01

Highlights: • Levels of EEN expression paralleled with the rate of cell proliferation. • EEN was involved in the proliferation and survival of multiple myeloma (MM) cells. • EEN regulated the activity of IGF-1-Akt/mTOR pathway. • EEN regulated proliferation and survival of MM cells by enhancing IGF-1 secretion. - Abstract: The molecular mechanisms of multiple myeloma are not well defined. EEN is an endocytosis-regulating molecule. Here we report that EEN regulates the proliferation and survival of multiple myeloma cells, by regulating IGF-1 secretion. In the present study, we observed that EEN expression paralleled with cell proliferation, EEN accelerated cell proliferation, facilitated cell cycle transition from G1 to S phase by regulating cyclin-dependent kinases (CDKs) pathway, and delayed cell apoptosis via Bcl2/Bax-mitochondrial pathway. Mechanistically, we found that EEN was indispensable for insulin-like growth factor-1 (IGF-1) secretion and the activation of protein kinase B-mammalian target of rapamycin (Akt-mTOR) pathway. Exogenous IGF-1 overcame the phenotype of EEN depletion, while IGF-1 neutralization overcame that of EEN over-expression. Collectively, these data suggest that EEN may play a pivotal role in excessive cell proliferation and insufficient cell apoptosis of bone marrow plasma cells in multiple myeloma. Therefore, EEN may represent a potential diagnostic marker or therapeutic target for multiple myeloma

EEN regulates the proliferation and survival of multiple myeloma cells by potentiating IGF-1 secretion

Energy Technology Data Exchange (ETDEWEB)

Huang, Er-Wen [Guangzhou Institute of Forensic Science, Guangzhou (China); Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou (China); Xue, Sheng-Jiang [Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou (China); Li, Xiao-Yan [Department of Pharmacy, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou (China); Xu, Suo-Wen [Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou (China); Cheng, Jian-Ding; Zheng, Jin-Xiang [Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou (China); Shi, He; Lv, Guo-Li; Li, Zhi-Gang; Li, Yue; Liu, Chang-Hui; Chen, Xiao-Hui; Liu, Hong [Guangzhou Institute of Forensic Science, Guangzhou (China); Li, Jie, E-mail: mdlijie@sina.com [Department of Anaesthesiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou (China); Liu, Chao, E-mail: liuchaogaj@21cn.com [Guangzhou Institute of Forensic Science, Guangzhou (China)

2014-05-02

Highlights: • Levels of EEN expression paralleled with the rate of cell proliferation. • EEN was involved in the proliferation and survival of multiple myeloma (MM) cells. • EEN regulated the activity of IGF-1-Akt/mTOR pathway. • EEN regulated proliferation and survival of MM cells by enhancing IGF-1 secretion. - Abstract: The molecular mechanisms of multiple myeloma are not well defined. EEN is an endocytosis-regulating molecule. Here we report that EEN regulates the proliferation and survival of multiple myeloma cells, by regulating IGF-1 secretion. In the present study, we observed that EEN expression paralleled with cell proliferation, EEN accelerated cell proliferation, facilitated cell cycle transition from G1 to S phase by regulating cyclin-dependent kinases (CDKs) pathway, and delayed cell apoptosis via Bcl2/Bax-mitochondrial pathway. Mechanistically, we found that EEN was indispensable for insulin-like growth factor-1 (IGF-1) secretion and the activation of protein kinase B-mammalian target of rapamycin (Akt-mTOR) pathway. Exogenous IGF-1 overcame the phenotype of EEN depletion, while IGF-1 neutralization overcame that of EEN over-expression. Collectively, these data suggest that EEN may play a pivotal role in excessive cell proliferation and insufficient cell apoptosis of bone marrow plasma cells in multiple myeloma. Therefore, EEN may represent a potential diagnostic marker or therapeutic target for multiple myeloma.

[IgE myeloma. Laboratory typing difficulties].

Science.gov (United States)

Bovone, Nora S; Fuente, María Cristina; Gastiazoro, Ana María; Alfonso, Graciela; Freitas, María Josefina

2014-01-01

The IgE multiple myeloma is a rare neoplasm of plasma cell accounting for 0.01% of all plasma cell dyscrasias. They are generally of more aggressive development and to date there are no more than 50 cases published in current literature. Laboratory studies are, in these cases, essential for the classification of the monoclonal component in serum and urine. The aim of this presentation is to report a patient diagnosed with IgE myeloma and to point out that the laboratory difficulties noted in these rare cases can lead to an erroneous report.

Myeloma cell-induced disruption of bone remodelling compartments leads to osteolytic lesions and generation of osteoclast-myeloma hybrid cells

DEFF Research Database (Denmark)

Andersen, Thomas L; Søe, Kent; Søndergaard, Teis Esben

2010-01-01

on the physical organisation of the myeloma cell microenvironment. The proximity between myeloma cells and osteoclasts or osteoblasts was shown to be conditioned by the recently discovered layer of flat cells that separates the osteoclasts and osteoblasts from the bone marrow, by forming a canopy over bone...

Heterogeneity in the multiple myeloma tumor clone

NARCIS (Netherlands)

Guikema, JEJ; Hovenga, S; Vellenga, E; Bos, NA

Multiple Myeloma ( MM) is a plasma cell malignancy which is characterized by a very heterogeneous disease outcome. Heterogeneity in plasma cell characteristics, including morphology, maturation status, immunophenotype and genetic abnormalities partly account for the variable disease outcome.

NF-κB2 mutation targets survival, proliferation and differentiation pathways in the pathogenesis of plasma cell tumors

Directory of Open Access Journals (Sweden)

McCarthy Brian A

2012-05-01

Full Text Available Abstract Background Abnormal NF-κB2 activation has been implicated in the pathogenesis of multiple myeloma, a cancer of plasma cells. However, a causal role for aberrant NF-κB2 signaling in the development of plasma cell tumors has not been established. Also unclear is the molecular mechanism that drives the tumorigenic process. We investigated these questions by using a transgenic mouse model with lymphocyte-targeted expression of p80HT, a lymphoma-associated NF-κB2 mutant, and human multiple myeloma cell lines. Methods We conducted a detailed histopathological characterization of lymphomas developed in p80HT transgenic mice and microarray gene expression profiling of p80HT B cells with the goal of identifying genes that drive plasma cell tumor development. We further verified the significance of our findings in human multiple myeloma cell lines. Results Approximately 40% of p80HT mice showed elevated levels of monoclonal immunoglobulin (M-protein in the serum and developed plasma cell tumors. Some of these mice displayed key features of human multiple myeloma with accumulation of plasma cells in the bone marrow, osteolytic bone lesions and/or diffuse osteoporosis. Gene expression profiling of B cells from M-protein-positive p80HT mice revealed aberrant expression of genes known to be important in the pathogenesis of multiple myeloma, including cyclin D1, cyclin D2, Blimp1, survivin, IL-10 and IL-15. In vitro assays demonstrated a critical role of Stat3, a key downstream component of IL-10 signaling, in the survival of human multiple myeloma cells. Conclusions These findings provide a mouse model for human multiple myeloma with aberrant NF-κB2 activation and suggest a molecular mechanism for NF-κB2 signaling in the pathogenesis of plasma cell tumors by coordinated regulation of plasma cell generation, proliferation and survival.

Heterogeneity in the multiple myeloma tumor clone

NARCIS (Netherlands)

Guikema, Jeroen E. J.; Hovenga, Sjoerd; Vellenga, Edo; Bos, Nicolaas A.

2004-01-01

Multiple Myeloma (MM) is a plasma cell malignancy which is characterized by a very heterogeneous disease outcome. Heterogeneity in plasma cell characteristics, including morphology, maturation status, immunophenotype and genetic abnormalities partly account for the variable disease outcome. Although

Targeting paraprotein biosynthesis for non-invasive characterization of myeloma biology.

Directory of Open Access Journals (Sweden)

Katharina Lückerath

Full Text Available PURPOSE: Multiple myeloma is a hematologic malignancy originating from clonal plasma cells. Despite effective therapies, outcomes are highly variable suggesting marked disease heterogeneity. The role of functional imaging for therapeutic management of myeloma, such as positron emission tomography with 2-deoxy-2-[¹⁸F]fluoro-D-glucose (¹⁸F-FDG-PET, remains to be determined. Although some studies already suggested a prognostic value of ¹⁸F-FDG-PET, more specific tracers addressing hallmarks of myeloma biology, e.g. paraprotein biosynthesis, are needed. This study evaluated the amino acid tracers L-methyl-[¹¹C]-methionine (¹¹C-MET and [¹⁸F]-fluoroethyl-L-tyrosine ((¹⁸F-Fet for their potential to image myeloma and to characterize tumor heterogeneity. EXPERIMENTAL DESIGN: To study the utility of ¹¹C-MET, ¹⁸F-Fet and ¹⁸F-FDG for myeloma imaging, time activity curves were compared in various human myeloma cell lines (INA-6, MM1.S, OPM-2 and correlated to cell-biological characteristics, such as marker gene expression and immunoglobulin levels. Likewise, patient-derived CD138⁺ plasma cells were characterized regarding uptake and biomedical features. RESULTS: Using myeloma cell lines and patient-derived CD138⁺ plasma cells, we found that the relative uptake of ¹¹C-MET exceeds that of ¹⁸F-FDG 1.5- to 5-fold and that of ¹⁸F-Fet 7- to 20-fold. Importantly, ¹¹C-MET uptake significantly differed between cell types associated with worse prognosis (e.g. t(4;14 in OPM-2 cells and indolent ones and correlated with intracellular immunoglobulin light chain and cell surface CD138 and CXCR4 levels. Direct comparison of radiotracer uptake in primary samples further validated the superiority of ¹¹C-MET. CONCLUSION: These data suggest that ¹¹C-MET might be a versatile biomarker for myeloma superior to routine functional imaging with ¹⁸F-FDG regarding diagnosis, risk stratification, prognosis and discrimination of tumor

IL-6-induced Bcl6 variant 2 supports IL-6-dependent myeloma cell proliferation and survival through STAT3

International Nuclear Information System (INIS)

Tsuyama, Naohiro; Danjoh, Inaho; Otsuyama, Ken-ichiro; Obata, Masanori; Tahara, Hidetoshi; Ohta, Tsutomu; Ishikawa, Hideaki

2005-01-01

IL-6 is a growth and survival factor for myeloma cells, although the mechanism by which it induces myeloma cell proliferation through gene expression is largely unknown. Microarray analysis showed that some B-cell lymphoma-associated oncogenes such as Bcl6, which is absent in normal plasma cells, were upregulated by IL-6 in IL-6-dependent myeloma cell lines. We found that Bcl6 variant 2 was upregulated by STAT3. ChIP assay and EMSA showed that STAT3 bound to the upstream region of variant 2 DNA. Expression of p53, a direct target gene of Bcl6, was downregulated in the IL-6-stimulated cells, and this process was impaired by an HDAC inhibitor. Bcl6 was knocked down by introducing small hairpin RNA, resulting in decreased proliferation and increased sensitivity to a DNA damaging agent. Thus, STAT3-inducible Bcl6 variant 2 appears to generate an important IL-6 signal that supports proliferation and survival of IL-6-dependent myeloma cells

Palliative radiotherapy in plasma cell myeloma

International Nuclear Information System (INIS)

Adamietz, I.A.; Schoeber, C.; Schulte, R.W.M.; Renner, K.; Peest, D.

1991-01-01

Pain symptoms caused by bone lesions of multiple myeloma can be relieved by a local irradiation treatment. To estimate the influence of systemic treatment on the palliative effect of local radiotherapy the records of 70 myeloma patients treated with chemotherapy combined with or followed by local irradiation were reviewed. The local response rate, defined as complete pain relief at the irradiated site, was 80 percent in patients receiving irradiation during chemotherapy (melphalan and prednisone) and this palliative effect endured 31.8+-3.6 months. If irradiation was started in the period without systemic treatment the local response rate was 39.6 percent and lasted 24.8+-17.9 months. In sites treated with more than one radiotherapy course 94 percent response after the 1st treatment, 56 percent after the 2nd and no response after the 3rd was achieved. The duration of local pain control was positively related to the applied radiation dose. It is concluded that irradiation during concomitant chemotherapy is superior to radiotherapy performed in a period without systemic treatment. Local long-term palliation can only be achieved by a sufficient high radiation dose. (author). 24 refs.; 2 figs.; 2 tabs

Establishment of a murine graft-versus-myeloma model using allogeneic stem cell transplantation.

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Marilène Binsfeld

Full Text Available Multiple myeloma (MM is a malignant plasma cell disorder with poor long-term survival and high recurrence rates. Despite evidence of graft-versus-myeloma (GvM effects, the use of allogeneic hematopoietic stem cell transplantation (allo-SCT remains controversial in MM. In the current study, we investigated the anti-myeloma effects of allo-SCT from B10.D2 mice into MHC-matched myeloma-bearing Balb/cJ mice, with concomitant development of chronic graft-versus-host disease (GvHD.Balb/cJ mice were injected intravenously with luciferase-transfected MOPC315.BM cells, and received an allogeneic (B10.D2 donor or autologous (Balb/cJ donor transplant 30 days later. We observed a GvM effect in 94% of the allogeneic transplanted mice, as the luciferase signal completely disappeared after transplantation, whereas all the autologous transplanted mice showed myeloma progression. Lower serum paraprotein levels and lower myeloma infiltration in bone marrow and spleen in the allogeneic setting confirmed the observed GvM effect. In addition, the treated mice also displayed chronic GvHD symptoms. In vivo and in vitro data suggested the involvement of effector memory CD4 and CD8 T cells associated with the GvM response. The essential role of CD8 T cells was demonstrated in vivo where CD8 T-cell depletion of the graft resulted in reduced GvM effects. Finally, TCR Vβ spectratyping analysis identified Vβ families within CD4 and CD8 T cells, which were associated with both GvM effects and GvHD, whereas other Vβ families within CD4 T cells were associated exclusively with either GvM or GvHD responses.We successfully established an immunocompetent murine model of graft-versus-myeloma. This is the first murine GvM model using immunocompetent mice that develop MM which closely resembles human MM disease and that are treated after disease establishment with an allo-SCT. Importantly, using TCR Vβ spectratyping, we also demonstrated the presence of GvM unique responses

Maxillary Swelling as the First Evidence of Multiple Myeloma

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Atsushi Kasamatsu

2015-01-01

Full Text Available Multiple myeloma is a malignant neoplasm of plasma cells characterized by proliferation of a single clone of abnormal immunoglobulin-secreting plasma cells. Since the amount of hemopoietic bone marrow is decreased in the maxilla, oral manifestations of multiple myeloma are less common in the maxilla than in the mandible. We report the case of 33-year-old Japanese man who presented with a mass in the right maxillary alveolar region. Computed tomography and magnetic resonance images showed a soft tissue mass in the right maxilla eroding the anterior and lateral walls of the maxillary sinus and extending into the buccal space. The biopsy results, imaging, and laboratory investigations led to the diagnosis of multiple myeloma. This case report suggests that oral surgeons and dentists should properly address oral manifestations as first indications of multiple myeloma.

Maxillary Swelling as the First Evidence of Multiple Myeloma

Science.gov (United States)

Kasamatsu, Atsushi; Kimura, Yasushi; Tsujimura, Hideki; Kanazawa, Harusachi; Koide, Nao; Miyamoto, Isao; Endo-Sakamoto, Yosuke; Shiiba, Masashi; Tanzawa, Hideki; Uzawa, Katsuhiro

2015-01-01

Multiple myeloma is a malignant neoplasm of plasma cells characterized by proliferation of a single clone of abnormal immunoglobulin-secreting plasma cells. Since the amount of hemopoietic bone marrow is decreased in the maxilla, oral manifestations of multiple myeloma are less common in the maxilla than in the mandible. We report the case of 33-year-old Japanese man who presented with a mass in the right maxillary alveolar region. Computed tomography and magnetic resonance images showed a soft tissue mass in the right maxilla eroding the anterior and lateral walls of the maxillary sinus and extending into the buccal space. The biopsy results, imaging, and laboratory investigations led to the diagnosis of multiple myeloma. This case report suggests that oral surgeons and dentists should properly address oral manifestations as first indications of multiple myeloma. PMID:26640721

The Glycome of Normal and Malignant Plasma Cells

Science.gov (United States)

Hose, Dirk; Andrulis, Mindaugas; Moreaux, Jèrôme; Hielscher, Thomas; Willhauck-Fleckenstein, Martina; Merling, Anette; Bertsch, Uta; Jauch, Anna; Goldschmidt, Hartmut; Klein, Bernard; Schwartz-Albiez, Reinhard

2013-01-01

The glycome, i.e. the cellular repertoire of glycan structures, contributes to important functions such as adhesion and intercellular communication. Enzymes regulating cellular glycosylation processes are related to the pathogenesis of cancer including multiple myeloma. Here we analyze the transcriptional differences in the glycome of normal (n = 10) and two cohorts of 332 and 345 malignant plasma-cell samples, association with known multiple myeloma subentities as defined by presence of chromosomal aberrations, potential therapeutic targets, and its prognostic impact. We found i) malignant vs. normal plasma cells to show a characteristic glycome-signature. They can ii) be delineated by a lasso-based predictor from normal plasma cells based on this signature. iii) Cytogenetic aberrations lead to distinct glycan-gene expression patterns for t(11;14), t(4;14), hyperdiploidy, 1q21-gain and deletion of 13q14. iv) A 38-gene glycome-signature significantly delineates patients with adverse survival in two independent cohorts of 545 patients treated with high-dose melphalan and autologous stem cell transplantation. v) As single gene, expression of the phosphatidyl-inositol-glycan protein M as part of the targetable glycosyl-phosphatidyl-inositol-anchor-biosynthesis pathway is associated with adverse survival. The prognostically relevant glycome deviation in malignant cells invites novel strategies of therapy for multiple myeloma. PMID:24386263

The glycome of normal and malignant plasma cells.

Directory of Open Access Journals (Sweden)

Thomas M Moehler

Full Text Available The glycome, i.e. the cellular repertoire of glycan structures, contributes to important functions such as adhesion and intercellular communication. Enzymes regulating cellular glycosylation processes are related to the pathogenesis of cancer including multiple myeloma. Here we analyze the transcriptional differences in the glycome of normal (n = 10 and two cohorts of 332 and 345 malignant plasma-cell samples, association with known multiple myeloma subentities as defined by presence of chromosomal aberrations, potential therapeutic targets, and its prognostic impact. We found i malignant vs. normal plasma cells to show a characteristic glycome-signature. They can ii be delineated by a lasso-based predictor from normal plasma cells based on this signature. iii Cytogenetic aberrations lead to distinct glycan-gene expression patterns for t(11;14, t(4;14, hyperdiploidy, 1q21-gain and deletion of 13q14. iv A 38-gene glycome-signature significantly delineates patients with adverse survival in two independent cohorts of 545 patients treated with high-dose melphalan and autologous stem cell transplantation. v As single gene, expression of the phosphatidyl-inositol-glycan protein M as part of the targetable glycosyl-phosphatidyl-inositol-anchor-biosynthesis pathway is associated with adverse survival. The prognostically relevant glycome deviation in malignant cells invites novel strategies of therapy for multiple myeloma.

CDK2 phosphorylation of Smad2 disrupts TGF-beta transcriptional regulation in resistant primary bone marrow myeloma cells.

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Baughn, Linda B; Di Liberto, Maurizio; Niesvizky, Ruben; Cho, Hearn J; Jayabalan, David; Lane, Joseph; Liu, Fang; Chen-Kiang, Selina

2009-02-15

Resistance to growth suppression by TGF-beta1 is common in cancer; however, mutations in this pathway are rare in hematopoietic malignancies. In multiple myeloma, a fatal cancer of plasma cells, malignant cells accumulate in the TGF-beta-rich bone marrow due to loss of both cell cycle and apoptotic controls. Herein we show that TGF-beta activates Smad2 but fails to induce cell cycle arrest or apoptosis in primary bone marrow myeloma and human myeloma cell lines due to its inability to activate G(1) cyclin-dependent kinase (CDK) inhibitors (p15(INK4b), p21(CIP1/WAF1), p27(KIP1), p57(KIP2)) or to repress c-myc and Bcl-2 transcription. Correlating with aberrant activation of CDKs, CDK-dependent phosphorylation of Smad2 on Thr(8) (pT8), a modification linked to impaired Smad activity, is elevated in primary bone marrow myeloma cells, even in asymptomatic monoclonal gammopathy of undetermined significance. Moreover, CDK2 is the predominant CDK that phosphorylates Smad2 on T8 in myeloma cells, leading to inhibition of Smad2-Smad4 association that precludes transcriptional regulation by Smad2. Our findings provide the first direct evidence that pT8 Smad2 couples dysregulation of CDK2 to TGF-beta resistance in primary cancer cells, and they suggest that disruption of Smad2 function by CDK2 phosphorylation acts as a mechanism for TGF-beta resistance in multiple myeloma.

Osteoclast nuclei of myeloma patients show chromosome translocations specific for the myeloma cell clone: a new type of cancer-host partnership?

DEFF Research Database (Denmark)

Levin Andersen, Thomas; Boissy, Patrice; Sondergaard, T E

2007-01-01

through fusion between myeloma cells and osteoclasts. In conclusion, malignant cells contribute significantly to the formation of bone-resorbing osteoclasts in multiple myeloma. Osteoclast-myeloma clone hybrids reflect a previously unrecognized mechanism of bone destruction in which malignant cells...

Competition between clonal plasma cells and normal cells for potentially overlapping bone marrow niches is associated with a progressively altered cellular distribution in MGUS vs myeloma.

Science.gov (United States)

Paiva, B; Pérez-Andrés, M; Vídriales, M-B; Almeida, J; de las Heras, N; Mateos, M-V; López-Corral, L; Gutiérrez, N C; Blanco, J; Oriol, A; Hernández, M T; de Arriba, F; de Coca, A G; Terol, M-J; de la Rubia, J; González, Y; Martín, A; Sureda, A; Schmidt-Hieber, M; Schmitz, A; Johnsen, H E; Lahuerta, J-J; Bladé, J; San-Miguel, J F; Orfao, A

2011-04-01

Disappearance of normal bone marrow (BM) plasma cells (PC) predicts malignant transformation of monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM) into symptomatic multiple myeloma (MM). The homing, behavior and survival of normal PC, but also CD34(+) hematopoietic stem cells (HSC), B-cell precursors, and clonal PC largely depends on their interaction with stromal cell-derived factor-1 (SDF-1) expressing, potentially overlapping BM stromal cell niches. Here, we investigate the distribution, phenotypic characteristics and competitive migration capacity of these cell populations in patients with MGUS, SMM and MM vs healthy adults (HA) aged >60 years. Our results show that BM and peripheral blood (PB) clonal PC progressively increase from MGUS to MM, the latter showing a slightly more immature immunophenotype. Of note, such increased number of clonal PC is associated with progressive depletion of normal PC, B-cell precursors and CD34(+) HSC in the BM, also with a parallel increase in PB. In an ex vivo model, normal PC, B-cell precursors and CD34(+) HSC from MGUS and SMM, but not MM patients, were able to abrogate the migration of clonal PC into serial concentrations of SDF-1. Overall, our results show that progressive competition and replacement of normal BM cells by clonal PC is associated with more advanced disease in patients with MGUS, SMM and MM.

Tetraspanin 7 (TSPAN7) expression is upregulated in multiple myeloma patients and inhibits myeloma tumour development in vivo

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Cheong, Chee Man [Myeloma Research Laboratory, School of Medical Sciences, University of Adelaide, and South Australian Health and Medical Research Institute (SAHMRI), Adelaide 5000, SA (Australia); Chow, Annie W.S. [Myeloma Research Laboratory, School of Medical Sciences, University of Adelaide, and South Australian Health and Medical Research Institute (SAHMRI), Adelaide 5000, SA (Australia); Department of Haematology, SA Pathology, Adelaide 5000, SA (Australia); Fitter, Stephen [Myeloma Research Laboratory, School of Medical Sciences, University of Adelaide, and South Australian Health and Medical Research Institute (SAHMRI), Adelaide 5000, SA (Australia); Hewett, Duncan R. [Myeloma Research Laboratory, School of Medical Sciences, University of Adelaide, and South Australian Health and Medical Research Institute (SAHMRI), Adelaide 5000, SA (Australia); School of Medicine, University of Adelaide, Adelaide 5005, SA (Australia); Martin, Sally K. [Myeloma Research Laboratory, School of Medical Sciences, University of Adelaide, and South Australian Health and Medical Research Institute (SAHMRI), Adelaide 5000, SA (Australia); Department of Haematology, SA Pathology, Adelaide 5000, SA (Australia); School of Medicine, University of Adelaide, Adelaide 5005, SA (Australia); Williams, Sharon A. [Myeloma Research Laboratory, School of Medical Sciences, University of Adelaide, and South Australian Health and Medical Research Institute (SAHMRI), Adelaide 5000, SA (Australia); To, L. Bik [Department of Haematology, SA Pathology, Adelaide 5000, SA (Australia); and others

2015-03-01

Background: Increased expression of the tetraspanin TSPAN7 has been observed in a number of cancers; however, it is unclear how TSPAN7 plays a role in cancer progression. Methods: We investigated the expression of TSPAN7 in the haematological malignancy multiple myleoma (MM) and assessed the consequences of TSPAN7 expression in the adhesion, migration and growth of MM plasma cells (PC) in vitro and in bone marrow (BM) homing and tumour growth in vivo. Finally, we characterised the association of TSPAN7 with cell surface partner molecules in vitro. Results: TSPAN7 was found to be highly expressed at the RNA and protein level in CD138{sup +} MM PC from approximately 50% of MM patients. TSPAN7 overexpression in the murine myeloma cell line 5TGM1 significantly reduced tumour burden in 5TGM1/KaLwRij mice 4 weeks after intravenous adminstration of 5TGM1 cells. While TSPAN7 overexpression did not affect cell proliferation in vitro, TSPAN7 increased 5TGM1 cell adhesion to BM stromal cells and transendothelial migration. In addition, TSPAN7 was found to associate with the molecular chaperone calnexin on the cell surface. Conclusion: These results suggest that elevated TSPAN7 may be associated with better outcomes for up to 50% of MM patients. - Highlights: • TSPAN7 expression is upregulated in newly-diagnosed patients with active multiple myeloma. • Overexpression of TSPAN7 inhibits myeloma tumour development in vivo. • TSPAN7 interacts with calnexin at the plasma membrane in a myeloma cell line.

The selective Aurora B kinase inhibitor AZD1152 is a potential new treatment for multiple myeloma.

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Evans, Robert P; Naber, Claudia; Steffler, Tara; Checkland, Tamara; Maxwell, Christopher A; Keats, Jonathan J; Belch, Andrew R; Pilarski, Linda M; Lai, Raymond; Reiman, Tony

2008-02-01

Aurora kinases are potential targets for cancer therapy. Previous studies have validated Aurora kinase A as a therapeutic target in multiple myeloma (MM), and have demonstrated in vitro anti-myeloma effects of small molecule Aurora kinase inhibitors that inhibit both Aurora A and B. This study demonstrated that Aurora B kinase was strongly expressed in myeloma cell lines and primary plasma cells. The selective Aurora B inhibitor AZD1152-induced apoptotic death in myeloma cell lines at nanomolar concentrations, with a cell cycle phenotype consistent with that reported previously for Aurora B inhibition. In some cases, AZD1152 in combination with dexamethasone showed increased anti-myeloma activity compared with the use of either agent alone. AZD1152 was active against sorted CD138(+) BM plasma cells from myeloma patients but also, as expected, was toxic to CD138(-) marrow cells from the same patients. In a murine myeloma xenograft model, AZD1152-inhibited tumour growth at well-tolerated doses and induced cell death in established tumours, with associated mild, transient leucopenia. AZD1152 shows promise in these preclinical studies as a novel treatment for MM.

T cells in multiple myeloma display features of exhaustion and senescence at the tumor site

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Claudia Zelle-Rieser

2016-11-01

Full Text Available Abstract Background Multiple myeloma is an incurable plasma cell malignancy that is mostly restricted to the bone marrow. Cancer-induced dysfunction of cytotoxic T cells at the tumor site may be responsible for immune evasion and therapeutical failure of immunotherapies. Therefore, enhanced knowledge about the actual status of T cells in myeloma bone marrow is urgently needed. Here, we assessed the expression of inhibitory molecules PD-1, CTLA-4, 2B4, CD160, senescence marker CD57, and CD28 on T cells of naive and treated myeloma patients in the bone marrow and peripheral blood and collected data on T cell subset distribution in both compartments. In addition, T cell function concerning proliferation and expression of T-bet, IL-2, IFNγ, and CD107a was investigated after in vitro stimulation by CD3/CD28. Finally, data was compared to healthy, age-matched donor T cells from both compartments. Methods Multicolor flow cytometry was utilized for the analyses of surface molecules, intracellular staining of cytokines was also performed by flow cytometry, and proliferation was assessed by 3H-thymidine incorporation. Statistical analyses were performed utilizing unpaired T test and Mann-Whitney U test. Results We observed enhanced T cell exhaustion and senescence especially at the tumor site. CD8+ T cells expressed several molecules associated with T cell exhaustion (PD-1, CTLA-4, 2B4, CD160 and T cell senescence (CD57, lack of CD28. This phenotype was associated with lower proliferative capacity and impaired function. Despite a high expression of the transcription factor T-bet, CD8+ T cells from the tumor site failed to produce IFNγ after CD3/CD28 in vitro restimulation and displayed a reduced ability to degranulate in response to T cell stimuli. Notably, the percentage of senescent CD57+CD28− CD8+ T cells was significantly lower in treated myeloma patients when compared to untreated patients. Conclusions T cells from the bone marrow of myeloma

CT features of abdominal plasma cell neoplasms

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Monill, J.; Pernas, J.; Montserrat, E.; Perez, C.; Clavero, J.; Martinez-Noguera, A.; Guerrero, R.; Torrubia, S.

2005-01-01

The aim of this study was to describe the CT features of abdominal plasma cell neoplasms. We reviewed CT imaging findings in 11 patients (seven men, four women; mean age 62 years) with plasma cell neoplasms and abdominal involvement. Helical CT of the entire abdomen and pelvis was performed following intravenous administration of contrast material. Images were analyzed in consensus by two radiologists. Diagnoses were made from biopsy, surgery and/or clinical follow-up findings. Multiple myeloma was found in seven patients and extramedullary plasmacytoma in four patients. All patients with multiple myeloma had multifocal disease with involvement of perirenal space (4/7), retroperitoneal and pelvic lymph nodes (3/7), peritoneum (3/7), liver (2/7), subcutaneous tissues (2/7) and kidney (1/7). In three of the four patients with extramedullary plasmacytoma, a single site was involved, namely stomach, vagina and retroperitoneum. In the fourth patient, a double site of abdominal involvement was observed with rectal and jejunal masses. Plasma cell neoplasm should be considered in the differential diagnosis of single or multiple enhancing masses in the abdomen or pelvis. Abdominal plasma cell neoplasms were most frequently seen as well-defined enhancing masses (10/11). (orig.)

(18)F-FDG dynamic PET/CT in patients with multiple myeloma: patterns of tracer uptake and correlation with bone marrow plasma cell infiltration rate.

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Sachpekidis, Christos; Mai, Elias K; Goldschmidt, Hartmut; Hillengass, Jens; Hose, Dirk; Pan, Leyun; Haberkorn, Uwe; Dimitrakopoulou-Strauss, Antonia

2015-06-01

The value of F-FDG PET in the diagnostic approach of multiple myeloma (MM) remains incompletely elicited. Little is known about the kinetics of F-FDG in the bone marrow and extramedullary sites in MM. This study aimed to evaluate quantitative data on kinetics and distribution patterns of F-FDG in MM patients with regard to pelvic bone marrow plasma cell infiltration. The study included 40 patients with primary MM. Dynamic PET/CT scanning of the lower lumbar spine and pelvis was performed after the administration of F-FDG. Whole-body PET/CT studies were performed. Sites of focal increased tracer uptake were considered as highly suggestive of myelomatous involvement after taking into account the patient history and CT findings. Bone marrow of the os ilium without pathologic tracer accumulation served as reference. The evaluation of dynamic PET/CT studies was based in addition to the conventional visual (qualitative) assessment, on semiquantitative (SUV) calculations, as well as on absolute quantitative estimations after application of a 2-tissue compartment model and a noncompartmental approach. F-FDG quantitative information and corresponding distribution patterns were correlated with pelvic bone marrow plasma cell infiltration. Fifty-two myelomatous lesions were detected in the pelvis. All parameters in suspected MM lesions ranged in significantly higher levels than in reference tissue (P PET/CT imaging demonstrated 4 patterns of tracer uptake; these are as follows: negative, focal, diffuse, and mixed (focal/diffuse) tracer uptake. Patients with a mixed pattern of radiotracer uptake had the highest mean plasma cell infiltration rate in their bone marrow, whereas those with negative PET/CT scans demonstrated the lowest bone marrow plasma cell infiltration. In total, 265 focal myeloma-indicative F-FDG-avid lesions were detected, 129 of which correlated with low-dose CT osteolytic findings. No significant correlation between the number of focal lesions detected in PET

Localized extramedullary relapse after autologous hematopoietic stem cell transplantation in multiple myeloma

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Erkus, Muhan; Meteoglu, Ibrahim; Bolaman, Zahit; Kadikoylu, Gurhan

2005-01-01

Extramedullary plasmacytomas are rare manifestation of plasma cell malignancies. After hematopoietic stem cell transplantation HSCT, presentation of localized plasmacytoma with extramedullary growth is very unusual. We report a case of a 56-year-old woman with Dune-Salmon stage IIIA immunoglobulin A-kappa multiple myeloma, which presented 120 days after autologous HSCT with extramedullary plasmacytoma arising from a lymph node in supraclavicular region. The patient had no pretransplant-history related with extramedullary disease. There was no increase of plasma cells in bone marrow or monoclonal protein in urine or serum. Aspiration smears of lymph node revealed a population of plasmacytoid cells at various stages of maturation. The patient was successfully treated with local radiotherapy and has remained progression-free for more than 20 months. (author)

Radiographic features of plasma cell leukemia in the maxilla: A case report

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Wong, Phillip; Kashtwari, Deeba; Nair, Madhu K. [Dept. of Oral and Maxillofacial Radiology, Oral and Maxillofacial Diagnostic Sciences/Radiology, Colleges of Dentistry/Medicine, University of Florida, Gainesville (United States)

2016-12-15

Plasma cell leukemia (PCL) is an aggressive form of multiple myeloma where there is hematogenous spread of abnormal plasma cells into the periphery. This is opposed to multiple myeloma, where the abnormal plasma cells stay in the bone marrow. PCL is more common in males than females, and is also more common in African-Americans than Caucasians. Signs and symptoms of PCL include, but are not limited to, renal insufficiency, hypercalcemia, anemia, lytic bone lesions, thrombocytopenia, hepatomegaly, and splenomegaly. Here, we discussed a case of a 71-year-old Caucasian female recently diagnosed with primary PCL with radiographic features of this disease throughout the body, with an emphasis on the maxillofacial skeleton and relevance from a dental standpoint.

Thymidine secretion by hybridoma and myeloma cells

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Spilsberg, Bjorn; Rise, Frode; Petersen, Dirk; Nissen-Meyer, Jon

2006-01-01

Secretion of thymidine appeared to be a common property of hybridoma and myeloma cells, but not of other cell types, which were tested. Of three hybridoma cell lines tested, all secreted thymidine in amounts resulting in the accumulation of thymidine to concentrations of 10-20 μM in the culture medium. Also three of five myeloma cell lines that were analyzed secrete thymidine, but none of the other cell types that were studied. Thymidine was purified to homogeneity (4 mg purified from 3 l of culture medium) and identified as such by nuclear magnetic resonance spectroscopy. The cells that secreted thymidine showed high resistance to the growth inhibitory effect of thymidine

Multiple myeloma: diagnosis and treatment.

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Nau, Konrad C; Lewis, William D

2008-10-01

Multiple myeloma, the most common bone malignancy, is occurring with increasing frequency in older persons. Typical symptoms are bone pain, malaise, anemia, renal insufficiency, and hypercalcemia. Incidental discovery on comprehensive laboratory panels is common. The disease is diagnosed with serum or urine protein electrophoresis or immunofixation and bone marrow aspirate analysis. Skeletal radiographs are important in staging multiple myeloma and revealing lytic lesions, vertebral compression fractures, and osteoporosis. Magnetic resonance imaging and positron emission tomography or computed tomography are emerging as useful tools in the evaluation of patients with myeloma; magnetic resonance imaging is preferred for evaluating acute spinal compression. Nuclear bone scans and dual energy x-ray absorptiometry have no role in the diagnosis and staging of myeloma. The differential diagnosis of monoclonal gammopathies includes monoclonal gammopathy of uncertain significance, smoldering (asymptomatic) and symptomatic multiple myeloma, amyloidosis, B-cell non-Hodgkin lymphoma, Waldenström macroglobulinemia, and rare plasma cell leukemia and heavy chain diseases. Patients with monoclonal gammopathy of uncertain significance or smoldering multiple myeloma should be followed closely, but not treated. Symptomatic multiple myeloma is treated with chemotherapy followed by autologous stem cell transplantation, if possible. Melphalan, prednisolone, dexamethasone, vincristine, doxorubicin, bortezomib, and thalidomide and its analogue lenalidomide have been used successfully. It is important that family physicians recognize and appropriately treat multiple myeloma complications. Bone pain is treated with opiates, bisphosphonates, radiotherapy, vertebroplasty, or kyphoplasty; nephrotoxic nonsteroidal anti-inflammatory drugs should be avoided. Hypercalcemia is treated with isotonic saline infusions, steroids, furosemide, or bisphosphonates. Because of susceptibility to infections

The pituitary tumor transforming gene 1 (PTTG-1: An immunological target for multiple myeloma

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Gagliano Nicoletta

2008-04-01

Full Text Available Abstract Background Multiple Myeloma is a cancer of B plasma cells, which produce non-specific antibodies and proliferate uncontrolled. Due to the potential relapse and non-specificity of current treatments, immunotherapy promises to be more specific and may induce long-term immunity in patients. The pituitary tumor transforming gene 1 (PTTG-1 has been shown to be a novel oncogene, expressed in the testis, thymus, colon, lung and placenta (undetectable in most other tissues. Furthermore, it is over expressed in many tumors such as the pituitary adenoma, breast, gastrointestinal cancers, leukemia, lymphoma, and lung cancer and it seems to be associated with tumorigenesis, angiogenesis and cancer progression. The purpose was to investigate the presence/rate of expression of PTTG-1 in multiple myeloma patients. Methods We analyzed the PTTG-1 expression at the transcriptional and the protein level, by PCR, immunocytochemical methods, Dot-blot and ELISA performed on patient's sera in 19 multiple myeloma patients, 6 different multiple myeloma cell lines and in normal human tissue. Results We did not find PTTG-1 presence in the normal human tissue panel, but PTTG-1 mRNA was detectable in 12 of the 19 patients, giving evidence of a 63% rate of expression (data confirmed by ELISA. Four of the 6 investigated cell lines (66.6% were positive for PTTG-1. Investigations of protein expression gave evidence of 26.3% cytoplasmic expression and 16% surface expression in the plasma cells of multiple myeloma patients. Protein presence was also confirmed by Dot-blot in both cell lines and patients. Conclusion We established PTTG-1's presence at both the transcriptional and protein levels. These data suggest that PTTG-1 is aberrantly expressed in multiple myeloma plasma cells, is highly immunogenic and is a suitable target for immunotherapy of multiple myeloma.

Epigenetic Activity of Peroxisome Proliferator-Activated Receptor Gamma Agonists Increases the Anticancer Effect of Histone Deacetylase Inhibitors on Multiple Myeloma Cells.

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Nassera Aouali

Full Text Available Epigenetic modifications play a major role in the development of multiple myeloma. We have previously reported that the PPARγ agonist pioglitazone (PIO enhances, in-vitro, the cytotoxic effect of the Histone deacetylase inhibitor (HDACi, valproic acid (VPA, on multiple myeloma cells. Here, we described the development of a new multiple myeloma mouse model using MOLP8 cells, in order to evaluate the effect of VPA/PIO combination on the progression of myeloma cells, by analyzing the proliferation of bone marrow plasma cells. We showed that VPA/PIO delays the progression of the disease and the invasion of myeloma cells in the bone marrow. Mechanistically, we demonstrated that VPA/PIO increases the cleavage of caspase 3 and PARP, and induces the acetylation of Histone 3 (H3. Furthermore, we provided evidence that PPARγ agonist is able to enhance the action of other HDACi such as Vorinostat or Mocetinostat. Using PPARγ antagonist or siPPARγ, we strongly suggest that, as described during adipogenesis, PIO behaves as an epigenetic regulator by improving the activity of HDACi. This study highlights the therapeutic benefit of PIO/VPA combination, compared to VPA treatment as a single-arm therapy on multiple myeloma and further highlights that such combination may constitute a new promising treatment strategy which should be supported by clinical trials.

RECENT ADVANCES IN PATHO-BIOLOGY OF MYELOMA BONE DISEASE: CLINICOPATHOLOGY AND LITERATURE OF REVIEW

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Lohit Kumar

2016-03-01

Full Text Available Bone disease is a hallmark of multiple myeloma, presenting as lytic lesions associated with bone pain, pathological fractures requiring surgery and/or radiation to bone, spinal cord compression and hypercalcaemia. Increased osteoclastic activity unaccompanied by a compensatory increase in osteoblast function, leading to enhanced bone resorption results in bone disease. The interaction of plasma cells with the bone marrow microenvironment has been shown to play a vital role. Also, interactions of myeloma cells with osteoclasts enhance myeloma growth and survival, and thereby create a vicious cycle leading to extensive bone destruction and myeloma cell expansion.

Induction of potent NK cell-dependent anti-myeloma cytotoxic T cells in response to combined mapatumumab and bortezomib.

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Neeson, Paul J; Hsu, Andy K; Chen, Yin R; Halse, Heloise M; Loh, Joanna; Cordy, Reece; Fielding, Kate; Davis, Joanne; Noske, Josh; Davenport, Alex J; Lindqvist-Gigg, Camilla A; Humphreys, Robin; Tai, Tsin; Prince, H Miles; Trapani, Joseph A; Smyth, Mark J; Ritchie, David S

2015-09-01

There is increasing evidence that some cancer therapies can promote tumor immunogenicity to boost the endogenous antitumor immune response. In this study, we used the novel combination of agonistic anti-TRAIL-R1 antibody (mapatumumab, Mapa) with low dose bortezomib (LDB) for this purpose. The combination induced profound myeloma cell apoptosis, greatly enhanced the uptake of myeloma cell apoptotic bodies by dendritic cell (DC) and induced anti-myeloma cytotoxicity by both CD8 + T cells and NK cells. Cytotoxic lymphocyte expansion was detected within 24 h of commencing therapy and was maximized when myeloma-pulsed DC were co-treated with low dose bortezomib and mapatumumab (LDB+Mapa) in the presence of NK cells. This study shows that Mapa has two distinct but connected modes of action against multiple myeloma (MM). First, when combined with LDB, Mapa produced powerful myeloma cell apoptosis; secondly, it promoted DC priming and an NK cell-mediated expansion of anti-myeloma cytotoxic lymphocyte (CTL). Overall, this study indicates that Mapa can be used to drive potent anti-MM immune responses.

[A wrong move in an amateur football player reveals a light chain myeloma].

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Peyneau, Marine; Nassiri, Shiva; Myara, Anne; Ohana, Salomon; Laplanche, Sophie

2016-01-01

Light chain multiple myeloma is a hematologic malignancy characterized by an excess of tumor plasma cells in the bone marrow and a monoclonal light chain in blood. It is generally diagnosed in patients aged 60-75 years old. Hypercalcemia, anemia, kidney failure, and bone pains are the main clinical and biological signs. Here is an atypical case report about a 30 year-old man who was diagnosed a light chain multiple myeloma. This patient had been suffering from back pain for 5 months. Osteolytic lesions were discovered on X-rays prescribed by the family practitioner. Admitted to the Emergency department, all blood tests showed results within the normal range. The serum protein electrophoresis was also normal. Only the urine analysis showed proteinuria. The urine immunofixation electrophoresis showed a massive κ light chain. The bone marrow aspiration cell count confirmed the myeloma diagnosis with an infiltration of dystrophic plasma cells. The patient was transferred to the hematology ward of Necker Hospital for treatment of light chain myeloma.

Vindesine in plasma cell tumors.

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Salvagno, L; Paccagnella, A; Chiarion Sileni, V; De Besi, P; Frizzarin, M; Casara, D; Fiorentino, M V

1985-12-31

Twenty-one patients with plasma cell tumors received vindesine (VDS) at the dose of 3 mg/m2 i.v. on day 1 plus prednisone at the dose of 100 mg p.o. from day 1 to 5, recycling every 8 days 3 times and then every 10-12 days. In 3 patients with gastric or duodenal ulcer prednisone was not administered. All but one patient were heavily pretreated and resistant to M-2 regimen. Overall there were 4 objective responses (19%): 2 among 15 patients (13%) with multiple myeloma and 2 among 6 patients (33%) with extramedullary plasmacytoma (EMP). The responses lasted for 2, 12, 15 and 48+ months. One previously untreated EMP patient received VDS without prednisone and obtained a complete long-lasting remission. The association of VDS with high-dose prednisone seems to have some activity in plasma cell tumors; probably in multiple myeloma the objective responses are due to the high dose of cortisone rather than to VDS. On the contrary, in EMP patients, VDS may be an active agent, even if administered without cortisone.

Noninvasive imaging of multiple myeloma using near infrared fluorescent molecular probe

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Hathi, Deep; Zhou, Haiying; Bollerman-Nowlis, Alex; Shokeen, Monica; Akers, Walter J.

2016-03-01

Multiple myeloma is a plasma cell malignancy characterized by monoclonal gammopathy and osteolytic bone lesions. Multiple myeloma is most commonly diagnosed in late disease stages, presenting with pathologic fracture. Early diagnosis and monitoring of disease status may improve quality of life and long-term survival for multiple myeloma patients from what is now a devastating and fatal disease. We have developed a near-infrared targeted fluorescent molecular probe with high affinity to the α4β1 integrin receptor (VLA-4)overexpressed by a majority of multiple myeloma cells as a non-radioactive analog to PET/CT tracer currently being developed for human diagnostics. A near-infrared dye that emits about 700 nm was conjugated to a high affinity peptidomimmetic. Binding affinity and specificity for multiple myeloma cells was investigated in vitro by tissue staining and flow cytometry. After demonstration of sensitivity and specificity, preclinical optical imaging studies were performed to evaluate tumor specificity in murine subcutaneous and metastatic multiple myeloma models. The VLA-4-targeted molecular probe showed high affinity for subcutaneous MM tumor xenografts. Importantly, tumor cells specific accumulation in the bone marrow of metastatic multiple myeloma correlated with GFP signal from transfected cells. Ex vivo flow cytometry of tumor tissue and bone marrow further corroborated in vivo imaging data, demonstrating the specificity of the novel agent and potential for quantitative imaging of multiple myeloma burden in these models.

Correlation of proliferative and clonogenic tumor cells in multiple myeloma

International Nuclear Information System (INIS)

Karp, J.E.; Burke, P.J.; Saylor, P.L.; Humphrey, R.L.

1984-01-01

To expand on the findings from previous clinical trials that the growth of residual tumor is increased at a predictable time following initial drug administration, malignant plasma cells from bone marrows of patients with multiple myeloma (MM) were examined for changes in proliferation and clonogenicity induced in vivo by cyclophosphamide and in vitro by drug-induced humoral stimulatory activity. Peak plasma cell [ 3 H]thymidine labeling index (LI) occurred predictably following drug and paralleled changes in agar colony formation by marrow cells obtained during therapy. Colony-forming capacity of pretreatment MM marrow populations was enhanced when those cells were cultured with humoral stimulatory activity, similar to the increased colony formation detected in Day 9 postcyclophosphamide marrows at the time of peak plasma cell LI. To further define a relationship between proliferative plasma cells and colony-forming tumor cells, MM marrows were fractionated by sedimentation on an isokinetic gradient. Enrichment of a proliferative tumor cell cohort was achieved, evidenced by [ 3 H]thymidine LI. Colony-forming cells were also enriched by isokinetic gradient sedimentation, and agar colony formation by MM marrow cell fractions correlated with the kinetic characteristics of the isolated subpopulations. These studies of whole and fractionated human MM marrow cell populations suggest that the kinetically active cells which are induced to proliferate in vivo and in vitro are closely related to the clonogenic tumor cells which produce colonies in agar and which, like those cells measured by [ 3 H]thymidine LI, respond to growth stimulation by drug-induced humoral stimulatory activity

Drugs Approved for Multiple Myeloma

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This page lists cancer drugs approved by the Food and Drug Administration (FDA) for multiple myeloma and other plasma cell neoplasms. The list includes generic names, brand names, and common drug combinations, which are shown in capital letters. The drug names link to NCI's Cancer Drug Information summaries.

Bone morphogenic protein 6 : a member of a novel class of prognostic factors expressed by normal and malignant plasma cells inhibiting proliferation and angiogenesis

NARCIS (Netherlands)

Seckinger, A.; Meissner, T.; Moreaux, J.; Goldschmidt, H.; Fuhler, G. M.; Benner, A.; Hundemer, M.; Reme, T.; Shaughnessy, J. D.; Barlogie, B.; Bertsch, U.; Hillengass, J.; Ho, A. D.; Pantesco, V.; Jauch, A.; De Vos, J.; Rossi, J. F.; Moehler, T.; Klein, B.; Hose, D.

2009-01-01

Pathogenesis of multiple myeloma is associated with an aberrant expression of pro-proliferative, pro-angiogenic and bone-metabolism-modifying factors by malignant plasma cells. Given the frequently long time span from diagnosis of early-stage plasma cell dyscrasias to overt myeloma and the mostly

Gene expression profiling for molecular classification of multiple myeloma in newly diagnosed patients

NARCIS (Netherlands)

Broyl, Annemiek; Hose, Dirk; Lokhorst, Henk; de Knegt, Yvonne; Peeters, Justine; Jauch, Anna; Bertsch, Uta; Buijs, Arjan; Stevens-Kroef, Marian; Beverloo, H. Berna; Vellenga, Edo; Zweegman, Sonja; Kersten, Marie-Josée; van der Holt, Bronno; el Jarari, Laila; Mulligan, George; Goldschmidt, Hartmut; van Duin, Mark; Sonneveld, Pieter

2010-01-01

To identify molecularly defined subgroups in multiple myeloma, gene expression profiling was performed on purified CD138(+) plasma cells of 320 newly diagnosed myeloma patients included in the Dutch-Belgian/German HOVON-65/GMMG-HD4 trial. Hierarchical clustering identified 10 subgroups; 6

The expression of p53 protein in patients with multiple myeloma

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Marković Olivera

2007-01-01

Full Text Available Introduction: Although mutations of p53 are one of the most often acquired genetic changes in malignant tumors, these mutations are rare events in patients with newly diagnosed multiple myeloma (MM. Moreover, there are a few literature data about clinical significance of p53 overexpression in multiple myeloma. Objective The aim of our study was to evaluate the clinical significance of p53 immunoexpression in multiple myeloma. Method A total of 58 patients with newly diagnosed MM (26 females and 32 males, mean age 62 years were enrolled in the study. The diagnosis of MM was made according to criteria of Chronic Leukemia-Myeloma Task Force. Clinical staging was done according to Durie and Salmon classification (4 patients had disease stage I, 15 patients stage II and 39 patients stage III. The histological grade and histological stage were determined according to predominant plasma cell morphology and volume of myeloma infiltration, respectively. Standard immunohistochemical analysis with p53 antibody in B5-fixed and paraffin- embedded bone marrow specimens was used to evaluate the expression of p53 in myeloma cells. The specimens were considered positive when ≥5% of plasma cells exhibited clear nuclear positivity. Results Out of 58 patients, p53 expression was detected in 9 (15.52%. No significant correlation was found between p53 expression and clinical stage (I+II vs. III, Я2-microglobulin level (≤6 mg/L vs. >6mg/L, histological grade (I vs. II+III, histological stage (<20% vs. 21-50% vs. >50% and the extent of osteolytic lesions (≤3 vs. >3 lesions. Median survival of patients with p53 immunoreactivity in =>5% of plasma cells was 10 months, whilst median survival of patients with p53 immunoreactivity in <5% of plasma cells was 36 months. However, such difference was not significant (p=0.2. Conclusion The frequency of p53 immunoexpression in our group of newly diagnosed MM was relatively low. Although p53 immunoexpression was not

Constitutive activation of p38 MAPK in tumor cells contributes to osteolytic bone lesions in multiple myeloma

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Yang, Jing; He, Jin; Wang, Ji; Cao, Yabing; Ling, Jianhua; Qian, Jianfei; Lu, Yong; Li, Haiyan; Zheng, Yuhuan; Lan, Yongsheng; Hong, Sungyoul; Matthews, Jairo; Starbuck, Michael W; Navone, Nora M; Orlowski, Robert Z.; Lin, Pei; Kwak, Larry W.; Yi, Qing

2012-01-01

Bone destruction is a hallmark of multiple myeloma and affects more than 80% of patients. However, current therapy is unable to completely cure and/or prevent bone lesions. Although it is accepted that myeloma cells mediate bone destruction by inhibition of osteoblasts and activation of osteoclasts, the underlying mechanism is still poorly understood. This study demonstrates that constitutive activation of p38 mitogen-activated protein kinase in myeloma cells is responsible for myeloma-induced osteolysis. Our results show that p38 is constitutively activated in most myeloma cell lines and primary myeloma cells from patients. Myeloma cells with high/detectable p38 activity, but not those with low/undetectable p38 activity, injected into SCID or SCID-hu mice caused bone destruction. Inhibition or knockdown of p38 in human myeloma reduced or prevented myeloma-induced osteolytic bone lesions without affecting tumor growth, survival, or homing to bone. Mechanistic studies showed that myeloma cell p38 activity inhibited osteoblastogenesis and bone formation and activated osteoclastogenesis and bone resorption in myeloma-bearing SCID mice. This study elucidates a novel molecular mechanism—sactivation of p38 signaling in myeloma cells—by which myeloma cells induce osteolytic bone lesions and indicates that targeting myeloma cell p38 may be a viable approach to treating or preventing myeloma bone disease. PMID:22425892

Evolutionary Dynamics of Tumor-Stroma Interactions in Multiple Myeloma.

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Javad Salimi Sartakhti

Full Text Available Cancer cells and stromal cells cooperate by exchanging diffusible factors that sustain tumor growth, a form of frequency-dependent selection that can be studied in the framework of evolutionary game theory. In the case of multiple myeloma, three types of cells (malignant plasma cells, osteoblasts and osteoclasts exchange growth factors with different effects, and tumor-stroma interactions have been analysed using a model of cooperation with pairwise interactions. Here we show that a model in which growth factors have autocrine and paracrine effects on multiple cells, a more realistic assumption for tumor-stroma interactions, leads to different results, with implications for disease progression and treatment. In particular, the model reveals that reducing the number of malignant plasma cells below a critical threshold can lead to their extinction and thus to restore a healthy balance between osteoclast and osteoblast, a result in line with current therapies against multiple myeloma.

PET/CT and MR imaging in myeloma

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Mulligan, Michael E. [University of Maryland Medical Center, Department of Radiology, Baltimore, MD (United States); Badros, Ashraf Z. [University of Maryland, Department of Medicine, Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD (United States)

2007-01-15

Myeloma is the most common primary bone malignancy. It accounts for 10% of all hematological malignancies and 1% of all cancers. In the United States, there are an estimated 16,000 new cases and over 11,000 deaths yearly due to myeloma. Plasma cell dyscrasias manifest themselves in a variety of forms that range from MGUS (monoclonal gammopathy of undetermined significance) and smoldering myeloma that require no therapy, to the ''malignant'' form of multiple myeloma. The role of imaging in the management of myeloma includes: an assessment of the extent of intramedullary bone disease, detection of any extramedullary foci, and severity of the disease at presentation; the identification and characterization of complications; subsequent assessment of disease status. This review will focus on the use of PET/CT and MR imaging for myeloma patients at the time of initial diagnosis and for follow-up management, based on current reports in the literature and our practice at the Marlene and Stewart Greenebaum Cancer Center, University of Maryland Medical Center in Baltimore, USA. (orig.)

Resveratrol inhibits myeloma cell growth, prevents osteoclast formation, and promotes osteoblast differentiation

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Boissy, Patrice; Andersen, Thomas L; Abdallah, Basem M

2005-01-01

, a challenge for treating multiple myeloma is discovering drugs targeting not only myeloma cells but also osteoclasts and osteoblasts. Because resveratrol (trans-3,4',5-trihydroxystilbene) is reported to display antitumor activities on a variety of human cancer cells, we investigated the effects...... of this natural compound on myeloma and bone cells. We found that resveratrol reduces dose-dependently the growth of myeloma cell lines (RPMI 8226 and OPM-2) by a mechanism involving cell apoptosis. In cultures of human primary monocytes, resveratrol inhibits dose-dependently receptor activator of nuclear factor......RNA and cell surface protein levels and a decrease of NFATc1 stimulation and NF-kappaB nuclear translocation, whereas the gene expression of c-fms, CD14, and CD11a is up-regulated. Finally, resveratrol promotes dose-dependently the expression of osteoblast markers like osteocalcin and osteopontin in human bone...

Bortezomib in the management of multiple myeloma

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Jacob P Laubach

2009-09-01

Full Text Available Jacob P Laubach, Constantine S Mitsiades, Teru Hideshima, Robert Schlossman, Dharminder Chauhan, Nikhil Munshi, Irene Ghobrial, Nicole Carreau, Kenneth C Anderson, Paul G RichardsonDepartment of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USAAbstract: Multiple myeloma (MM is a B-cell malignancy characterized by clonal expansion of plasma cells within the bone marrow, the presence of a serum and/or urine monoclonal protein, lytic bone lesions, and anemia. On a cellular level, the disease is characterized by complex interactions between tumor cells and the surrounding bone marrow microenvironment. Understanding of the relationship between malignant plasma cells and the microenvironment has sparked ongoing efforts to develop targeted therapeutic agents for treatment of this disease. The successful development of the first-in-class small-molecule proteasome inhibitor bortezomib occurred as a result of these efforts. This review focuses on the rationale for bortezomib therapy in the treatment of patients with newly diagnosed and relapsed MM, important treatment-related side effects, and future directions for use of bortezomib and other, emerging proteasome inhibitors.Keywords: multiple myeloma, bortezomib, stem cell transplantation, peripheral neuropathy

A case of multiple myeloma presenting as a bullous dermatosis

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Gul Ulker

2008-01-01

Full Text Available Multiple myeloma is a malignant plasma cell proliferative disorder that produces a monoclonal immunoglobulin protein. The skin involvement and the development of bullous disease are rarely seen features in multiple myeloma. We present a 55-year-old man with a longstanding, large, tense bullous eruption and hypertrophic scars over his body accompanied recently with weight loss and fatique. He had no response to the previous treatments, which included oral glucocorticoids and dapsone. Histologic examination of the lesions revealed subepidermal bullae, while no immunoflourescence staining was observed. In a further detailed labarotory examination, multiple myeloma was detected. After the treatment of multiple myeloma with chemotherapy, the lesions regressed. Patients with longstanding, recurrent, unusual bullous eruption should be investigated for the development of multiple myeloma.

Role of Bruton's tyrosine kinase (BTK) in growth and metastasis of INA6 myeloma cells

International Nuclear Information System (INIS)

Bam, R; Venkateshaiah, S U; Khan, S; Ling, W; Randal, S S; Li, X; Zhang, Q; Rhee, F van; Barlogie, B; Epstein, J; Yaccoby, S

2014-01-01

Bruton's tyrosine kinase (BTK) and the chemokine receptor CXCR4 are linked in various hematologic malignancies. The aim of the study was to understand the role of BTK in myeloma cell growth and metastasis using the stably BTK knockdown luciferase-expressing INA6 myeloma line. BTK knockdown had reduced adhesion to stroma and migration of myeloma cells toward stromal cell-derived factor-1. BTK knockdown had no effect on short-term in vitro growth of myeloma cells, although clonogenicity was inhibited and myeloma cell growth was promoted in coculture with osteoclasts. In severe combined immunodeficient-rab mice with contralaterally implanted pieces of bones, BTK knockdown in myeloma cells promoted their proliferation and growth in the primary bone but suppressed metastasis to the contralateral bone. BTK knockdown myeloma cells had altered the expression of genes associated with adhesion and proliferation and increased mammalian target of rapamycin signaling. In 176 paired clinical samples, BTK and CXCR4 expression was lower in myeloma cells purified from a focal lesion than from a random site. BTK expression in random-site samples was correlated with proportions of myeloma cells expressing cell surface CXCR4. Our findings highlight intratumoral heterogeneity of myeloma cells in the bone marrow microenvironment and suggest that BTK is involved in determining proliferative, quiescent or metastatic phenotypes of myeloma cells

Report from the European Myeloma Network on interphase FISH in multiple myeloma and related disorders

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Ross, Fiona M; Avet-Loiseau, Hervé; Ameye, Geneviève

2012-01-01

The European Myeloma Network has organized two workshops on fluorescence in situ hybridization in multiple myeloma. The first aimed to identify specific indications and consensus technical approaches of current practice. A second workshop followed a quality control exercise in which 21 laboratories...... analyzed diagnostic cases of purified plasma cells for recurrent abnormalities. The summary report was discussed at the EHA Myeloma Scientific Working Group Meeting 2010. During the quality control exercise, there was acceptable agreement on more than 1,000 tests. The conclusions from the exercise were...... that the primary clinical applications for FISH analysis were for newly diagnosed cases of MM or frank relapse cases. A range of technical recommendations included: 1) material should be part of the first draw of the aspirate; 2) samples should be sent at suitable times to allow for the lengthy processing...

The potential role of curcumin (diferuloylmethane in plasma cell dyscrasias/paraproteinemia

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Terry Golombick

2008-03-01

Full Text Available Terry Golombick, Terry DiamondDepartment of Endocrinology, St George Hospital, Kogarah, AustraliaAbstract: Plasma cell dyscrasias, most commonly associated with paraproteinemia, are a diverse group of diseases. Monoclonal gammopathy of undefined significance (MGUS can precede multiple myeloma, a progressive neoplastic disease. MGUS occurs in association with a variety of other diseases and currently no treatment is recommended but rather “watchful waiting”. Given that the size of the M-protein is a risk factor for disease progression, early intervention with the aim of reducing the paraprotein load would provide an innovative therapeutic tool. Preliminary results from our pilot study show a drop of between 5% and 30% serum paraprotein in patients taking curcumin compared with patients on placebo. Curcumin is a diferuloylmethane present in extracts of the rhizome of the Curcuma longa plant. As a natural product, this has exciting potential in the treatment of plasma cell dyscrasias.Keywords: plasma cell dyscrasias, MGUS, myeloma, curcumin, paraproteinemia

Plasma Cell Dyscrasia; LCDD vs Immunotactoid glomerulopathy

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Jabur Wael

2008-01-01

Full Text Available Light chain deposit disease is a plasma cell disorder characterized by production of a large amount of monoclonal immunoglobulin light chain or part of it, which is usually deposited as an amorphous substance in the kidneys. Immunotactoid glomerulopathy is an uncommon disease, which might be related to plasma cell dyscrasia, and characteristically manifest as organized glomerular ultra structural fibrils or microtubules. In this article, we report a case of a combined presentation of light chain disease and immunotactoid glomerulopathy in a patient with multiple myeloma and reversible advanced renal failure.

Multiple myeloma with extramedullary disease.

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Oriol, Albert

2011-11-01

Plasmacytoma is a tumor mass consisting of atypical plasma cells. Incidence of plasmacytomas associated with multiple myeloma range from 7% to 17% at diagnosis and from 6% to 20% during the course of the disease. In both situations, occurrence of extramedullary disease has been consistently associated with a poorer prognosis of myeloma. Extramedullary relapse or progression occurs in a variety of clinical circumstances and settings, and therefore requires individualization of treatment. Alkylating agents, bortezomib, and immunomodulatory drugs, along with corticoids, have been used to treat extramedullary relapse but, because of the relatively low frequency or detection rate of extramedullary relapse, no efficacy data are available from controlled studies in this setting.

Hypoxia promotes IL-32 expression in myeloma cells, and high expression is associated with poor survival and bone loss.

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Zahoor, Muhammad; Westhrin, Marita; Aass, Kristin Roseth; Moen, Siv Helen; Misund, Kristine; Psonka-Antonczyk, Katarzyna Maria; Giliberto, Mariaserena; Buene, Glenn; Sundan, Anders; Waage, Anders; Sponaas, Anne-Marit; Standal, Therese

2017-12-26

Multiple myeloma (MM) is a hematologic cancer characterized by expansion of malignant plasma cells in the bone marrow. Most patients develop an osteolytic bone disease, largely caused by increased osteoclastogenesis. The myeloma bone marrow is hypoxic, and hypoxia may contribute to MM disease progression, including bone loss. Here we identified interleukin-32 (IL-32) as a novel inflammatory cytokine expressed by a subset of primary MM cells and MM cell lines. We found that high IL-32 gene expression in plasma cells correlated with inferior survival in MM and that IL-32 gene expression was higher in patients with bone disease compared with those without. IL-32 was secreted from MM cells in extracellular vesicles (EVs), and those EVs, as well as recombinant human IL-32, promoted osteoclast differentiation both in vitro and in vivo. The osteoclast-promoting activity of the EVs was IL-32 dependent. Hypoxia increased plasma-cell IL-32 messenger RNA and protein levels in a hypoxia-inducible factor 1α-dependent manner, and high expression of IL-32 was associated with a hypoxic signature in patient samples, suggesting that hypoxia may promote expression of IL-32 in MM cells. Taken together, our results indicate that targeting IL-32 might be beneficial in the treatment of MM bone disease in a subset of patients.

Pathogenesis of Renal Failure in Multiple Myeloma: Any Role of Contrast Media?

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Mussap, Michele; Merlini, Giampaolo

2014-01-01

The spectrum of kidney disease-associated monoclonal immunoglobulin and plasma cell malignancies is remarkably broad and encompasses nearly all nephropathologic entities. Multiple myeloma with kidney impairment at presentation is a medical emergency since the recovery of kidney function is associated with survival benefits. In most cases, kidney impairment may be the first clinical manifestation of malignant plasma cell dyscrasias like multiple myeloma and light chain amyloidosis. Multiple myeloma per se cannot be considered a main risk factor for developing acute kidney injury following intravascular administration of iodinated contrast media. The risk is increased by comorbidities such as chronic kidney disease, diabetes, hypercalcemia, dehydration, and use of nephrotoxic drugs. Before the administration of contrast media, the current recommended laboratory tests for assessing kidney function are serum creatinine measurement and the estimation of glomerular filtration rate by using the CKD-EPI equation. The assessment of Bence Jones proteinuria is unnecessary for evaluating the risk of kidney failure in patients with multiple myeloma, since this test cannot be considered a surrogate biomarker of kidney function. PMID:24877060

Pathogenesis of Renal Failure in Multiple Myeloma: Any Role of Contrast Media?

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Michele Mussap

2014-01-01

Full Text Available The spectrum of kidney disease-associated monoclonal immunoglobulin and plasma cell malignancies is remarkably broad and encompasses nearly all nephropathologic entities. Multiple myeloma with kidney impairment at presentation is a medical emergency since the recovery of kidney function is associated with survival benefits. In most cases, kidney impairment may be the first clinical manifestation of malignant plasma cell dyscrasias like multiple myeloma and light chain amyloidosis. Multiple myeloma per se cannot be considered a main risk factor for developing acute kidney injury following intravascular administration of iodinated contrast media. The risk is increased by comorbidities such as chronic kidney disease, diabetes, hypercalcemia, dehydration, and use of nephrotoxic drugs. Before the administration of contrast media, the current recommended laboratory tests for assessing kidney function are serum creatinine measurement and the estimation of glomerular filtration rate by using the CKD-EPI equation. The assessment of Bence Jones proteinuria is unnecessary for evaluating the risk of kidney failure in patients with multiple myeloma, since this test cannot be considered a surrogate biomarker of kidney function.

Bortezomib consolidation after autologous stem cell transplantation in multiple myeloma

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Mellqvist, Ulf-Henrik; Gimsing, Peter; Hjertner, Oyvind

2013-01-01

The Nordic Myeloma Study Group conducted an open randomized trial to compare bortezomib as consolidation therapy given after high-dose therapy and autologous stem cell transplantation (ASCT) with no consolidation in bortezomib-naive patients with newly diagnosed multiple myeloma. Overall, 370...

Heparanase promotes myeloma progression by inducing mesenchymal features and motility of myeloma cells.

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Li, Juan; Pan, Qianying; Rowan, Patrick D; Trotter, Timothy N; Peker, Deniz; Regal, Kellie M; Javed, Amjad; Suva, Larry J; Yang, Yang

2016-03-08

Bone dissemination and bone disease occur in approximately 80% of patients with multiple myeloma (MM) and are a major cause of patient mortality. We previously demonstrated that MM cell-derived heparanase (HPSE) is a major driver of MM dissemination to and progression in new bone sites. However the mechanism(s) by which HPSE promotes MM progression remains unclear. In the present study, we investigated the involvement of mesenchymal features in HPSE-promoted MM progression in bone. Using a combination of molecular, biochemical, cellular, and in vivo approaches, we demonstrated that (1) HPSE enhanced the expression of mesenchymal markers in both MM and vascular endothelial cells; (2) HPSE expression in patient myeloma cells positively correlated with the expression of the mesenchymal markers vimentin and fibronectin. Additional mechanistic studies revealed that the enhanced mesenchymal-like phenotype induced by HPSE in MM cells is due, at least in part, to the stimulation of the ERK signaling pathway. Finally, knockdown of vimentin in HPSE expressing MM cells resulted in significantly attenuated MM cell dissemination and tumor growth in vivo. Collectively, these data demonstrate that the mesenchymal features induced by HPSE in MM cells contribute to enhanced tumor cell motility and bone-dissemination.

Case Report: Multiple Myeloma with Gangrene of Extremities

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N Gharahi

2009-07-01

Full Text Available Introduction: Multiple myeloma represents a malignant proliferation of plasma cells derived from a single clone and it results in bone pain or fracture, renal failure, susceptibility to infections, anemia and hypercalcemia. The hyper viscosity syndrome is rare. Cryoglobulins are immunoglubulins that precipitate at temperatures less than 37degrees Celsius. Monoclonal cryoglobulins are usually present along with a specific hematologic disorder and are often asymptomatic. We report a second case of multiple myeloma with gangrene of all four extremities. Case: The Patient was a 77 year–old farmer with a 2 weeks history of coldness, pain and discoloration of the fingers of both the extremities which had extended to the mid forearm and shin regions. It was accompanied by skin erosions of the lower extremities, dark spots on the ear auricles and discoloration of the tip of the nose. On physical examination, quadrigangrene associated with ischemia of the auricles and tip of nose was seen. Serum proteins electrophoresis demonstrated monoclonal gammopathy and serum was positive for cryoglobulin, Bone marrow study showed neoplastic plasma cells infiltration. The patient was diagnosed as cryoglobulinemia based on multiple myeloma and treated accordingly.

Multiple myeloma presenting as CEA-producing rectal cancer.

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Talamo, Giampaolo; Barochia, Amitkumar; Zangari, Maurizio; Loughran, Thomas P

2010-03-31

We report the case of a 57-year-old patient with multiple myeloma, characterized by extramedullary involvement of the rectum at presentation. Malignant plasma cells were found to produce carcinoembryonic antigen (CEA), a tumor antigen more commonly associated with rectal adenocarcinomas.

A case of Fanconi syndrome accompanied by crystal depositions in tubular cells in a patient with multiple myeloma

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Do Hee Kim

2014-06-01

Full Text Available Fanconi syndrome (FS is a rare condition that is characterized by defects in the proximal tubular function. A 48-year-old woman was admitted for evaluation of proteinuria. The patient showed normal anion gap acidosis, normoglycemic glycosuria, hypophosphatemia, and hypouricemia. Thus, her condition was compatible with FS. The M peak was found behind the beta globulin region in urine protein electrophoresis. Upon bone marrow examination, we found that 24% of cells were CD138+ plasma cells with kappa restriction. From a kidney biopsy, we found crystalline inclusions within proximal tubular epithelial cells. Thereafter, she was diagnosed with FS accompanied by multiple myeloma. The patient received chemotherapy and autologous stem cell transplantation, and obtained very good partial hematologic response. However, proximal tubular dysfunction was persistent until 1 year after autologous stem cell transplantation. In short, we report a case of FS accompanied by multiple myeloma, demonstrating crystalline inclusion in proximal tubular cells on kidney biopsy.

In vitro sensitization of human lymphocytes to a myeloma cell-related antigen

International Nuclear Information System (INIS)

Whitson, M.E.; Griffin, G.D.; Novelli, G.D.; Solomon, A.

1981-01-01

Peripheral blood lymphocytes from normal human donors were cocultivated with cells from two established human multiple myeloma cell lines, RPMI 8226 and K-737, and with lymphoblastoid cells from a third B cell line, RAMM. After a comparison of three methods of lymphocyte sensitization, a 6-day incubation protocol with equal numbers of normal lymphocytes and mitomycin C-treated tumor cells was selected. Cells fom the RPMI 8226 myeloma line stimulated the differentiation of lymphocytes into cytotoxic effector cells as measured by 51 Cr release from labeled target cells. The RPMI 8226-sensitized lymphocytes were cytotoxic for myeloma cells (RPMI 8226 and K-737) and for lymphoblastoid cells (RAMM) but not for cells from human lung tumor lines (A549, A427, MB9812), a breast carcinoma line (ALAB), a normal diploid fibroblast line (HSBP), or normal lymphocytes

In vitro sensitization of human lymphocytes to a myeloma cell-related antigen

Energy Technology Data Exchange (ETDEWEB)

Whitson, M.E. (Univ. of South Carolina, Columbia); Griffin, G.D.; Novelli, G.D.; Solomon, A.

1981-01-01

Peripheral blood lymphocytes from normal human donors were cocultivated with cells from two established human multiple myeloma cell lines, RPMI 8226 and K-737, and with lymphoblastoid cells from a third B cell line, RAMM. After a comparison of three methods of lymphocyte sensitization, a 6-day incubation protocol with equal numbers of normal lymphocytes and mitomycin C-treated tumor cells was selected. Cells fom the RPMI 8226 myeloma line stimulated the differentiation of lymphocytes into cytotoxic effector cells as measured by /sup 51/Cr release from labeled target cells. The RPMI 8226-sensitized lymphocytes were cytotoxic for myeloma cells (RPMI 8226 and K-737) and for lymphoblastoid cells (RAMM) but not for cells from human lung tumor lines (A549, A427, MB9812), a breast carcinoma line (ALAB), a normal diploid fibroblast line (HSBP), or normal lymphocytes.

Multiple myeloma presenting as mandibular pain

LENUS (Irish Health Repository)

Crowley, Miriam

2016-10-01

Introduction: Multiple myeloma (MM) is a systemic malignancy of plasma cells defined by monoclonal production of circulating immunoglobulins. Bone pain is a presenting feature in the majority of cases. Treatment may involve intravenous use of bisphosphonates, chemotherapy or haematopoietic stem cell transplantation. Here, we illustrate a first presentation of MM in a patient with mandibular pain and discuss radiographic, diagnostic and treatment challenges of orofacial issues in patients with MM.\\r\

Destabilization of Akt Promotes the Death of Myeloma Cell Lines

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Yanan Zhang

2014-01-01

Full Text Available Constitutive activation of Akt is believed to be an oncogenic signal in multiple myeloma and is associated with poor patient prognosis and resistance to available treatment. The stability of Akt proteins is regulated by phosphorylating the highly conserved turn motif (TM of these proteins and the chaperone protein HSP90. In this study we investigate the antitumor effects of inhibiting mTORC2 plus HSP90 in myeloma cell lines. We show that chronic exposure of cells to rapamycin can inhibit mTORC2 pathway, and AKT will be destabilized by administration of the HSP90 inhibitor 17-allylamino-geldanamycin (17-AAG. Finally, we show that the rapamycin synergizes with 17-AAG and inhibits myeloma cells growth and promotes cell death to a greater extent than either drug alone. Our studies provide a clinical rationale of use mTOR inhibitors and chaperone protein inhibitors in combination regimens for the treatment of human blood cancers.

Multiple myeloma presenting as CEA-producing rectal cancer

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Giampaolo Talamo

2010-03-01

Full Text Available We report the case of a 57-year old patient with multiple myeloma, characterized by extramedullary involvement of the rectum at presentation. Malignant plasma cells were found to produce carcinoembryonic antigen (CEA, a tumor antigen more commonly associated with rectal adenocarcinomas.

Cannabinoids synergize with carfilzomib, reducing multiple myeloma cells viability and migration.

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Nabissi, Massimo; Morelli, Maria Beatrice; Offidani, Massimo; Amantini, Consuelo; Gentili, Silvia; Soriani, Alessandra; Cardinali, Claudio; Leoni, Pietro; Santoni, Giorgio

2016-11-22

Several studies showed a potential anti-tumor role for cannabinoids, by modulating cell signaling pathways involved in cancer cell proliferation, chemo-resistance and migration. Cannabidiol (CBD) was previously noted in multiple myeloma (MM), both alone and in synergy with the proteasome inhibitor bortezomib, to induce cell death. In other type of human cancers, the combination of CBD with Δ9-tetrahydrocannabinol (THC) was found to act synergistically with other chemotherapeutic drugs suggesting their use in combination therapy. In the current study, we evaluated the effects of THC alone and in combination with CBD in MM cell lines. We found that CBD and THC, mainly in combination, were able to reduce cell viability by inducing autophagic-dependent necrosis. Moreover, we showed that the CBD-THC combination was able to reduce MM cells migration by down-regulating expression of the chemokine receptor CXCR4 and of the CD147 plasma membrane glycoprotein. Furthermore, since the immuno-proteasome is considered a new target in MM and also since carfilzomib (CFZ) is a new promising immuno-proteasome inhibitor that creates irreversible adducts with the β5i subunit of immuno-proteasome, we evaluated the effect of CBD and THC in regulating the expression of the β5i subunit and their effect in combination with CFZ. Herein, we also found that the CBD and THC combination is able to reduce expression of the β5i subunit as well as to act in synergy with CFZ to increase MM cell death and inhibits cell migration. In summary, these results proved that this combination exerts strong anti-myeloma activities.

Detection of Extramedullary Multiple Myeloma in Liver by FDG-PET/CT

International Nuclear Information System (INIS)

Kim, Daeweung; Kim, Woo Hyoung; Kim, Myoung Hyoun; Choi, Keum Ha; Kim, Chang Guhn

2014-01-01

We present the case of a 42-year-old man with a painful mass lesion in the right shoulder that was detected by contrast-enhanced computed tomography (CT) and 18 F-fluoro-2-deoxyglucose ( 18 F-FDG) positron emission tomography (PET)/CT. Excisional biopsy revealed infiltration of plasma cells with anaplastic features, consistent with solitary plasmacytoma (PC). Serum analysis showed elevation of serum free lambda light chain levels (27.78 mg/l), with an abnormally high kappa:lambda ratio (2.33) and high total proteins (10.4 g/dl). Serum protein electrophoresis revealed an M spike in the gamma-globulin region (56.1 %=5.8 g/dl). Subsequently, 18 F-FDG PET/CT revealed another hypermetabolic mass in the right lobe of the liver. CT-guided biopsy of the liver lesion revealed plasma cell myeloma, consistent with multiple myeloma. Multiple myeloma presenting as nodular liver masses is very rare in clinical practice. In a retrospective review of more than 2,000 patients, Talamo et al. reported only nine cases where there was nodular involvement of the liver by multiple myeloma. The organ most commonly involved was the liver, followed by pancreas, stomach, peritoneum with malignant ascites, colon, rectum, duodenum and ileum. Therefore, the literature published thus far has been limited to a few reports and case series. Among these reports, some had demonstrated the PET or PET/CT findings of nodular liver involvement of multiple myeloma. About 10 % of the solitary myelomas appeared as extramedullary PC or solitary PC of bone. In spite of the advances in therapy, the treatment of multiple myeloma is still palliative. However, solitary PC could be cured by resection or radiation therapy. Thus, differentiation between PC and multiple myeloma is essential in making a decision for the appropriate therapeutic regimen. 18 F-FDG PET/CT has the unique ability to detect and characterize malignant lesions in one single examination. Schirrmeister et al. reported that 18 F-FDG PET revealed

Plasma cell leukemia: update on biology and therapy.

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Mina, Roberto; D'Agostino, Mattia; Cerrato, Chiara; Gay, Francesca; Palumbo, Antonio

2017-07-01

Plasma cell leukemia (PCL) is a rare, but very aggressive, plasma cell dyscrasia, representing a distinct clinicopathological entity as compared to multiple myeloma (MM), with peculiar biological and clinical features. A hundred times rarer than MM, the disease course is characterized by short remissions and poor survival. PCL is defined by an increased percentage (>20%) and absolute number (>2 × 10 9 /l) of plasma cells in the peripheral blood. PCL is defined as 'primary' when peripheral plasmacytosis is detected at diagnosis, 'secondary' when leukemization occurs in a patient with preexisting MM. Novel agents have revolutionized the outcomes of MM patients and have been introduced also for the treatment of PCL. Here, we provide an update on biology and treatment options for PCL.

Syntaxin-4 is essential for IgE secretion by plasma cells

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Rahman, Arman; DeCourcey, Joseph; Larbi, Nadia Ben [Immunomodulation Group, School of Biotechnology, Dublin City University (Ireland); Loughran, Sinéad T.; Walls, Dermot [School of Biotechnology and National Centre for Sensor Research, Dublin City University (Ireland); Loscher, Christine E., E-mail: christine.loscher@dcu.ie [Immunomodulation Group, School of Biotechnology, Dublin City University (Ireland)

2013-10-11

Highlights: •Knock-down of syntaxin-4 in U266 plasma cells resulted in reduction of IgE secretion. •Knock-down of syntaxin-4 also leads to the accumulation of IgE in the cell. •Immuno-fluorescence staining shows co-localisation of IgE and syntaxin-4 in U266 cells. •Findings suggest a critical requirement for syntaxin-4 in IgE secretion from plasma cells. -- Abstract: The humoral immune system provides a crucial first defense against the invasion of microbial pathogens via the secretion of antigen specific immunoglobulins (Ig). The secretion of Ig is carried out by terminally differentiated B-lymphocytes called plasma cells. Despite the key role of plasma cells in the immune response, the mechanisms by which they constitutively traffic large volumes of Ig out of the cell is poorly understood. The involvement of Soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins in the regulation of protein trafficking from cells has been well documented. Syntaxin-4, a member of the Qa SNARE syntaxin family has been implicated in fusion events at the plasma membrane in a number of cells in the immune system. In this work we show that knock-down of syntaxin-4 in the multiple myeloma U266 human plasma cell line results in a loss of IgE secretion and accumulation of IgE within the cells. Furthermore, we show that IgE co-localises with syntaxin-4 in U266 plasma cells suggesting direct involvement in secretion at the plasma membrane. This study demonstrates that syntaxin-4 plays a critical role in the secretion of IgE from plasma cells and sheds some light on the mechanisms by which these cells constitutively traffic vesicles to the surface for secretion. An understanding of this machinery may be beneficial in identifying potential therapeutic targets in multiple myeloma and autoimmune disease where over-production of Ig leads to severe pathology in patients.

Syntaxin-4 is essential for IgE secretion by plasma cells

International Nuclear Information System (INIS)

Rahman, Arman; DeCourcey, Joseph; Larbi, Nadia Ben; Loughran, Sinéad T.; Walls, Dermot; Loscher, Christine E.

2013-01-01

Highlights: •Knock-down of syntaxin-4 in U266 plasma cells resulted in reduction of IgE secretion. •Knock-down of syntaxin-4 also leads to the accumulation of IgE in the cell. •Immuno-fluorescence staining shows co-localisation of IgE and syntaxin-4 in U266 cells. •Findings suggest a critical requirement for syntaxin-4 in IgE secretion from plasma cells. -- Abstract: The humoral immune system provides a crucial first defense against the invasion of microbial pathogens via the secretion of antigen specific immunoglobulins (Ig). The secretion of Ig is carried out by terminally differentiated B-lymphocytes called plasma cells. Despite the key role of plasma cells in the immune response, the mechanisms by which they constitutively traffic large volumes of Ig out of the cell is poorly understood. The involvement of Soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins in the regulation of protein trafficking from cells has been well documented. Syntaxin-4, a member of the Qa SNARE syntaxin family has been implicated in fusion events at the plasma membrane in a number of cells in the immune system. In this work we show that knock-down of syntaxin-4 in the multiple myeloma U266 human plasma cell line results in a loss of IgE secretion and accumulation of IgE within the cells. Furthermore, we show that IgE co-localises with syntaxin-4 in U266 plasma cells suggesting direct involvement in secretion at the plasma membrane. This study demonstrates that syntaxin-4 plays a critical role in the secretion of IgE from plasma cells and sheds some light on the mechanisms by which these cells constitutively traffic vesicles to the surface for secretion. An understanding of this machinery may be beneficial in identifying potential therapeutic targets in multiple myeloma and autoimmune disease where over-production of Ig leads to severe pathology in patients

Characterization of CD4+ T cell-mediated cytotoxicity in patients with multiple myeloma.

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Zhang, Xiaole; Gao, Lei; Meng, Kai; Han, Chunting; Li, Qiang; Feng, Zhenjun; Chen, Lei

2018-05-01

Multiple myeloma (MM) is an incurable cancer characterized by the development of malignant plasma cells. The CD8 T cell-mediated cytotoxicity is considered a major player in antitumor immunity, but in MM patients, the CD8 T cells displayed senescence markers and were functionally impaired. To investigate whether cytotoxic CD4 T cells could act as a treatment alternative in MM, we examined the frequency and function of naturally occurring cytotoxic CD4 T cells in MM patients. The cytotoxic CD4 T cells were identified as granzyme-A, granzyme B-, and perforin-expressing CD4 T cells, and their frequencies were significantly upregulated in MM patients when compared with healthy controls. The frequencies of cytotoxic CD4 T cells in MM patients were not associated with the frequencies of cytotoxic CD8 T cells, but were negatively associated with disease severity. Interestingly, the expression levels of inhibitory molecules, including PD-1 and CTLA-4, were significantly lower in cytotoxic CD4 T cells than in cytotoxic CD8 T cells. When co-incubated with autologous CD38 + CD138 + plasma cells, CD4 T cells were capable of eliminating plasma cells with varying degrees of efficacy. In MM patients, the frequency of circulating plasma cells was negatively correlated with the frequency of cytotoxic CD4 T cells. Therefore, CD4 T cell-mediated cytotoxicity existed naturally in MM patients and could potentially act as an option in antitumor therapies. Copyright © 2018 Elsevier Inc. All rights reserved.

Nelfinavir augments proteasome inhibition by bortezomib in myeloma cells and overcomes bortezomib and carfilzomib resistance

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Kraus, M; Bader, J; Overkleeft, H; Driessen, C

2013-01-01

HIV protease inhibitors (HIV-PI) are oral drugs for HIV treatment. HIV-PI have antitumor activity via induction of ER-stress, inhibition of phospho-AKT (p-AKT) and the proteasome, suggesting antimyeloma activity. We characterize the effects of all approved HIV-PI on myeloma cells. HIV-PI were compared regarding cytotoxicity, proteasome activity, ER-stress induction and AKT phosphorylation using myeloma cells in vitro. Nelfinavir is the HIV-PI with highest cytotoxic activity against primary myeloma cells and with an IC 50 near therapeutic drug blood levels (8–14 μM), irrespective of bortezomib sensitivity. Only nelfinavir inhibited intracellular proteasome activity in situ at drug concentrations <40 μℳ. Ritonavir, saquinavir and lopinavir inhibited p-AKT comparable to nelfinavir, and showed similar synergistic cytotoxicity with bortezomib against bortezomib-sensitive cells. Nelfinavir had superior synergistic activity with bortezomib/carfilzomib in particular against bortezomib/carfilzomib-resistant myeloma cells. It inhibited not only the proteasomal β1/β5 active sites, similar to bortezomib/carfilzomib, but in addition the β2 proteasome activity not targeted by bortezomib/carfilzomib. Additional inhibition of β2 proteasome activity is known to sensitize cells for bortezomib and carfilzomib. Nelfinavir has unique proteasome inhibiting activity in particular on the bortezomib/carfilzomib-insensitive tryptic (β2) proteasome activity in intact myeloma cells, and is active against bortezomib/carfilzomib-resistant myeloma cells in vitro

Unsuspected multiples myeloma presenting as bilateral pleural effusion – a cytological diagnosis

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Dhingra Kajal

2007-01-01

Full Text Available Abstract Background Multiple Myeloma presenting as a pleural effusion is extremely rare. It is usually a late complication and is associated with a poor prognosis. Case Presentation A 40-year-old male presented with dyspnea and fever of six months duration. Clinical diagnosis of pulmonary tuberculosis was considered. X-ray chest showed bilateral pleural effusion. Pleural cytology revealed numerous plasma cells, some of which were binucleated and atypical. Cytological differential diagnosis included: Myelomatous effusion and Non-Hodgkin's Lymphoma deposit (Immunoblastic type. Bone marrow biopsy, serum protein electrophoresis and bone scan confirmed the diagnosis of multiple myeloma (Plasmablastic type. Conclusion Myelomatous pleural effusion as an initial presentation although extremely rare, should always be considered in presence of atypical plasma cells irrespective of age.

Plasmablastic myeloma presenting as rapidly progressive renal failure in a young adult

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M Srija

2014-01-01

Full Text Available Multiple myeloma (MM is a condition where there is malignant proliferation of plasma cells. There is a strong correlation with age, peaking at 60-70 years. The clinical course in adolescents and young individuals is generally indolent and the survival is longer. We report a case of a 28-year-old male, who was diagnosed to have plasmablastic myeloma, an atypical variant of MM with a poor prognosis, presenting as rapidly progressive renal failure. He was given induction chemotherapy and then underwent autologous peripheral blood stem cell transplantation.

Phosphoinositide protein kinase PDPK1 is a crucial cell signaling mediator in multiple myeloma.

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Chinen, Yoshiaki; Kuroda, Junya; Shimura, Yuji; Nagoshi, Hisao; Kiyota, Miki; Yamamoto-Sugitani, Mio; Mizutani, Shinsuke; Sakamoto, Natsumi; Ri, Masaki; Kawata, Eri; Kobayashi, Tsutomu; Matsumoto, Yosuke; Horiike, Shigeo; Iida, Shinsuke; Taniwaki, Masafumi

2014-12-15

Multiple myeloma is a cytogenetically/molecularly heterogeneous hematologic malignancy that remains mostly incurable, and the identification of a universal and relevant therapeutic target molecule is essential for the further development of therapeutic strategy. Herein, we identified that 3-phosphoinositide-dependent protein kinase 1 (PDPK1), a serine threonine kinase, is expressed and active in all eleven multiple myeloma-derived cell lines examined regardless of the type of cytogenetic abnormality, the mutation state of RAS and FGFR3 genes, or the activation state of ERK and AKT. Our results revealed that PDPK1 is a pivotal regulator of molecules that are essential for myelomagenesis, such as RSK2, AKT, c-MYC, IRF4, or cyclin Ds, and that PDPK1 inhibition caused the growth inhibition and the induction of apoptosis with the activation of BIM and BAD, and augmented the in vitro cytotoxic effects of antimyeloma agents in myeloma cells. In the clinical setting, PDPK1 was active in myeloma cells of approximately 90% of symptomatic patients at diagnosis, and the smaller population of patients with multiple myeloma exhibiting myeloma cells without active PDPK1 showed a significantly less frequent proportion of the disease stage III by the International Staging System and a significantly more favorable prognosis, including the longer overall survival period and the longer progression-free survival period by bortezomib treatment, than patients with active PDPK1, suggesting that PDPK1 activation accelerates the disease progression and the resistance to treatment in multiple myeloma. Our study demonstrates that PDPK1 is a potent and a universally targetable signaling mediator in multiple myeloma regardless of the types of cytogenetic/molecular profiles. ©2014 American Association for Cancer Research.

Raman spectroscopy differentiates between sensitive and resistant multiple myeloma cell lines

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Franco, Domenico; Trusso, Sebastiano; Fazio, Enza; Allegra, Alessandro; Musolino, Caterina; Speciale, Antonio; Cimino, Francesco; Saija, Antonella; Neri, Fortunato; Nicolò, Marco S.; Guglielmino, Salvatore P. P.

2017-12-01

Current methods for identifying neoplastic cells and discerning them from their normal counterparts are often nonspecific and biologically perturbing. Here, we show that single-cell micro-Raman spectroscopy can be used to discriminate between resistant and sensitive multiple myeloma cell lines based on their highly reproducible biomolecular spectral signatures. In order to demonstrate robustness of the proposed approach, we used two different cell lines of multiple myeloma, namely MM.1S and U266B1, and their counterparts MM.1R and U266/BTZ-R subtypes, resistant to dexamethasone and bortezomib, respectively. Then, micro-Raman spectroscopy provides an easily accurate and noninvasive method for cancer detection for both research and clinical environments. Characteristic peaks, mostly due to different DNA/RNA ratio, nucleic acids, lipids and protein concentrations, allow for discerning the sensitive and resistant subtypes. We also explored principal component analysis (PCA) for resistant cell identification and classification. Sensitive and resistant cells form distinct clusters that can be defined using just two principal components. The identification of drug-resistant cells by confocal micro-Raman spectroscopy is thus proposed as a clinical tool to assess the development of resistance to glucocorticoids and proteasome inhibitors in myeloma cells.

Detection of Extramedullary Multiple Myeloma in Liver by FDG-PET/CT

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Kim, Daeweung; Kim, Woo Hyoung; Kim, Myoung Hyoun; Choi, Keum Ha; Kim, Chang Guhn [Wonkwang Univ. School of Medicine, Iksan (Korea, Republic of)

2014-06-15

We present the case of a 42-year-old man with a painful mass lesion in the right shoulder that was detected by contrast-enhanced computed tomography (CT) and {sup 18}F-fluoro-2-deoxyglucose ({sup 18}F-FDG) positron emission tomography (PET)/CT. Excisional biopsy revealed infiltration of plasma cells with anaplastic features, consistent with solitary plasmacytoma (PC). Serum analysis showed elevation of serum free lambda light chain levels (27.78 mg/l), with an abnormally high kappa:lambda ratio (2.33) and high total proteins (10.4 g/dl). Serum protein electrophoresis revealed an M spike in the gamma-globulin region (56.1 %=5.8 g/dl). Subsequently, {sup 18}F-FDG PET/CT revealed another hypermetabolic mass in the right lobe of the liver. CT-guided biopsy of the liver lesion revealed plasma cell myeloma, consistent with multiple myeloma. Multiple myeloma presenting as nodular liver masses is very rare in clinical practice. In a retrospective review of more than 2,000 patients, Talamo et al. reported only nine cases where there was nodular involvement of the liver by multiple myeloma. The organ most commonly involved was the liver, followed by pancreas, stomach, peritoneum with malignant ascites, colon, rectum, duodenum and ileum. Therefore, the literature published thus far has been limited to a few reports and case series. Among these reports, some had demonstrated the PET or PET/CT findings of nodular liver involvement of multiple myeloma. About 10 % of the solitary myelomas appeared as extramedullary PC or solitary PC of bone. In spite of the advances in therapy, the treatment of multiple myeloma is still palliative. However, solitary PC could be cured by resection or radiation therapy. Thus, differentiation between PC and multiple myeloma is essential in making a decision for the appropriate therapeutic regimen. {sup 18}F-FDG PET/CT has the unique ability to detect and characterize malignant lesions in one single examination. Schirrmeister et al. reported that

B cell lymphoma and myeloma in murine Gaucher's disease

NARCIS (Netherlands)

Pavlova, E. V.; Wang, S. Z.; Archer, J.; Dekker, N. [=Nick; Aerts, J. M. F. G.; Karlsson, S.; Cox, T. M.

2013-01-01

Multiple myeloma and B cell lymphoma are leading causes of death in Gaucher's disease but the nature of the stimulus driving the often noted clonal expansion of immunoglobulin-secreting B cells and cognate lymphoid malignancy is unknown. We investigated the long-term development of B cell

Recent Advances in the Pathogenesis and Management of Cast Nephropathy (Myeloma Kidney

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Stephanie Stringer

2011-01-01

Full Text Available Multiple myeloma is an incurable plasma cell malignancy that is often accompanied by renal failure; there are a number of potential causes of this, of which cast nephropathy is the most important. Renal failure is highly significant in myeloma, as patient survival can be stratified by the severity of the renal impairment. Consequently, there is an ongoing focus on the pathological basis of cast nephropathy and the optimal treatment regimens in this setting, including effective chemotherapy regimens to reduce light chain production and emerging extracorporeal techniques to remove circulating light chains. This paper bridges recent advances in the pathogenesis and management of cast nephropathy in multiple myeloma.

Association between intracranial plasmacytoma and multiple myeloma: clinicopathological outcome study.

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Schwartz, T H; Rhiew, R; Isaacson, S R; Orazi, A; Bruce, J N

2001-11-01

Intracranial plasmacytomas are rare lesions that can arise from the calvarium, dura, or cranial base and exhibit a benign course unless associated with myeloma. Attention has recently been focused on the role of the cell adhesion molecules CD56 and CD31 in the pathogenesis of myeloma. No such information is available for intracranial plasmacytomas and myeloma-associated lesions. We investigated the relationship between CD56 and CD31 expression, intracranial location, and progression to myeloma for a series of nine intracranial plasmacytomas (three dural, one calvarial, and five cranial base lesions). These parameters were also correlated with proliferation indices, as assessed by MIB-1 immunostaining of the histological sections. A single pathologist (AO) performed immunohistochemical analyses and reviewed all slides. Intracranial plasmacytomas presented more commonly in female patients (89%). The three dural lesions were CD56- and CD31-negative and exhibited MIB-1 staining of less than 10%; no patient developed myeloma or recurrence. Of the five cranial base lesions, three were CD56-positive, none was CD31-positive, and two exhibited MIB-1 labeling of more than 45%, with plasmablastic morphological features. Compared with other intracranial plasmacytomas, five of five patients with cranial base lesions developed bone marrow biopsy-proven myeloma (P myeloma soon after diagnosis. Both of the two highly proliferative plasmablastic lesions recurred, one after gross total resection without radiotherapy and the other after a biopsy and 2000-cGy radiotherapy. Among intracranial plasmacytomas, cranial base location was the strongest predictor of the development of multiple myeloma. Expression of the cell adhesion molecules CD31 and CD56 was not predictive of outcome. Extramedullary dural-based lesions were CD56-negative and were not associated with myeloma. A high proliferation index and plasmablastic morphological features were predictive of a short time to recurrence

Cytotoxic Effect on Human Myeloma Cells and Leukemic Cells by the Agaricus blazei Murill Based Mushroom Extract, Andosan™

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Jon-Magnus Tangen

2017-01-01

Full Text Available Agaricus blazei Murill is an edible mushroom of the Basidiomycetes family, which has been found to contain a number of compounds with antitumor properties, such as proteoglycans and ergosterol. In the present investigation, we show that the commercial mushroom product Andosan, which contains 82.4% Agaricus blazei Murill, together with medicinal mushrooms Hericium erinaceus (14.7% and Grifola frondosa (2.9%, has a cytotoxic effect on primary myeloma cells, other myeloma cell lines, and leukemia cell lines in vitro. Although the exact content and hence the mechanisms of action of the Andosan extract are unknown, we have found in this investigation indications of cell cycle arrest when myeloma cell lines are cultivated with Andosan. This may be one of the possible explanations for the cytotoxic effects of Andosan.

Recent progress in the biology of multiple myeloma and future directions in the treatment.

Science.gov (United States)

Pico, J L; Castagna, L; Bourhis, J H

1998-04-01

A great amount of scientific information, accumulated over recent years on the biology of Multiple Myeloma (MM), has fuelled speculation about the origin of malignant plasma cells, about a purported critical role played by the bone marrow stroma, and further still, on cytokine interactions and in particular that of IL-6 and its relationship with the immune system. Among the growth factors secreted by stroma cells, IL-6 is a potent stimulator of myeloma cells in vitro but does not induce a malignant phenotype in normal plasma cells. Many efforts have been produced to identify the stem cell in MM and probably memory B lymphocytes are the best candidates. The demonstration of a Graft vs Myeloma effect in the allogeneic setting strongly supports the immunotherapy in MM. Recent data also suggest that a virus (Kaposi-associated herpes virus, HHV-8) may be significantly associated with the development of MM. In parallel, progress has been achieved in the treatment of this incurable disease with well defined prognostic factors, more efficient supportive care and its corollary, improved quality of life and dose-intensified chemo-radiotherapy followed by autologous hematopoietic stem cell support. Improving the quality of grafts with the selection of CD34 positive cells is another approach aimed at reducing plasma cell contamination without impairing haematological recovery. An EBMT randomized study assessing the role of CD34 selection has been initiated by our group Increasingly efficient first-line therapy, better quality autografts and improved post-remission treatment with, for example, anti-idiopathic vaccination are the most promising future directions.

NF-kappa B modulation is involved in celastrol induced human multiple myeloma cell apoptosis.

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Haiwen Ni

Full Text Available Celastrol is an active compound extracted from the root bark of the traditional Chinese medicine Tripterygium wilfordii Hook F. To investigate the effect of celastrol on human multiple myeloma cell cycle arrest and apoptosis and explore its molecular mechanism of action. The activity of celastrol on LP-1 cell proliferation was detected by WST-8 assay. The celastrol-induced cell cycle arrest was analyzed by flow cytometry after propidium iodide staining. Nuclear translocation of the nuclear factor kappa B (NF-κB was observed by fluorescence microscope. Celastrol inhibited cell proliferation of LP-1 myeloma cell in a dose-dependent manner with IC50 values of 0.8817 µM, which was mediated through G1 cell cycle arrest and p27 induction. Celastrol induced apoptosis in LP-1 and RPMI 8226 myeloma cells in a time and dose dependent manner, and it involved Caspase-3 activation and NF-κB pathway. Celastrol down-modulated antiapoptotic proteins including Bcl-2 and survivin expression. The expression of NF-κB and IKKa were decreased after celastrol treatment. Celastrol effectively blocked the nuclear translocation of the p65 subunit and induced human multiple myeloma cell cycle arrest and apoptosis by p27 upregulation and NF-kB modulation. It has been demonstrated that the effect of celastrol on NF-kB was HO-1-independent by using zinc protoporphyrin-9 (ZnPPIX, a selective heme oxygenase inhibitor. From the results, it could be inferred that celastrol may be used as a NF-kB inhibitor to inhibit myeloma cell proliferation.

B-cell activating factor in the pathophysiology of multiple myeloma: a target for therapy?

International Nuclear Information System (INIS)

Hengeveld, P J; Kersten, M J

2015-01-01

Multiple myeloma (MM) is a currently incurable malignancy of plasma cells. Malignant myeloma cells (MMCs) are heavily dependent upon the bone marrow (BM) microenvironment for their survival. One component of this tumor microenvironment, B-Cell Activating Factor (BAFF), has been implicated as a key player in this interaction. This review discusses the role of BAFF in the pathophysiology of MM, and the potential of BAFF-inhibitory therapy for the treatment of MM. Multiple studies have shown that BAFF functions as a survival factor for MMCs. Furthermore, MMCs express several BAFF-binding receptors. Of these, only Transmembrane Activator and CAML Interactor (TACI) correlates with the MMC's capability to ligate BAFF. Additionally, the level of expression of TACI correlates with the level of the MMC's BM dependency. Ligation of BAFF receptors on MMCs causes activation of the Nuclear Factor of κ-B (NF-κB) pathway, a crucial pathway for the pathogenesis of many B-cell malignancies. Serum BAFF levels are significantly elevated in MM patients when compared to healthy controls, and correlate inversely with overall survival. BAFF signaling is thus an interesting target for the treatment of MM. Several BAFF-inhibitory drugs are currently under evaluation for the treatment of MM. These include BAFF-monoclonal antibodies (tabalumab) and antibody-drug conjugates (GSK2857916)

Cellular Proliferation by Multiplex Immunohistochemistry Identifies High-Risk Multiple Myeloma in Newly Diagnosed, Treatment-Naive Patients.

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Ely, Scott; Forsberg, Peter; Ouansafi, Ihsane; Rossi, Adriana; Modin, Alvin; Pearse, Roger; Pekle, Karen; Perry, Arthur; Coleman, Morton; Jayabalan, David; Di Liberto, Maurizio; Chen-Kiang, Selina; Niesvizky, Ruben; Mark, Tomer M

2017-12-01

Therapeutic options for multiple myeloma (MM) are growing, yet clinical outcomes remain heterogeneous. Cytogenetic analysis and disease staging are mainstays of risk stratification, but data suggest a complex interplay between numerous abnormalities. Myeloma cell proliferation is a metric shown to predict outcomes, but available methods are not feasible in clinical practice. Multiplex immunohistochemistry (mIHC), using multiple immunostains simultaneously, is universally available for clinical use. We tested mIHC as a method to calculate a plasma cell proliferation index (PCPI). By mIHC, marrow trephine core biopsy samples were costained for CD138, a plasma cell-specific marker, and Ki-67. Myeloma cells (CD138 + ) were counted as proliferating if coexpressing Ki-67. Retrospective analysis was performed on 151 newly diagnosed, treatment-naive patients divided into 2 groups on the basis of myeloma cell proliferation: low (PCPI ≤ 5%, n = 87), and high (PCPI > 5%, n = 64). Median overall survival (OS) was not reached versus 78.9 months (P = .0434) for the low versus high PCPI groups. Multivariate analysis showed that only high-risk cytogenetics (hazard ratio [HR] = 2.02; P = .023), International Staging System (ISS) stage > I (HR = 2.30; P = .014), and PCPI > 5% (HR = 1.70; P = .041) had independent effects on OS. Twenty-three (36%) of the 64 patients with low-risk disease (ISS stage 1, without high-risk cytogenetics) were uniquely reidentified as high risk by PCPI. PCPI is a practical method that predicts OS in newly diagnosed myeloma and facilitates broader use of MM cell proliferation for risk stratification. Copyright © 2017 Elsevier Inc. All rights reserved.

S-phase induction by interleukin-6 followed by chemotherapy in patients with refractory multiple myeloma

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de Nully Brown, P; Jensen, P O; Diamant, M

1998-01-01

.0 microg/kg (n = 6) by subcutaneous injection once daily for 5 days and chemotherapy was administered on the last day of rhIL-6 injection. The effect of rhIL-6 treatment on labeling index (LI) was heterogeneous, but no statistically significant change was noted for this particular group as a whole. In two......The plasma cell labeling index (PCLI) in patients with multiple myeloma (MM) is relatively low and this has been associated with the low rate of remission following chemotherapy. Interleukin-6 (IL-6) has been demonstrated to be a major growth factor of myeloma cells. In order to increase the S......-phase proportion of myeloma cells, which might increase the sensitivity to chemotherapy, we gave rhIL-6 followed by chemotherapy to 15 myeloma patients with refractory disease. A total of 25 treatment cycles were administered since ten patients had two cycles. The rhIL-6 dose was 2.5 (n = 3), 5.0 (n = 6) and 10...

Non-invasive markers of bone turnover and plasma cytokines differ in osteoporotic patients with multiple myeloma and monoclonal gammopathies of undetermined significance

International Nuclear Information System (INIS)

Diamond, T.; Levy, S.; Smith, A.; Day, P.; Manoharan, A.

2001-01-01

Multiple myeloma (MM) is a common malignancy manifest by bone marrow infiltration with malignant plasma cells, the production of a paraprotein and lytic bone lesions. Monoclonal gammopathy of undetermined significance (MGUS) is assumed to be the precursor of clinically apparent myeloma, with one or more additional genetic events being required for progression to MM. Elderly patients presenting with osteoporosis and skeletal fractures are not infrequently found to have elevated serum paraprotein concentrations suggestive of either MM or MGUS. Differentiating between these two clinical disorders may prove challenging, despite bone marrow biopsy evidence of plasmacytosis. The underlying pathogenesis of bone loss in these conditions is complex and may be attributed to cytokine-induced osteoclastogenesis coupled with increased osteoclastic bone resorption. In the present study, various markers of bone turnover and plasma cytokines were measured in order to determine whether they may be of value in differentiating between these two disorders. It is concluded that the urinary deoxypyridinoline excretion rate is a sensitive marker of bone resorption and of underlying bone disease activity. It may also help to differentiate between MM and MGUS

MicroRNA Transfer Between Bone Marrow Adipose and Multiple Myeloma Cells.

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Soley, Luna; Falank, Carolyne; Reagan, Michaela R

2017-06-01

Multiple myeloma remains an incurable disease, largely due to the tumor-supportive role of the bone marrow microenvironment. Bone marrow adipose tissue (BMAT) is one component of the fertile microenvironment which is believed to contribute to myeloma progression and drug resistance, as well as participate in a vicious cycle of osteolysis and tumor growth. MicroRNAs (miRNAs) have recently emerged as instrumental regulators of cellular processes that enable the development and dissemination of cancer. This review highlights the intersection between two emerging research fields and pursues the scientific and clinical implications of miRNA transfer between BMAT and myeloma cells. This review provides a concise and provocative summary of the evidence to support exosome-mediated transfer of tumor-supportive miRNAs. The work may prompt researchers to better elucidate the mechanisms by which this novel means of genetic communication between tumor cells and their environment could someday yield targeted therapeutics.

Immunological Dysregulation in Multiple Myeloma Microenvironment

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Romano, Alessandra; Conticello, Concetta; Cavalli, Maide; Vetro, Calogero; La Fauci, Alessia; Parrinello, Nunziatina Laura; Di Raimondo, Francesco

2014-01-01

Multiple Myeloma (MM) is a systemic hematologic disease due to uncontrolled proliferation of monoclonal plasma cells (PC) in bone marrow (BM). Emerging in other solid and liquid cancers, the host immune system and the microenvironment have a pivotal role for PC growth, proliferation, survival, migration, and resistance to drugs and are responsible for some clinical manifestations of MM. In MM, microenvironment is represented by the cellular component of a normal bone marrow together with extr...

Infiltration patterns in monoclonal plasma cell disorders: correlation of magnetic resonance imaging with matched bone marrow histology

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Andrulis, Mindaugas [Institute of Pathology, University of Heidelberg, Heidelberg (Germany); Bäuerle, Tobias [Department of Diagnostic and Interventional Radiology, University of Hamburg, Hamburg (Germany); Goldschmidt, Hartmut [Department of Hematology and Oncology, University of Heidelberg, Heidelberg (Germany); Delorme, Stefan [Department of Radiology, German Cancer Research Center (DKFZ), Heidelberg (Germany); Landgren, Ola [Multiple Myeloma Section, Metabolism Branch, National Cancer Institute, Bethesda (United States); Schirmacher, Peter [Institute of Pathology, University of Heidelberg, Heidelberg (Germany); Hillengass, Jens, E-mail: jens.hillengass@med.uni-heidelberg.de [Department of Hematology and Oncology, University of Heidelberg, Heidelberg (Germany); Department of Radiology, German Cancer Research Center (DKFZ), Heidelberg (Germany)

2014-06-15

Objectives: To investigate how plasma cell infiltration patterns detected by MRI match the plasma cell distribution in bone marrow biopsy. Methods: We assessed 50 patients with monoclonal plasma cell disorders of all clinical stages. MRI infiltration pattern was compared with matched BM histology from the same anatomic region. Results: MRI revealed a minimal (n = 11, 22%), focal (n = 5, 10%), diffuse (n = 14, 28%) and mixed (n = 20, 40%) infiltration pattern. Diffuse MRI pattern was predominant in smoldering myeloma patients whereas the MRI patterns with “focal component” (i.e. focal and mixed) were most common in symptomatic myeloma (p < 0.01). In histology an interstitial (n = 13, 26%), nodular (n = 23, 46%) and packed marrow (n = 14, 28%) was found respectively. All three histological types of infiltration were observed in patients with diffuse and mixed MRI patterns. Minimal MRI pattern was found in all MGUS patients and was associated with an interstitial BM infiltration. In two patients with minimal MRI pattern an extensive micro-nodular BM infiltration was found in histology. Conclusions: Infiltration patterns in MRI represent different histological growth patterns of plasma cells, but the MRI resolution is not sufficient to visualize micro-nodular aggregates of plasma cells.

Infiltration patterns in monoclonal plasma cell disorders: correlation of magnetic resonance imaging with matched bone marrow histology

International Nuclear Information System (INIS)

Andrulis, Mindaugas; Bäuerle, Tobias; Goldschmidt, Hartmut; Delorme, Stefan; Landgren, Ola; Schirmacher, Peter; Hillengass, Jens

2014-01-01

Objectives: To investigate how plasma cell infiltration patterns detected by MRI match the plasma cell distribution in bone marrow biopsy. Methods: We assessed 50 patients with monoclonal plasma cell disorders of all clinical stages. MRI infiltration pattern was compared with matched BM histology from the same anatomic region. Results: MRI revealed a minimal (n = 11, 22%), focal (n = 5, 10%), diffuse (n = 14, 28%) and mixed (n = 20, 40%) infiltration pattern. Diffuse MRI pattern was predominant in smoldering myeloma patients whereas the MRI patterns with “focal component” (i.e. focal and mixed) were most common in symptomatic myeloma (p < 0.01). In histology an interstitial (n = 13, 26%), nodular (n = 23, 46%) and packed marrow (n = 14, 28%) was found respectively. All three histological types of infiltration were observed in patients with diffuse and mixed MRI patterns. Minimal MRI pattern was found in all MGUS patients and was associated with an interstitial BM infiltration. In two patients with minimal MRI pattern an extensive micro-nodular BM infiltration was found in histology. Conclusions: Infiltration patterns in MRI represent different histological growth patterns of plasma cells, but the MRI resolution is not sufficient to visualize micro-nodular aggregates of plasma cells

Study of the adhesion interaction using 51Cr labelling method between the myeloma cell lines and the endothelial cells

International Nuclear Information System (INIS)

Zhang Xueguang; Wang Jiangfang; Mao Zijun

1995-06-01

Using 51 Cr labelled multiple myeloma (MM) cell lines U266/XG-7, the regulatory effect of cytokines on the adhesive interaction between myeloma-cell lines U266/XG-7 and the endothelial cells, and the effects of these cytokines on expression of adhesion molecules and secretion of other cytokines were studied. The experimental results were as follows: (1) IL-6 and IL-6 Rgp 130-associated growth factors (such as GM-CSF) are not only myeloma cell growth factors, but also can enhance the adhesion between MM cells and endothelial cells and thus facilitated the metastasis of tumor cells. (2) Cytokines could induce increase in the expression of CD54 and CD44 on the endothelial cells and the secretion of IL-6 and TNF by the endothelial cells. On the other hand, the adhesion could also cause the change of CD11a, CD54, CD44 and VLA-4 on surface of myeloma cells XG-7. Finally, the interaction between MM cells and stromal cells from murine bone marrow could rapidly induce autocrine of IL-6 in human IL-6-dependent MM cells. (3) The interaction between stromal cells and tumor cells regulated by the cytokines and adhesion molecules was a key element in the pathogenesis and development of human MM. Among these factors, VLA-4 might be one of the molecules involved in U266/XG-7-EC interaction. (5 tabs., 8 figs.)

Illegitimate WNT signaling promotes proliferation of multiple myeloma cells

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Derksen, Patrick W. B.; Tjin, Esther; Meijer, Helen P.; Klok, Melanie D.; Mac Gillavry, Harold D.; van Oers, Marinus H. J.; Lokhorst, Henk M.; Bloem, Andries C.; Clevers, Hans; Nusse, Roel; van der Neut, Ronald; Spaargaren, Marcel; Pals, Steven T.

2004-01-01

The unrestrained growth of tumor cells is generally attributed to mutations in essential growth control genes, but tumor cells are also influenced by signals from the environment. In multiple myeloma (MM), the factors and signals coming from the bone marrow microenvironment are possibly even essential for the growth of the tumor cells. As targets for intervention, these signals may be equally important as mutated oncogenes. Given their oncogenic potential, WNT signals form a class of paracrine growth factors that could act to influence MM cell growth. In this paper, we report that MM cells have hallmarks of active WNT signaling, whereas the cells have not undergone detectable mutations in WNT signaling genes such as adenomatous polyposis coli and β-catenin (CTNNB1). We show that the malignant MM plasma cells overexpress β-catenin, including its N-terminally unphosphorylated form, suggesting active β-catenin/T cell factor-mediated transcription. Further accumulation and nuclear localization of β-catenin, and/or increased cell proliferation, was achieved by stimulation of WNT signaling with either Wnt3a, LiCl, or the constitutively active S33Y mutant of β-catenin. In contrast, by blocking WNT signaling by dominant-negative T cell factor, we can interfere with the growth of MM cells. We therefore suggest that MM cells are dependent on an active WNT signal, which may have important implications for the management of this incurable form of cancer. PMID:15067127

Genome-wide association study identifies multiple susceptibility loci for multiple myeloma

DEFF Research Database (Denmark)

Mitchell, Jonathan S; Li, Ni; Weinhold, Niels

2016-01-01

Multiple myeloma (MM) is a plasma cell malignancy with a significant heritable basis. Genome-wide association studies have transformed our understanding of MM predisposition, but individual studies have had limited power to discover risk loci. Here we perform a meta-analysis of these GWAS, add a ...

Zingiber officinale, Piper retrofractum and Combination Induced Apoptosis and p53 Expression in Myeloma and WiDr Cell Lines

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HENY EKOWATI

2012-09-01

Full Text Available In previous studies, Zingiber officinale, Piper retrofractum, and the combination showed cytotoxic activity, induced apoptosis, and p53 expression of HeLa, T47D, and MCF-7 cell lines. This study was conducted to investigate the cytotoxic and apoptotic activity of Zingiber officinale (ZO, Piper retrofractum (PR, and the combination as well as their effect to p53 expression on Myeloma and WiDr cells. The powder of ZO, PR, and ZO + PR combination (1:1 were macerated with 96% ethanol for 3 x 24 hours. MTT cytotoxic assay was performed on Myeloma and WiDr cell lines. Apoptotic cells were stained with ethidium bromide and acridine orange. Imunohistochemical expression of p53 was examined on Myeloma and WiDr cell lines. Doxorubicin was used as positive control in all assays. Results showed that ZO, PR, and ZO + PR combination had cytotoxic activity on Myeloma cells with IC50 of 28, 36, and 55 mg/ml respectively and WiDr cell lines with IC50 of 74, 158, and 64 mg/ml respectively, induced apoptotic activity, and increased p53 expression on Myeloma and WiDr cells. These results suggest that ZO, PR, and their combination induced Myeloma and WiDr cells in apoptosis through p53 expression.

CARs in the Lead Against Multiple Myeloma

DEFF Research Database (Denmark)

Ormhøj, Maria; Bedoya, Felipe; Frigault, Matthew J.

2017-01-01

The recent clinical success of CD19-directed chimeric antigen receptor (CAR) T cell therapy in chronic and acute leukemia has led to increased interest in broadening this technology to other hematological malignancies and solid tumors. Now, advances are being made using CAR T cell technology...... to target myeloma antigens such as B cell maturation antigen (BCMA), CD138, and kappa-light chain as well as CD19 on putative myeloma stem cells. To date, only a limited number of multiple myeloma patients have received CAR T cell therapy but preliminary results have been encouraging. In this review, we...... summarize the recently reported results of clinical trials conducted utilizing CAR T cell therapy in multiple myeloma (MM)....

Multiple Myeloma Macrophages: Pivotal Players in the Tumor Microenvironment

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Simona Berardi

2013-01-01

Full Text Available Tumor microenvironment is essential for multiple myeloma (MM growth, progression, and drug resistance through provision of survival signals and secretion of growth and proangiogenic factors. This paper examines the importance of macrophages within MM bone marrow (BM microenvironment, referred to as MM-associated macrophages, as a potential niche component that supports tumor plasma cells. These macrophages are derived from peripheral blood monocytes recruited into the tumor. Upon activation by MM plasma cells and mesenchymal stromal cells, macrophages can release growth factors, proteolytic enzymes, cytokines, and inflammatory mediators that promote plasma cell growth and survival. Macrophages promote tumor progression through several mechanisms including angiogenesis, growth, and drug resistance. Indeed, these macrophages are essential for the induction of an angiogenic response through vasculogenic mimicry, and this ability proceeds in step with progression of the plasma cell tumors. Data suggest that macrophages play an important role in the biology and survival of patients with MM, and they may be a target for the MM antivascular management.

MAGE-A inhibits apoptosis in proliferating myeloma cells through repression of Bax and maintenance of survivin.

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Nardiello, Tricia; Jungbluth, Achim A; Mei, Anna; Diliberto, Maurizio; Huang, Xiangao; Dabrowski, Ania; Andrade, Valéria C C; Wasserstrum, Rebecca; Ely, Scott; Niesvizky, Ruben; Pearse, Roger; Coleman, Morton; Jayabalan, David S; Bhardwaj, Nina; Old, Lloyd J; Chen-Kiang, Selina; Cho, Hearn Jay

2011-07-01

The type I Melanoma Antigen GEnes (MAGEs) are commonly expressed in cancers, fueling speculation that they may be therapeutic targets with oncogenic potential. They form complexes with RING domain proteins that have E3 ubiquitin ligase activity and promote p53 degradation. MAGE-A3 was detected in tumor specimens from patients with multiple myeloma and its expression correlated with higher frequencies of Ki-67(+) malignant cells. In this report, we examine the mechanistic role of MAGE-A in promoting survival of proliferating multiple myeloma cells. The impact of MAGE-A3 expression on survival and proliferation in vivo was examined by immunohistochemical analysis in an independent set of tumor specimens segregated into two groups: newly diagnosed, untreated patients and patients who had relapsed after chemotherapy. The mechanisms of MAGE-A3 activity were investigated in vitro by silencing its expression by short hairpin RNA interference in myeloma cell lines and primary cells and assessing the resultant effects on proliferation and apoptosis. MAGE-A3 was detected in a significantly higher percentage of relapsed patients compared with newly diagnosed, establishing a novel correlation with progression of disease. Silencing of MAGE-A showed that it was dispensable for cell cycling, but was required for survival of proliferating myeloma cells. Loss of MAGE-A led to apoptosis mediated by p53-dependent activation of proapoptotic Bax expression and by reduction of survivin expression through both p53-dependent and -independent mechanisms. These data support a role for MAGE-A in the pathogenesis and progression of multiple myeloma by inhibiting apoptosis in proliferating myeloma cells through two novel mechanisms.

Targeting HSP90 and monoclonal protein trafficking modulates the unfolded protein response, chaperone regulation and apoptosis in myeloma cells

International Nuclear Information System (INIS)

Born, E J; Hartman, S V; Holstein, S A

2013-01-01

Multiple myeloma is characterized by the production of substantial quantities of monoclonal protein. We have previously demonstrated that select inhibitors of the isoprenoid biosynthetic pathway (IBP) induce apoptosis of myeloma cells via inhibition of Rab geranylgeranylation, leading to disruption of monoclonal protein trafficking and induction of the unfolded protein response (UPR) pathway. Heat-shock protein 90 (HSP90) inhibitors disrupt protein folding and are currently under clinical investigation in myeloma. The effects of combining IBP and HSP90 inhibitors on cell death, monoclonal protein trafficking, the UPR and chaperone regulation were investigated in monoclonal protein-producing cells. An enhanced induction of cell death was observed following treatment with IBP and HSP90 inhibitors, which occurred through both ER stress and non-ER stress pathways. The HSP90 inhibitor 17-AAG abrogated the effects of the IBP inhibitors on intracellular monoclonal protein levels and localization as well as induction of the UPR in myeloma cells. Disparate effects on chaperone expression were observed in myeloma vs amyloid light chain cells. Here we demonstrate that the novel strategy of targeting MP trafficking in concert with HSP90 enhances myeloma cell death via a complex modulation of ER stress, UPR, and cell death pathways

MULTIPLE MYELOMA PRESENTED AS AN ANTERIOR CHEST WALL MASS DIAGNOSED BY CYTOLOGICAL EXAMINATION : A CASE REPORT

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Parvathi

2015-02-01

Full Text Available Myeloma is a malignancy of terminally differentiated B cells (plasma cells that produce a complete and / or partial monoclonal immunoglobulin protein. Myeloma accounts for approximately 1% of all malignancies and 10% of haematological tumors. It becomes difficult to arrive at early diagnosis because myeloma manifests itself in different forms. The disease usually presents as bone pains, pathological fractures and anemia but can also present as swelling in jaw, orbit, rib, sternoclavicular area, scalp, paraspinal region and tonsil. We present a case of multiple myeloma in 63 year old male which presented as a soft tissue mass on anterior chest wall and diagnosed by FNAC . This case is presented because diagnosis was made on cytology and not many cases have been reported in literature where FNAC helped in making the diagnosis. This increases the hope of early diagnosis so that treatment can be advocated

Single-cell analysis of targeted transcriptome predicts drug sensitivity of single cells within human myeloma tumors.

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Mitra, A K; Mukherjee, U K; Harding, T; Jang, J S; Stessman, H; Li, Y; Abyzov, A; Jen, J; Kumar, S; Rajkumar, V; Van Ness, B

2016-05-01

Multiple myeloma (MM) is characterized by significant genetic diversity at subclonal levels that have a defining role in the heterogeneity of tumor progression, clinical aggressiveness and drug sensitivity. Although genome profiling studies have demonstrated heterogeneity in subclonal architecture that may ultimately lead to relapse, a gene expression-based prediction program that can identify, distinguish and quantify drug response in sub-populations within a bulk population of myeloma cells is lacking. In this study, we performed targeted transcriptome analysis on 528 pre-treatment single cells from 11 myeloma cell lines and 418 single cells from 8 drug-naïve MM patients, followed by intensive bioinformatics and statistical analysis for prediction of proteasome inhibitor sensitivity in individual cells. Using our previously reported drug response gene expression profile signature at the single-cell level, we developed an R Statistical analysis package available at https://github.com/bvnlabSCATTome, SCATTome (single-cell analysis of targeted transcriptome), that restructures the data obtained from Fluidigm single-cell quantitative real-time-PCR analysis run, filters missing data, performs scaling of filtered data, builds classification models and predicts drug response of individual cells based on targeted transcriptome using an assortment of machine learning methods. Application of SCATT should contribute to clinically relevant analysis of intratumor heterogeneity, and better inform drug choices based on subclonal cellular responses.

Analysis of the immune system of multiple myeloma patients achieving long-term disease control by multidimensional flow cytometry

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Pessoa de Magalhães, Roberto J.; Vidriales, María-Belén; Paiva, Bruno; Fernandez-Gimenez, Carlos; García-Sanz, Ramón; Mateos, Maria-Victoria; Gutierrez, Norma C.; Lecrevisse, Quentin; Blanco, Juan F; Hernández, Jose; de las Heras, Natalia; Martinez-Lopez, Joaquin; Roig, Monica; Costa, Elaine Sobral; Ocio, Enrique M.; Perez-Andres, Martin; Maiolino, Angelo; Nucci, Marcio; De La Rubia, Javier; Lahuerta, Juan-Jose; San-Miguel, Jesús F.; Orfao, Alberto

2013-01-01

Multiple myeloma remains largely incurable. However, a few patients experience more than 10 years of relapse-free survival and can be considered as operationally cured. Interestingly, long-term disease control in multiple myeloma is not restricted to patients with a complete response, since some patients revert to having a profile of monoclonal gammopathy of undetermined significance. We compared the distribution of multiple compartments of lymphocytes and dendritic cells in the bone marrow and peripheral blood of multiple myeloma patients with long-term disease control (n=28), patients with newly diagnosed monoclonal gammopathy of undetermined significance (n=23), patients with symptomatic multiple myeloma (n=23), and age-matched healthy adults (n=10). Similarly to the patients with monoclonal gammopathy of undetermined significance and symptomatic multiple myeloma, patients with long-term disease control showed an expansion of cytotoxic CD8+ T cells and natural killer cells. However, the numbers of bone marrow T-regulatory cells were lower in patients with long-term disease control than in those with symptomatic multiple myeloma. It is noteworthy that B cells were depleted in patients with monoclonal gammopathy of undetermined significance and in those with symptomatic multiple myeloma, but recovered in both the bone marrow and peripheral blood of patients with long-term disease control, due to an increase in normal bone marrow B-cell precursors and plasma cells, as well as pre-germinal center peripheral blood B cells. The number of bone marrow dendritic cells and tissue macrophages differed significantly between patients with long-term disease control and those with symptomatic multiple myeloma, with a trend to cell count recovering in the former group of patients towards levels similar to those found in healthy adults. In summary, our results indicate that multiple myeloma patients with long-term disease control have a constellation of unique immune changes

Primary tumor cells of myeloma patients induce interleukin-6 secretion in long-term bone marrow cultures

NARCIS (Netherlands)

Lokhorst, H. M.; Lamme, T.; de Smet, M.; Klein, S.; de Weger, R. A.; van Oers, R.; Bloem, A. C.

1994-01-01

Long-term bone marrow cultures (LTBMC) from patients with multiple myeloma (MM) and normal donors were analyzed for immunophenotype and cytokine production. Both LTBMC adherent cells from myeloma and normal donor origin expressed CD10, CD13, the adhesion molecules CD44, CD54, vascular cell adhesion

Ibrutinib targets microRNA-21 in multiple myeloma cells by inhibiting NF-κB and STAT3.

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Ma, Jing; Gong, Wei; Liu, Su; Li, Qian; Guo, Mengzheng; Wang, Jinhan; Wang, Suying; Chen, Naiyao; Wang, Yafei; Liu, Qiang; Zhao, Hui

2018-01-01

The oncogenic microRNA-21 contributes to the pathogenesis of multiple myeloma. Ibrutinib (also referred to as PCI-32765), an inhibitor of Bruton's tyrosine kinase, while its effects on multiple myeloma have not been well described. Here, we show that microRNA-21 is an oncogenic marker closely linked with progression of multiple myeloma. Moreover, ibrutinib attenuates microRNA-21 expression in multiple myeloma cells by inhibiting nuclear factor-κB and signal transducer and activator of transcription 3 signaling pathways. Taken together, our results suggest that ibrutinib is a promising potential treatment for multiple myeloma. Further investigation of mechanisms of ibrutinib function in multiple myeloma will be necessary to evaluate its use as a novel multiple myeloma treatment.

The first report of myeloma with IgD κ and free κ in Indonesia

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Riadi Wirawan

2011-08-01

Full Text Available IgD κ myeloma is a rare plasma cell neoplasm case and has never been reported before in Indonesia. In normal condition, IgD level in blood is very low, therefore increase of IgD level in myeloma could be missed by serum protein electrophoresis. A case of a 59 years old female with severe bone pain is reported. In radiology evaluation, there were thoracal compression fracture and thoracal foramen narrowing. For this patient, the myeloma diagnosis was based on WHO criteria, the stage IIIb was based on Durie and Salmon criteria, and bad prognosis with prognostic index stage III diagnosis was based on International Prognostic Index from International Myeloma Working Group, respectively. In serum protein electrophoresis we found a very small monoclonal spike and in immunofi xation there were monoclonal IgD κ and free light chain κ. (Med J Indones 2011; 20:217-21Keywords: immunofixation, myeloma IgD κ, protein electrophoresis

Immunomodulation of multiple myeloma.

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Tohnya, Tanyifor M; Figg, William D

2004-11-01

Multiple myeloma is a multi-process disease, and these different processes are responsible for the reduced sensitivity to chemotherapy and radiotherapy, hence the relapse and refractory nature of multiple myeloma. Emphasis is now placed on the hypothesis that myeloma cell growth, inhibition of apoptosis and drug resistance are dependent on immunomodulatory cytokines such as IL-6 and pro-angiogenic factors such as VEGF. In addition to its anti-angiogenic effects, the immunomodulatory properties of thalidomide make it a possible therapy for patients with advanced multiple myeloma. This has lead to the clinical development of a number of immunomodulatory thalidomide analogues (IMiDs) which are more potent and have less side effects than the parent drug, thalidomide. In the August 15(th) issue of Journal of Clinical Oncology, Schey SA et al. suggested that an IMiD (CC-4047) maybe efficacious due to T-cell co-stimulation, and safe in patients with relapsed or refractory multiple myeloma. This article demonstrates a supporting role for IMiDs as immunomodulatory adjuvant therapy.

Technetium-99m Sestamibi in Multiple Myeloma

International Nuclear Information System (INIS)

Saber, R.A.

2002-01-01

Technetium-99m 2-methoxy - isobutyl - isonitrile (99mTc-MIBI) has been reported to be useful in evaluating patients with multiple myeloma. The aim of this study is to evaluate the role of technetium-99m sestamibi (99mTc-MIBI) scintigraphy in the diagnosis. staging and follow-up of patients with multiple myeloma. Methods and Materials: twenty-five consecutive patients with multiple myeloma were studied using 99mTc- MIBI. Of the 25 patients included in this study, 6 were in stage I, II in stage II and 8 in stage III. Anterior and posterior whole-body imaging were obtained 20 min after I.V. injection of 740 MBq of 99mTc-MIBI. Four different MIBI patterns could be described in our patients: physiological (P), diffuse (D), focal (F) and combined diffuse and focal (D+F). All patients in stages II and III as well as 3 patients in stage I were treated with chemotherapy (cyclophosphamide and prednisone) then 99mTc-MlBI scans were repeated after 6 courses. Results: in comparison to conventional X-ray skeletal survey, 99mTc-MIBI scans showed a higher number of myeloma bone disease at diagnosis. All patients with stage II and III multiple myeloma were positive with 99mTc-MlBl scans at diagnosis. The pattern of positive MIBI accumulation was diffuse in 13 (52%) patients, focal in 4 (16%) and combined focal and diffuse in 6 (24%) patients. The intensity of 99mTc-MIBI correlated with disease activity as determined by lactate dehydrogenase (LDH), number of plasma cells in bone marrow and serum electrophoresis. There was a direct correlation between 99mTc-MIBI scan result and clinical outcome of patients following 6 courses of chemotherapy. Sensitivity and specificity of 99mTc-MIBI scintigraphy in detecting myeloma bone lesions were 92% and 90% respectively. Conclusion: 99mTc-MIBI scintigraphy is a reliable method to evaluate bone marrow activity in patients with multiple myeloma and follow-up of myeloma bone lesions

Insights on Genomic and Molecular Alterations in Multiple Myeloma and Their Incorporation towards Risk-Adapted Treatment Strategy: Concise Clinical Review

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Taiga Nishihori

2017-01-01

Full Text Available Although recent advances in novel treatment approaches and therapeutics have shifted the treatment landscape of multiple myeloma, it remains an incurable plasma cell malignancy. Growing knowledge of the genome and expressed genomic information characterizing the biologic behavior of multiple myeloma continues to accumulate. However, translation and incorporation of vast molecular understanding of complex tumor biology to deliver personalized and precision treatment to cure multiple myeloma have not been successful to date. Our review focuses on current evidence and understanding of myeloma biology with characterization in the context of genomic and molecular alterations. We also discuss future clinical application of the genomic and molecular knowledge, and more translational research is needed to benefit our myeloma patients.

Whole body MR in patients with multiple myeloma

International Nuclear Information System (INIS)

Piekarek, A.; Sosnowski, P.; Nowicki, A.; Komarnicki, M.

2009-01-01

Background: Multiple myeloma is a cancer of plasma cells which leads to bone marrow infiltration. Aim: Whole-body MR is the most sensitive imaging method available to detect multiple myeloma lesions. Ma terial and methods: MR scans were performed in 100 patients with multiple myeloma who were receiving treatment in the Haematology Clinic in Poznan in the years 2005 - 2006. Whole-body MR scans were performed with general coil 1.0 T in STIR sequences and T1 sequences, in coronal and sagittal planes with scanning area covering the head, neck, trunk and the limbs (FOV for specific regions was 36 -48 cm). The bone lesions were classified as focal (monofocal/multifocal lesions), infiltrative, mixed and 'salt and pepper' type. Depending on the size of the lesions the patients were included in one of three groups according to Salmon-Durie Plus classification. Results: Four main types of multiple myeloma were distinguished based on MR scans: focal (48 patients; monofocal in 10 patients), infiltrative (17 patients), mixed type (19 patients) and 'salt and pepper' type (4 patients). The remaining 12 patients had no multiple myeloma lesions in the bone marrow. Additionally, in 18% of patients a soft tissue mass could be observed. According to Salmon-Durie Plus categorisation 27 subjects were classified as having stage I, 16 patients stage and 57 patients stage III disease. In 12% of patients MR data changed the disease staging. Conclusions: WB MR is a sensitive and effective diagnostic method with an important impact on staging and further treatment of multiple myeloma. (authors)

BCL2-BH4 antagonist BDA-366 suppresses human myeloma growth.

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Deng, Jiusheng; Park, Dongkyoo; Wang, Mengchang; Nooka, Ajay; Deng, Qiaoya; Matulis, Shannon; Kaufman, Jonathan; Lonial, Sagar; Boise, Lawrence H; Galipeau, Jacques; Deng, Xingming

2016-05-10

Multiple myeloma (MM) is a heterogeneous plasma cell malignancy and remains incurable. B-cell lymphoma-2 (BCL2) protein correlates with the survival and the drug resistance of myeloma cells. BH3 mimetics have been developed to disrupt the binding between BCL2 and its pro-apoptotic BCL2 family partners for the treatment of MM, but with limited therapeutic efficacy. We recently identified a small molecule BDA-366 as a BCL2 BH4 domain antagonist, converting it from an anti-apoptotic into a pro-apoptotic molecule. In this study, we demonstrated that BDA-366 induces robust apoptosis in MM cell lines and primary MM cells by inducing BCL2 conformational change. Delivery of BDA-366 substantially suppressed the growth of human MM xenografts in NOD-scid/IL2Rγnull mice, without significant cytotoxic effects on normal hematopoietic cells or body weight. Thus, BDA-366 functions as a novel BH4-based BCL2 inhibitor and offers an entirely new tool for MM therapy.

Stimulation of Toll-like receptor-1/2 combined with Velcade increases cytotoxicity to human multiple myeloma cells

International Nuclear Information System (INIS)

Abdi, J; Mutis, T; Garssen, J; Redegeld, F

2013-01-01

An increasing body of evidence supports the important role of adhesion to bone marrow microenvironment components for survival and drug resistance of multiple myeloma (MM) cells. Previous studies suggested that stimulation of Toll-like receptors by endogenous ligands released during inflammation and tissue damage may be pro-tumorigenic, but no studies have been performed in relation to modulation of cell adhesion and drug cytotoxicity. Here, we investigated the effect of TLR1/2 activation on adhesion of human myeloma cells to fibronectin, and their sensitivity to the proteasome inhibitor Velcade. It was found that TLR1/2 activation with Pam3CSK4 increased the cytotoxicity of Velcade in L363, OPM-2 and U266 human myeloma cells. This effect was not related to a decreased adhesion of the cells to fibronectin, but TLR1/2 activation stimulated the caspase-3 activity in Velcade-treated myeloma cells, which may be responsible for the enhanced cell death. Inhibitors of NF-κB and MAPK reduced the stimulatory effect. These findings indicate that TLR activation of MM cells could bypass protective effects of cell adhesion and suggest that TLR signaling may also have antitumorigenic potential

POOR HEMOPOIETIC STEM CELL MOBILIZERS IN MULTIPLE MYELOMA : A SINGLE INSTITUTION EXPERIENCE

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Guillermo Jose Ruiz-Delgado

2010-06-01

Full Text Available In a single institution, in a group of 28 myeloma patients deemed eligible for autologous transplant, stem cell mobilization was attempted using filgrastim: 26 individuals were given 31 autografts employing 1-4 (median three apheresis sessions, to obtain a target stem cell dose of 1 x 106 CD34 viable cells / Kg of the recipient. The median number of grafted CD34 cells was 7.56 x 106  / Kg of the recipient; the range being 0.92 to 14.8.  By defining as poor mobilizers individuals in which a cell collection of 1 x 106 CD34 viable cells / Kg was better (80% at 80 months than those grafted with < 1 x 106 CD34 viable cells / Kg (67% at 76 months. Methods to improve stem cell mobilization are needed and may result in obtaining better results when autografting multiple myeloma patients.

Targeting Ongoing DNA Damage in Multiple Myeloma: Effects of DNA Damage Response Inhibitors on Plasma Cell Survival

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Ana Belén Herrero

2017-05-01

Full Text Available Human myeloma cell lines (HMCLs and a subset of myeloma patients with poor prognosis exhibit high levels of replication stress (RS, leading to DNA damage. In this study, we confirmed the presence of DNA double-strand breaks (DSBs in several HMCLs by measuring γH2AX and RAD51 foci and analyzed the effect of various inhibitors of the DNA damage response on MM cell survival. Inhibition of ataxia telangiectasia and Rad3-related protein (ATR, the main kinase mediating the response to RS, using the specific inhibitor VE-821 induced more cell death in HMCLs than in control lymphoblastoid cells and U266, an HMCL with a low level of DNA damage. The absence of ATR was partially compensated by ataxia telangiectasia-mutated protein (ATM, since chemical inhibition of both kinases using VE-821 and KU-55933 significantly increased the death of MM cells with DNA damage. We found that ATM and ATR are involved in DSB repair by homologous recombination (HR in MM. Inhibition of both kinases resulted in a stronger inhibition that may underlie cell death induction, since abolition of HR using two different inhibitors severely reduced survival of HMCLs that exhibit DNA damage. On the other hand, inhibition of the other route involved in DSB repair, non-homologous end joining (NHEJ, using the DNA-PK inhibitor NU7441, did not affect MM cell viability. Interestingly, we found that NHEJ inhibition did not increase cell death when HR was simultaneously inhibited with the RAD51 inhibitor B02, but it clearly increased the level of cell death when HR was inhibited with the MRE11 inhibitor mirin, which interferes with recombination before DNA resection takes place. Taken together, our results demonstrate for the first time that MM cells with ongoing DNA damage rely on an intact HR pathway, which thereby suggests therapeutic opportunities. We also show that inhibition of HR after the initial step of end resection might be more appropriate for inducing MM cell death, since it

SAHA-induced TRAIL-sensitisation of Multiple Myeloma cells is enhanced in 3D cell culture.

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Arhoma, A; Chantry, A D; Haywood-Small, S L; Cross, N A

2017-11-15

Multiple Myeloma (MM) is currently incurable despite many novel therapies. Tumour Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) is a potential anti-tumour agent although effects as a single agent are limited. In this study, we investigated whether the Histone Deacetylase (HDAC) inhibitor SAHA can enhance TRAIL-induced apoptosis and target TRAIL resistance in both suspension culture, and 3D cell culture as a model of disseminated MM lesions that form in bone. The effects of SAHA and/or TRAIL in 6 Multiple Myeloma cell lines were assessed in both suspension cultures and in an Alginate-based 3D cell culture model. The effect of SAHA and/or TRAIL was assessed on apoptosis by assessment of nuclear morphology using Hoechst 33342/Propidium Iodide staining. Viable cell number was assessed by CellTiter-Glo luminescence assay, Caspase-8 and -9 activities were measured by Caspase-Glo™ assay kit. TRAIL-resistant cells were generated by culture of RPMI 8226 and NCI-H929 by acute exposure to TRAIL followed by selection of TRAIL-resistant cells. TRAIL significantly induced apoptosis in a dose-dependent manner in OPM-2, RPMI 8226, NCI-H929, U266, JJN-3 MM cell lines and ADC-1 plasma cell leukaemia cells. SAHA amplified TRAIL responses in all lines except OPM-2, and enhanced TRAIL responses were both via Caspase-8 and -9. SAHA treatment induced growth inhibition that further increased in the combination treatment with TRAIL in MM cells. The co-treatment of TRAIL and SAHA reduced viable cell numbers all cell lines. TRAIL responses were further potentiated by SAHA in 3D cell culture in NCI-H929, RPMI 8226 and U266 at lower TRAIL + SAHA doses than in suspension culture. However TRAIL responses in cells that had been selected for TRAIL resistance were not further enhanced by SAHA treatment. SAHA is a potent sensitizer of TRAIL responses in both TRAIL sensitive and resistant cell lines, in both suspension and 3D culture, however SAHA did not sensitise TRAIL-sensitive cell

UPDATE ON THE ROLE OF AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION IN MULTIPLE MYELOMA

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Patrizia Tosi

2012-11-01

Full Text Available Autologous stem cell transplantation is considered the standard of care for multiple myeloma patients aged < 65 years with no relevant comorbidities. The addition of drugs acting both on bone marrow microenvironment and on neoplastic plasma cells has significantly increased the proportion of patients achieving a complete remission after induction therapy, and these results are mantained after high-dose melphalan, leading to a prolonged disease control. Studies are being carried out in order to evaluate whether short term consolidation or long-term maintenance therapy can result into disease eradication at the molecular level thus increasing also patients survival. The efficacy of these new drugs has raised the issue of deferring the transplant after achivng a second response upon relapse. Another controversial point is the optimal treatment strategy for high-risk patients, that do not benefit from autologous stem cell transplantation and for whom the efficacy of new drugs is still matter of debate.

IgM myeloma: A multicenter retrospective study of 134 patients.

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Castillo, Jorge J; Jurczyszyn, Artur; Brozova, Lucie; Crusoe, Edvan; Czepiel, Jacek; Davila, Julio; Dispenzieri, Angela; Eveillard, Marion; Fiala, Mark A; Ghobrial, Irene M; Gozzetti, Alessandro; Gustine, Joshua N; Hajek, Roman; Hungria, Vania; Jarkovsky, Jiri; Jayabalan, David; Laubach, Jacob P; Lewicka, Barbara; Maisnar, Vladimir; Manasanch, Elisabet E; Moreau, Philippe; Morgan, Elizabeth A; Nahi, Hareth; Niesvizky, Ruben; Paba-Prada, Claudia; Pika, Tomas; Pour, Ludek; Reagan, John L; Richardson, Paul G; Shah, Jatin; Spicka, Ivan; Vij, Ravi; Waszczuk-Gajda, Anna; Gertz, Morie A

2017-08-01

IgM myeloma is a rare hematologic malignancy for which the clinicopathological features and patient outcomes have not been extensively studied. We carried out a multicenter retrospective study in patients with diagnosis of IgM myeloma defined by >10% marrow involvement by monoclonal plasma cells, presence of an IgM monoclonal paraproteinemia of any size, and anemia, renal dysfunction, hypercalcemia, lytic lesions and/or t(11;14) identified by FISH. A total of 134 patients from 20 centers were included in this analysis. The median age at diagnosis was 65.5 years with a male predominance (68%). Anemia, renal dysfunction, elevated calcium and skeletal lytic lesions were found in 37, 43, 19, and 70%, respectively. The median serum IgM level was 2,895 mg dL -1 with 19% of patients presenting with levels >6,000 mg dL -1 . International Staging System (ISS) stages 1, 2, and 3 were seen in 40 (33%), 54 (44%), and 29 (24%) of patients, respectively. The malignant cells expressed CD20 (58%) and cyclin D1 (67%), and t(11;14) was the most common cytogenetic finding (39%). The median overall survival (OS) was 61 months. Higher ISS score was associated with worse survival (P = 0.02). Patients with IgM myeloma present with similar characteristics and outcomes as patients with more common myeloma subtypes. © 2017 Wiley Periodicals, Inc.

Autologous bone marrow Th cells can support multiple myeloma cell proliferation in vitro and in xenografted mice.

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Wang, D; Fløisand, Y; Myklebust, C V; Bürgler, S; Parente-Ribes, A; Hofgaard, P O; Bogen, B; Taskén, K; Tjønnfjord, G E; Schjesvold, F; Dalgaard, J; Tveita, A; Munthe, L A

2017-10-01

Multiple myeloma (MM) is a plasma cell malignancy where MM cell growth is supported by the bone marrow (BM) microenvironment with poorly defined cellular and molecular mechanisms. MM cells express CD40, a receptor known to activate autocrine secretion of cytokines and elicit proliferation. Activated T helper (Th) cells express CD40 ligand (CD40L) and BM Th cells are significantly increased in MM patients. We hypothesized that activated BM Th cells could support MM cell growth. We here found that activated autologous BM Th cells supported MM cell growth in a contact- and CD40L-dependent manner in vitro. MM cells had retained the ability to activate Th cells that reciprocated and stimulated MM cell proliferation. Autologous BM Th cells supported MM cell growth in xenografted mice and were found in close contact with MM cells. MM cells secreted chemokines that attracted Th cells, secretion was augmented by CD40-stimulation. Within 14 days of culture of whole BM aspirates in autologous serum, MM cells and Th cells mutually stimulated each other, and MM cells required Th cells for further expansion in vitro and in mice. The results suggest that Th cells may support the expansion of MM cells in patients.

The myeloma stem cell concept, revisited: From phenomenology to operational terms

NARCIS (Netherlands)

H.E. Johnsen (Hans); M. Bøgsted (Martin); A. Schmitz; Bødker, J.S. (Julie Støve); El-Galaly, T.C. (Tarec Christoffer); Johansen, P. (Preben); P. Valent (Peter); Zojer, N. (Niklas); E. van Valckenborgh (Els); Vanderkerken, K. (Karin); M. van Duin (Mark); P. Sonneveld (Pieter); M. Perez-Andres; A. Orfao (Alberto); K. Dybkær (Karen)

2016-01-01

textabstractThe concept of the myeloma stem cell may have important therapeutic implications, yet its demonstration has been hampered by a lack of consistency in terms and definitions. Here, we summarize the current documentation and propose single-cell in vitro studies for future translational

Up-regulation of hexokinaseII in myeloma cells: targeting myeloma cells with 3-bromopyruvate.

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Nakano, Ayako; Miki, Hirokazu; Nakamura, Shingen; Harada, Takeshi; Oda, Asuka; Amou, Hiroe; Fujii, Shiro; Kagawa, Kumiko; Takeuchi, Kyoko; Ozaki, Shuji; Matsumoto, Toshio; Abe, Masahiro

2012-02-01

Hexokinase II (HKII), a key enzyme of glycolysis, is widely over-expressed in cancer cells. However, HKII levels and its roles in ATP production and ATP-dependent cellular process have not been well studied in hematopoietic malignant cells including multiple myeloma (MM) cells.We demonstrate herein that HKII is constitutively over-expressed in MM cells. 3-bromopyruvate (3BrPA), an inhibitor of HKII, promptly and substantially suppresses ATP production and induces cell death in MM cells. Interestingly, cocultures with osteoclasts (OCs) but not bone marrow stromal cells (BMSCs) enhanced the phosphorylation of Akt along with an increase in HKII levels and lactate production in MM cells. The enhancement of HKII levels and lactate production in MM cells by OCs were mostly abrogated by the PI3K inhibitor LY294002, suggesting activation of glycolysis in MM cells by OCs via the PI3K-Akt-HKII pathway. Although BMSCs and OCs stimulate MM cell growth and survival, 3BrPA induces cell death in MM cells even in cocultures with OCs as well as BMSCs. Furthermore, 3BrPA was able to diminish ATP-dependent ABC transporter activity to restore drug retention in MM cells in the presence of OCs. These results may underpin possible clinical application of 3BrPA in patients with MM.

Recent advances in multiple myeloma: a Korean perspective

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Hong, Junshik; Lee, Jae Hoon

2016-01-01

Epidemiologically, multiple myeloma (MM) is a malignant disorder of plasma cells with a higher incidence among Western populations than among Asians. However, there is growing evidence of a recent increase in the age-standardized incidence rate (ASR) of MM in Asian countries, particularly Korea. Application of novel agents has resulted in significant improvement of treatment outcomes, and the advances are ongoing with the recent introduction and U.S. Food and Drug Administration?s approval of...

Amelioration of NK cell function driven by Vα24+ invariant NKT cell activation in multiple myeloma.

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Iyoda, Tomonori; Yamasaki, Satoru; Hidaka, Michihiro; Kawano, Fumio; Abe, Yu; Suzuki, Kenshi; Kadowaki, Norimitsu; Shimizu, Kanako; Fujii, Shin-Ichiro

2018-02-01

NK cells represent a first line of immune defense, but are progressively dysregulated in multiple myeloma (MM) patients. To restore and facilitate their antitumor effect, NK cells are required in sufficient quantities and must be stimulated. We initially assessed the proportions of NKT and NK cells in 34 MM patients. The frequencies of both in PBMC populations correlated with those in BMMNCs irrespective of low BMMNC numbers. We then assessed the adjunctive effect of stimulating NKT cells with CD1d and α-GalCer complexes on the NK cells. The expression of NKG2D on CD56 dim CD16 + NK cells and DNAM-1 on CD56 bright CD16 - NK cells increased after NKT cell activation. Apparently, NK cell-mediated anti-tumor effects were dependent on NKG2D and DNAM-1 ligands on myeloma cells. Thus, NK cell function in patients could be ameliorated, beyond the effect of immunosuppression, by NKT cell activation. This NKT-driven NK cell therapy could represent a potential new treatment modality. Copyright © 2017 Elsevier Inc. All rights reserved.

Pre-clinical evaluation of CD38 chimeric antigen receptor engineered T cells for the treatment of multiple myeloma

DEFF Research Database (Denmark)

Drent, Esther; Groen, Richard W. J.; Noort, Willy A. Noort

2016-01-01

Adoptive transfer of chimeric antigen receptor-transduced T cells is a promising strategy for cancer immunotherapy. The CD38 molecule, with its high expression on multiple myeloma cells, appears a suitable target for antibody therapy. Prompted by this, we used three different CD38 antibody...... sequences to generate second-generation retroviral CD38- chimeric antigen receptor constructs with which we transduced T cells from healthy donors and multiple myeloma patients. We then evaluated the preclinical efficacy and safety of the transduced T cells. Irrespective of the donor and antibody sequence......, CD38-chimeric antigen receptor-transduced T cells proliferated, produced inflammatory cytokines and effectively lysed malignant cell lines and primary malignant cells from patients with acute myeloid leukemia and multi-drug resistant multiple myeloma in a cell-dose, and CD38-dependent manner, despite...

Blood erythrocyte concentrations of cadmium and lead and the risk of B-cell non-Hodgkin's lymphoma and multiple myeloma: a nested case-control study.

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Rachel S Kelly

Full Text Available BACKGROUND: Cadmium (Cd and lead (Pb are hypothesised to be risk factors for non-Hodgkin's lymphoma (NHL, a group of haematological malignancies with a suspected environmental aetiology. Within the EnviroGenoMarkers study we utilised pre-diagnostic erythrocyte concentrations of Cd and Pb to determine whether exposure was associated with risk of B-cell NHL and multiple myeloma. METHODS: 194 incident cases of B-cell NHL and 76 cases of multiple myeloma diagnosed between 1990 and 2006 were identified from two existing cohorts; EPIC-Italy and the Northern Sweden Health and Disease Study. Cases were matched to healthy controls by centre, age, gender and date of blood collection. Cd and Pb were measured in blood samples provided at recruitment using inductively coupled plasma-mass spectrometry. Logistic regression was applied to assess the association with risk. Analyses were stratified by cohort and gender and by subtype where possible. RESULTS: There was little evidence of an increased risk of B-cell NHL or multiple myeloma with exposure to Cd (B-cell NHL: OR 1.09 95%CI 0.61, 1.93, MM: OR 1.16 95% CI: 0.40, 3.40 or Pb (B-cell NHL: 0.93 95% CI 0.43, 2.02, multiple myeloma: OR 1.63 95%CI 0.45, 5.94 in the total population when comparing the highest to the lowest quartile of exposure. However, gender and cohort specific differences in results were observed. In females the risk of B-cell NHL was more than doubled in those with a body burden of Cd >1 µg/L (OR 2.20 95%CI; 1.04, 4.65. CONCLUSIONS: This nested case-control study does not support a consistent positive association between Cd or Pb and NHL, but there is some indication of a gender specific effect suggesting further research is warranted.

Noncanonical SQSTM1/p62-Nrf2 pathway activation mediates proteasome inhibitor resistance in multiple myeloma cells via redox, metabolic and translational reprogramming

OpenAIRE

Riz, Irene; Hawley, Teresa S.; Marsal, Jeffrey W.; Hawley, Robert G.

2016-01-01

Multiple Myeloma (MM) is a B-cell malignancy characterized by the accumulation of clonal plasma cells in the bone marrow, with drug resistance being a major cause of therapeutic failure. We established a carfilzomib-resistant derivative of the LP-1 MM cell line (LP-1/Cfz) and found that the transcription factor NF-E2 p45-related factor 2 (Nrf2; gene symbol NFE2L2) contributes to carfilzomib resistance. The mechanism of Nrf2 activation involved enhanced translation of Nrf2 as well as its posit...

Apoptotic effects of non-edible parts of Punica granatum on human multiple myeloma cells.

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Kiraz, Yağmur; Neergheen-Bhujun, Vidushi S; Rummun, Nawraj; Baran, Yusuf

2016-02-01

Multiple myeloma is of great concern since existing therapies are unable to cure this clinical condition. Alternative therapeutic approaches are mandatory, and the use of plant extracts is considered interesting. Punica granatum and its derived products were suggested as potential anticancer agents due to the presence of bioactive compounds. Thus, polypenolic-rich extracts of the non-edible parts of P. granatum were investigated for their antiproliferative and apoptotic effects on U266 multiple myeloma cells. We demonstrated that there were dose-dependent decreases in the proliferation of U266 cells in response to P. granatum extracts. Also, exposure to the extracts triggered apoptosis with significant increases in loss of mitochondrial membrane potential in U266 cells exposed to the leaves and stem extracts, while the flower extract resulted in slight increases in loss of MMP. These results were confirmed by Annexin-V analysis. These results documented the cytotoxic and apoptotic effects of P. granatum extracts on human U266 multiple myeloma cells via disruption of mitochondrial membrane potential and increasing cell cycle arrest. The data suggest that the extracts can be envisaged in cancer chemoprevention and call for further exploration into the potential application of these plant parts.

Modern imaging techniques in patients with multiple myeloma

International Nuclear Information System (INIS)

Bannas, Peter; Adam, G.; Derlin, T.; Kroeger, N.

2013-01-01

Imaging studies are essential for both diagnosis and initial staging of multiple myeloma, as well as for differentiation from other monoclonal plasma cell diseases. Apart from conventional radiography, a variety of newer imaging modalities including whole-body low-dose-CT, whole-body MRI and 18F-FDG PET/CT may be used for detection of osseous and extraosseous myeloma manifestations. Despite of known limitations such as limited sensitivity and specificity and the inability to detect extraosseous lesions, conventional radiography still remains the gold standard for staging newly diagnosed myeloma, partly due to its wide availability and low costs. Whole-body low-dose CT is increasingly used due to its higher sensitivity for the detection of osseous lesions and its ability to diagnose extraosseous lesions, and is replacing conventional radiography at selected centres. The highest sensitivity for both detection of bone marrow disease and extraosseous lesions can be achieved with whole-body MRI or 18F-FDG PET/CT. Diffuse bone marrow infiltration may be visualized by whole-body MRI with high sensitivity. Whole-body MRI is at least recommended in all patients with normal conventional radiography and in all patients with an apparently solitary plasmacytoma of bone. To obtain the most precise readings, optimized examination protocols and dedicated radiologists and nuclear medicine physicians familiar with the complex and variable morphologies of myeloma lesions are required. (orig.)

Histone deacetylase inhibitors in multiple myeloma

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Sarah Deleu

2009-06-01

Full Text Available Novel drugs such as bortezomib and high dose chemotherapy combined with stem cell transplantation improved the outcome of multiple myeloma patients in the past decade. However, multiple myeloma often remains incurable due to the development of drug resistance governed by the bone marrow micro-environment. Therefore targeting new pathways to overcome this resistance is needed. Histone deacetylase (HDAC inhibitors represent a new class of anti-myeloma agents. Inhibiting HDACs results in histone hyperacetylation and alterations in chromatine structure, which, in turn, cause growth arrest differentiation and/or apoptosis in several tumor cells. Here we summarize the molecular actions of HDACi as a single agent or in combination with other drugs in different in vitro and in vivo myeloma models and in (preclinical trials.

A novel signaling pathway associated with Lyn, PI 3-kinase and Akt supports the proliferation of myeloma cells

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Iqbal, Mohd S. [Department of Bio-Signal Analysis, Applied Medical Engineering Science, Graduate School of Medicine, Yamaguchi University, Ube, Yamaguchi 755-8505 (Japan); Enteric and Food Microbiology Laboratory, Laboratory Sciences Division, International Center for Diarrhoeal Disease Research, Bangladesh, P.O. Box 128, Dhaka 1000 (Bangladesh); Tsuyama, Naohiro [Department of Analytical Molecular Medicine and Devices, Division of Frontier Medical Science, Graduate School of Medical Sciences, Hiroshima University, Hiroshima, Hiroshima 734-8553 (Japan); Obata, Masanori [Department of Bio-Signal Analysis, Applied Medical Engineering Science, Graduate School of Medicine, Yamaguchi University, Ube, Yamaguchi 755-8505 (Japan); Ishikawa, Hideaki, E-mail: hishika@yamaguchi-u.ac.jp [Department of Bio-Signal Analysis, Applied Medical Engineering Science, Graduate School of Medicine, Yamaguchi University, Ube, Yamaguchi 755-8505 (Japan)

2010-02-12

Interleukin-6 (IL-6) is a growth factor for human myeloma cells. We have recently found that in myeloma cells the activation of both signal transducer and activator of transcription (STAT) 3 and extracellular signal-regulated kinase (ERK) 1/2 is not sufficient for the IL-6-induced proliferation, which further requires the activation of the src family kinases, such as Lyn. Here we showed that the Lyn-overexpressed myeloma cell lines had the higher proliferative rate with IL-6 and the enhanced activation of the phosphatidylinositol (PI) 3-kinase and Akt. The IL-6-induced phosphorylation of STAT3 and ERK1/2 was not up-regulated in the Lyn-overexpressed cells, indicating that the Lyn-PI 3-kinase-Akt pathway is independent of these pathways. The PI 3-kinase was co-precipitated with Lyn in the Lyn-overexpressed cells of which proliferation with IL-6 was abrogated by the specific inhibitors for PI 3-kinase or Akt, suggesting that the activation of the PI 3-kinase-Akt pathway associated with Lyn is indeed related to the concomitant augmentation of myeloma cell growth. Furthermore, the decreased expression of p53 and p21{sup Cip1} proteins was observed in the Lyn-overexpressed cells, implicating a possible downstream target of Akt. This study identifies a novel IL-6-mediated signaling pathway that certainly plays a role in the proliferation of myeloma cells and this novel mechanism of MM tumor cell growth associated with Lyn would eventually contribute to the development of MM treatment.

Patients with Multiple Myeloma Develop SOX2-Specific Autoantibodies after Allogeneic Stem Cell Transplantation

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Sebastian Kobold

2011-01-01

Full Text Available The occurrence of SOX2-specific autoantibodies seems to be associated with an improved prognosis in patients with monoclonal gammopathy of undetermined significance (MGUS. However, it is unclear if SOX2-specific antibodies also develop in established multiple myeloma (MM. Screening 1094 peripheral blood (PB sera from 196 MM patients and 100 PB sera from healthy donors, we detected SOX2-specific autoantibodies in 7.7% and 2.0% of patients and donors, respectively. We identified SOX2211–230 as an immunodominant antibody-epitope within the full protein sequence. SOX2 antigen was expressed in most healthy tissues and its expression did not correlate with the number of BM-resident plasma cells. Accordingly, anti-SOX2 immunity was not related to SOX2 expression levels or tumor burden in the patients’ BM. The only clinical factor predicting the development of anti-SOX2 immunity was application of allogeneic stem cell transplantation (alloSCT. Anti-SOX2 antibodies occurred more frequently in patients who had received alloSCT (n=74. Moreover, most SOX2-seropositive patients had only developed antibodies after alloSCT. This finding indicates that alloSCT is able to break tolerance towards this commonly expressed antigen. The questions whether SOX2-specific autoantibodies merely represent an epiphenomenon, are related to graft-versus-host effects or participate in the immune control of myeloma needs to be answered in prospective studies.

Neovascular niche for human myeloma cells in immunodeficient mouse bone.

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Hirono Iriuchishima

Full Text Available The interaction with bone marrow (BM plays a crucial role in pathophysiological features of multiple myeloma (MM, including cell proliferation, chemoresistance, and bone lesion progression. To characterize the MM-BM interactions, we utilized an in vivo experimental model for human MM in which a GFP-expressing human MM cell line is transplanted into NOG mice (the NOG-hMM model. Transplanted MM cells preferentially engrafted at the metaphyseal region of the BM endosteum and formed a complex with osteoblasts and osteoclasts. A subpopulation of MM cells expressed VE-cadherin after transplantation and formed endothelial-like structures in the BM. CD138(+ myeloma cells in the BM were reduced by p53-dependent apoptosis following administration of the nitrogen mustard derivative bendamustine to mice in the NOG-hMM model. Bendamustine maintained the osteoblast lining on the bone surface and protected extracellular matrix structures. Furthermore, bendamustine suppressed the growth of osteoclasts and mesenchymal cells in the NOG-hMM model. Since VE-cadherin(+ MM cells were chemoresistant, hypoxic, and HIF-2α-positive compared to the VE-cadherin(- population, VE-cadherin induction might depend on the oxygenation status. The NOG-hMM model described here is a useful system to analyze the dynamics of MM pathophysiology, interactions of MM cells with other cellular compartments, and the utility of novel anti-MM therapies.

The 5T mouse multiple myeloma model: Absence of c-myc oncogene rearrangement in early transplant generations

NARCIS (Netherlands)

Radl, J.; Punt, Y.A.; Enden-Vieveen, M.H.M. van den; Bentvelzen, P.A.J.; Bakkus, M.H.C.; Akker T., W. van den; Benner, R.

1990-01-01

Consistent chromosomal translocations involving the c-myc cellular oncogene and one of the three immunoglobulin loci are typical for human Burkitt's lymphoma, induced mouse plasmacytoma (MPC) and spontaneously arising rat immunocytoma (RIC). Another plasma cell malignancy, multiple myeloma (MM),

Alpha-particles induce autophagy in multiple myeloma cells

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Joelle Marcelle Gaschet

2015-10-01

Full Text Available Objectives: Radiations emitted by the radionuclides in radioimmunotherapy (RIT approaches induce direct killing of the targeted cells as well as indirect killing through bystander effect. Our research group is dedicated to the development of α-RIT, i.e RIT using α-particles especially for the treatment of multiple myeloma (MM. γ-irradiation and β-irradiation have been shown to trigger apoptosis in tumor cells. Cell death mode induced by 213Bi α-irradiation appears more controversial. We therefore decided to investigate the effects of 213Bi on MM cell radiobiology, notably cell death mechanisms as well as tumor cell immunogenicity after irradiation.Methods: Murine 5T33 and human LP-1 multiple myeloma (MM cell lines were used to study the effects of such α-particles. We first examined the effects of 213Bi on proliferation rate, double strand DNA breaks, cell cycle and cell death. Then, we investigated autophagy after 213Bi irradiation. Finally, a co-culture of dendritic cells (DC with irradiated tumour cells or their culture media was performed to test whether it would induce DC activation.Results: We showed that 213Bi induces DNA double strand breaks, cell cycle arrest and autophagy in both cell lines but we detected only slight levels of early apoptosis within the 120 hours following irradiation in 5T33 and LP-1. Inhibition of autophagy prevented 213Bi induced inhibition of proliferation in LP-1 suggesting that this mechanism is involved in cell death after irradiation. We then assessed the immunogenicity of irradiated cells and found that irradiated LP-1 can activate DC through the secretion of soluble factor(s, however no increase in membrane or extracellular expression of danger associated molecular patterns (DAMPs was observed after irradiation.Conclusion: This study demonstrates that 213Bi induces mainly necrosis in MM cells, low levels of apoptosis and also autophagy that might be involved in tumor cell death.

Imaging findings of abdominal extraosseous plasma cell neoplasm

International Nuclear Information System (INIS)

Park, Yang Sin; Byun, Jae Ho; Won, Hyung Jin; Kim, Ah Young; Shin, Yong Moon; Kim, Pyo Nyun; Ha, Hyun Kwon; Lee, Moon Gyu; Bae, Kyung Soo

2006-01-01

To evaluate the imaging findings of abdominal extraosseous plasma cell neoplasm. From April 2000 to January 2005, eight patients (four men, four women; mean age, 50.6 years) with pathologically proved, extraosseous plasma cell neoplasm involving the abdominal organs were included in this study. The diagnoses were based on consensus agreement between two radiologists who retrospectively reviewed CT, ultrasonography, and enteroclysis findings. We evaluated the findings by focusing on the location, size, margin, and enhancement pattern of the lesion, and lymphadenopathy on each image. There were multiple myeloma in four patients and extramedullary plasmacytoma in the remaining four. Involved abdominal organs were the liver (n = 4), spleen (n 4), lymph node (n = 3), stomach (n = 1), small bowel (n = 1), and colon (n 1). The hepatic involvement of plasma cell neoplasm presented as a homogeneous, well-defined, solitary mass (n = 1), multiple nodules (n = 1), and hepatomegaly (n = 2). Its involvement of the spleen and lymph node appeared as splenomegaly and lymphadenopathy, respectively. Its involvement of the gastrointestinal tract including the stomach, small bowel, and colon, presented as a homogeneous, diffuse wall thickening or mass in the gastrointestinal tract. Abdominal extraosseous plasma cell neoplasm involves occasionally the liver, spleen, and lymph node, and rarely the gastrointestinal tract. When we encounter a well-defined, homogeneous lesion of the abdominal organs in patients diagnosed or suspected as having plasma cell neoplasm, we should consider its involvement of the abdominal organs

[Multiple myeloma : What has been confirmed in therapy?

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Baertsch, M-A; Goldschmidt, H

2017-12-01

Multiple myeloma (MM) is a malignancy of terminally differentiated B cells/plasma cells and is primarily located in the bone marrow. Symptomatic multiple myeloma typically presents with osteolyses, anemia, reduced renal function, and/or hypercalcemia. In the case of such MM-related end organ damage, urgent systemic treatment is indicated. In order to prevent end organ damage, current guidelines now recommend treatment initiation already when certain biomarkers are met. Current first-line treatment is based on proteasome inhibition and immunomodulation. Eligible patients still benefit from the addition of high-dose chemotherapy and autologous stem cell transplantation. Radiotherapy and orthopedic interventions play an important role in the treatment of localized skeletal complications. For relapsed MM, five novel agents have been approved in Europe during the last two years. These are second-generation proteasome inhibitors (carfilzomib, ixazomib) as well as first-in-class monoclonal antibodies (daratumumab, elotuzumab) and a histone deacetylase inhibitor (panobinostat). Triple combinations based on the established regimens lenalidomide/dexamethasone and bortezomib/dexamethasone plus one of the novel agents have been shown to significantly prolong progression-free survival. Median overall survival of patients with MM has doubled since the turn of the millennium.

Isolation of Human CD138+ Microparticles from the Plasma of Patients with Multiple Myeloma

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Sabna Rajeev Krishnan

2016-01-01

Full Text Available The confinement of multiple myeloma (MM to the bone marrow microenvironment requires an invasive bone marrow biopsy to monitor the malignant compartment. The existing clinical tools used to determine treatment response and tumor relapse are limited in sensitivity mainly because they indirectly measure tumor burden inside the bone marrow and fail to capture the patchy, multisite tumor infiltrates associated with MM. Microparticles (MPs are 0.1- to 1.0-μm membrane vesicles, which contain the cellular content of their originating cell. MPs are functional mediators and convey prothrombotic, promalignant, proresistance, and proinflammatory messages, establishing intercellular cross talk and bypassing the need for direct cell-cell contact in many pathologies. In this study, we analyzed plasma cell–derived MPs (CD138+ from deidentified MM patients (n = 64 and normal subjects (n = 18 using flow cytometry. The morphology and size of the MPs were further analyzed using scanning electron microscopy. Our study shows the proof of a systemic signature of MPs in MM patients. We observed that the levels of MPs were significantly elevated in MM corresponding to the tumor burden. We provide the first evidence for the presence of MPs in the peripheral blood of MM patients with potential applications in personalized MM clinical monitoring.

UPDATE ON THE ROLE OF AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION IN MULTIPLE MYELOMA

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Patrizia Tosi

2012-01-01

Full Text Available

Autologous stem cell transplantation is considered the standard of care for multiple myeloma patients aged < 65 years with no relevant comorbidities. The addition of drugs acting both on bone marrow microenvironment and on neoplastic plasma cells has significantly increased the proportion of patients achieving a complete remission after induction therapy, and these results are mantained after high-dose melphalan, leading to a prolonged disease control. Studies are being carried out in order to evaluate whether short term consolidation or long-term maintenance therapy can result into disease eradication at the molecular level thus increasing also patients survival. The efficacy of these new drugs has raised the issue of deferring the transplant after achivng a second response upon relapse. Another controversial point is the optimal treatment strategy for high-risk patients, that do not benefit from autologous stem cell transplantation and for whom the efficacy of new drugs is still matter of debate.

Translocations at 8q24 juxtapose MYC with genes that harbor superenhancers resulting in overexpression and poor prognosis in myeloma patients

International Nuclear Information System (INIS)

Walker, B A; Wardell, C P; Brioli, A; Boyle, E; Kaiser, M F; Begum, D B; Dahir, N B; Johnson, D C; Ross, F M; Davies, F E; Morgan, G J

2014-01-01

Secondary MYC translocations in myeloma have been shown to be important in the pathogenesis and progression of disease. Here, we have used a DNA capture and massively parallel sequencing approach to identify the partner chromosomes in 104 presentation myeloma samples. 8q24 breakpoints were identified in 21 (20%) samples with partner loci including IGH, IGK and IGL, which juxtapose the immunoglobulin (Ig) enhancers next to MYC in 8/23 samples. The remaining samples had partner loci including XBP1, FAM46C, CCND1 and KRAS, which are important in B-cell maturation or myeloma pathogenesis. Analysis of the region surrounding the breakpoints indicated the presence of superenhancers on the partner chromosomes and gene expression analysis showed increased expression of MYC in these samples. Patients with MYC translocations had a decreased progression-free and overall survival. We postulate that translocation breakpoints near MYC result in colocalization of the gene with superenhancers from loci, which are important in the development of the cell type in which they occur. In the case of myeloma these are the Ig loci and those important for plasma cell development and myeloma pathogenesis, resulting in increased expression of MYC and an aggressive disease phenotype

Sarcoidosis and multiple myeloma: Concurrent presentation of an unusual association

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Vidya Nair

2016-01-01

Full Text Available Literature on concurrent association of sarcoidosis with lymphoproliferative malignancies other than lymphoma e.g. multiple myeloma is meager. The rarity of the situation prompted us to report this patient who was a 51-year-old woman with a 2-years history of breathlessness, cough with expectoration, chest pain and backache. Initial evaluation revealed mild anemia, increased alkaline phosphatase with chest skiagram showing both lower zone non homogenous opacities with calcified hilar lymph nodes. CECT chest showed mediastinal with bilateral hilar lymphadenopathy, parenchymal fibrosis, traction bronchiectasis, ground glass opacities, septal and peribronchovascular thickening affecting mid and lower lung zones bilaterally. MRI Dorsolumbar spine was suggestive of marrow infiltrative disorder. EBUS FNA of intrathoracic nodes, EBB and TBLB confirmed sarcoidosis. PET CT revealed hyper metabolic activity in lung, multiple lymph nodes and lytic bone lesions. Serum protein electrophoresis and immunofixation revealed a monoclonal paraprotein, immunoglobulin IgG kappa type. Bone marrow biopsy revealed an increase in plasma cells (15%, but no granulomas. Diagnosis of Indolent or multiple myeloma with sarcoidosis was established. 12 cases of sarcoidosis and multiple myeloma have been reported in literature, and mostly preceding the onset of multiple myeloma by many years, in our case both were diagnosed concurrently.

Rheumatic masks of plasma cell dyscrasias

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Vladimir Ivanovich Vasilyev

2012-01-01

Full Text Available Objective: to consider clinical practice problems in the differential diagnosis of different types of plasma cell dyscrasias (PCD. Subjects and methods. Fourteen patients (8 men and 6 women aged 52±12 years, in whom rheumatic diseases (RD were ruled out and who were diagnosed as having primary PCD: different types of myeloma in 7 patients, myeloma + AL-amyloidosis in 2, AL-amyloidosis in 3, and Waldenstrom’s macroglobulinemia in 2, were examined. Results and discussion. The most common maldiagnosed RDs in patients with PCD were seronegative rheumatoid arthritis (RA, systemic lupus erythematosus, Sjogren’s disease, and different forms of vasculitis. The most frequent masks of RD were kidney (78% and osteoarticular system (64% lesions, vascular disorders (36%, peripheral polyneuropathies (36%, and enlarged salivary glands with xerostomia (28.5%. Serum and urine immunochemical study should be performed in all patients who have clinical manifestations of seropositive RA, spondyloarthritis, intensive bone pain syndrome, ulceronecrotic vasculitis, enlarged submandibular salivary glands with macroglossia in the absence of markers of autoimmune disease for the timely diagnosis of PCD and the exclusion of RD. The paper estimates the sensitivity and specificity of main methods used to diagnose different types of PCD.

Smoldering multiple myeloma: prevalence and current evidence guiding treatment decisions

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Blum A

2018-04-01

Full Text Available Agnieszka Blum, Despina Bazou, Peter O’Gorman Department of Hematology, Mater Misericordiae University Hospital, Dublin, UK Abstract: Smoldering multiple myeloma (SMM is an asymptomatic plasma cell proliferative disorder associated with risk of progression to symptomatic multiple myeloma (MM or amyloidosis. In comparison to monoclonal gammopathy of undetermined significance (MGUS, SMM has a much higher risk of progression to MM. Thanks to advances in our understanding of the risk factors, the subset of patients with ultra-high risk of progression to MM (80%–90% at 2 years has been identified. The revision of the diagnostic criteria resulted in changes in the management of this cohort of patients. In contrast to the management guidelines for MGUS patients, SMM patients need to be studied more intensively in order to identify biomarkers necessary for accurate risk stratification. In this review, we focus on the risk of progression from SMM to MM, as well as the influence of early treatment on overall survival, time to progression and quality of life. Keywords: smoldering multiple myeloma, risk factor, biomarker, genomic aberrations, glycan analysis

Non-invasive imaging provides spatiotemporal information on disease progression and response to therapy in a murine model of multiple myeloma.

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Simone S Riedel

Full Text Available Multiple myeloma (MM is a B-cell malignancy, where malignant plasma cells clonally expand in the bone marrow of older people, causing significant morbidity and mortality. Typical clinical symptoms include increased serum calcium levels, renal insufficiency, anemia, and bone lesions. With standard therapies, MM remains incurable; therefore, the development of new drugs or immune cell-based therapies is desirable. To advance the goal of finding a more effective treatment for MM, we aimed to develop a reliable preclinical MM mouse model applying sensitive and reproducible methods for monitoring of tumor growth and metastasis in response to therapy.A mouse model was created by intravenously injecting bone marrow-homing mouse myeloma cells (MOPC-315.BM that expressed luciferase into BALB/c wild type mice. The luciferase in the myeloma cells allowed in vivo tracking before and after melphalan treatment with bioluminescence imaging (BLI. Homing of MOPC-315.BM luciferase+ myeloma cells to specific tissues was examined by flow cytometry. Idiotype-specific myeloma protein serum levels were measured by ELISA. In vivo measurements were validated with histopathology.Strong bone marrow tropism and subsequent dissemination of MOPC-315.BM luciferase(+ cells in vivo closely mimicked the human disease. In vivo BLI and later histopathological analysis revealed that 12 days of melphalan treatment slowed tumor progression and reduced MM dissemination compared to untreated controls. MOPC-315.BM luciferase(+ cells expressed CXCR4 and high levels of CD44 and α4β1 in vitro which could explain the strong bone marrow tropism. The results showed that MOPC-315.BM cells dynamically regulated homing receptor expression and depended on interactions with surrounding cells.This study described a novel MM mouse model that facilitated convenient, reliable, and sensitive tracking of myeloma cells with whole body BLI in living animals. This model is highly suitable for monitoring

Endocarditis due to Gemella haemolysans in a newly diagnosed multiple myeloma patient

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Dongyan Liu

2016-09-01

Full Text Available An 87-year-old Caucasian woman with hypertension, diabetes mellitus type 2, and COPD was admitted with 1-week duration of back pain and weight gain. The physical examination revealed jugular venous distention, rales in the left lower lung field, and severe pitting edema over lower extremities. As workup for leukocytosis, blood cultures grew Gemella haemolysans. Subsequently, a transthoracic echocardiogram revealed vegetation on the non-coronary aortic leaflet and mild aortic stenosis. She was treated with ampicillin and gentamicin. After further investigation, the patient was diagnosed with plasma cell myeloma, the monoclonal lambda type. This is the first reported case of G. haemolysans endocarditis in a multiple myeloma patient.

A murine model of human myeloma bone disease

NARCIS (Netherlands)

Garrett, I.R.; Dallas, S.; Radl, J.; Mundy, G.R.

1997-01-01

Myeloma causes a devastating and unique form of osteolytic bone disease. Although osteoclast activation is responsible for bone destruction, the precise mechanisms by which myeloma cells increase osteoclast activity have not been defined. An animal model of human myeloma bone disease mould help in

Management of monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM).

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Kyle, Robert A; Rajkumar, S Vincent

2011-06-01

Monoclonal gammopathy of undetermined significance (MGUS) is defined as a serum M protein level of less than 3 g/dL, less than 10% clonal plasma cells in the bone marrow, and the absence of end-organ damage. The prevalence of MGUS is 3.2% in the white population but is approximately twice that high in the black population. MGUS may progress to multiple myeloma, AL amyloidosis, Waldenström macroglobulinemia, or lymphoma. The risk of progression is approximately 1% per year, but the risk continues even after more than 25 years of observation. Risk factors for progression include the size of the serum M protein, the type of serum M protein, the number of plasma cells in the bone marrow, and the serum free light chain ratio. Smoldering (asymptomatic) multiple myeloma (SMM) is characterized by the presence of an M protein level of 3 g/dL or higher and/or 10% or more monoclonal plasma cells in the bone marrow but no evidence of end-organ damage. The overall risk of progression to a malignant condition is 10% per year for the first 5 years, approximately 3% per year for the next 5 years, and 1% to 2% per year for the following 10 years. Patients with both MGUS and SMM must be followed up for their lifetime.

[Lentivirus-mediated shRNA silencing of LAMP2A inhibits the proliferation of multiple myeloma cells].

Science.gov (United States)

Li, Lixuan; Li, Jia

2015-05-01

To study the effects of lentivirus-mediated short hairpin RNA (shRNA) silencing of lysosome-associated membrane protein type 2A (LAMP2A) expression on the proliferation of multiple myeloma cells. The constructed shRNA lentiviral vector was applied to infect human multiple myeloma cell line MM.1S, and stable expression cell line was obtained by puromycin screening. Western blotting was used to verify the inhibitory effect on LAMP2A protein expression. MTT assay was conducted to detect the effect of knocked-down LAMP2A on MM.1S cell proliferation, and the anti-tumor potency of suberoylanilide hydroxamic acid (SAHA) against the obtained MM.1S LAMP2A(shRNA) stable cell line. Lactate assay was performed to observe the impact of low LAMP2A expression on cell glycolysis. The stable cell line with low LAMP2A expression were obtained with the constructed human LAMP2A-shRNA lentiviral vector. Down-regulation of LAMP2A expression significantly inhibited MM.1S cell proliferation and enhanced the anti-tumor activity of SAHA. Interestingly, decreased LAMP2A expression also inhibited MM.1S cell lactic acid secretion. Down-regulation of LAMP2A expression could inhibit cell proliferation in multiple myeloma cells.

Determinação da expressão da molécula de adesão CD56 em plasmócitos no mieloma múltiplo através de estudo imuno-histoquímico CD56 adhesion molecule expression by plasma cells in multiple myeloma immunohistochemistry

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Ana L. Coradazzi

2003-01-01

Full Text Available O papel das moléculas de adesão celular, na fisiopatologia do mieloma múltiplo (MM, tem sido alvo de vários estudos nos últimos anos. A expressão de CD56 pelos plasmócitos tumorais está associada a comportamento clínico menos agressivo da doença, e sua perda tem sido descrita na fase de leucemização plasmocitária. A determinação da expressão da molécula CD56 pelos plasmócitos tumorais pode ser obtida através de citometria em fluxo, revelando positividade em 55% a 78% dos casos. No presente estudo, objetivamos verificar a expressão da molécula CD56 por plasmócitos tumorais na medula óssea de portadores de MM, utilizando o estudo imuno-histoquímico das amostras histológicas obtidas ao diagnóstico. Analisamos as amostras de medula óssea de vinte portadores de MM, e realizamos o estudo imuno-histoquímico para determinação da expressão das cadeias leves kappa e lambda e da molécula CD56 pelos plasmócitos tumorais. A expressão da molécula CD56 foi importante em três casos, moderada em seis, discreta em quatro e negativa em sete. O estudo imuno-histoquímico mostrou-se válido para determinação da expressão de CD56 por plasmócitos tumorais em portadores de MM, fornecendo resultados semelhantes aos descritos para os obtidos por citometria em fluxo. Através do estudo imuno-histoquímico, foi possível observar variações da expressão da molécula CD56.The role of adhesion molecules in the physiopathology of multiple myeloma has been the target of many studies over the last years. The CD56 expression by neoplastic plasma cells is related to a less aggressive clinical course, and its loss is described in plasma cell leukemia. The evaluation of the CD56 expression may be obtained by flow cytometry, with positivity in 55% to 78% of cases. In this study, we verified the CD56 expression by plasma cells in bone marrow of myeloma patients using immunohistochemistry in samples obtained at diagnosis. We analyzed bone

Cannabinoids synergize with carfilzomib, reducing multiple myeloma cells viability and migration

OpenAIRE

Nabissi, Massimo; Morelli, Maria Beatrice; Offidani, Massimo; Amantini, Consuelo; Gentili, Silvia; Soriani, Alessandra; Cardinali, Claudio; Leoni, Pietro; Santoni, Giorgio

2016-01-01

Several studies showed a potential anti-tumor role for cannabinoids, by modulating cell signaling pathways involved in cancer cell proliferation, chemo-resistance and migration. Cannabidiol (CBD) was previously noted in multiple myeloma (MM), both alone and in synergy with the proteasome inhibitor bortezomib, to induce cell death. In other type of human cancers, the combination of CBD with ?9-tetrahydrocannabinol (THC) was found to act synergistically with other chemotherapeutic drugs suggest...

Glutamine-derived 2-hydroxyglutarate is associated with disease progression in plasma cell malignancies

Science.gov (United States)

Gonsalves, Wilson I.; Hitosugi, Taro; Ghosh, Toshi; Jevremovic, Dragan; Petterson, Xuan-Mai; Wellik, Linda; Kumar, Shaji K.; Nair, K. Sreekumaran

2018-01-01

The production of the oncometabolite 2-hydroxyglutarate (2-HG) has been associated with c-MYC overexpression. c-MYC also regulates glutamine metabolism and drives progression of asymptomatic precursor plasma cell (PC) malignancies to symptomatic multiple myeloma (MM). However, the presence of 2-HG and its clinical significance in PC malignancies is unknown. By performing 13C stable isotope resolved metabolomics (SIRM) using U[13C6]Glucose and U[13C5]Glutamine in human myeloma cell lines (HMCLs), we show that 2-HG is produced in clonal PCs and is derived predominantly from glutamine anaplerosis into the TCA cycle. Furthermore, the 13C SIRM studies in HMCLs also demonstrate that glutamine is preferentially utilized by the TCA cycle compared with glucose. Finally, measuring the levels of 2-HG in the BM supernatant and peripheral blood plasma from patients with precursor PC malignancies such as smoldering MM (SMM) demonstrates that relatively elevated levels of 2-HG are associated with higher levels of c-MYC expression in the BM clonal PCs and with a subsequent shorter time to progression (TTP) to MM. Thus, measuring 2-HG levels in BM supernatant or peripheral blood plasma of SMM patients offers potential early identification of those patients at high risk of progression to MM, who could benefit from early therapeutic intervention. PMID:29321378

Daratumumab-mediated lysis of primary multiple myeloma cells is enhanced in combination with the human anti-KIR antibody IPH2102 and lenalidomide

DEFF Research Database (Denmark)

Nijhof, I. S.; Lammerts van Bueren, J. J.; van Kessel, B.

2015-01-01

Despite recent treatment improvements, multiple myeloma remains an incurable disease. Since antibody-dependent cell-mediated cytotoxicity is an important effector mechanism of daratumumab, we explored the possibility of improving daratumumab-mediated cell-mediated cytotoxicity by blocking natural...... killer cell inhibitory receptors with the human monoclonal anti-KIR antibody IPH2102, next to activation of natural killer cells with the immune modulatory drug lenalidomide. In 4-hour antibody-dependent cell-mediated cytotoxicity assays, IPH2102 did not induce lysis of multiple myeloma cell lines...... effective treatment strategies can be designed for multiple myeloma by combining daratumumab with agents that independently modulate natural killer cell function....

PSMB4 promotes multiple myeloma cell growth by activating NF-κB-miR-21 signaling

Energy Technology Data Exchange (ETDEWEB)

Zheng, Peihao; Guo, Honggang [Department of Hematology, Navy General Hospital, Beijing 100048 (China); Li, Guangchao [School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006 (China); Han, Siqi [Department of Medical Oncology, Jinling Hospital, Nanjing 210002 (China); Luo, Fei [Department of Stomatology, Jinling Hospital, Nanjing 210002 (China); Liu, Yi, E-mail: liuyi2033@163.com [Department of Hematology, Navy General Hospital, Beijing 100048 (China)

2015-03-06

Proteasomal subunit PSMB4, was recently identified as potential cancer driver genes in several tumors. However, the regulatory mechanism of PSMB4 on carcinogenesis process remains unclear. In this study, we investigated the expression and roles of PSMB4 in multiple myeloma (MM). We found a significant up-regulation of PSMB4 in MM plasma and cell lines. Ectopic overexpression of PSMB4 promoted cell growth and colony forming ability of MM cells, whereas inhibition of PSMB4 led to a decrease of such events. Furthermore, our results demonstrated the up-regulation of miR-21 and a positive correlation between the levels of miR-21 and PSMB4 in MM. Re-expression of miR-21 markedly rescued PSMB4 knockdown-mediated suppression of cell proliferation and clone-formation. Additionally, while enforced expression of PSMB4 profoundly increased NF-κB activity and the level of miR-21, PSMB4 knockdown or NF-κB inhibition suppressed miR-21 expression in MM cells. Taken together, our results demonstrated that PSMB4 regulated MM cell growth in part by activating NF-κB-miR-21 signaling, which may represent promising targets for novel specific therapies. - Highlights: • First reported upregulation of PSMB4 in MM plasma and cell lines. • PSMB4 promoted MM cell growth and colony forming ability. • Further found miR-21 was up-regulated by PSMB4 in MM plasma and cell lines. • PSMB4-induced miR-21 expression was modulated by NF-κB. • PSMB4-NF-κB-miR-21 axis may be potential therapeutic targets of MM.

Effects of daratumumab on natural killer cells and impact on clinical outcomes in relapsed or refractory multiple myeloma

DEFF Research Database (Denmark)

Casneuf, Tineke; Xu, Xu Steven; Adams, Homer C

2017-01-01

Daratumumab, a human CD38 imunoglobulin G 1κ monoclonal antibody, has demonstrated clinical activity and a manageable safety profile in monotherapy and combination therapy clinical trials in relapsed and/or refractory multiple myeloma. CD38 is expressed at high levels on myeloma cells and......, to a lesser extent, on immune effector cells, including natural killer (NK) cells, which are important for daratumumab-mediated antibody-dependent cellular cytotoxicity (ADCC). Here, the pharmacodynamic effects of daratumumab monotherapy on NK cells, and the effect of NK cell dynamics on daratumumab efficacy...

Development of Novel Immunotherapies for Multiple Myeloma

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Ensaf M. Al-Hujaily

2016-09-01

Full Text Available Multiple myeloma (MM is a disorder of terminally differentiated plasma cells characterized by clonal expansion in the bone marrow (BM. It is the second-most common hematologic malignancy. Despite significant advances in therapeutic strategies, MM remains a predominantly incurable disease emphasizing the need for the development of new treatment regimens. Immunotherapy is a promising treatment modality to circumvent challenges in the management of MM. Many novel immunotherapy strategies, such as adoptive cell therapy and monoclonal antibodies, are currently under investigation in clinical trials, with some already demonstrating a positive impact on patient survival. In this review, we will summarize the current standards of care and discuss major new approaches in immunotherapy for MM.

Bone marrow uptake of 99mTc-MIBI in patients with multiple myeloma

International Nuclear Information System (INIS)

Fonti, R.; Del Vecchio, S.; Zannetti, A.; Di Gennaro, F.; Pace, L.; Salvatore, M.; De Renzo, A.; Catalano, L.; Califano, C.; Rotoli, B.

2001-01-01

In a previous study, we showed the ability of technetium-99m methoxyisobutylisonitrile ( 99m Tc-MIBI) scan to identify active disease in patients with multiple myeloma (Eur J Nucl Med 1998; 25: 714-720). In particular, a semiquantitative score of the extension and intensity of bone marrow uptake was derived and correlated with both the clinical status of the disease and plasma cell bone marrow infiltration. In order to estimate quantitatively 99m Tc-MIBI bone marrow uptake and to verify the intracellular localization of the tracer, bone marrow samples obtained from 24 multiple myeloma patients, three patients with monoclonal gammopathy of undetermined significance (MGUS) and two healthy donors were studied for in vitro uptake. After centrifugation over Ficoll-Hypaque gradient, cell suspensions were incubated with 99m Tc-MIBI and the uptake was expressed as the percentage of radioactivity specifically retained within the cells. The cellular localization of the tracer was assessed by micro-autoradiography. Twenty-two out of 27 patients underwent 99m Tc-MIBI scan within a week of bone marrow sampling. Whole-body images were obtained 10 min after intravenous injection of 555 MBq of the tracer; the extension and intensity of 99m Tc-MIBI uptake were graded using the semiquantitative score. A statistically significant correlation was found between in vitro uptake of 99m Tc-MIBI and both plasma cell infiltration (Pearson's coefficient of correlation r=0.69, P 99m Tc-MIBI inside the plasma cells infiltrating the bone marrow. Therefore, our findings show that the degree of tracer uptake both in vitro and in vivo is related to the percentage of infiltrating plasma cells which accumulate the tracer in their inner compartments. (orig.)

Endothelial cell-driven regulation of CD9 or motility-related protein-1 expression in multiple myeloma cells within the murine 5T33MM model and myeloma patients

DEFF Research Database (Denmark)

De Bruyne, E; Levin Andersen, Thomas; De Raeve, H

2006-01-01

The cell surface expression of CD9, a glycoprotein of the tetraspanin family influencing several processes including cell motility and metastasis, inversely correlates with progression in several solid tumors. In the present work, we studied the expression and role of CD9 in multiple myeloma (MM...... interaction of the cells with BMEC and that CD9 is involved in transendothelial invasion, thus possibly mediating homing and/or spreading of the MM cells....

Germline mutations in lysine specific demethylase 1 (LSD1/KDM1A) confer susceptibility to multiple myeloma.

Science.gov (United States)

Wei, Xiaomu; Calvo-Vidal, M Nieves; Chen, Siwei; Wu, Gang; Revuelta, Maria V; Sun, Jian; Zhang, Jinghui; Walsh, Michael F; Nichols, Kim E; Joseph, Vijai; Snyder, Carrie; Vachon, Celine M; McKay, James D; Wang, Shu-Ping; Jayabalan, David S; Jacobs, Lauren M; Becirovic, Dina; Waller, Rosalie G; Artomov, Mykyta; Viale, Agnes; Patel, Jayeshkumar; Phillip, Jude M; Chen-Kiang, Selina; Curtin, Karen; Salama, Mohamed; Atanackovic, Djordje; Niesvizky, Ruben; Landgren, Ola; Slager, Susan L; Godley, Lucy A; Churpek, Jane; Garber, Judy E; Anderson, Kenneth C; Daly, Mark J; Roeder, Robert G; Dumontet, Charles; Lynch, Henry T; Mullighan, Charles G; Camp, Nicola J; Offit, Kenneth; Klein, Robert J; Yu, Haiyuan; Cerchietti, Leandro; Lipkin, Steven M

2018-03-20

Given the frequent and largely incurable occurrence of multiple myeloma (MM), identification of germline genetic mutations that predispose cells to MM may provide insight into disease etiology and the developmental mechanisms of its cell of origin, the plasma cell. Here we identified familial and early-onset MM kindreds with truncating mutations in lysine-specific demethylase 1 (LSD1/KDM1A), an epigenetic transcriptional repressor that primarily demethylates histone H3 on lysine 4 and regulates hematopoietic stem cell self-renewal. Additionally, we found higher rates of germline truncating and predicted deleterious missense KDM1A mutations in MM patients unselected for family history compared to controls. Both monoclonal gammopathy of unknown significance (MGUS) and MM cells have significantly lower KDM1A transcript levels compared with normal plasma cells. Transcriptome analysis of MM cells from KDM1A mutation carriers shows enrichment of pathways and MYC target genes previously associated with myeloma pathogenesis. In mice, antigen challenge followed by pharmacological inhibition of KDM1A promoted plasma cell expansion, enhanced secondary immune response, elicited appearance of serum paraprotein, and mediated upregulation of MYC transcriptional targets. These changes are consistent with the development of MGUS. Collectively, our findings show KDM1A is the first autosomal dominant MM germline predisposition gene, providing new insights into its mechanistic roles as a tumor suppressor during post-germinal center B cell differentiation. Copyright ©2018, American Association for Cancer Research.

Chalazia development in multiple myeloma: a new complication associated with bortezomib therapy

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Charles Yun

2015-06-01

Full Text Available Multiple myeloma (MM is a neoplasm of plasma cells within the bone marrow. A major impact on improving survival in MM has been the use of the boronic acid-derived proteasome inhibitor bortezomib, a first-in-class selective inhibitor of the 26S proteasome. Ocular side effects of bortezomib are rare. In this report, we present 2 patients with active MM in whom persistent chalazia became a therapy-interfering complication of treatment with bortezomib. Both patients had relapsed ISS III B kappa light chain myeloma, and they were responding to treatment with bortezomib until chalazia − which caused intolerable discomfort − started. In both patients discontinuation of bortezomib was necessary for chalazia to heal, and restarting of bortezomib was associated with relapse of chalazia.

Immunological dysregulation in multiple myeloma microenvironment.

Science.gov (United States)

Romano, Alessandra; Conticello, Concetta; Cavalli, Maide; Vetro, Calogero; La Fauci, Alessia; Parrinello, Nunziatina Laura; Di Raimondo, Francesco

2014-01-01

Multiple Myeloma (MM) is a systemic hematologic disease due to uncontrolled proliferation of monoclonal plasma cells (PC) in bone marrow (BM). Emerging in other solid and liquid cancers, the host immune system and the microenvironment have a pivotal role for PC growth, proliferation, survival, migration, and resistance to drugs and are responsible for some clinical manifestations of MM. In MM, microenvironment is represented by the cellular component of a normal bone marrow together with extracellular matrix proteins, adhesion molecules, cytokines, and growth factors produced by both stromal cells and PC themselves. All these components are able to protect PC from cytotoxic effect of chemo- and radiotherapy. This review is focused on the role of immunome to sustain MM progression, the emerging role of myeloid derived suppressor cells, and their potential clinical implications as novel therapeutic target.

Immunological Dysregulation in Multiple Myeloma Microenvironment

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Alessandra Romano

2014-01-01

Full Text Available Multiple Myeloma (MM is a systemic hematologic disease due to uncontrolled proliferation of monoclonal plasma cells (PC in bone marrow (BM. Emerging in other solid and liquid cancers, the host immune system and the microenvironment have a pivotal role for PC growth, proliferation, survival, migration, and resistance to drugs and are responsible for some clinical manifestations of MM. In MM, microenvironment is represented by the cellular component of a normal bone marrow together with extracellular matrix proteins, adhesion molecules, cytokines, and growth factors produced by both stromal cells and PC themselves. All these components are able to protect PC from cytotoxic effect of chemo- and radiotherapy. This review is focused on the role of immunome to sustain MM progression, the emerging role of myeloid derived suppressor cells, and their potential clinical implications as novel therapeutic target.

Nuclear medicine imaging of multiple myeloma, particularly in the relapsed setting

Energy Technology Data Exchange (ETDEWEB)

Waal, Esther G.M. de; Vellenga, Edo [University of Groningen, University Medical Center Groningen, Department of Hematology, PO Box 30001, Groningen (Netherlands); Glaudemans, Andor W.J.M. [University of Groningen, University Medical Center Groningen, Department of Nuclear Medicine and Molecular Imaging, Groningen (Netherlands); Schroeder, Carolien P. [University of Groningen, University Medical Center Groningen, Department of Medical Oncology, Groningen (Netherlands); Slart, Riemer H.J.A. [University of Groningen, University Medical Center Groningen, Department of Nuclear Medicine and Molecular Imaging, Groningen (Netherlands); University of Twente, Department of Biomedical Photonic Imaging, Enschede (Netherlands)

2017-02-15

Multiple myeloma (MM) is characterized by a monoclonal plasma cell population in the bone marrow. Lytic lesions occur in up to 90 % of patients. For many years, whole-body X-ray (WBX) was the method of choice for detecting skeleton abnormalities. However, the value of WBX in relapsing disease is limited because lesions persist post-treatment, which restricts the capacity to distinguish between old, inactive skeletal lesions and new, active ones. Therefore, alternative techniques are necessary to visualize disease activity. Modern imaging techniques such as magnetic resonance imaging, positron emission tomography and computed tomography offer superior detection of myeloma bone disease and extramedullary manifestations. In particular, the properties of nuclear imaging enable the identification of disease activity by directly targeting the specific cellular properties of malignant plasma cells. In this review, an overview is provided of the effectiveness of radiopharmaceuticals that target metabolism, surface receptors and angiogenesis. The available literature data for commonly used nuclear imaging tracers, the promising first results of new tracers, and our pilot work indicate that a number of these radiopharmaceutical applications can be used effectively for staging and response monitoring of relapsing MM patients. Moreover, some tracers can potentially be used for radio immunotherapy. (orig.)

Therapeutic advancements in multiple myeloma

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Alessandro eGozzetti

2014-09-01

Full Text Available Multiple myeloma survival has significantly improved in latest years, due to a broad spectrum of novel agents available for treatment. The introduction of thalidomide, bortezomib and lenalidomide together with autologous stem cell transplantation has dramatically prolonged complete remissions rate, progression free survivals resulting ultimately in prolonged survivals in myeloma patients. Moreover, novel strategies of treatment such as consolidation and maintenance are being used to implement responses. A number of new drugs such as carfilzomib and pomalidomide are already in clinical practice, and new kids on the block are entering, making the future of myeloma patients brighter.

A compound chimeric antigen receptor strategy for targeting multiple myeloma.

Science.gov (United States)

Chen, K H; Wada, M; Pinz, K G; Liu, H; Shuai, X; Chen, X; Yan, L E; Petrov, J C; Salman, H; Senzel, L; Leung, E L H; Jiang, X; Ma, Y

2018-02-01

Current clinical outcomes using chimeric-antigen receptors (CARs) against multiple myeloma show promise in the eradication of bulk disease. However, these anti-BCMA (CD269) CARs observe relapse as a common phenomenon after treatment due to the reemergence of either antigen-positive or -negative cells. Hence, the development of improvements in CAR design to target antigen loss and increase effector cell persistency represents a critical need. Here, we report on the anti-tumor activity of a CAR T-cell possessing two complete and independent CAR receptors against the multiple myeloma antigens BCMA and CS1. We determined that the resulting compound CAR (cCAR) T-cell possesses consistent, potent and directed cytotoxicity against each target antigen population. Using multiple mouse models of myeloma and mixed cell populations, we are further able to show superior in vivo survival by directed cytotoxicity against multiple populations compared to a single-expressing CAR T-cell. These findings indicate that compound targeting of BCMA and CS1 on myeloma cells can potentially be an effective strategy for augmenting the response against myeloma bulk disease and for initiation of broader coverage CAR therapy.

Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies

Science.gov (United States)

2017-12-11

Acute Biphenotypic Leukemia; Acute Erythroid Leukemia in Remission; Acute Leukemia in Remission; Acute Megakaryoblastic Leukemia; Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Acute Myeloid Leukemia in Remission; Acute Myeloid Leukemia With FLT3/ITD Mutation; Acute Myeloid Leukemia With Inv(3) (q21.3;q26.2) or t(3;3) (q21.3;q26.2); GATA2, MECOM; Acute Myeloid Leukemia With Inv(3) (q21.3;q26.2); GATA2, MECOM; Acute Myeloid Leukemia With Multilineage Dysplasia; Acute Myeloid Leukemia With t(6;9) (p23;q34.1); DEK-NUP214; Acute Undifferentiated Leukemia; Adult Acute Lymphoblastic Leukemia in Complete Remission; B Acute Lymphoblastic Leukemia With t(1;19)(q23;p13.3); E2A-PBX1 (TCF3-PBX1); B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1; Burkitt Lymphoma; Childhood Acute Lymphoblastic Leukemia in Complete Remission; DS Stage II Plasma Cell Myeloma; DS Stage III Plasma Cell Myeloma; Myelodysplastic Syndrome; Recurrent Anaplastic Large Cell Lymphoma; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Follicular Lymphoma; Recurrent Hodgkin Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Plasma Cell Myeloma; Refractory Plasma Cell Myeloma; Secondary Acute Myeloid Leukemia; T Lymphoblastic Lymphoma

Systemic amyloidosis due to unknown multiple myeloma in small bowel pseudo-obstruction: case report

Directory of Open Access Journals (Sweden)

Giuseppe Caparrotti

2016-03-01

Full Text Available Amyloidosis is a pathologic diagnosis characterized by extracellular deposition of insoluble protein fibrils in various organs and tissues. There are two main forms of amyloidosis, primary amyloidosis, and secondary amyloidosis. Gastrointestinal involvement is common in both amyloidosis forms. We describe the case of a 78-year-old woman taken to the operating room for small bowel obstruction, found to have pseudo-obstruction and enteritis. Exploratory laparotomy revealed gastric mass and histological examen showed extensive amyloid deposition consistent with amyloidosis. Hematological evaluation revealed unknown multiple myeloma. This case report and literature data suggest to perform a hematological examination in patients with amyloidosis diagnosis to exclude a multiple myeloma or other plasma cell disorders

Immune resistance of Multiple Myeloma : the role of the microenvironment

NARCIS (Netherlands)

de Haart, SJ

2017-01-01

Immunotherapeutic strategies in Multiple Myeloma are under development. In this thesis we present a new perspective in optimizing immunotherapy in Multiple Myeloma patient. We propose that currently, immunotherapy is limited in efficacy through interactions of Multiple Myeloma cells with the bone

Small interfering RNA-mediated silencing of nicotinamide phosphoribosyltransferase (NAMPT and lysosomal trafficking regulator (LYST induce growth inhibition and apoptosis in human multiple myeloma cells: A preliminary study

Directory of Open Access Journals (Sweden)

Ivyna Pau Ni Bong

2016-11-01

Full Text Available Multiple myeloma (MM is a malignancy of B lymphocytes or plasma cells. Our array-based comparative genomic hybridization findings revealed chromosomal gains at 7q22.3 and 1q42.3, where nicotinamide (NAM phosphoribosyltransferase (NAMPT and lysosomal trafficking regulator (LYST genes are localized, respectively. This led us to further study the functions of these genes in myeloma cells. NAMPT is a key enzyme involved in nicotinamide adenine dinucleotide salvage pathway, and it is frequently overexpressed in human cancers. In contrast, little is known about the function of LYST in cancer. The expression of LYST is shown to affect lysosomal size, granule size, and autophagy in human cells. In this study, the effects of small interfering RNA (siRNA-mediated silencing of NAMPT and LYST on cell proliferation and apoptosis were evaluated in RPMI 8226 myeloma cells. Transfection efficiencies were determined by quantitative real time reverse transcriptase PCR. Cell proliferation was determined using MTT assay, while apoptosis was analyzed with flow cytometry using Annexin V-fluorescein isothiocyanate/propidium iodide assay. The NAMPT protein expression in siRNA-treated cells was estimated by enzyme-linked immunosorbent assay. Our results showed that NAMPT and LYST were successfully knockdown by siRNA transfection (p < 0.05. NAMPT or LYST gene silencing significantly inhibited cell proliferation and induced apoptosis in RPMI 8226 cells (p < 0.05. Silencing of NAMPT gene also decreased NAMPT protein levels (p < 0.01. Our study demonstrated that NAMPT and LYST play pivotal roles in the molecular pathogenesis of MM. This is the first report describing the possible functions of LYST in myelomagenesis and its potential role as a therapeutic target in MM.

Small interfering RNA-mediated silencing of nicotinamide phosphoribosyltransferase (NAMPT) and lysosomal trafficking regulator (LYST) induce growth inhibition and apoptosis in human multiple myeloma cells: A preliminary study

Science.gov (United States)

Bong, Ivyna Pau Ni; Ng, Ching Ching; Fakiruddin, Shaik Kamal; Lim, Moon Nian; Zakaria, Zubaidah

2016-01-01

Multiple myeloma (MM) is a malignancy of B lymphocytes or plasma cells. Our array-based comparative genomic hybridization findings revealed chromosomal gains at 7q22.3 and 1q42.3, where nicotinamide (NAM) phosphoribosyltransferase (NAMPT) and lysosomal trafficking regulator (LYST) genes are localized, respectively. This led us to further study the fprotein expression in unctions of these genes in myeloma cells. NAMPT is a key enzyme involved in nicotinamide adenine dinucleotide salvage pathway, and it is frequently overexpressed in human cancers. In contrast, little is known about the function of LYST in cancer. The expression of LYST is shown to affect lysosomal size, granule size, and autophagy in human cells. In this study, the effects of small interfering RNA (siRNA)-mediated silencing of NAMPT and LYST on cell proliferation and apoptosis were evaluated in RPMI 8226 myeloma cells. Transfection efficiencies were determined by quantitative real time reverse transcriptase PCR. Cell proliferation was determined using MTT assay, while apoptosis was analyzed with flow cytometry using Annexin V-fluorescein isothiocyanate/propidium iodide assay. The NAMPT protein expression in siRNA-treated cells was estimated by enzyme-linked immunosorbent assay. Our results showed that NAMPT and LYST were successfully knockdown by siRNA transfection (p < 0.05). NAMPT or LYST gene silencing significantly inhibited cell proliferation and induced apoptosis in RPMI 8226 cells (p < 0.05). Silencing of NAMPT gene also decreased NAMPT protein levels (p < 0.01). Our study demonstrated that NAMPT and LYST play pivotal roles in the molecular pathogenesis of MM. This is the first report describing the possible functions of LYST in myelomagenesis and its potential role as a therapeutic target in MM. PMID:27754828

BTK inhibitor ibrutinib is cytotoxic to myeloma and potently enhances bortezomib and lenalidomide activities through NF-κB.

Science.gov (United States)

Rushworth, Stuart A; Bowles, Kristian M; Barrera, Lawrence N; Murray, Megan Y; Zaitseva, Lyubov; MacEwan, David J

2013-01-01

Ibrutinib (previously known as PCI-32765) has recently shown encouraging clinical activity in chronic lymphocytic leukaemia (CLL) effecting cell death through inhibition of Bruton's tyrosine kinase (BTK). In this study we report for the first time that ibrutinib is cytotoxic to malignant plasma cells from patients with multiple myeloma (MM) and furthermore that treatment with ibrutinib significantly augments the cytotoxic activity of bortezomib and lenalidomide chemotherapies. We describe that the cytotoxicity of ibrutinib in MM is mediated via an inhibitory effect on the nuclear factor-κB (NF-κB) pathway. Specifically, ibrutinib blocks the phosphorylation of serine-536 of the p65 subunit of NF-κB, preventing its nuclear translocation, resulting in down-regulation of anti-apoptotic proteins Bcl-xL, FLIP(L) and survivin and culminating in caspase-mediated apoptosis within the malignant plasma cells. Taken together these data provide a platform for clinical trials of ibrutinib in myeloma and a rationale for its use in combination therapy, particularly with bortezomib. Copyright © 2012 Elsevier Inc. All rights reserved.

Myeloablative radioimmunotherapies in the conditioning of patients with AML, MDS and multiple myeloma prior to stem cell transplantation

International Nuclear Information System (INIS)

Buchmann, I.

2008-01-01

Aggressive consolidation chemotherapy and hematopoietic stem cell transplantation have improved the prognosis of patients with acute myeloid leukemia (AML), myelodyplastic syndrome (MDS) and multiple myeloma. Nevertheless, only a minor fraction of patients achieve long-term disease-free survival after stem cell transplantation with disease recurrence being the most common cause of treatment failure. In addition, therapy-related effects such as toxicity of chemotherapy and complications of stem cell transplantation increase mortality rates significantly. Myeloablative radioimmunotherapy uses radiolabeled monoclonal antibodies (mAb) with affinity for the hematopoietic marrow. It applies high radiation doses in the bone marrow but spares normal organs. Adding myeloablative radioimmunotherapy to the conditioning schemes of AML, MDS and multiple myeloma before stem cell transplantation allows for the achievement of a pronounced antileukemic/antimyeloma effect for the reduction of relapse rates without significant increase of acute organ toxicity and therapy-related mortality. In order to optimise therapy, a rational design of the nuclide-antibody combination is necessary. 90 Y, 188 Re and 131 I are the most frequently used β - -particles. Of these, 90 Y is the most qualified nuclide for myeloablation. Backbone stabilised DTPA are ideal chelators to stably conjugate 90 Y to antibodies so far. For myeloablative conditioning, anti-CD66-, -45- and -33-mAb are used. The anti-CD66-antibody BW250/183 binds to normal hematopoietic cells but not to leukemic blasts and myeloma cells. The 90 Y-2B3M-DTPA-BW250/183 is the most suited radioimmunoconjugate for patients with an infiltration grade of leukemic blasts in the bone marrow 90 Y-anti-CD45-mAb YAML568 are 6.4 ± 1.2 (bone marrow), 3.9 ± 1.4 (liver) and 1.1 ± 0.4 (kidneys). CD45 is expressed also on the extramedullar clonogenic myeloma progenitor cell that circulates in the peripheral blood. Thus, the conditioning of

[Multiple myeloma (IgG-kappa) infiltrating central nervous system, lymph nodes, liver, and kidneys, and with elevation of IgE].

Science.gov (United States)

Toyota, Shigeo; Nakamura, Norihiko; Dan, Kazuo

2004-05-01

A 63-year-old man was admitted because of general malaise, fever, headache, generalized lymphadenopathy and hepatomegaly in July 2002. He was diagnosed as having multiple myeloma (MM) (IgG-kappa type) with atypical plasma cells in the bone marrow, lymph nodes and cerebrospinal fluid. Systemic and intrathecal chemotherapy were effective. Because of an increase of polyclonal IgE, electrophoretic patterns revealed an M-peak which was not as sharp as that in IgG myeloma. IgE production is not impaired by the pathologic process in MM patients.

Quantitation of multiple myeloma oncogene 1/interferon-regulatory factor 4 gene expression in malignant B-cell proliferations and normal leukocytes.

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Yamada, M; Asanuma, K; Kobayashi, D; Moriai, R; Yajima, T; Yagihashi, A; Yamamori, S; Watanabe, N

2001-01-01

We studied multiple myeloma oncogene 1/interferon-regulatory factor 4 (MUM1/IRF4) mRNA expression in various malignant human hematopoietic cell lines and normal leukocyte fractions. A quantitative reverse transcription-polymerase chain reaction was used to assess expression and chromosomes were examined for anomalies by fluorescent in situ hybridization. Among 12 cell lines examined, mRNA transcripts were expressed only in B-lymphoblastic and myeloma cell lines. Myeloma cells and malignant cell lines derived from mature B cells expressed more transcript than cell lines derived from immature B cells. Transcript levels, however, showed no association with chromosomal translocations. Expression in B-cell fractions from healthy donors was much less than in the malignant cells. In addition, MUM1/IRF4 mRNA expressed in samples from patients with acute lymphoblastic leukemia derived from B cells but not T cells. Our results suggested that MUM1/IRF4 gene expression is related to stage of differentiation of malignant B cells and they indicated the possibility that the quantitative analysis of MUM1/IRF4 gene is a useful tool for detection of malignant B-cell proliferations in clinical laboratory tests.

Preclinical studies in support of defibrotide for the treatment of multiple myeloma and other neoplasias.

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Mitsiades, Constantine S; Rouleau, Cecile; Echart, Cinara; Menon, Krishna; Teicher, Beverly; Distaso, Maria; Palumbo, Antonio; Boccadoro, Mario; Anderson, Kenneth C; Iacobelli, Massimo; Richardson, Paul G

2009-02-15

Defibrotide, an orally bioavailable polydisperse oligonucleotide, has promising activity in hepatic veno-occlusive disease, a stem cell transplantation-related toxicity characterized by microangiopathy. The antithrombotic properties of defibrotide and its minimal hemorrhagic risk could serve for treatment of cancer-associated thrombotic complications. Given its cytoprotective effect on endothelium, we investigated whether defibrotide protects tumor cells from cytotoxic antitumor agents. Further, given its antiadhesive properties, we evaluated whether defibrotide modulates the protection conferred to multiple myeloma cells by bone marrow stromal cells. Defibrotide lacks significant single-agent in vitro cytotoxicity on multiple myeloma or solid tumor cells and does not attenuate their in vitro response to dexamethasone, bortezomib, immunomodulatory thalidomide derivatives, and conventional chemotherapeutics, including melphalan and cyclophosphamide. Importantly, defibrotide enhances in vivo chemosensitivity of multiple myeloma and mammary carcinoma xenografts in animal models. In cocultures of multiple myeloma cells with bone marrow stromal cells in vitro, defibrotide enhances the multiple myeloma cell sensitivity to melphalan and dexamethasone, and decreases multiple myeloma-bone marrow stromal cell adhesion and its sequelae, including nuclear factor-kappaB activation in multiple myeloma and bone marrow stromal cells, and associated cytokine production. Moreover, defibrotide inhibits expression and/or function of key mediators of multiple myeloma interaction with bone marrow stromal cell and endothelium, including heparanase, angiogenic cytokines, and adhesion molecules. Defibrotide's in vivo chemosensitizing properties and lack of direct in vitro activity against tumor cells suggest that it favorably modulates antitumor interactions between bone marrow stromal cells and endothelia in the tumor microenvironment. These data support clinical studies of defibrotide in

Myeloma Cell Dynamics in Response to Treatment Supports a Model of Hierarchical Differentiation and Clonal Evolution.

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Tang, Min; Zhao, Rui; van de Velde, Helgi; Tross, Jennifer G; Mitsiades, Constantine; Viselli, Suzanne; Neuwirth, Rachel; Esseltine, Dixie-Lee; Anderson, Kenneth; Ghobrial, Irene M; San Miguel, Jesús F; Richardson, Paul G; Tomasson, Michael H; Michor, Franziska

2016-08-15

Since the pioneering work of Salmon and Durie, quantitative measures of tumor burden in multiple myeloma have been used to make clinical predictions and model tumor growth. However, such quantitative analyses have not yet been performed on large datasets from trials using modern chemotherapy regimens. We analyzed a large set of tumor response data from three randomized controlled trials of bortezomib-based chemotherapy regimens (total sample size n = 1,469 patients) to establish and validate a novel mathematical model of multiple myeloma cell dynamics. Treatment dynamics in newly diagnosed patients were most consistent with a model postulating two tumor cell subpopulations, "progenitor cells" and "differentiated cells." Differential treatment responses were observed with significant tumoricidal effects on differentiated cells and less clear effects on progenitor cells. We validated this model using a second trial of newly diagnosed patients and a third trial of refractory patients. When applying our model to data of relapsed patients, we found that a hybrid model incorporating both a differentiation hierarchy and clonal evolution best explains the response patterns. The clinical data, together with mathematical modeling, suggest that bortezomib-based therapy exerts a selection pressure on myeloma cells that can shape the disease phenotype, thereby generating further inter-patient variability. This model may be a useful tool for improving our understanding of disease biology and the response to chemotherapy regimens. Clin Cancer Res; 22(16); 4206-14. ©2016 AACR. ©2016 American Association for Cancer Research.

[Multiple myeloma with significant multifocal osteolysis in a dog without a detectible gammopathy].

Science.gov (United States)

Souchon, F; Koch, A; Sohns, A

2013-01-01

Description of a variant of multiple myeloma in a dog lacking the gammopathy normally associated with this type of neoplasm. A Border Collie mongrel was presented with symptoms of progressive hind-leg weakness, lethargy and tiredness, which had started to appear 6 weeks previously. Radiographic examination showed small osteolytic areas in the spinal column, but also diffuse small areas of increased opacity as well as evidence of decreased bone density in the pelvis and of both femoral necks. Moderate regenerative anaemia, hypogammopathy and hypercalcaemia were diagnosed. Computed tomography scans displayed multifocal osteolysis and bone destruction in the skull, spinal column, scapulae, proximal humeri, pelvis and femoral necks. H&E staining of the biopsies showed bone destruction and monomorphic plasmacyotid cell populations, causing infiltrative bone marrow lesions and osteolysis. In many areas neoplastic plasma cell infiltration of the bone marrow was 70% and in some areas reached 100%. The diagnosis was non-secretory multiple myeloma without apparent secretion of paraproteins into the blood.

Paradoxical expression of INK4c in proliferative multiple myeloma tumors: bi-allelic deletion vs increased expression

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Hanamura Ichiro

2006-10-01

Full Text Available Abstract Background A high proliferative capacity of tumor cells usually is associated with shortened patient survival. Disruption of the RB pathway, which is critically involved in regulating the G1 to S cell cycle transition, is a frequent target of oncogenic events that are thought to contribute to increased proliferation during tumor progression. Previously, we determined that p18INK4c, an essential gene for normal plasma cell differentiation, was bi-allelically deleted in five of sixteen multiple myeloma (MM cell lines. The present study was undertaken to investigate a possible role of p18INK4c in increased proliferation of myeloma tumors as they progress. Results Thirteen of 40 (33% human myeloma cell lines do not express normal p18INK4c, with bi-allelic deletion of p18 in twelve, and expression of a mutated p18 fragment in one. Bi-allelic deletion of p18, which appears to be a late progression event, has a prevalence of about 2% in 261 multiple myeloma (MM tumors, but the prevalence is 6 to10% in the 50 tumors with a high expression-based proliferation index. Paradoxically, 24 of 40 (60% MM cell lines, and 30 of 50 (60% MM tumors with a high proliferation index express an increased level of p18 RNA compared to normal bone marrow plasma cells, whereas this occurs in only five of the 151 (3% MM tumors with a low proliferation index. Tumor progression is often accompanied by increased p18 expression and an increased proliferation index. Retroviral-mediated expression of exogenous p18 results in marked growth inhibition in three MM cell lines that express little or no endogenous p18, but has no effect in another MM cell line that already expresses a high level of p18. Conclusion Paradoxically, although loss of p18 appears to contribute to increased proliferation of nearly 10% of MM tumors, most MM cell lines and proliferative MM tumors have increased expression of p18. Apart from a small fraction of cell lines and tumors that have inactivated

[HSP90 Inhibitor 17-AAG Inhibits Multiple Myeloma Cell Proliferation by Down-regulating Wnt/β-Catenin Signaling Pathway].

Science.gov (United States)

Chen, Kan-Kan; He, Zheng-Mei; Ding, Bang-He; Chen, Yue; Zhang, Li-Juan; Yu, Liang; Gao, Jian

2016-02-01

To investigate the inhibitory effect of HSP90 inhibitory 17-AAG on proliferation of multiple myeloma cells and its main mechanism. The multiple myeloma cells U266 were treated with 17-AAG of different concentrations (200, 400, 600 and 800 nmol/L) for 24, 48, and 72 hours respectively, then the proliferation rate, expression levels of β-catenin and C-MYC protein, as well as cell cycle of U266 cells were treated with 17-AAG and were detected by MTT method, Western blot and flow cytometry, respectively. The 17-AAG showed inhibitory effect on the proliferation of U266 cells in dose- and time-depetent manners (r = -0.518, P AAG displayed no inhibitory effect on proliferation of U266 cells (P > 0.05). The result of culturing U266 cells for 72 hours by 17-AAG of different concentrations showed that the more high of 17-AAG concentration, the more low level of β-catenin and C-MYC proteins (P AAG concentration, the more high of cell ratio in G1 phase (P AAG, the more long time of culture, the more high of cell ratio in G1 phase (P AAG can inhibit the proliferation of multiple myeloma cells, the down-regulation of Wnt/β-catenin signaling pathway and inhibition of HSP90 expression may be the main mechnisms of 17-AAG effect.

Implications of Heterogeneity in Multiple Myeloma

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Sanjay de Mel

2014-01-01

Full Text Available Multiple myeloma is the second most common hematologic malignancy in the world. Despite improvement in outcome, the disease is still incurable for most patients. However, not all myeloma are the same. With the same treatment, some patients can have very long survival whereas others can have very short survival. This suggests that there is underlying heterogeneity in myeloma. Studies over the years have revealed multiple layers of heterogeneity. First, clinical parameters such as age and tumor burden could significantly affect outcome. At the genetic level, there are also significant heterogeneity ranging for chromosome numbers, genetic translocations, and genetic mutations. At the clonal level, there appears to be significant clonal heterogeneity with multiple clones coexisting in the same patient. At the cell differentiation level, there appears to be a hierarchy of clonally related cells that have different clonogenic potential and sensitivity to therapies. These levels of complexities present challenges in terms of treatment and prognostication as well as monitoring of treatment. However, if we can clearly delineate and dissect this heterogeneity, we may also be presented with unique opportunities for precision and personalized treatment of myeloma. Some proof of concepts of such approaches has been demonstrated.

The therapeutic effect of modified Huangqi Guizhi Wuwu Tang for multiple myeloma

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Tian, Mingmin; Huang, Huang

2017-01-01

Abstract Rationale: Multiple myeloma (MM) is a hematologic malignancy characterized by proliferation of clonal plasma cells in the bone marrow. The median survival has increased to 6 years in recent years. But MM remains incurable. Some studies about the effects of Chinese herb medicine on MM have been carried out. Long survival in MM patients through Traditional Chinese Medicine (TCM) therapies has been reported rarely before. Patient concerns: We report a case of a female patient who was di...

Increased level of both CD4+FOXP3+ regulatory T cells and CD14+HLA-DR⁻/low myeloid-derived suppressor cells and decreased level of dendritic cells in patients with multiple myeloma

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Brimnes, M K; Vangsted, Annette Juul; Knudsen, L M

2010-01-01

Patients with multiple myeloma (MM) suffer from a general impaired immunity comprising deficiencies in humoral responses, T-cell responses as well as dendritic cell (DC) function. Thus, to achieve control of tumour growth through immune therapy constitutes a challenge. Careful evaluation of the i......Patients with multiple myeloma (MM) suffer from a general impaired immunity comprising deficiencies in humoral responses, T-cell responses as well as dendritic cell (DC) function. Thus, to achieve control of tumour growth through immune therapy constitutes a challenge. Careful evaluation...

Interleukin-6 counteracts therapy-induced cellular oxidative stress in multiple myeloma by up-regulating manganese superoxide dismutase

OpenAIRE

Brown, Charles O.; Salem, Kelley; Wagner, Brett A.; Bera, Soumen; Singh, Neeraj; Tiwari, Ajit; Choudhury, Amit; Buettner, Garry R.; Goel, Apollina

2012-01-01

IL (interleukin)-6, an established growth factor for multiple myeloma cells, induces myeloma therapy resistance, but the resistance mechanisms remain unclear. The present study determines the role of IL-6 in re-establishing intracellular redox homoeostasis in the context of myeloma therapy. IL-6 treatment increased myeloma cell resistance to agents that induce oxidative stress, including IR (ionizing radiation) and Dex (dexamethasone). Relative to IR alone, myeloma cells treated with IL-6 plu...

Involvement of multiple myeloma cell-derived exosomes in osteoclast differentiation

OpenAIRE

Raimondi, Lavinia; De Luca, Angela; Amodio, Nicola; Manno, Mauro; Raccosta, Samuele; Taverna, Simona; Bellavia, Daniele; Naselli, Flores; Fontana, Simona; Schillaci, Odessa; Giardino, Roberto; Fini, Milena; Tassone, Pierfrancesco; Santoro, Alessandra; De Leo, Giacomo

2015-01-01

Bone disease is the most frequent complication in multiple myeloma (MM) resulting in osteolytic lesions, bone pain, hypercalcemia and renal failure. In MM bone disease the perfect balance between bone-resorbing osteoclasts (OCs) and bone-forming osteoblasts (OBs) activity is lost in favour of OCs, thus resulting in skeletal disorders. Since exosomes have been described for their functional role in cancer progression, we here investigate whether MM cell-derived exosomes may be involved in OCs ...

Multiple myeloma-derived MMP-13 mediates osteoclast fusogenesis and osteolytic disease

DEFF Research Database (Denmark)

Fu, Jing; Li, Shirong; Feng, Rentian

2016-01-01

Multiple myeloma (MM) cells secrete osteoclastogenic factors that promote osteolytic lesions; however, the identity of these factors is largely unknown. Here, we performed a screen of human myeloma cells to identify pro-osteoclastogenic agents that could potentially serve as therapeutic targets...

The application of Gadopentate-Dimeneglumin has no impact on progression free and overall survival as well as renal function in patients with monoclonal plasma cell disorders if general precautions are taken

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Hillengass, J. [University of Heidelberg, Department of Hematology, Oncology and Rheumatology, Heidelberg (Germany); German Cancer Research Center Heidelberg, Department of Radiology, Heidelberg (Germany); Stoll, J.; Wagner, B.; Goldschmidt, H. [University of Heidelberg, Department of Hematology, Oncology and Rheumatology, Heidelberg (Germany); Zechmann, C.M. [Rinecker Proton Therapy Center, Munich (Germany); Kunz, C.; Heiss, C. [German Cancer Research Center Heidelberg, Department of Biostatistics, Heidelberg (Germany); Sumkauskaite, M. [University of Heidelberg, Department of Radiology, Heidelberg (Germany); Moehler, T.M. [InVentiv Health Clinical, Wiesbaden (Germany); Schlemmer, H.P.; Delorme, S. [German Cancer Research Center Heidelberg, Department of Radiology, Heidelberg (Germany)

2014-10-31

The current analysis investigated the prognostic significance of gadopentetate dimeglumine on survival and renal function in patients with monoclonal plasma cell disorders. In this study 263 patients who had received gadopentetate dimeglumine within a prospective trial investigating dynamic contrast-enhanced magnetic resonance imaging (MRI) were compared with 335 patients who had undergone routine, unenhanced MRI. We found no significant prognostic impact of the application of contrast agent on progression-free survival in patients with either monoclonal gammopathy of undetermined significance, smouldering or symptomatic myeloma and no significant prognostic impact on overall survival in patients with symptomatic myeloma. Since renal impairment is a frequent complication of myeloma, and decreased renal function is associated with a higher risk of complications in patients receiving contrast agents, we evaluated the impact of contrast agent on renal function after 1 year. In the present analysis the only significant adverse impact on kidney function occurred in symptomatic myeloma patients who already had impaired renal parameters at baseline. Here, the renal function did not recover during therapy, whereas it did so in patients with normal or only slightly impaired renal function. If general recommendations are adhered to, gadopentetate dimeglumine can be safely applied in patients with monoclonal plasma cell disease. (orig.)

SENP1 inhibition induces apoptosis and growth arrest of multiple myeloma cells through modulation of NF-κB signaling

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Xu, Jun [Graduate School of Anhui Medical University, Hefei (China); Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850 (China); Sun, Hui-Yan; Xiao, Feng-Jun; Wang, Hua [Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850 (China); Yang, Yang [Department of Hematology, General Hospital of Air Force, Beijing (China); Wang, Lu; Gao, Chun-Ji [Department of Hematology, PLA General Hospital, Beijing (China); Guo, Zi-Kuan [Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850 (China); Wu, Chu-Tse [Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850 (China); Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu (China); Wang, Li-Sheng, E-mail: Wangls@bmi.ac.cn [Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850 (China); Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu (China)

2015-05-01

SUMO/sentrin specific protease 1 (Senp1) is an important regulation protease in the protein sumoylation, which affects the cell cycle, proliferation and differentiation. The role of Senp1 mediated protein desumoylation in pathophysiological progression of multiple myeloma is unknown. In this study, we demonstrated that Senp1 is overexpressed and induced by IL-6 in multiple myeloma cells. Lentivirus-mediated Senp1 knockdown triggers apoptosis and reduces viability, proliferation and colony forming ability of MM cells. The NF-κB family members including P65 and inhibitor protein IkBα play important roles in regulation of MM cell survival and proliferation. We further demonstrated that Senp1 inhibition decreased IL-6-induced P65 and IkBα phosphorylation, leading to inactivation of NF-kB signaling in MM cells. These results delineate a key role for Senp1in IL-6 induced proliferation and survival of MM cells, suggesting it may be a potential new therapeutic target in MM. - Highlights: • Senp1 is overexpressed and induced by IL-6 in multiple myeloma cells. • Senp1 knockdown triggers apoptosis and reduces proliferation of MM cells. • Senp1 inhibition decreased IL-6-induced P65 and IkBα phosphorylation.

SENP1 inhibition induces apoptosis and growth arrest of multiple myeloma cells through modulation of NF-κB signaling

International Nuclear Information System (INIS)

Xu, Jun; Sun, Hui-Yan; Xiao, Feng-Jun; Wang, Hua; Yang, Yang; Wang, Lu; Gao, Chun-Ji; Guo, Zi-Kuan; Wu, Chu-Tse; Wang, Li-Sheng

2015-01-01

SUMO/sentrin specific protease 1 (Senp1) is an important regulation protease in the protein sumoylation, which affects the cell cycle, proliferation and differentiation. The role of Senp1 mediated protein desumoylation in pathophysiological progression of multiple myeloma is unknown. In this study, we demonstrated that Senp1 is overexpressed and induced by IL-6 in multiple myeloma cells. Lentivirus-mediated Senp1 knockdown triggers apoptosis and reduces viability, proliferation and colony forming ability of MM cells. The NF-κB family members including P65 and inhibitor protein IkBα play important roles in regulation of MM cell survival and proliferation. We further demonstrated that Senp1 inhibition decreased IL-6-induced P65 and IkBα phosphorylation, leading to inactivation of NF-kB signaling in MM cells. These results delineate a key role for Senp1in IL-6 induced proliferation and survival of MM cells, suggesting it may be a potential new therapeutic target in MM. - Highlights: • Senp1 is overexpressed and induced by IL-6 in multiple myeloma cells. • Senp1 knockdown triggers apoptosis and reduces proliferation of MM cells. • Senp1 inhibition decreased IL-6-induced P65 and IkBα phosphorylation

Suppressing miRNA-15a/-16 expression by interleukin-6 enhances drug-resistance in myeloma cells

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Chang Hong

2011-09-01

Full Text Available Abstract The bone marrow microenvironment facilitates the survival, differentiation, and proliferation of myeloma (MM cells. This study identified that microRNA-15a and -16 expressions tightly correlated with proliferation and drug sensitivity of MM cells. miRNA-15a/-16 expression in MM cells was significantly increased after treatment with cytotoxic agents. The interaction of bone marrow stromal cells (BMSC with MM cells resulted in decreased miRNA-15a/-16 expression and promoted the survival of the MM cells. Interleukin-6 (IL-6 produced by BMSCs suppressed the expression of miRNA-15a and 16 in a time- and dose- dependent pattern, with the suppression on miRNA-15a being more significant than on miRNA-16. miRNA-15a-transfected MM cells were found to be arrested in G1/S checkpoint, and the transfected MM cells had decreased growth and survival. In conclusion, our data suggest that via suppressing miRNA-15a and -16 expressions, IL-6 secreted by BMSCs promotes drug-resistance in myeloma cells.

RITA (Reactivating p53 and Inducing Tumor Apoptosis) is efficient against TP53abnormal myeloma cells independently of the p53 pathway.

Science.gov (United States)

Surget, Sylvanie; Descamps, Géraldine; Brosseau, Carole; Normant, Vincent; Maïga, Sophie; Gomez-Bougie, Patricia; Gouy-Colin, Nadège; Godon, Catherine; Béné, Marie C; Moreau, Philippe; Le Gouill, Steven; Amiot, Martine; Pellat-Deceunynck, Catherine

2014-06-14

The aim of this study was to evaluate the efficacy of the p53-reactivating drugs RITA and nutlin3a in killing myeloma cells. A large cohort of myeloma cell lines (n = 32) and primary cells (n = 21) was used for this study. This cohort contained cell lines with various TP53 statuses and primary cells with various incidences of deletion of chromosome 17. Apoptosis was evaluated using flow cytometry with Apo2.7 staining of the cell lines or via the loss of the myeloma-specific marker CD138 in primary cells. Apoptosis was further confirmed by the appearance of a subG1 peak and the activation of caspases 3 and 9. Activation of the p53 pathway was monitored using immunoblotting via the expression of the p53 target genes p21, Noxa, Bax and DR5. The involvement of p53 was further studied in 4 different p53-silenced cell lines. Both drugs induced the apoptosis of myeloma cells. The apoptosis that was induced by RITA was not related to the TP53 status of the cell lines or the del17p status of the primary samples (p = 0.52 and p = 0.80, respectively), and RITA did not commonly increase the expression level of p53 or p53 targets (Noxa, p21, Bax or DR5) in sensitive cells. Moreover, silencing of p53 in two TP53(mutated) cell lines failed to inhibit apoptosis that was induced by RITA, which confirmed that RITA-induced apoptosis in myeloma cells was p53 independent. In contrast, apoptosis induced by nutlin3a was directly linked to the TP53 status of the cell lines and primary samples (p RITA, in contrast to nutlin3a, effectively induced apoptosis in a subset of MM cells independently of p53. The findings and could be of interest for patients with a 17p deletion, who are resistant to current therapies.

Intratibial injection of human multiple myeloma cells in NOD/SCID IL-2Rγ(null mice mimics human myeloma and serves as a valuable tool for the development of anticancer strategies.

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Julia Schueler

Full Text Available BACKGROUND: We systematically analyzed multiple myeloma (MM cell lines and patient bone marrow cells for their engraftment capacity in immunodeficient mice and validated the response of the resulting xenografts to antimyeloma agents. DESIGN AND METHODS: Using flow cytometry and near infrared fluorescence in-vivo-imaging, growth kinetics of MM cell lines L363 and RPMI8226 and patient bone marrow cells were investigated with use of a murine subcutaneous bone implant, intratibial and intravenous approach in NOD/SCID, NOD/SCID treated with CD122 antibody and NOD/SCID IL-2Rγ(null mice (NSG. RESULTS: Myeloma growth was significantly increased in the absence of natural killer cell activity (NSG or αCD122-treated NOD/SCID. Comparison of NSG and αCD122-treated NOD/SCID revealed enhanced growth kinetics in the former, especially with respect to metastatic tumor sites which were exclusively observed therein. In NSG, MM cells were more tumorigenic when injected intratibially than intravenously. In NOD/SCID in contrast, the use of juvenile long bone implants was superior to intratibial or intravenous cancer cell injection. Using the intratibial NSG model, mice developed typical disease symptoms exclusively when implanted with human MM cell lines or patient-derived bone marrow cells, but not with healthy bone marrow cells nor in mock-injected animals. Bortezomib and dexamethasone delayed myeloma progression in L363- as well as patient-derived MM cell bearing NSG. Antitumor activity could be quantified via flow cytometry and in vivo imaging analyses. CONCLUSIONS: Our results suggest that the intratibial NSG MM model mimics the clinical situation of the disseminated disease and serves as a valuable tool in the development of novel anticancer strategies.

Multiple myeloma of the jaw: A case report

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Shubhasini A Raghavan

2014-01-01

Full Text Available Multiple myeloma is a systemic B-cell lymphoproliferative disease that causes osteolytic lesions in the vertebra, ribs, pelvic bone, skull and jaw. Rarely jaw lesions are seen as the first sign in multiple myeloma. This is a case report with follow up of a 57-year-old female patient, previously treated for osteoporosis, who presented with a swelling of the jaw. On radiographic examination, she was found to have osteolytic lesions in the mandible and skull bones. These conventional aids led to the diagnosis of multiple myeloma thereby proving that the osteoporotic lesions were a part of the spectrum of multiple myeloma. The patient underwent chemotherapy and is currently on follow-up. This case report emphasizes the importance of early diagnosis of multiple myeloma in the jaw using readily available technologies and illustrates the contribution that oral assessment can provide.

Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma

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Lokhorst, Henk M; Plesner, Torben; Laubach, Jacob P

2015-01-01

BACKGROUND: Multiple myeloma cells uniformly overexpress CD38. We studied daratumumab, a CD38-targeting, human IgG1κ monoclonal antibody, in a phase 1-2 trial involving patients with relapsed myeloma or relapsed myeloma that was refractory to two or more prior lines of therapy. METHODS: In part 1...... interval [CI], 4.2 to 8.1), and 65% (95% CI, 28 to 86) of the patients who had a response did not have progression at 12 months. CONCLUSIONS: Daratumumab monotherapy had a favorable safety profile and encouraging efficacy in patients with heavily pretreated and refractory myeloma. (Funded by Janssen...

Modern imaging techniques in patients with multiple myeloma; Moderne Bildgebungsverfahren beim Multiplen Myelom

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Bannas, Peter; Adam, G.; Derlin, T. [Universitaetsklinikum Hamburg-Eppendorf, Hamburg (Germany). Klinik und Poliklinik fuer Diagnostische und Interventionelle Radiologie; Kroeger, N. [Universitaetsklinikum Hamburg-Eppendorf, Hamburg (Germany). Klinik und Poliklinik fuer Stammzelltransplantation

2013-01-15

Imaging studies are essential for both diagnosis and initial staging of multiple myeloma, as well as for differentiation from other monoclonal plasma cell diseases. Apart from conventional radiography, a variety of newer imaging modalities including whole-body low-dose-CT, whole-body MRI and 18F-FDG PET/CT may be used for detection of osseous and extraosseous myeloma manifestations. Despite of known limitations such as limited sensitivity and specificity and the inability to detect extraosseous lesions, conventional radiography still remains the gold standard for staging newly diagnosed myeloma, partly due to its wide availability and low costs. Whole-body low-dose CT is increasingly used due to its higher sensitivity for the detection of osseous lesions and its ability to diagnose extraosseous lesions, and is replacing conventional radiography at selected centres. The highest sensitivity for both detection of bone marrow disease and extraosseous lesions can be achieved with whole-body MRI or 18F-FDG PET/CT. Diffuse bone marrow infiltration may be visualized by whole-body MRI with high sensitivity. Whole-body MRI is at least recommended in all patients with normal conventional radiography and in all patients with an apparently solitary plasmacytoma of bone. To obtain the most precise readings, optimized examination protocols and dedicated radiologists and nuclear medicine physicians familiar with the complex and variable morphologies of myeloma lesions are required. (orig.)

Free light chains of immunoglobulins in the diagnosis and prognosis of multiple myeloma

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N. V. Lyubimova

2017-01-01

Full Text Available Background: Analysis of free light chains of immunoglobulins (FLC in the serum is an effective method in the diagnosis of multiple myeloma. Plasma cells produce two types of FLC: κand λ-FLC. FLC, which are not incorporated into monoclonal intact immunoglobulins, are released into circulation, and then are filtered and reabsorbed in kidneys depending on their molecular weight. Circulating FLC commonly form homodimers, known as Bence-Jones protein, which is a biomarker of Bence-Jones multiple myeloma. According to the international guidelines, the ratio κ/λ FLC is an important diagnostic criterion of multiple myeloma. Aim: To evaluate the diagnostic and prognostic value of serum FLC in multiple myeloma patients. Materials and methods: We examined 118 patients with multiple myeloma, admitted to the Department of Hemoblastosis Chemotherapy of N.N. Blokhin Russian Cancer Research Center from 2010 to 2016, and 68 healthy men and women. Serum concentrations of FLC were measured with an immunoturbidimetric method using the test-system Freelite Human Lambda and Freelite Human Kappa (Binding Site Inc.. Results: The levels of monoclonal κor λ-FLC in patients with G-, A-myeloma and Bence-Jones multiple myeloma were significantly higher than those in the control group (p < 0.005. The diagnostic sensitivity of quantification of FLC and their ratio was 87.3% and 89.8%, and in combination with the use of immune electrophoresis it was close to 100%. Analysis of progression free survival and overall survival showed significant differences (p < 0.04 between the groups of patients according their κ/λ FLC ratio. The basal value of κ/λ FLC ratio of less than 0.04 and more than 140 was a  predictor of unfavorable outcome. Conclusion: The inclusion of the determination of serum FLC into the assessment plan of patients with suspected monoclonal gammapathy makes it possible to increase diagnostic sensitivity of the available methods for paraprotein

Interleukin-6 counteracts therapy-induced cellular oxidative stress in multiple myeloma by up-regulating manganese superoxide dismutase.

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Brown, Charles O; Salem, Kelley; Wagner, Brett A; Bera, Soumen; Singh, Neeraj; Tiwari, Ajit; Choudhury, Amit; Buettner, Garry R; Goel, Apollina

2012-06-15

IL (interleukin)-6, an established growth factor for multiple myeloma cells, induces myeloma therapy resistance, but the resistance mechanisms remain unclear. The present study determines the role of IL-6 in re-establishing intracellular redox homoeostasis in the context of myeloma therapy. IL-6 treatment increased myeloma cell resistance to agents that induce oxidative stress, including IR (ionizing radiation) and Dex (dexamethasone). Relative to IR alone, myeloma cells treated with IL-6 plus IR demonstrated reduced annexin/propidium iodide staining, caspase 3 activation, PARP [poly(ADP-ribose) polymerase] cleavage and mitochondrial membrane depolarization with increased clonogenic survival. IL-6 combined with IR or Dex increased early intracellular pro-oxidant levels that were causally related to activation of NF-κB (nuclear factor κB) as determined by the ability of N-acetylcysteine to suppress both pro-oxidant levels and NF-κB activation. In myeloma cells, upon combination with hydrogen peroxide treatment, relative to TNF (tumour necrosis factor)-α, IL-6 induced an early perturbation in reduced glutathione level and increased NF-κB-dependent MnSOD (manganese superoxide dismutase) expression. Furthermore, knockdown of MnSOD suppressed the IL-6-induced myeloma cell resistance to radiation. MitoSOX Red staining showed that IL-6 treatment attenuated late mitochondrial oxidant production in irradiated myeloma cells. The present study provides evidence that increases in MnSOD expression mediate IL-6-induced resistance to Dex and radiation in myeloma cells. The results of the present study indicate that inhibition of antioxidant pathways could enhance myeloma cell responses to radiotherapy and/or chemotherapy.

A novel phthalimide derivative, TC11, has preclinical effects on high-risk myeloma cells and osteoclasts.

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Maiko Matsushita

Full Text Available Despite the recent advances in the treatment of multiple myeloma (MM, MM patients with high-risk cytogenetic changes such as t(4;14 translocation or deletion of chromosome 17 still have extremely poor prognoses. With the goal of helping these high-risk MM patients, we previously developed a novel phthalimide derivative, TC11. Here we report the further characterization of TC11 including anti-myeloma effects in vitro and in vivo, a pharmacokinetic study in mice, and anti-osteoclastogenic activity. Intraperitoneal injections of TC11 significantly delayed the growth of subcutaneous tumors in human myeloma-bearing SCID mice. Immunohistochemical analyses showed that TC11 induced apoptosis of MM cells in vivo. In the pharmacokinetic analyses, the Cmax was 2.1 μM at 1 h after the injection of TC11, with 1.2 h as the half-life. TC11 significantly inhibited the differentiation and function of tartrate-resistant acid phosphatase (TRAP-positive multinucleated osteoclasts in mouse osteoclast cultures using M-CSF and RANKL. We also revealed that TC11 induced the apoptosis of myeloma cells accompanied by α-tubulin fragmentation. In addition, TC11 and lenalidomide, another phthalimide derivative, directly bound to nucleophosmin 1 (NPM1, whose role in MM is unknown. Thus, through multiple molecular interactions, TC11 is a potentially effective drug for high-risk MM patients with bone lesions. The present results suggest the possibility of the further development of novel thalidomide derivatives by drug designing.

Apigenin inhibits proliferation and induces apoptosis in human multiple myeloma cells through targeting the trinity of CK2, Cdc37 and Hsp90

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Xu Yuan-Ji

2011-08-01

Full Text Available Abstract Background Multiple myeloma (MM is a B-cell malignancy that is largely incurable and is characterized by the accumulation of malignant plasma cells in the bone marrow. Apigenin, a common flavonoid, has been reported to suppress proliferation in a wide variety of solid tumors and hematological cancers; however its mechanism is not well understood and its effect on MM cells has not been determined. Results In this study, we investigated the effects of apigenin on MM cell lines and on primary MM cells. Cell viability assays demonstrated that apigenin exhibited cytotoxicity against both MM cell lines and primary MM cells but not against normal peripheral blood mononuclear cells. Together, kinase assays, immunoprecipitation and western blot analysis showed that apigenin inhibited CK2 kinase activity, decreased phosphorylation of Cdc37, disassociated the Hsp90/Cdc37/client complex and induced the degradation of multiple kinase clients, including RIP1, Src, Raf-1, Cdk4 and AKT. By depleting these kinases, apigenin suppressed both constitutive and inducible activation of STAT3, ERK, AKT and NF-κB. The treatment also downregulated the expression of the antiapoptotic proteins Mcl-1, Bcl-2, Bcl-xL, XIAP and Survivin, which ultimately induced apoptosis in MM cells. In addition, apigenin had a greater effects in depleting Hsp90 clients when used in combination with the Hsp90 inhibitor geldanamycin and the histone deacetylase inhibitor vorinostat. Conclusions Our results suggest that the primary mechanisms by which apigenin kill MM cells is by targeting the trinity of CK2-Cdc37-Hsp90, and this observation reveals the therapeutic potential of apigenin in treating multiple myeloma.

Flow Cytometry Method as a Diagnostic Tool for Pleural Fluid Involvement in a Patient with Multiple Myeloma

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Muzaffer Keklik

2012-10-01

Full Text Available Multiple myeloma is a malignant proliferation of plasma cells that mainly affects bone marrow. Pleural effusions secondary to pleural myelomatous involvement have rarely been reported in the literature. As it is rarely detected, we aimed to report a case in which pleural effusion of a multiple myeloma was confirmed as true myelomatous involvement by flow cytometry method. A 52-years old man presented to our clinic with chest and back pain lasting for 3 months. On the chest radiography, pleural fluid was detected in left hemithorax. Pleural fluid flow cytometry was performed. In the flow cytometry, CD56, CD38 and CD138 found to be positive, while CD19 was negative. True myelomatous pleural effusions are very uncommon, with fewer than 100 cases reported worldwide. Flow cytometry is a potentially useful diagnostic tool for clinical practice. We presented our case; as it has been rarely reported, although flow cytometer is a simple method for detection of pleural fluid involvement in multiple myeloma.

Circulating hematopoietic progenitors and CD34(+) cells predicted successful hematopoietic stem cell harvest in myeloma and lymphoma patients: experiences from a single institution.

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Yu, Jui-Ting; Cheng, Shao-Bin; Yang, Youngsen; Chang, Kuang-Hsi; Hwang, Wen-Li; Teng, Chieh-Lin Jerry

2016-01-01

Previous studies have shown that the numbers of both circulating hematopoietic progenitor cell (HPC) and CD34(+) cell are positively correlated with CD34(+) cell harvest yield. However, the minimal numbers of both circulating HPCs and CD34(+) cells required for performing an efficient hematopoietic stem cell (HSC) harvest in lymphoma and myeloma patients have not been defined in our institution. Medical records of 50 lymphoma and myeloma patients undergoing peripheral blood HSC harvest in our institution were retrospectively reviewed. The minimal and optimal HSC harvest yield required for the treatment was considered to be ≥2×10(6) CD34(+) cells/kg and ≥5×10(6) CD34(+) cells/kg, respectively. The minimally required or optimal HSC yield obtained was not influenced by age (≥60 years), sex, underlying malignancies, disease status, multiple rounds of chemotherapy, or history of radiotherapy. The numbers of both circulating HPC and CD34(+) cell were higher in patients with minimally required HSC yields (P=0.000 for HPC and P=0.000 for CD34(+) cell) and also in patients with optimal HSC yields (P=0.011 for HPC and P=0.006 for CD34(+) cell). The cell count cutoff for obtaining minimally required HSC harvest was determined to be 20/mm(3) for HPCs and 10/mm(3) for CD34(+) cells. Furthermore, the cell count cutoff for obtaining optimal HSC harvest was determined to be 60/mm(3) for HPCs and 35/mm(3) for CD34(+) cells. A total of 60/mm(3) of HPCs and 35/mm(3) of CD34(+) cells in peripheral blood predicted optimal HSC harvest in lymphoma and myeloma patients.

Novel tumor suppressor function of glucocorticoid-induced TNF receptor GITR in multiple myeloma.

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Yang Liu

Full Text Available Glucocorticoid-induced TNF receptor (GITR plays a crucial role in modulating immune response and inflammation, however the role of GITR in human cancers is poorly understood. In this study, we demonstrated that GITR is inactivated during tumor progression in Multiple Myeloma (MM through promoter CpG island methylation, mediating gene silencing in primary MM plasma cells and MM cell lines. Restoration of GITR expression in GITR deficient MM cells led to inhibition of MM proliferation in vitro and in vivo and induction of apoptosis. These findings were supported by the presence of induction of p21 and PUMA, two direct downstream targets of p53, together with modulation of NF-κB in GITR-overexpressing MM cells. Moreover, the unbalanced expression of GITR in clonal plasma cells correlated with MM disease progression, poor prognosis and survival. These findings provide novel insights into the pivotal role of GITR in MM pathogenesis and disease progression.

Withanolide D Exhibits Similar Cytostatic Effect in Drug-Resistant and Drug-Sensitive Multiple Myeloma Cells

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Mark E. Issa

2017-09-01

Full Text Available In spite of recent therapeutic advances, multiple myeloma (MM remains a malignancy with very low curability. This has been partly attributed to the existence of a drug-resistant subpopulation known as cancer stem cells (CSCs. MM-CSCs are equipped with the necessary tools that render them highly resistant to virtually all conventional therapies. In this study, the growth inhibitory effects of withanolide D (WND, a steroidal lactone isolated from Withania somnifera, on drug-sensitive tumoral plasma cells and drug-resistant MM cells have been investigated. In MTT/XTT assays, WND exhibited similar cytostatic effects between drug-resistant and drug-sensitive cell lines in the nM range. WND also induced cell death and apoptosis in MM-CSCs and RPMI 8226 cells, as examined by the calcein/ethidium homodimer and annexin V/propidium iodide stainings, respectively. To determine whether P-glycoprotein (P-gp efflux affected the cytostatic activity of WND, P-gp was inhibited with verapamil and results indicated that the WND cytostatic effect in MM-CSCs was independent of P-gp efflux. Furthermore, WND did not increase the accumulation of the fluorescent P-gp substrate rhodamine 123 in MM-CSCs, suggesting that WND may not inhibit P-gp at the tested relevant doses. Therefore, the WND-induced cytostatic effect may be independent of P-gp efflux. These findings warrant further investigation of WND in MM-CSC animal models.

Circulating hematopoietic progenitors and CD34+ cells predicted successful hematopoietic stem cell harvest in myeloma and lymphoma patients: experiences from a single institution

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Yu JT

2016-02-01

Full Text Available Jui-Ting Yu,1,2,* Shao-Bin Cheng,3,* Youngsen Yang,1 Kuang-Hsi Chang,4 Wen-Li Hwang,1 Chieh-Lin Jerry Teng,1,5,6 1Division of Hematology/Medical Oncology, Department of Medicine, Taichung Veterans General Hospital, 2Division of Hematology/Medical Oncology, Tungs' Taichung MetroHarbor Hospital, 3Division of General Surgery, Department of Surgery, 4Department of Medical Research and Education, Taichung Veterans General Hospital, 5Department of Life Science, Tunghai University, 6School of Medicine, Chung Shan Medical University, Taichung, Taiwan, Republic of China *These authors contributed equally to this work Background: Previous studies have shown that the numbers of both circulating hematopoietic progenitor cell (HPC and CD34+ cell are positively correlated with CD34+ cell harvest yield. However, the minimal numbers of both circulating HPCs and CD34+ cells required for performing an efficient hematopoietic stem cell (HSC harvest in lymphoma and myeloma patients have not been defined in our institution. Patients and methods: Medical records of 50 lymphoma and myeloma patients undergoing peripheral blood HSC harvest in our institution were retrospectively reviewed. The minimal and optimal HSC harvest yield required for the treatment was considered to be ≥2×106 CD34+ cells/kg and ≥5×106 CD34+ cells/kg, respectively. Results: The minimally required or optimal HSC yield obtained was not influenced by age (≥60 years, sex, underlying malignancies, disease status, multiple rounds of chemotherapy, or history of radiotherapy. The numbers of both circulating HPC and CD34+ cell were higher in patients with minimally required HSC yields (P=0.000 for HPC and P=0.000 for CD34+ cell and also in patients with optimal HSC yields (P=0.011 for HPC and P=0.006 for CD34+ cell. The cell count cutoff for obtaining minimally required HSC harvest was determined to be 20/mm3 for HPCs and 10/mm3 for CD34+ cells. Furthermore, the cell count cutoff for obtaining

Radiotherapy for solitary plasmacytoma and multiple myeloma

International Nuclear Information System (INIS)

Schmaus, M.C.; Neuhof, D.

2014-01-01

Solitary plasmacytoma and multiple myeloma require a differentiated radiotherapy. The irradiation for plasmacytoma with an adequate total dose (medullary 40-50 Gy or extramedullary 50-60 Gy) leads to a high degree of local control with a low rate of side effects. In cases of multiple myeloma radiotherapy will achieve effective palliation, both in terms of recalcification as well as reduction of neurological symptoms and analgesia. In terms of analgesia the rule is the higher the single dose fraction the faster the reduction of pain. As part of a conditioning treatment prior to stem cell transplantation radiotherapy contributes to the establishment of a graft versus myeloma effect (GVM). (orig.) [de

Molecular Classification and Pharmacogenetics of Primary Plasma Cell Leukemia: An Initial Approach toward Precision Medicine.

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Simeon, Vittorio; Todoerti, Katia; La Rocca, Francesco; Caivano, Antonella; Trino, Stefania; Lionetti, Marta; Agnelli, Luca; De Luca, Luciana; Laurenzana, Ilaria; Neri, Antonino; Musto, Pellegrino

2015-07-30

Primary plasma cell leukemia (pPCL) is a rare and aggressive variant of multiple myeloma (MM) which may represent a valid model for high-risk MM. This disease is associated with a very poor prognosis, and unfortunately, it has not significantly improved during the last three decades. New high-throughput technologies have allowed a better understanding of the molecular basis of this disease and moved toward risk stratification, providing insights for targeted therapy studies. This knowledge, added to the pharmacogenetic profile of new and old agents in the analysis of efficacy and safety, could contribute to help clinical decisions move toward a precision medicine and a better clinical outcome for these patients. In this review, we describe the available literature concerning the genomic characterization and pharmacogenetics of plasma cell leukemia (PCL).

The shaping and functional consequences of the dosage effect landscape in multiple myeloma.

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Samur, Mehmet K; Shah, Parantu K; Wang, Xujun; Minvielle, Stéphane; Magrangeas, Florence; Avet-Loiseau, Hervé; Munshi, Nikhil C; Li, Cheng

2013-10-02

Multiple myeloma (MM) is a malignant proliferation of plasma B cells. Based on recurrent aneuploidy such as copy number alterations (CNAs), myeloma is divided into two subtypes with different CNA patterns and patient survival outcomes. How aneuploidy events arise, and whether they contribute to cancer cell evolution are actively studied. The large amount of transcriptomic changes resultant of CNAs (dosage effect) pose big challenges for identifying functional consequences of CNAs in myeloma in terms of specific driver genes and pathways. In this study, we hypothesize that gene-wise dosage effect varies as a result from complex regulatory networks that translate the impact of CNAs to gene expression, and studying this variation can provide insights into functional effects of CNAs. We propose gene-wise dosage effect score and genome-wide karyotype plot as tools to measure and visualize concordant copy number and expression changes across cancer samples. We find that dosage effect in myeloma is widespread yet variable, and it is correlated with gene expression level and CNA frequencies in different chromosomes. Our analysis suggests that despite the enrichment of differentially expressed genes between hyperdiploid MM and non-hyperdiploid MM in the trisomy chromosomes, the chromosomal proportion of dosage sensitive genes is higher in the non-trisomy chromosomes. Dosage-sensitive genes are enriched by genes with protein translation and localization functions, and dosage resistant genes are enriched by apoptosis genes. These results point to future studies on differential dosage sensitivity and resistance of pro- and anti-proliferation pathways and their variation across patients as therapeutic targets and prognosis markers. Our findings support the hypothesis that recurrent CNAs in myeloma are selected by their functional consequences. The novel dosage effect score defined in this work will facilitate integration of copy number and expression data for identifying driver

Targeted therapy of multiple myeloma.

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Dolloff, Nathan G; Talamo, Giampaolo

2013-01-01

Multiple myeloma (MM) is a plasma cell malignancy and the second most common hematologic cancer. MM is characterized by the accumulation of malignant plasma cells within the bone marrow, and presents clinically with a broad range of symptoms, including hypercalcemia, renal insufficiency, anemia, and lytic bone lesions. MM is a heterogeneous disease associated with genomic instability, where patients may express multiple genetic abnormalities that affect several oncogenic pathways. Commonly detected genetic aberrations are translocations involving immunoglobulin heavy chain (IgH) switch regions (chromosome 14q32) and oncogenes such as c-maf [t(14:16)], cyclin D1 [t(11:14)], and FGFR3/MMSET [t(4:14)]. Advances in the basic understanding of MM and the development of novel agents, such as the immunomodulatory drugs (IMiDs) thalidomide and lenalidomide and the proteasome inhibitor bortezomib, have increased therapeutic response rates and prolonged patient survival. Despite these advances MM remains incurable in the majority of patients, and it is therefore critical to identify additional therapeutic strategies and targets for its treatment. In this chapter, we review the underlying genetic components of MM and discuss the results of recent clinical trials that demonstrate the effectiveness of targeted agents in the management of MM. In addition, we discuss experimental therapies that are currently in clinical development along with their molecular rationale in the treatment of MM.

The Imipridone ONC201 Induces Apoptosis and Overcomes Chemotherapy Resistance by Up-Regulation of Bim in Multiple Myeloma

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Yong-sheng Tu

2017-10-01

Full Text Available In multiple myeloma, despite recent improvements offered by new therapies, disease relapse and drug resistance still occur in the majority of patients. Therefore, there is an urgent need for new drugs that can overcome drug resistance and prolong patient survival after failure of standard therapies. The imipridone ONC201 causes downstream inactivation of ERK1/2 signaling and has tumoricidal activity against a variety of tumor types, while its efficacy in preclinical models of myeloma remains unclear. In this study, we treated human myeloma cell lines and patient-derived tumor cells with ONC201. Treatment decreased cellular viability and induced apoptosis in myeloma cell lines, with IC50 values of 1 to 1.5 μM, even in those with high risk features or TP53 loss. ONC201 increased levels of the pro-apoptotic protein Bim in myeloma cells, resulting from decreased phosphorylation of degradation-promoting Bim Ser69 by ERK1/2. In addition, myeloma cell lines made resistant to several standard-of-care agents (by chronic exposure were equally sensitive to ONC201 as their drug-naïve counterparts, and combinations of ONC201 with proteasome inhibitors had synergistic anti-myeloma activity. Overall, these findings demonstrate that ONC201 kills myeloma cells regardless of resistance to standard-of-care therapies, making it promising for clinical testing in relapsed/refractory myeloma.

Interferon-alpha in the treatment of multiple myeloma

DEFF Research Database (Denmark)

Khoo, T.L.; Joshua, D.; Gibson, J.

2011-01-01

Interferons are soluble proteins produced naturally by cells in response to viruses. It has both anti-proliferative and immunomodulating properties and is one of the first examples of a biological response modifier use to treat the hematological malignancy multiple myeloma. Interferon has been used......-induction agent with other chemotherapy regimens, and as maintenance therapy after conventional chemotherapy or complete remission after autologous or allogeneic transplantation. Interferon as a single induction agent or co-induction agent with other chemotherapy agents appears only to have minimal benefit...... in myeloma. Its role as maintenance therapy in the plateau phase of myeloma also remains uncertain. More recently, the use of interferon must now compete with the "new drugs" - thalidomide, lenalidomide and bortezomib in myeloma treatment. Will there be a future role of interferon in the treatment...

Diagnostic performance of whole-body MRI for the detection of persistent or relapsing disease in multiple myeloma after stem cell transplantation

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Bannas, Peter; Hentschel, Hannah B.; Bley, Thorsten A.; Derlin, Thorsten; Yamamura, Jin; Adam, Gerhard; Weber, Christoph [University Medical Center Hamburg-Eppendorf, Department of Diagnostic and Interventional Radiology, Hamburg (Germany); Treszl, Andras; Eulenburg, Christine [University Medical Center Hamburg-Eppendorf, Department of Medical Biometry and Epidemiology, Hamburg (Germany); Stuebig, Thomas; Kroeger, Nicolaus [University Medical Center Hamburg-Eppendorf, Department of Stem Cell Transplantation, Hamburg (Germany)

2012-09-15

To compare the diagnostic performance of whole-body MRI (WBMRI) with haematological parameters for detecting persistent or relapsing disease in patients with multiple myeloma after stem cell transplantation. Sixty-six WBMRI acquisitions were performed in 33 patients with multiple myeloma at two time points after stem cell transplantation. Extent of disease and inter-test dynamics of intra- and extramedullary myeloma manifestations were compared (kappa statistics) with Uniform Response Criteria, comprising haematological parameters. Using data from 66 sequential WBMRI acquisitions in 33 patients, 10 patients (30.3 %) were classified as having progressive disease and 23 (69.7 %) as being in remission. Eight (80 %) of the ten patients with progressive disease revealed intramedullary lesions, and two patients (20 %) had intra- and extramedullary lesions. WBMRI and laboratory tests were concordant in 26/33 (78.8 %) patients. We found an agreement of 51.2 %, 95 % confidence interval 19.8 %-82.6 %, between results from WBMRI and haematological parameters. WBMRI had a sensitivity of 63.6 %, specificity of 86.4 %, PPV of 70.0 %, NPV of 82.6 % and accuracy of 78.8 % for detection of remission. WBMRI allows the detection and exact localisation of intra- and extramedullary myeloma manifestations after stem cell transplantation, but shows only moderate agreement with routinely performed laboratory tests for determination of remission. (orig.)

Ex Vivo Maintenance of Primary Human Multiple Myeloma Cells through the Optimization of the Osteoblastic Niche.

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Zhang, Wenting; Gu, Yexin; Sun, Qiaoling; Siegel, David S; Tolias, Peter; Yang, Zheng; Lee, Woo Y; Zilberberg, Jenny

2015-01-01

We previously reported a new approach for culturing difficult-to-preserve primary patient-derived multiple myeloma cells (MMC) using an osteoblast (OSB)-derived 3D tissue scaffold constructed in a perfused microfluidic environment and a culture medium supplemented with patient plasma. In the current study, we used this biomimetic model to show, for the first time, that the long-term survival of OSB is the most critical factor in maintaining the ex vivo viability and proliferative capacity of MMC. We found that the adhesion and retention of MMC to the tissue scaffold was meditated by osteoblastic N-cadherin, as one of potential mechanisms that regulate MMC-OSB interactions. However, in the presence of MMC and patient plasma, the viability and osteogenic activity of OSB became gradually compromised, and consequently MMC could not remain viable over 3 weeks. We demonstrated that the long-term survival of both OSB and MMC could be enhanced by: (1) optimizing perfusion flow rate and patient-derived plasma composition in the culture medium and (2) replenishing OSB during culture as a practical means of prolonging MMC's viability beyond several weeks. These findings were obtained using a high-throughput well plate-based perfusion device from the perspective of optimizing the ex vivo preservation of patient-derived MM biospecimens for downstream use in biological studies and chemosensitivity analyses.

Ex Vivo Maintenance of Primary Human Multiple Myeloma Cells through the Optimization of the Osteoblastic Niche.

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Wenting Zhang

Full Text Available We previously reported a new approach for culturing difficult-to-preserve primary patient-derived multiple myeloma cells (MMC using an osteoblast (OSB-derived 3D tissue scaffold constructed in a perfused microfluidic environment and a culture medium supplemented with patient plasma. In the current study, we used this biomimetic model to show, for the first time, that the long-term survival of OSB is the most critical factor in maintaining the ex vivo viability and proliferative capacity of MMC. We found that the adhesion and retention of MMC to the tissue scaffold was meditated by osteoblastic N-cadherin, as one of potential mechanisms that regulate MMC-OSB interactions. However, in the presence of MMC and patient plasma, the viability and osteogenic activity of OSB became gradually compromised, and consequently MMC could not remain viable over 3 weeks. We demonstrated that the long-term survival of both OSB and MMC could be enhanced by: (1 optimizing perfusion flow rate and patient-derived plasma composition in the culture medium and (2 replenishing OSB during culture as a practical means of prolonging MMC's viability beyond several weeks. These findings were obtained using a high-throughput well plate-based perfusion device from the perspective of optimizing the ex vivo preservation of patient-derived MM biospecimens for downstream use in biological studies and chemosensitivity analyses.

Gemcitabine radiosensitizes multiple myeloma cells to low let, but not high let, irradiation

International Nuclear Information System (INIS)

Supiot, Stephane; Thillays, Francois; Rio, Emmanuel; Gouard, Sebastien; Morgenstern, Alfred; Bruchertseifer, Frank; Mahe, Marc-Andre; Chatal, Jean-Francois; Davodeau, Francois; Cherel, Michel

2007-01-01

The radiosensitizing properties of gemcitabine in relation to low Linear Energy Transfer (LET) particles (Cobalt 60) and high-LET particles (alpha-RIT 213 Bi-radiolabeled CHX-DTPA-B-B4) were analyzed. Three multiple myeloma cell lines (LP1, RPMI 8226, U266) were irradiated with or without 10 nM gemcitabine 24 h prior to radiation. Gemcitabine led to radiosensitization of LP1 and U266 cells with low-LET (Radiation Enhancement Ratio: 1.55 and 1.49, respectively) but did not radiosensitize any cell line when combined with high-LET

A novel nano-immunoassay method for quantification of proteins from CD138-purified myeloma cells: biological and clinical utility.

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Misiewicz-Krzeminska, Irena; Corchete, Luis Antonio; Rojas, Elizabeta A; Martínez-López, Joaquín; García-Sanz, Ramón; Oriol, Albert; Bladé, Joan; Lahuerta, Juan-José; Miguel, Jesús San; Mateos, María-Victoria; Gutiérrez, Norma C

2018-05-01

Protein analysis in bone marrow samples from patients with multiple myeloma has been limited by the low concentration of proteins obtained after CD138 + cell selection. A novel approach based on capillary nano-immunoassay could make it possible to quantify dozens of proteins from each myeloma sample in an automated manner. Here we present a method for the accurate and robust quantification of the expression of multiple proteins extracted from CD138-purified multiple myeloma samples frozen in RLT Plus buffer, which is commonly used for nucleic acid preservation and isolation. Additionally, the biological and clinical value of this analysis for a panel of 12 proteins essential to the pathogenesis of multiple myeloma was evaluated in 63 patients with newly diagnosed multiple myeloma. The analysis of the prognostic impact of CRBN /Cereblon and IKZF1 /Ikaros mRNA/protein showed that only the protein levels were able to predict progression-free survival of patients; mRNA levels were not associated with prognosis. Interestingly, high levels of Cereblon and Ikaros proteins were associated with longer progression-free survival only in patients who received immunomodulatory drugs and not in those treated with other drugs. In conclusion, the capillary nano-immunoassay platform provides a novel opportunity for automated quantification of the expression of more than 20 proteins in CD138 + primary multiple myeloma samples. Copyright © 2018 Ferrata Storti Foundation.

Design and development of the Australian and New Zealand (ANZ myeloma and related diseases registry

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Krystal Bergin

2016-11-01

Full Text Available Abstract Background Plasma cell dyscrasias (PCD are a spectrum of disorders resulting from the clonal expansion of plasma cells, ranging from the pre-malignant condition monoclonal gammopathy of undetermined significance (MGUS to multiple myeloma (MM. MM generates a significant burden of disease on the community and it is predicted that it will increase in both incidence and prevalence owing to an ageing population and longer survival secondary to new therapeutic options. Robust and comprehensive clinical data are currently lacking but are required to define current diagnostic, investigational and management patterns in Australia and New Zealand (ANZ for comparison to both local and international guidelines for standards of care. A clinical registry can provide this information and subsequently support development of strategies to address any differences, including providing a platform for clinical trials. The Myeloma and Related Diseases Registry (MRDR was developed to monitor and explore variations in practices, processes and outcomes in ANZ and provide benchmark outcomes nationally and internationally for PCD. This paper describes the MRDR aims, development and implementation and discusses challenges encountered in the process. Methods The MRDR was established in 2012 as an online database for a multi-centre collaboration across ANZ, collecting prospective data on patients with a diagnosis of MGUS, MM, solitary plasmacytoma or plasma cell leukaemia. Development of the MRDR required multi-disciplinary team participation, IT and biostatistical support as well as financial resources. Results More than 1250 patients have been enrolled at 23 sites to date. Here we describe how database development, data entry and securing ethics approval have been major challenges for participating sites and the coordinating centre, and our approaches to resolving them. Now established, the MRDR will provide clinically relevant and credible monitoring, therapy and

A Next-Generation Sequencing Strategy for Evaluating the Most Common Genetic Abnormalities in Multiple Myeloma.

Science.gov (United States)

Jiménez, Cristina; Jara-Acevedo, María; Corchete, Luis A; Castillo, David; Ordóñez, Gonzalo R; Sarasquete, María E; Puig, Noemí; Martínez-López, Joaquín; Prieto-Conde, María I; García-Álvarez, María; Chillón, María C; Balanzategui, Ana; Alcoceba, Miguel; Oriol, Albert; Rosiñol, Laura; Palomera, Luis; Teruel, Ana I; Lahuerta, Juan J; Bladé, Joan; Mateos, María V; Orfão, Alberto; San Miguel, Jesús F; González, Marcos; Gutiérrez, Norma C; García-Sanz, Ramón

2017-01-01

Identification and characterization of genetic alterations are essential for diagnosis of multiple myeloma and may guide therapeutic decisions. Currently, genomic analysis of myeloma to cover the diverse range of alterations with prognostic impact requires fluorescence in situ hybridization (FISH), single nucleotide polymorphism arrays, and sequencing techniques, which are costly and labor intensive and require large numbers of plasma cells. To overcome these limitations, we designed a targeted-capture next-generation sequencing approach for one-step identification of IGH translocations, V(D)J clonal rearrangements, the IgH isotype, and somatic mutations to rapidly identify risk groups and specific targetable molecular lesions. Forty-eight newly diagnosed myeloma patients were tested with the panel, which included IGH and six genes that are recurrently mutated in myeloma: NRAS, KRAS, HRAS, TP53, MYC, and BRAF. We identified 14 of 17 IGH translocations previously detected by FISH and three confirmed translocations not detected by FISH, with the additional advantage of breakpoint identification, which can be used as a target for evaluating minimal residual disease. IgH subclass and V(D)J rearrangements were identified in 77% and 65% of patients, respectively. Mutation analysis revealed the presence of missense protein-coding alterations in at least one of the evaluating genes in 16 of 48 patients (33%). This method may represent a time- and cost-effective diagnostic method for the molecular characterization of multiple myeloma. Copyright © 2017 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.

Prolonged early G1 arrest by selective CDK4/CDK6 inhibition sensitizes myeloma cells to cytotoxic killing through cell cycle–coupled loss of IRF4

Science.gov (United States)

Huang, Xiangao; Di Liberto, Maurizio; Jayabalan, David; Liang, Jun; Ely, Scott; Bretz, Jamieson; Shaffer, Arthur L.; Louie, Tracey; Chen, Isan; Randolph, Sophia; Hahn, William C.; Staudt, Louis M.; Niesvizky, Ruben; Moore, Malcolm A. S.

2012-01-01

Dysregulation of cyclin-dependent kinase 4 (CDK4) and CDK6 by gain of function or loss of inhibition is common in human cancer, including multiple myeloma, but success in targeting CDK with broad-spectrum inhibitors has been modest. By selective and reversible inhibition of CDK4/CDK6, we have developed a strategy to both inhibit proliferation and enhance cytotoxic killing of cancer cells. We show that induction of prolonged early-G1 arrest (pG1) by CDK4/CDK6 inhibition halts gene expression in early-G1 and prevents expression of genes programmed for other cell-cycle phases. Removal of the early-G1 block leads to S-phase synchronization (pG1-S) but fails to completely restore scheduled gene expression. Consequently, the IRF4 protein required to protect myeloma cells from apoptosis is markedly reduced in pG1 and further in pG1-S in response to cytotoxic agents, such as the proteasome inhibitor bortezomib. The coordinated loss of IRF4 and gain of Bim sensitize myeloma tumor cells to bortezomib-induced apoptosis in pG1 in the absence of Noxa and more profoundly in pG1-S in cooperation with Noxa in vitro. Induction of pG1 and pG1-S by reversible CDK4/CDK6 inhibition further augments tumor-specific bortezomib killing in myeloma xenografts. Reversible inhibition of CDK4/CDK6 in sequential combination therapy thus represents a novel mechanism-based cancer therapy. PMID:22718837

Prolonged early G(1) arrest by selective CDK4/CDK6 inhibition sensitizes myeloma cells to cytotoxic killing through cell cycle-coupled loss of IRF4.

Science.gov (United States)

Huang, Xiangao; Di Liberto, Maurizio; Jayabalan, David; Liang, Jun; Ely, Scott; Bretz, Jamieson; Shaffer, Arthur L; Louie, Tracey; Chen, Isan; Randolph, Sophia; Hahn, William C; Staudt, Louis M; Niesvizky, Ruben; Moore, Malcolm A S; Chen-Kiang, Selina

2012-08-02

Dysregulation of cyclin-dependent kinase 4 (CDK4) and CDK6 by gain of function or loss of inhibition is common in human cancer, including multiple myeloma, but success in targeting CDK with broad-spectrum inhibitors has been modest. By selective and reversible inhibition of CDK4/CDK6, we have developed a strategy to both inhibit proliferation and enhance cytotoxic killing of cancer cells. We show that induction of prolonged early-G(1) arrest (pG1) by CDK4/CDK6 inhibition halts gene expression in early-G(1) and prevents expression of genes programmed for other cell-cycle phases. Removal of the early-G(1) block leads to S-phase synchronization (pG1-S) but fails to completely restore scheduled gene expression. Consequently, the IRF4 protein required to protect myeloma cells from apoptosis is markedly reduced in pG1 and further in pG1-S in response to cytotoxic agents, such as the proteasome inhibitor bortezomib. The coordinated loss of IRF4 and gain of Bim sensitize myeloma tumor cells to bortezomib-induced apoptosis in pG1 in the absence of Noxa and more profoundly in pG1-S in cooperation with Noxa in vitro. Induction of pG1 and pG1-S by reversible CDK4/CDK6 inhibition further augments tumor-specific bortezomib killing in myeloma xenografts. Reversible inhibition of CDK4/CDK6 in sequential combination therapy thus represents a novel mechanism-based cancer therapy.

[Unilateral exophthalmos as the debut of a non-secretory multiple myeloma].

Science.gov (United States)

Castro-Rebollo, M; Cañones-Zafra, R; Vleming-Pinilla, E N; Drake-Rodríguez-Casanova, P; Pérez-Rico, C

2009-12-01

A 56 year-old male presented blurred vision and diplopia for 2 months, left unilateral exophthalmos, restricted ocular motility and papilledema. The imaging proofs showed osteolytic lesions in the left sphenoid bone, fourth rib and fourth dorsal vertebral body with associated masses of soft tissues. Biopsy was performed and the diagnosis of plasma cell neoplasm was established. The diagnosis of non-secretory multiple myeloma was made by analytical criteria and bone marrow biopsy. Local radiotherapy and polychemotherapy was prescribed. The ophthalmologist can play an important role in the diagnosis of systemic neoplasms that require the intervention of a multidisciplinary team.

The Imipridone ONC201 Induces Apoptosis and Overcomes Chemotherapy Resistance by Up-Regulation of Bim in Multiple Myeloma.

Science.gov (United States)

Tu, Yong-Sheng; He, Jin; Liu, Huan; Lee, Hans C; Wang, Hua; Ishizawa, Jo; Allen, Joshua E; Andreeff, Michael; Orlowski, Robert Z; Davis, Richard E; Yang, Jing

2017-10-01

In multiple myeloma, despite recent improvements offered by new therapies, disease relapse and drug resistance still occur in the majority of patients. Therefore, there is an urgent need for new drugs that can overcome drug resistance and prolong patient survival after failure of standard therapies. The imipridone ONC201 causes downstream inactivation of ERK1/2 signaling and has tumoricidal activity against a variety of tumor types, while its efficacy in preclinical models of myeloma remains unclear. In this study, we treated human myeloma cell lines and patient-derived tumor cells with ONC201. Treatment decreased cellular viability and induced apoptosis in myeloma cell lines, with IC50 values of 1 to 1.5 μM, even in those with high risk features or TP53 loss. ONC201 increased levels of the pro-apoptotic protein Bim in myeloma cells, resulting from decreased phosphorylation of degradation-promoting Bim Ser69 by ERK1/2. In addition, myeloma cell lines made resistant to several standard-of-care agents (by chronic exposure) were equally sensitive to ONC201 as their drug-naïve counterparts, and combinations of ONC201 with proteasome inhibitors had synergistic anti-myeloma activity. Overall, these findings demonstrate that ONC201 kills myeloma cells regardless of resistance to standard-of-care therapies, making it promising for clinical testing in relapsed/refractory myeloma. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Signaling Interplay between Bone Marrow Adipose Tissue and Multiple Myeloma cells.

Science.gov (United States)

Falank, Carolyne; Fairfield, Heather; Reagan, Michaela R

2016-01-01

In the year 2000, Hanahan and Weinberg (1) defined the six Hallmarks of Cancer as: self-sufficiency in growth signals, evasion of apoptosis, insensitivity to antigrowth mechanisms, tissue invasion and metastasis, limitless replicative potential, and sustained angiogenesis. Eleven years later, two new Hallmarks were added to the list (avoiding immune destruction and reprograming energy metabolism) and two new tumor characteristics (tumor-promoting inflammation and genome instability and mutation) (2). In multiple myeloma (MM), a destructive cancer of the plasma cell that grows predominantly in the bone marrow (BM), it is clear that all these hallmarks and characteristics are in play, contributing to tumor initiation, drug resistance, disease progression, and relapse. Bone marrow adipose tissue (BMAT) is a newly recognized contributor to MM oncogenesis and disease progression, potentially affecting MM cell metabolism, immune action, inflammation, and influences on angiogenesis. In this review, we discuss the confirmed and hypothetical contributions of BMAT to MM development and disease progression. BMAT has been understudied due to technical challenges and a previous lack of appreciation for the endocrine function of this tissue. In this review, we define the dynamic, responsive, metabolically active BM adipocyte. We then describe how BMAT influences MM in terms of: lipids/metabolism, hypoxia/angiogenesis, paracrine or endocrine signaling, and bone disease. We then discuss the connection between BMAT and systemic inflammation and potential treatments to inhibit the feedback loops between BM adipocytes and MM cells that support MM progression. We aim for researchers to use this review to guide and help prioritize their experiments to develop better treatments or a cure for cancers, such as MM, that associate with and may depend on BMAT.

TALEN-mediated genetic tailoring as a tool to analyze the function of acquired mutations in multiple myeloma cells

International Nuclear Information System (INIS)

Wu, X; Blackburn, P R; Tschumper, R C; Ekker, S C; Jelinek, D F

2014-01-01

Multiple myeloma (MM) is a clonal plasma cell malignancy that is initiated by a number of mutations and the process of disease progression is characterized by further acquisition of mutations. The identification and functional characterization of these myelomagenic mutations is necessary to better understand the underlying pathogenic mechanisms in this disease. Recent advancements in next-generation sequencing have made the identification of most of these mutations a reality. However, the functional characterization of these mutations has been hampered by the lack of proper and efficient tools to dissect these mutations. Here we explored the possible utility of transcription activator-like effector nuclease (TALEN) genome engineering technology to tailoring the genome of MM cells. To test this possibility, we targeted the HPRT1 gene and found that TALENs are a very robust and efficient genome-editing tool in MM cells. Using cotransfected green fluorescent protein as an enrichment marker, single-cell subclones with desirable TALEN modifications in the HPRT1 gene were obtained in as little as 3–4 weeks of time. We believe that TALENs will greatly facilitate the functional study of somatic mutations in MM as well as other cancers

Immunogenicity and persistence of the 13-valent Pneumococcal Conjugate Vaccine (PCV13) in patients with untreated Smoldering Multiple Myeloma (SMM): A pilot study.

Science.gov (United States)

Bahuaud, Mathilde; Bodilis, Hélène; Malphettes, Marion; Maugard Landre, Anaïs; Matondo, Caroline; Bouscary, Didier; Batteux, Frédéric; Launay, Odile; Fermand, Jean-Paul

2017-11-01

Smoldering multiple myeloma (SMM) is an asymptomatic clonal plasma cell disorder that frequently progress to multiple myeloma (MM), a disease at high risk of pneumococcal infections. Moreover, if the polysaccharide vaccine is poorly immunogenic in MM, the 13-valent conjugated vaccine has never been tested in clonal plasma cell disorders. We evaluated its immunogenicity for 7 serotypes in 20 patients ≥ 50 years of age with smoldering multiple myeloma (SMM) pre and post routine-vaccination with PCV13. Concentrations of IgG specific for 7 serotypes were measured at baseline, 1, 6, and 12 months after vaccination by standardized ELISA and an Opsonophagocytic Assay (OPA). The primary endpoint was the proportion of patients responding to at least 5 of the 7 serotypes by ELISA at one month. At 1 month post vaccination, 12 patients (60%) were responders by ELISA, among whom 8 were also responders by OPA. At 6 months, 6 (30% of total) of the 12 responders had persistent immunity, and only 2 (10% of total) at 12 months. These results suggested a partial response in this population and a rapid decrease in antibody levels in the first months of vaccination. Although one injection of the 13-valent pneumococcal conjugate vaccine is immunogenic in some patients with SMM, the response is transient. Repeated injections are likely to be needed for effective and sustained protection.

Large Population-Based Study Reveals Disparities in Myeloma Precursor Disease | Center for Cancer Research

Science.gov (United States)

Multiple myeloma (MM) is a cancer of plasma cells, which are antibody-producing white blood cells. Patients with MM have a characteristic excess of monoclonal antibodies, so called M proteins, in their serum, urine, or both and plasma cell infiltration into their bone marrow at multiple sites. African Americans are more than twice as likely as whites to develop MM, but the reason for this higher prevalence is not entirely clear. Since MM is nearly always preceded by the premalignant condition monoclonal gammopathy of undetermined significance (MGUS), Ola Landgren, M.D., Ph.D., a Senior Investigator in CCR’s Lymphoid Malignancies Branch, and colleagues from NCI’s Division of Cancer Epidemiology and Genetics, the Mayo Clinic, and the Centers for Disease Control and Prevention (CDC), wanted to determine whether there were also disparities in MGUS prevalence or in biomarkers associated with a high risk of MGUS progression to MM.

B and T cell screen

Science.gov (United States)

... leukemia ) A viral infection called infectious mononucleosis Blood cancer that starts in the plasma cells in the bone marrow ( multiple myeloma ) Syphilis, an STD Toxoplasmosis, an infection due to a parasite Tuberculosis An increased B cell count may be ...

Immunogenic Targets for Specific Immunotherapy in Multiple Myeloma

Directory of Open Access Journals (Sweden)

Lu Zhang

2012-01-01

Full Text Available Multiple myeloma remains an incurable disease although the prognosis has been improved by novel therapeutics and agents recently. Relapse occurs in the majority of patients and becomes fatal finally. Immunotherapy might be a powerful intervention to maintain a long-lasting control of minimal residual disease or to even eradicate disseminated tumor cells. Several tumor-associated antigens have been identified in patients with multiple myeloma. These antigens are expressed in a tumor-specific or tumor-restricted pattern, are able to elicit immune response, and thus could serve as targets for immunotherapy. This review discusses immunogenic antigens with therapeutic potential for multiple myeloma.

Recent advances in multiple myeloma: a Korean perspective.

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Hong, Junshik; Lee, Jae Hoon

2016-09-01

Epidemiologically, multiple myeloma (MM) is a malignant disorder of plasma cells with a higher incidence among Western populations than among Asians. However, there is growing evidence of a recent increase in the age-standardized incidence rate (ASR) of MM in Asian countries, particularly Korea. Application of novel agents has resulted in significant improvement of treatment outcomes, and the advances are ongoing with the recent introduction and U.S. Food and Drug Administration's approval of newer agents, including carfilzomib, ixazomib, elotuzumab, and daratumumab. In concert with the technical advances in the cytogenetic and molecular diagnostics of MM, modifications of its diagnosis and staging system have been attempted for better risk stratification. The modified diagnostic criteria from the International Myeloma Working Group in 2014 enabled a strategy of more active treatment for some patients with smoldering MM, with an ultra-high risk of progression, and fine-tuned the definition of end-organ damage, known as CRAB (hypercalcemia, renal insufficiency, anemia, and bone lesions). Considering Korea's trend of aging at an unprecedented rate, we can expect that the ASR of MM will maintain a gradual increase for many years to come; therefore, MM will be a cancer of critical importance from both medical and socioeconomic perspectives in Korea.

Intrapleural cisplatin for management of malignant pleural effusion in a patient with plasma cell leucaemia.

Science.gov (United States)

Agarwal, Abhishek; Klair, Jagpal; Patolia, Setu; Meena, Nikhil K

2015-06-29

Plasma cell leucaemia (PCL) is a rare aggressive form of multiple myeloma. It occasionally involves the pleura, causing malignant pleural effusion (MPE). MPE presents a management dilemma for physicians, given the different treatment options available with varying efficacy and side effects. We report a case of a 64-year-old man with MPE due to PCL, successfully managed with intrapleural cisplatin and a tunnelled pleural catheter. We believe this to be the first report of management of PCL-associated MPE with intrapleural cisplatin. 2015 BMJ Publishing Group Ltd.

New experimental model of multiple myeloma.

Science.gov (United States)

Telegin, G B; Kalinina, A R; Ponomarenko, N A; Ovsepyan, A A; Smirnov, S V; Tsybenko, V V; Homeriki, S G

2001-06-01

NSO/1 (P3x63Ay 8Ut) and SP20 myeloma cells were inoculated to BALB/c OlaHsd mice. NSO/1 cells allowed adequate stage-by-stage monitoring of tumor development. The adequacy of this model was confirmed in experiments with conventional cytostatics: prospidium and cytarabine caused necrosis of tumor cells and reduced animal mortality.

Characterization of IGH locus breakpoints in multiple myeloma indicates a subset of translocations appear to occur in pregerminal center B cells.

Science.gov (United States)

Walker, Brian A; Wardell, Christopher P; Johnson, David C; Kaiser, Martin F; Begum, Dil B; Dahir, Nasrin B; Ross, Fiona M; Davies, Faith E; Gonzalez, David; Morgan, Gareth J

2013-04-25

Translocations in myeloma are thought to occur solely in mature B cells in the germinal center through class switch recombination (CSR). We used a targeted captured technique followed by massively parallel sequencing to determine the exact breakpoints in both the immunoglobulin heavy chain (IGH) locus and the partner chromosome in 61 presentation multiple myeloma samples. The majority of samples (62%) have a breakpoint within the switch regions upstream of the IGH constant genes and are generated through CSR in a mature B cell. However, the proportion of CSR translocations is not consistent between cytogenetic subgroups. We find that 100% of t(4;14) are CSR-mediated; however, 21% of t(11;14) and 25% of t(14;20) are generated through DH-JH recombination activation gene-mediated mechanisms, indicating they occur earlier in B-cell development at the pro-B-cell stage in the bone marrow. These 2 groups also generate translocations through receptor revision, as determined by the breakpoints and mutation status of the segments used in 10% and 50% of t(11;14) and t(14;20) samples, respectively. The study indicates that in a significant number of cases the translocation-based etiological events underlying myeloma may arise at the pro-B-cell hematological progenitor cell level, much earlier in B-cell development than was previously thought.

Andrographolide inhibits multiple myeloma cells by inhibiting the TLR4/NF-κB signaling pathway.

Science.gov (United States)

Gao, Hui; Wang, Jianrong

2016-02-01

Andrographolide is an active component from the extract of Andrographis paniculata [(Burm.f) Nees], a medicinal plant from the Acanthaceae family. Pharmacological studies have revealed that andrographolide possesses anti-bacterial, anti-inflammatory, anti-viral, immune regulatory and hepatoprotective properties, and is efficacious in the treatment of cardiovascular diseases, while exhibiting low toxicity and low cost. The present study aimed to determine the inhibitory effects of andrographolide on the growth of multiple myeloma (MM) cells and its possible impact on the Toll-like receptor (TLR)4/nuclear factor (NF)-κB signaling pathway. Cell proliferation was detected using an MTT assay, cellular apoptosis was measured using flow cytometry, and caspase-9/3 activation were assessed using colorimetric assay kits. Furthermore, TLR4 and NF-κB protein expression was determined by western blot analysis. The results revealed that andrographolide reduced the proliferation, while increasing cellular apoptosis and caspase-9/3 activation of MM cells, in addition to downregulating the expression of TLR4 and NF-κB protein. Of note, TLR4- or NF-κB-targeting small-interfering (si)RNA enhanced the andrographolide-induced inhibition of cell proliferation and induction of apoptosis of MM cells. The results of the present study therefore suggested that andrographolide inhibited multiple myeloma cells via the TLR4/NF-κB signaling pathway.

Interleukin-6, a new target for therapy in multiple myeloma?

NARCIS (Netherlands)

van Oers, M. H.; van Zaanen, H. C.; Lokhorst, H. M.

1993-01-01

During the past few years much insight has been gained into the immunobiology of multiple myeloma. It has become evident that the growth of myeloma cells is regulated by cytokines, notably interleukin-6. In this paper a brief review is given of the evidence derived from in vitro as well as in vivo

Synergistic induction of apoptosis in multiple myeloma cells by bortezomib and hypoxia-activated prodrug TH-302, in vivo and in vitro.

Science.gov (United States)

Hu, Jinsong; Van Valckenborgh, Els; Xu, Dehui; Menu, Eline; De Raeve, Hendrik; De Bruyne, Elke; De Bryune, Elke; Xu, Song; Van Camp, Ben; Handisides, Damian; Hart, Charles P; Vanderkerken, Karin

2013-09-01

Recently, we showed that hypoxia is a critical microenvironmental factor in multiple myeloma, and that the hypoxia-activated prodrug TH-302 selectively targets hypoxic multiple myeloma cells and improves multiple disease parameters in vivo. To explore approaches for sensitizing multiple myeloma cells to TH-302, we evaluated in this study the antitumor effect of TH-302 in combination with the clinically used proteasome inhibitor bortezomib. First, we show that TH-302 and bortezomib synergistically induce apoptosis in multiple myeloma cell lines in vitro. Second, we confirm that this synergism is related to the activation of caspase cascades and is mediated by changes of Bcl-2 family proteins. The combination treatment induces enhanced cleavage of caspase-3/8/9 and PARP, and therefore triggers apoptosis and enhances the cleavage of proapoptotic BH3-only protein BAD and BID as well as the antiapoptotic protein Mcl-1. In particular, TH-302 can abrogate the accumulation of antiapoptotic Mcl-1 induced by bortezomib, and decreases the expression of the prosurvival proteins Bcl-2 and Bcl-xL. Furthermore, we found that the induction of the proapoptotic BH3-only proteins PUMA (p53-upregulated modulator of apoptosis) and NOXA is associated with this synergism. In response to the genotoxic and endoplasmic reticulum stresses by TH-302 and bortezomib, the expression of PUMA and NOXA were upregulated in p53-dependent and -independent manners. Finally, in the murine 5T33MMvv model, we showed that the combination of TH-302 and bortezomib can improve multiple disease parameters and significantly prolong the survival of diseased mice. In conclusion, our studies provide a rationale for clinical evaluation of the combination of TH-302 and bortezomib in patients with multiple myeloma.

Clinical features, outcome, and prognostic factors for survival and evolution to multiple myeloma of solitary plasmacytomas: a report of the Greek myeloma study group in 97 patients.

Science.gov (United States)

Katodritou, Eirini; Terpos, Evangelos; Symeonidis, Argiris S; Pouli, Anastasia; Kelaidi, Charikleia; Kyrtsonis, Marie-Christine; Kotsopoulou, Maria; Delimpasi, Sosana; Christoforidou, Anna; Giannakoulas, Nikolaos; Viniou, Nora-Athina; Stefanoudaki, Ekaterini; Hadjiaggelidou, Christina; Christoulas, Dimitrios; Verrou, Evgenia; Gastari, Vassiliki; Papadaki, Sofia; Polychronidou, Genovefa; Papadopoulou, Athina; Giannopoulou, Evlambia; Kastritis, Efstathios; Kouraklis, Alexandra; Konstantinidou, Pavlina; Anagnostopoulos, Achilles; Zervas, Konstantinos; Dimopoulos, Meletios A

2014-08-01

Solitary plasmacytoma (SP) is a rare plasma cell dyscrasia characterized by the presence of bone or extramedullary plasma cell tumors. The treatment of choice is local radiotherapy (R/T) ± surgical excision. The role of adjuvant chemotherapy (C/T) or novel agents (NA) is uncertain. Data related to prognostic factors are inconclusive. Herein, we describe the clinical features, survival and prognosis of 97 consecutive patients, 65 with bone SP (SBP), and 32 with extramedullary SP (SEP), diagnosed and treated in 12 Greek Myeloma Centers. Objective response rate (≥PR) and complete response (CR) was 91.8% and 61.9%, respectively, and did not differ between the 2 groups. Overall, 38 patients relapsed or progressed to multiple myeloma (MM). After a median follow-up of 60 months, 5 and 10-year overall survival (OS) probability was 92% and 89% in SEP and 86% and 69% in SBP, respectively (P = 0.2). The 5- and 10-year MM-free survival (MMFS) probability was 90% and 70% for patients with SEP vs. 59% and 50% for patients with SBP, respectively (P = 0.054). Overall, the 5- and 10-year OS probability, plasmacytoma relapse-free survival (PRFS), progression-free survival and MMFS was 84% and 78%, 72% and 58%, 58% and 43%, and 70% and 59%, respectively. In the multivariate analysis, prolonged PRFS and young age were positive predictors of OS. Achievement of CR was the only positive predictor of PRFS. Immunoparesis was the only negative predictor of progression to MM. The addition of C/T or NA-based treatment increased toxicity without offering any survival advantage over R/T. © 2014 Wiley Periodicals, Inc.

A Pictorial Review on Extraosseous Manifestations of Multiple Myelomas

International Nuclear Information System (INIS)

Seo, Jung Min; Lee, Kyung Soo; Yi, Chin A; Kim, Seong Hyun; Park, Byung Kwan; Han, Boo Kyung; Kim, Hyung Jin

2011-01-01

Extraosseous involvement of multiple myelomas can be seen clinically or radiologically in approximately 10-20% of patients at the time of initial diagnosis and may develop in an additional 15% of patients over the course of the disease. The condition can arise in any tissue of the body and its presence has been associated with more aggressive disease, a guarded prognosis, or high-dose chemotherapy. Imaging findings of extraosseous multiple myelomas are diverse. They usually show high enhancement on contrast-medium enhanced CT scans, exhibit iso-signal intensity on both T1- and T2- weighted images, and variable 18F-fluorine deoxyglucose (FDG) uptake at PET. The disease may simulate an infectious condition since it may be concurrent with underlying multiple myelomas per se or it may occur during myeloma treatment including stem cell transplantation.

Reduced Intensity Preparative Regimen Followed by Stem Cell Transplant (FAB)

Science.gov (United States)

2016-03-29

Myelodysplastic and Myeloproliferative Disorders; Acute Myelogenous Leukemia; Acute Lymphoblastic Leukemia; Chronic Myelogenous Leukemia; Multiple Myeloma; Plasma Cell Dyscrasia; Lymphoproliferative Disorders; Hematologic Diseases

Modulation of cell metabolic pathways and oxidative stress signaling contribute to acquired melphalan resistance in multiple myeloma cells

DEFF Research Database (Denmark)

Zub, Kamila Anna; Sousa, Mirta Mittelstedt Leal de; Sarno, Antonio

2015-01-01

of the AKR1C family involved in prostaglandin synthesis contribute to the resistant phenotype. Finally, selected metabolic and oxidative stress response enzymes were targeted by inhibitors, several of which displayed a selective cytotoxicity against the melphalan-resistant cells and should be further...... and pathways not previously associated with melphalan resistance in multiple myeloma cells, including a metabolic switch conforming to the Warburg effect (aerobic glycolysis), and an elevated oxidative stress response mediated by VEGF/IL8-signaling. In addition, up-regulated aldo-keto reductase levels...

CG13250, a novel bromodomain inhibitor, suppresses proliferation of multiple myeloma cells in an orthotopic mouse model

International Nuclear Information System (INIS)

Imayoshi, Natsuki; Yoshioka, Makoto; Chauhan, Jay; Nakata, Susumu; Toda, Yuki; Fletcher, Steven; Strovel, Jeffrey W.; Takata, Kazuyuki; Ashihara, Eishi

2017-01-01

Multiple myeloma (MM) is characterized by the clonal proliferation of neoplastic plasma cells. Despite a stream of new molecular targets based on better understanding of the disease, MM remains incurable. Epigenomic abnormalities contribute to the pathogenesis of MM. bromodomain 4 (BRD4), a member of the bromodomain and extraterminal (BET) family, binds to acetylated histones during M/G1 transition in the cell cycle promoting progression to S phase. In this study, we investigated the effects of a novel BET inhibitor CG13250 on MM cells. CG13250 inhibited ligand binding to BRD4 in a dose-dependent manner and with an IC 50 value of 1.1 μM. It inhibited MM proliferation in a dose-dependent manner and arrested cells in G1, resulting in the induction of apoptosis through caspase activation. CG13250 inhibited the binding of BRD4 to c-MYC promoter regions suppressing the transcription of the c-MYC gene. Administered in vivo, CG13250 significantly prolonged survival of an orthotopic MM-bearing mice. In conclusion, CG13250 is a novel bromodomain inhibitor that is a promising molecular targeting agent against MM. - Highlights: • A novel bromodomain inhibitor CG13250 suppresses MM cell proliferation. • CG13250 decreases C-MYC expression, resulting in the induction of apoptosis. • CG13250 prolongs the survivals of MM-bearing mice.

Intracranial involvement in plasmacytomas and multiple myeloma: a pictorial essay

Energy Technology Data Exchange (ETDEWEB)

Cerase, Alfonso; Gennari, Paola; Monti, Lucia; Venturi, Carlo [Azienda Ospedaliera Universitaria Senese, Unit of Diagnostic and Therapeutic Neuroradiology, and InterDepartmental Center of Nuclear Magnetic Resonance, Policlinico ' Santa Maria alle Scotte' , Siena (Italy); Tarantino, Annachiara; Muccio, Carmine Franco [Azienda Ospedaliera ' G. Rummo' , Unit of Neuroradiology, Department of Neurosciences, Benevento (Italy); Gozzetti, Alessandro [University of Siena, Unit of Hematology and Transplants, Policlinico ' Santa Maria alle Scotte' , Siena (Italy); Di Blasi, Arturo [Azienda Ospedaliera ' G. Rummo' , Unit of Pathology, Department of Oncology, Benevento (Italy)

2008-08-15

The purpose of this pictorial essay is to increase awareness of the clinical presentation, neuroradiological findings, treatment options, and neuroradiological follow-up of plasmacytomas and multiple myeloma with intracranial growth. This pictorial essay reviews the clinical features and neuroradiological findings in seven patients (four women, three men; age range at diagnosis 62-82 years) followed in two institutions. Six patients, one with IgG-{kappa} plasmacytoma, and five with IgG-{kappa}(n=3), IgG-{lambda}(n=1), and nonsecretory (n=1) multiple myeloma, had been seen over a period of 9 years in one institution, and the other patient with IgG-{kappa} plasmacytoma had been seen over a period of 3.5 years in the other. Intracranial involvement is rare, most frequently resulting from osseous lesions in the cranial vault, skull base, nose, or paranasal sinuses. Primary dural or leptomeningeal involvement is rarer. Some typical findings of a dural and/or osseous plasmacytoma include iso- to hyperdensity on CT scan, T1 equal to high signal intensity and T2 markedly hypointense signal on MRI, and high vascularity possibly documented on intraarterial digital subtraction angiography. However, the neuroradiological findings generally lack specificity, since they are generally no different from those of meningioma, metastasis, lymphoma, dural sarcoma, plasma cell granuloma, infectious meningitis, and leptomeningeal carcinomatosis. The spectrum of clinical and neuroradiological evaluation shows that intracranial involvement from plasmacytoma and multiple myeloma must be taken into account in the differential diagnosis of cranial osseous and meningeal disease. (orig.)

Diagnosis of multiple myeloma on based the material obtained by fine needle aspiration biopsy of the lungs

Directory of Open Access Journals (Sweden)

Bokun Radojka

2004-01-01

Full Text Available The patient presented in this paper was admitted to the hospital for the evaluation of radiologically revealed shadow in both lungs. In the course of diagnostic procedures, fine needle aspiration biopsy of the intrathoracic mass was performed. Cytologic analysis of the smear was performed because of clinical suspicion of plasma cell proliferative disease that was confirmed by bone marrow aspiration. Thus, the cytologic finding of intrathoracic lesion preceded the diagnosis of multiple myeloma.

Therapy assessment in multiple myeloma with PET

Energy Technology Data Exchange (ETDEWEB)

Nanni, Cristina [Medicina Nucleare Metropolitana di Bologna, Bologna (Italy); Zamagni, Elena [Bologna University School of Medicine, Seragnoli Institute of Hematology, Bologna (Italy)

2017-08-15

Multiple myeloma is a plasma cell dyscrasia producing bone lytic lesions. In recent years, a wide spectrum of therapeutic approaches are available to treat the disease: an accurate therapy assessment has, therefore, become of utmost importance. In this field, imaging is becoming a cornerstone, especially in association with clinical parameters. Among imaging procedures, FDG PET/CT is recognized to provide reliable information, achieved in a very safe and fast procedure. The literature has produced very concordant results from different groups assessing the value of FDG PET/CT as a prognostic factor in general and in therapy assessment, but some issues remain regarding a standardization of image interpretation especially in borderline cases. So far, no data regarding nor other imaging compounds and the use of hybrid tomographs PET/MR are available to define therapy assessment in PET. (orig.)

Combination therapy with carfilzomib, lenalidomide and dexamethasone (KRd) results in an unprecedented purity of the stem cell graft in newly diagnosed patients with myeloma.

Science.gov (United States)

Tageja, Nishant; Korde, Neha; Kazandjian, Dickran; Panch, Sandhya; Manasanch, Elisabet; Bhutani, Manisha; Kwok, Mary; Mailankody, Sham; Yuan, Constance; Stetler-Stevenson, Maryalice; Leitman, Susan F; Sportes, Claude; Landgren, Ola

2018-05-04

Still, many physicians give 4 cycles of combination therapy to multiple myeloma patients prior to collection of stem cells for autologous bone marrow transplant. This tradition originates from older doxorubicin-containing regiments which limited the number of cycles due to cumulative cardiotoxicity. Using older regiments, most patients had residual myeloma cells in their autologous stem-cell grafts during collection. Emerging data show that newly diagnosed multiple myeloma patients treated with modern carfilzomib/lenalidomide/dexamethasone (KRd) therapy, on average, take 6 cycles until reaching minimal residual disease (MRD) negativity. We assessed newly diagnosed patients treated with KRd focusing MRD status both in the individual patient's bone marrow, and the corresponding autologous hematopoietic progenitor cell grafts during collection. Per protocol, stem-cell collection was allowed after 4 to 8 cycles of KRd. We found similar stem-cell yield independent of the number of cycles of KRd. At stem-cell collection, 11/30 patients (36.6%) were MRD negative in their bone marrow; all 11 patients had MRD negative hematopoietic progenitor cell grafts. Furthermore, 18/19 patients who were MRD positive in their bone marrows also had MRD negative hematopoietic progenitor cell grafts. These observations support 6 cycles of KRd as an efficacious and safe induction strategy prior to stem-cell collection.

Immunogenicity and persistence of the 13-valent Pneumococcal Conjugate Vaccine (PCV13 in patients with untreated Smoldering Multiple Myeloma (SMM: A pilot study

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Mathilde Bahuaud

2017-11-01

Full Text Available Smoldering multiple myeloma (SMM is an asymptomatic clonal plasma cell disorder that frequently progress to multiple myeloma (MM, a disease at high risk of pneumococcal infections. Moreover, if the polysaccharide vaccine is poorly immunogenic in MM, the 13-valent conjugated vaccine has never been tested in clonal plasma cell disorders. We evaluated its immunogenicity for 7 serotypes in 20 patients ≥ 50 years of age with smoldering multiple myeloma (SMM pre and post routine-vaccination with PCV13.Concentrations of IgG specific for 7 serotypes were measured at baseline, 1, 6, and 12 months after vaccination by standardized ELISA and an Opsonophagocytic Assay (OPA. The primary endpoint was the proportion of patients responding to at least 5 of the 7 serotypes by ELISA at one month.At 1 month post vaccination, 12 patients (60% were responders by ELISA, among whom 8 were also responders by OPA. At 6 months, 6 (30% of total of the 12 responders had persistent immunity, and only 2 (10% of total at 12 months. These results suggested a partial response in this population and a rapid decrease in antibody levels in the first months of vaccination.Although one injection of the 13-valent pneumococcal conjugate vaccine is immunogenic in some patients with SMM, the response is transient. Repeated injections are likely to be needed for effective and sustained protection. Keywords: Immunology, Vaccines, Infectious disease

Cyclophosphamide, thalidomide, and dexamethasone as induction therapy for newly diagnosed multiple myeloma patients destined for autologous stem-cell transplantation: MRC Myeloma IX randomized trial results

Science.gov (United States)

Morgan, Gareth J.; Davies, Faith E.; Gregory, Walter M.; Bell, Sue E.; Szubert, Alexander J.; Navarro Coy, Nuria; Cook, Gordon; Feyler, Sylvia; Johnson, Peter R.E.; Rudin, Claudius; Drayson, Mark T.; Owen, Roger G.; Ross, Fiona M.; Russell, Nigel H.; Jackson, Graham H.; Child, J. Anthony

2012-01-01

Background Thalidomide is active in multiple myeloma and is associated with minimal myelosuppression, making it a good candidate for induction therapy prior to high-dose therapy with autologous stem-cell transplantation. Design and Methods Oral cyclophosphamide, thalidomide, and dexamethasone was compared with infusional cyclophosphamide, vincristine, doxorubicin, and dexamethasone in patients with newly diagnosed multiple myeloma. Results The post-induction overall response rate (≥ partial response) for the intent-to-treat population was significantly higher with cyclophosphamide-thalidomide-dexamethasone (n=555) versus cyclophosphamide-vincristine-doxorubicin-dexamethasone (n=556); 82.5% versus 71.2%; odds ratio 1.91; 95% confidence interval 1.44–2.55; P<0.0001. The complete response rates were 13.0% with cyclophosphamide-thalidomide-dexamethasone and 8.1% with cyclophos-phamide-vincristine-doxorubicin-dexamethasone (P=0.0083), with this differential response being maintained in patients who received autologous stem-cell transplantation (post-transplant complete response 50.0% versus 37.2%, respectively; P=0.00052). Cyclophosphamide-thalidomide-dexamethasone was non-inferior to cyclophosphamide-vincristine-doxorubicin-dexamethasone for progression-free and overall survival, and there was a trend toward a late survival benefit with cyclophosphamide-thalidomide-dexamethasone in responders. A trend toward an overall survival advantage for cyclophosphamide-thalidomide-dexamethasone over cyclophosphamide-vincristine-doxorubicin-dexamethasone was also observed in a subgroup of patients with favorable interphase fluorescence in situ hybridization. Compared with cyclophosphamide-vincristine-doxorubicin-dexamethasone, cyclophosphamide-thalidomide-dexamethasone was associated with more constipation and somnolence, but a lower incidence of cytopenias. Conclusions The cyclophosphamide-thalidomide-dexamethasone regimen showed improved response rates and was not inferior

Monoclonal antibody-purged bone marrow transplantation therapy for multiple myeloma.

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Anderson, K C; Andersen, J; Soiffer, R; Freedman, A S; Rabinowe, S N; Robertson, M J; Spector, N; Blake, K; Murray, C; Freeman, A

1993-10-15

Forty patients with plasma cell dyscrasias underwent high-dose chemoradiotherapy and either anti-B-cell monoclonal antibody (MoAb)-treated autologous, anti-T-cell MoAb-treated HLA-matched sibling allogeneic or syngeneic bone marrow transplantation (BMT). The majority of patients had advanced Durie-Salmon stage myeloma at diagnosis, all were pretreated with chemotherapy, and 17 had received prior radiotherapy. At the time of BMT, all patients demonstrated good performance status with Karnofsky score of 80% or greater and had less than 10% marrow tumor cells; 34 patients had residual monoclonal marrow plasma cells and 38 patients had paraprotein. Following high-dose chemoradiotherapy, there were 18 complete responses (CR), 18 partial responses, one non-responder, and three toxic deaths. Granulocytes greater than 500/microL and untransfused platelets greater than 20,000/microL were noted at a median of 23 (range, 12 to 46) and 25 (range, 10 to 175) days posttransplant (PT), respectively, in 24 of the 26 patients who underwent autografting. In the 14 patients who received allogeneic or syngeneic grafts, granulocytes greater than 500/microL and untransfused platelets greater than 20,000/microL were noted at a median of 19 (range, 12 to 24) and 16 (range, 5 to 32) days PT, respectively. With 24 months median follow-up for survival after autologous BMT, 16 of 26 patients are alive free from progression at 2+ to 55+ months PT; of these, 5 patients remain in CR at 6+ to 55+ months PT. With 24 months median follow-up for survival after allogeneic and syngeneic BMT, 8 of 14 patients are alive free from progression at 8+ to 34+ months PT; of these, 5 patients remain in CR at 8+ to 34+ months PT. This therapy has achieved high response rates and prolonged progression-free survival in some patients and proven to have acceptable toxicity. However, relapses post-BMT, coupled with slow engraftment post-BMT in heavily pretreated patients, suggest that such treatment strategies

Haematopoietic stem cell transplantation as first-line treatment in myeloma: a global perspective of current concepts and future possibilities

Directory of Open Access Journals (Sweden)

Catriona Elizabeth Mactier

2012-10-01

Full Text Available Stem cell transplantation forms an integral part of the treatment for multiple myeloma. This paper reviews the current role of transplantation and the progress that has been made in order to optimize the success of this therapy. Effective induction chemotherapy is important and a combination regimen incorporating the novel agent bortezomib is now favorable. Adequate induction is a crucial adjunct to stem cell transplantation and in some cases may potentially postpone the need for transplant. Different conditioning agents prior to transplantation have been explored: high-dose melphalan is most commonly used and bortezomib is a promising additional agent. There is no well-defined superior transplantation protocol but single or tandem autologous stem cell transplantations are those most commonly used, with allogeneic transplantation only used in clinical trials. The appropriate timing of transplantation in the treatment plan is a matter of debate. Consolidation and maintenance chemotherapies, particularly thalidomide and bortezomib, aim to improve and prolong disease response to transplantation and delay recurrence. Prognostic factors for the outcome of stem cell transplant in myeloma have been highlighted. Despite good responses to chemotherapy and transplantation, the problem of disease recurrence persists. Thus, there is still much room for improvement. Treatments which harness the graft-versus-myeloma effect may offer a potential cure for this disease. Trials of novel agents are underway, including targeted therapies for specific antigens such as vaccines and monoclonal antibodies.

Presence of Donor-Derived DNA in Semen Samples From Cancer Survivors Who Underwent Donor Stem Cell Transplant

Science.gov (United States)

2014-12-08

Cancer Survivor; Chronic Myeloproliferative Disorders; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasms; Neuroblastoma; Testicular Germ Cell Tumor

Paclitaxel-Fe3O4 nanoparticles inhibit growth of CD138–  CD34– tumor stem-like cells in multiple myeloma-bearing mice

Directory of Open Access Journals (Sweden)

Yang C

2013-04-01

Full Text Available Cuiping Yang,1,3,* Jing Wang,2,* Dengyu Chen,1,* Junsong Chen,1 Fei Xiong,4 Hongyi Zhang,1 Yunxia Zhang,2 Ning Gu,4 Jun Dou11Department of Pathogenic Biology and Immunology, Medical School, 2Department of Gynecology and Obstetrics, Zhongda Hospital, Southeast University, Nanjing, 3Department of Pathogenic Biology and Immunology, School of Basic Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang, 4School of Biological Science and Medical Engineering, Southeast University, Nanjing, People’s Republic of China*These authors contributed equally to this workBackground: There is growing evidence that CD138– CD34– cells may actually be tumor stem cells responsible for initiation and relapse of multiple myeloma. However, effective drugs targeted at CD138– CD34– tumor stem cells are yet to be developed. The purpose of this study was to investigate the inhibitory effect of paclitaxel-loaded Fe3O4 nanoparticles (PTX-NPs on CD138– CD34– tumor stem cells in multiple myeloma-bearing mice.Methods: CD138– CD34– cells were isolated from a human U266 multiple myeloma cell line using an immune magnetic bead sorting method and then subcutaneously injected into mice with nonobese diabetic/severe combined immunodeficiency to develop a multiple myeloma-bearing mouse model. The mice were treated with Fe3O4 nanoparticles 2 mg/kg, paclitaxel 4.8 mg/kg, and PTX-NPs 0.64 mg/kg for 2 weeks. Tumor growth, pathological changes, serum and urinary interleukin-6 levels, and molecular expression of caspase-3, caspase-8, and caspase-9 were evaluated.Results: CD138– CD34– cells were found to have tumor stem cell characteristics. All the mice developed tumors in 40 days after injection of 1 × 106 CD138– CD34– tumor stem cells. Tumor growth in mice treated with PTX-NPs was significantly inhibited compared with the controls (P <  0.005, and the groups that received nanoparticles alone (P < 0.005 or paclitaxel alone (P < 0.05. In addition

Alpha Particles Induce Autophagy in Multiple Myeloma Cells.

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Gorin, Jean-Baptiste; Gouard, Sébastien; Ménager, Jérémie; Morgenstern, Alfred; Bruchertseifer, Frank; Faivre-Chauvet, Alain; Guilloux, Yannick; Chérel, Michel; Davodeau, François; Gaschet, Joëlle

2015-01-01

Radiation emitted by the radionuclides in radioimmunotherapy (RIT) approaches induce direct killing of the targeted cells as well as indirect killing through the bystander effect. Our research group is dedicated to the development of α-RIT, i.e., RIT using α-particles especially for the treatment of multiple myeloma (MM). γ-irradiation and β-irradiation have been shown to trigger apoptosis in tumor cells. Cell death mode induced by (213)Bi α-irradiation appears more controversial. We therefore decided to investigate the effects of (213)Bi on MM cell radiobiology, notably cell death mechanisms as well as tumor cell immunogenicity after irradiation. Murine 5T33 and human LP-1 MM cell lines were used to study the effects of such α-particles. We first examined the effects of (213)Bi on proliferation rate, double-strand DNA breaks, cell cycle, and cell death. Then, we investigated autophagy after (213)Bi irradiation. Finally, a coculture of dendritic cells (DCs) with irradiated tumor cells or their culture media was performed to test whether it would induce DC activation. We showed that (213)Bi induces DNA double-strand breaks, cell cycle arrest, and autophagy in both cell lines, but we detected only slight levels of early apoptosis within the 120 h following irradiation in 5T33 and LP-1. Inhibition of autophagy prevented (213)Bi-induced inhibition of proliferation in LP-1 suggesting that this mechanism is involved in cell death after irradiation. We then assessed the immunogenicity of irradiated cells and found that irradiated LP-1 can activate DC through the secretion of soluble factor(s); however, no increase in membrane or extracellular expression of danger-associated molecular patterns was observed after irradiation. This study demonstrates that (213)Bi induces mainly necrosis in MM cells, low levels of apoptosis, and autophagy that might be involved in tumor cell death.

Biological Therapy Following Chemotherapy and Peripheral Stem Cell Transplantation in Treating Patients With Cancer

Science.gov (United States)

2013-03-25

Breast Cancer; Chronic Myeloproliferative Disorders; Gestational Trophoblastic Tumor; Kidney Cancer; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Neuroblastoma; Ovarian Cancer; Sarcoma; Testicular Germ Cell Tumor

Dysregulation of CD47 and the ligands thrombospondin 1 and 2 in multiple myeloma

DEFF Research Database (Denmark)

Rendtlew Danielsen, Jannie M; Knudsen, Lene Meldgaard; Dahl, Inger Marie

2007-01-01

% of patients with monoclonal gammopathy of undetermined significance (MGUS) expressed CD47; median expression level increased 10-fold with progression from MGUS to MM. Elevated TSP1/TSP2 levels occurred in bone marrow cultures from MM patients compared with healthy donors. CD47 and TSP1/TSP2 may have......CD47 and thrombospondin 1 and 2 (TSP1 and TSP2) expression were analysed by real-time reverse transcription polymerase chain reaction in fluorescence-activated cell sorted plasma cells (PCs) from patients at consecutive stages of multiple myeloma (MM) development. 80% of MM patients, but only 39...... a potential role in the pathophysiology of MM, probably in the interaction between MM PCs and the microenvironment....

Targeting the Pim kinases in multiple myeloma.

LENUS (Irish Health Repository)

Keane, N A

2015-07-17

Multiple myeloma (MM) is a plasma cell malignancy that remains incurable. Novel treatment strategies to improve survival are urgently required. The Pims are a small family of serine\\/threonine kinases with increased expression across the hematological malignancies. Pim-2 shows highest expression in MM and constitutes a promising therapeutic target. It is upregulated by the bone marrow microenvironment to mediate proliferation and promote MM survival. Pim-2 also has a key role in the bone destruction typically seen in MM. Additional putative roles of the Pim kinases in MM include trafficking of malignant cells, promoting oncogenic signaling in the hypoxic bone marrow microenvironment and mediating resistance to therapy. A number of Pim inhibitors are now under development with lead compounds entering the clinic. The ATP-competitive Pim inhibitor LGH447 has recently been reported to have single agent activity in MM. It is anticipated that Pim inhibition will be of clinical benefit in combination with standard treatments and\\/or with novel drugs targeting other survival pathways in MM.

Hypothalamic digoxin, hemispheric chemical dominance, and oncogenesis: evidence from multiple myeloma.

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Kurup, Ravi Kumar; Kurup, Paramesware Achutha

2003-12-01

This study assessed the changes in the isoprenoid pathway and its metabolites digoxin, dolichol, and ubiquinone in multiple myeloma. The isoprenoid pathway and digoxin status were also studied for comparison in individuals of differing hemispheric dominance to find out the rote of cerebral dominance in the genesis of multiple myeloma and neoplasms. The following parameters were assessed: isoprenoid pathway metabolites, tyrosine and tryptophan catabolites, glycoconjugate metabolism, RBC membrane composition, and free radical metabolism--in multiple myeloma, as well as in individuals of differing hemispheric dominance. There was elevation in plasma HMG CoA reductase activity, serum digoxin, and dolichol, and a reduction in RBC membrane Na(+)-K+ ATPase activity, serum ubiquinone, and magnesium levels. Serum tryptophan, serotonin, nicotine, strychnine, and quinolinic acid were elevated, while tyrosine, dopamine, noradrenaline, and morphine were decreased. The total serum glycosaminoglycans and glycosaminoglycan fractions, the activity of GAG degrading enzymes and glycohydrolases, carbohydrate residues of glycoproteins, and serum glycolipids were elevated. The RBC membrane glycosaminoglycans, hexose, and fucose residues of glycoproteins, cholesterol, and phospholipids were reduced. The activity of all free-radical scavenging enzymes, concentration of glutathione, iron binding capacity, and ceruloplasmin decreased significantly, while the concentration of lipid peroxidation products and nitric oxide increased. Hyperdigoxinemia-related altered intracellular Ca++/Mg++ ratios mediated oncogene activation, dolichol-induced altered glycoconjugate metabolism, and ubiquinone deficiency-related mitochondrial dysfunction can contribute to the pathogenesis of multiple myeloma. The biochemical patterns obtained in multiple myeloma are similar to those obtained in left-handed/right hemispheric chemically dominant individuals by the dichotic listening test. But all the patients with

Acquired amylase production induced by radiotherapy in a myeloma patient

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Yamakawa, Tamami; Nagoshi, Haruhisa; Takahashi, Atushi [Saint Marianna Univ., Kawasaki, Kanagawa (Japan). School of Medicine] [and others

1995-10-01

A 55-year-old patient with multiple myeloma (IgG-{lambda}) diagnosed in November 1988 was admitted because of bone pain throughout the body. After plasmapheresis and several courses of chemotherapy, a massive tumor of the left thoracic wall involving the rib appeared. Radiotherapy was performed to ameliorate the severe chest pain, after which myelomatous pleural effusion appeared on the left side. The serum, urine and pleural effusion revealed increased activity of amylase of the salivary type. Amylase activity was also detected in the supernatant of myeloma cells cultured from pleural effusion. We reviewed 12 cases of ectopic amylase-producing multiple myeloma. All the cases except one have been reported from Japan, and hyperamylasemia in these cases was detected at diagnosis or during course of the illness. Moreover, cytogenetic analysis of myeloma cells of previous reports revealed structural abnormalities including chromosome 1, near the amylase gene locus. This case also showed t (1; 10) (q21?; q26) by examination of 8 metaphase derived from bone marrow. These observations suggested that ectopic amylase production was induced by irradiation to the plasmacytoma of thoracic wall. (author).

Acquired amylase production induced by radiotherapy in a myeloma patient

International Nuclear Information System (INIS)

Yamakawa, Tamami; Nagoshi, Haruhisa; Takahashi, Atushi

1995-01-01

A 55-year-old patient with multiple myeloma (IgG-λ) diagnosed in November 1988 was admitted because of bone pain throughout the body. After plasmapheresis and several courses of chemotherapy, a massive tumor of the left thoracic wall involving the rib appeared. Radiotherapy was performed to ameliorate the severe chest pain, after which myelomatous pleural effusion appeared on the left side. The serum, urine and pleural effusion revealed increased activity of amylase of the salivary type. Amylase activity was also detected in the supernatant of myeloma cells cultured from pleural effusion. We reviewed 12 cases of ectopic amylase-producing multiple myeloma. All the cases except one have been reported from Japan, and hyperamylasemia in these cases was detected at diagnosis or during course of the illness. Moreover, cytogenetic analysis of myeloma cells of previous reports revealed structural abnormalities including chromosome 1, near the amylase gene locus. This case also showed t (1; 10) (q21?; q26) by examination of 8 metaphase derived from bone marrow. These observations suggested that ectopic amylase production was induced by irradiation to the plasmacytoma of thoracic wall. (author)

Immune Recovery after Cyclophosphamide Treatment in Multiple Myeloma: Implication for Maintenance Immunotherapy

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Amir Sharabi

2011-01-01

Full Text Available Multiple myeloma (MM is a progressive B-lineage neoplasia characterized by clonal proliferation of malignant plasma cells. Increased numbers of regulatory T cells (Tregs were determined in mouse models and in patients with MM, which correlated with disease burden. Thus, it became rational to target Tregs for treating MM. The effects of common chemotherapeutic drugs on Tregs are reviewed with a focus on cyclophosphamide (CYC. Studies indicated that selective depletion of Tregs may be accomplished following the administration of a low-dose CYC. We report that continuous nonfrequent administrations of CYC at low doses block the renewal of Tregs in MM-affected mice and enable the restoration of an efficient immune response against the tumor cells, thereby leading to prolonged survival and prevention of disease recurrence. Hence, distinctive time-schedule injections of low-dose CYC are beneficial for breaking immune tolerance against MM tumor cells.

Curcumin Enhances Cytotoxic Effects of Bortezomib in Human Multiple Myeloma H929 Cells: Potential Roles of NF-κB/JNK

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Qing-Xian Bai

2012-04-01

Full Text Available Combined curcumin and PS-341 treatment has been reported to enhance cytotoxicity and minimize adverse effects through ERK and p38MAPK mechanisms in human multiple myeloma cells. However, whether JNK plays similar role in this process remains unclear. In the present study, we found combined treatment altered NF-κB p65 expressions and distributions in multiple myeloma H929 cells. Western blot analysis showed combined treatment inactivated NF-κB while activated JNK signaling. Pre-treatment with JNK inhibitor SP600125 could attenuate NF-κB inactivation and restored H929 cells’ survival. These results suggested that curcumin might enhance the cytotoxicity of PS-341 by interacting with NF-κB, at least in part, through JNK mechanism.

Curcumin Enhances Bortezomib Treatment of Myeloma by Inhibiting ...

African Journals Online (AJOL)

Keywords: Curcumin, Bortezomib, Myeloma cells, Cell growth, Apoptosis, Heat shock protein 90. Tropical Journal of ... strategies have been employed, including traditional chemotherapy, ... particularly on account of bortezomib's adverse effects such as nausea, diarrhea, ... (MM.1R), which were kindly provided by Dr.

Curcumin Enhances Bortezomib Treatment of Myeloma by Inhibiting ...

African Journals Online (AJOL)

Purpose: To investigate whether curcumin augments bortezomib-induced apoptosis in myeloma cells (MM1.R line), and to explore the molecular mechanism with regard to heat shock protein 90 (HSP90) expression. Methods: MTT cell viability assay was used to assess growth inhibition of MM1.R cells at different ...

Lactobacillus in Preventing Infection in Patients Undergoing a Donor Stem Cell Transplant for Hematologic Cancer or Myelodysplastic Syndrome

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2017-02-02

Breast Cancer; Chronic Myeloproliferative Disorders; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasms; Neuroblastoma; Ovarian Cancer; Testicular Germ Cell Tumor

Adipose, Bone, and Myeloma: Contributions from the Microenvironment.

Science.gov (United States)

McDonald, Michelle M; Fairfield, Heather; Falank, Carolyne; Reagan, Michaela R

2017-05-01

Researchers globally are working towards finding a cure for multiple myeloma (MM), a destructive blood cancer diagnosed yearly in ~750,000 people worldwide (Podar et al. in Expert Opin Emerg Drugs 14:99-127, 2009). Although MM targets multiple organ systems, it is the devastating skeletal destruction experienced by over 90 % of patients that often most severely impacts patient morbidity, pain, and quality of life. Preventing bone disease is therefore a priority in MM treatment, and understanding how and why myeloma cells target the bone marrow (BM) is fundamental to this process. This review focuses on a key area of MM research: the contributions of the bone microenvironment to disease origins, progression, and drug resistance. We describe some of the key cell types in the BM niche: osteoclasts, osteoblasts, osteocytes, adipocytes, and mesenchymal stem cells. We then focus on how these key cellular players are, or could be, regulating a range of disease-related processes spanning MM growth, drug resistance, and bone disease (including osteolysis, fracture, and hypercalcemia). We summarize the literature regarding MM-bone cell and MM-adipocyte relationships and subsequent phenotypic changes or adaptations in MM cells, with the aim of providing a deeper understanding of how myeloma cells grow in the skeleton to cause bone destruction. We identify avenues and therapies that intervene in these networks to stop tumor growth and/or induce bone regeneration. Overall, we aim to illustrate how novel therapeutic target molecules, proteins, and cellular mediators may offer new avenues to attack this disease while reviewing currently utilized therapies.

Antitumoral Effect of Hibiscus sabdariffa on Human Squamous Cell Carcinoma and Multiple Myeloma Cells.

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Malacrida, Alessio; Maggioni, Daniele; Cassetti, Arianna; Nicolini, Gabriella; Cavaletti, Guido; Miloso, Mariarosaria

2016-10-01

Cancer is a leading cause of death worldwide. Despite therapeutic improvements, some cancers are still untreatable. Recently there has been an increasing interest in the use of natural substances for cancer prevention and treatment. Hibiscus sabdariffa (HS) is a plant, belonging to Malvaceae family, widespread in South Asia and Central Africa. HS extract (HSE) used in folk medicine, gained researchers' interest thanks to its antioxidant, anti-inflammatory, and chemopreventive properties. In the present study, we initially assessed HSE effect on a panel of human tumor cell lines. Then we focused our study on the following that are most sensitive to HSE action cell lines: Multiple Myeloma (MM) cells (RPMI 8226) and Oral Squamous Cell Carcinoma (OSCC) cells (SCC-25). In both RPMI 8226 and SCC-25 cells, HSE impaired cell growth, exerted a reversible cytostatic effect, and reduced cell motility and invasiveness. We evaluated the involvement of MAPKs ERK1/2 and p38 in HSE effects by using specific inhibitors, U0126 and SB203580, respectively. For both SCC-25 and RPMI 8226, HSE cytostatic effect depends on p38 activation, whereas ERK1/2 modulation is crucial for cell motility and invasiveness. Our results suggest that HSE may be a potential therapeutic agent against MM and OSCC.

Cellular immune responses against CT7 (MAGE-C1) and humoral responses against other cancer-testis antigens in multiple myeloma patients.

Science.gov (United States)

Lendvai, Nikoletta; Gnjatic, Sacha; Ritter, Erika; Mangone, Michael; Austin, Wayne; Reyner, Karina; Jayabalan, David; Niesvizky, Ruben; Jagannath, Sundar; Bhardwaj, Nina; Chen-Kiang, Selina; Old, Lloyd J; Cho, Hearn Jay

2010-01-29

The type I melanoma antigen gene (MAGE) proteins CT7 (MAGE-C1) and MAGE-A3 are commonly expressed in multiple myeloma (MM), and their expression correlates with increased plasma cell proliferation and poor clinical outcome. They belong to the cancer-testis antigen (CTAg) group of tumor-associated proteins, some of which elicit spontaneous immune responses in cancer patients. CT7 and MAGE-A3 are promising antigenic targets for therapeutic tumor vaccines in myeloma; therefore, it is critical to determine if they are immunogenic in MM patients. We analyzed cellular and humoral immune responses against CTAgs in patients with plasma cell dyscrasias: MM, monoclonal gammopathy of undetermined significance (MGUS), and Waldenström's macroglobulinemia (WM). Bone marrow lymphocytes from two of four untreated MM patients exhibited CT7-specific cellular immune responses as measured by an autologous cellular immunity assay, the first such immune response to CT7 to be reported in cancer patients. Sera from 24 patients were screened by ELISA for humoral immune responses to CTAgs. Two patients with MM demonstrated positive titers, one for MAGE-A1 and the other for SSX1. These data demonstrate that CTAgs, particularly CT7, are immunogenic in MM patients and merit further exploration as targets of immunological therapy in MM.

Adding Fludarabine to Cyclophophamide-dexamethason induction therapy impair stem cell harvest in MM

DEFF Research Database (Denmark)

Johnsen, Hans Erik; Meldgaard Knudsen, Lene; Mylin, Anne Kærsgaard

BACKGROUND AND OBJECTIVES Recent data have indicated that the myeloma cell hierarchy includes resistant Recent data have indicated that the myeloma cell hierarchy includes resistant circulating clonal memory B cells, which differ considerably from the classical end stage plasma cells infiltrating......, placebo controlled, single blinded, phase II study evaluating This was a randomized, placebo controlled, single blinded, phase II study evaluating toxicity and safety of Fludarabine added to Cyclophosphamide and Dexamethasone (CyDex) as induction therapy in younger patients with untreated and treatment...

Bismuth adjuvant ameliorates adverse effects of high-dose chemotherapy in patients with multiple myeloma and malignant lymphoma undergoing autologous stem cell transplantation

DEFF Research Database (Denmark)

Hansen, Per Boye; Penkowa, Milena

2017-01-01

show for the first time that bismuth significantly reduces grade 2 stomatitis, febrile neutropenia and infections caused by melphalan in multiple myeloma, where adverse effects also were significantly linked to gender. In lymphoma patients, bismuth significantly reduces diarrhoea relative to placebo......PURPOSE: High-dose chemotherapy prior to autologous stem cell transplantation (ASCT) leads to adverse effects including mucositis, neutropenia and bacteremia. To reduce the toxicity, we treated myeloma and lymphoma patients with peroral bismuth as an adjuvant to chemotherapy to convey...

Development and biological evaluation of 99mTc-tocilizumab as molecular imaging agent in multiple myeloma

International Nuclear Information System (INIS)

Gutierrez, M.

2012-01-01

Multiple myeloma (M M) is a neoplasm characterized by infiltration of malignant plasma cells in the bone marrow, and is associated with high levels of monoclonal protein component or M. One of the key molecules involved in the pathogenesis of M M is the interleukin I L-6. This is a polypeptide belonging to the class of cytokines helical, having antiinflammatory activity and pro inflammatory and is secreted by a wide variety of cells. It has been found that high levels of I L-6 are directly related to the growth and survival of M M cell proliferation therefore I L antagonists may be of potential use therapeutic and diagnostic purposes. The Tocilizumab (Act emr To®) is a humanized monoclonal antibody directed against the receptor, both soluble and membrane I L-6 blocking cell signaling mediated by this. The possibility of combining Tocilizumab a gamma emitting isotope would determine l to topography where an increased expression of I L, with the consequent possibility that this associated with an infectious or neoplastic process is observed. In this way it could be used as a diagnostic method. Based on the above, the present work aims to develop the marking and evaluation of 99m Tc Tocilizumab, which could be used as diagnostic radiopharmaceutical to determine the location of the lesion and its extension, both debut in monitoring patients with multiple myeloma

Platelet factor-4 and its p17-70 peptide inhibit myeloma proliferation and angiogenesis in vivo

International Nuclear Information System (INIS)

Yang, Longjiang; Du, Juan; Hou, Jian; Jiang, Hua; Zou, Jianfeng

2011-01-01

Angiogenesis plays an important role in the development of multiple myeloma (MM). The interaction between MM cells and the bone marrow microenvironment stimulates the proliferation and migration of endothelial progenitor cells (EPCs). Vascular endothelial growth factor (VEGF) contributes to the formation of new blood vessels by actively recruiting circulating EPCs. The production of proangiogenic and antiangiogenic factors is also dysregulated in MM. Platelet factor 4 (PF4) is a potent angiostatic cytokine that inhibits angiogenesis and tumor growth in several animal models. In this study, we stably transfected human myeloma cell lines with the PF4 gene or the sequence encoding its more potent p17-70 peptide and investigated the effects of PF4 and p17-70 on angiogenesis and tumor growth in vitro and in a SCID-rab myeloma model. PF4 and p17-70 significantly attenuated VEGF production, both in vitro and in vivo. In a migration study using a Transwell system, PF4 or p17-70 markedly suppressed the migration of co-cultured human endothelial progenitor cells. PF4 or p17-70 also caused a significant reduction in microvessel densities in myeloma xenografts and markedly reduced the tumor volume in the SCID mice. Kaplan-Meier analysis demonstrated that PF4 and p17-70 significantly extended the overall survival of SCID mice bearing human myeloma xenografts. Our findings indicate that PF4 or p17-70 could be valuable in combating multiple myeloma by disrupting tumor angiogenesis

Auger electron emitter against multiple myeloma - targeted endo-radio-therapy with 125I-labeled thymidine analogue 5-iodo-4'-thio-2'-deoxyuridine

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Morgenroth, Agnieszka; Dinger, Cornelia; Zlatopolskiy, Boris D.; Al-Momani, Ehab; Glatting, Gerhard; Mottaghy, Felix M.; Reske, Sven N.

2011-01-01

Introduction: Multiple myeloma (MM) is a plasma cell malignancy characterized by accumulation of malignant, terminally differentiated B cells in the bone marrow. Despite advances in therapy, MM remains an incurable disease. Novel therapeutic approaches are, therefore, urgently needed. Auger electron-emitting radiopharmaceuticals are attractive for targeted nano-irradiation therapy, given that DNA of malignant cells is selectively addressed. Here we evaluated the antimyeloma potential of the Auger electron-emitting thymidine analogue 125 I-labeled 5-iodo-4'-thio-2'-deoxyuridine ([ 125 I]ITdU). Methods: Cellular uptake and DNA incorporation of [ 125 I]ITdU were determined in fluorodeoxyuridine-pretreated KMS12BM, U266, dexamethasone-sensitive MM1.S and -resistant MM1.R cell lines. The effect of stimulation with interleukin 6 (IL6) or insulin-like growth factor 1 (IGF1) on the intracellular incorporation of [ 125 I]ITdU was investigated in cytokine-sensitive MM1.S and MM1.R cell lines. Apoptotic cells were identified using Annexin V. Cleavage of caspase 3 and PARP was visualized by Western blot. DNA fragmentation was investigated using laddering assay. Therapeutic efficiency of [ 125 I]ITdU was proven by clonogenic assay. Results: [ 125 I]ITdU was shown to be efficiently incorporated into DNA of malignant cells, providing a promising mechanism for delivering highly toxic Auger radiation emitters into tumor DNA. [ 125 I]ITdU had a potent antimyeloma effect in cell lines representing distinct disease stages and, importantly, in cell lines sensitive or resistant to the conventional therapeutic agent, but was not toxic for normal plasma and bone marrow stromal cells. Furthermore, [ 125 I]ITdU abrogated the protective actions of IL6 and IGF1 on MM cells. [ 125 I]ITdU induced massive damage in the DNA of malignant plasma cells, which resulted in efficient inhibition of clonogenic growth. Conclusion: These studies may provide a novel treatment strategy for overcoming

A descriptive study of plasma cell dyscrasias in Egyptian population

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Kassem, N.M.; Kassem, H.A.; EL Zawam, H.; EL Nahas, T.; Abd El Azeeim, H.; Abd El Azeeim; El Husseiny, N.M.

2014-01-01

Background: Plasma cell dyscrasias (PCDs) refer to a spectrum of disorders characterized by the monoclonal proliferation of lymphoplasmacytic cells in the bone marrow and, sometimes, tissue deposition of monoclonal immunoglobulins or their components. These disorders include multiple myeloma (MM) and Waldenstrom’s macroglobulinemia, as well as rare conditions such as light-chain deposition disease (LCDD) and heavy-chain diseases (HCDs). The worldwide annual incidence of MM is estimated at 86,000, which is approximately 0.8% of all new cancer cases. Purpose: Our retrospective study aims to highlight the immunologic and epidemiological features of PCDs mainly MM in Egyptian patients and compare our results with those of other populations. Methods: Two hundred seventeen Egyptian patients with PCD were enrolled in the study. Serum, urine protein electrophoresis and immunofixation were used to demonstrate M protein. Results: One hundred thirty-eight patients (63.6%) had IgG monoclonal band, 38 patients (17.5%) had IgA, 12 patients (5.5%) had Waldenstrom’s macroglobulinemia (IgM monoclonal band) and 29 patients (13.4%) were light chain myeloma. One hundred fifty-one (70%) were Kappa chain positive and 66 patients (30%) were lumbda positive. Conventional cytogenetics was available for 40 patients; of them12 patients (30%) showed 13q-. Mean OS was 37.5 months (1-84 months). Survival analysis was statistically insignificant according to age, sex and ISS or type of treatment (P value >0.05). Conclusion: Long term follow up is required to further define the role of different therapeutic lines of treatment including ASCT in the various stages of PCD based on OS data.

A descriptive study of plasma cell dyscrasias in Egyptian population.

Science.gov (United States)

Kassem, Neemat M; El Zawam, Hamdy; Kassem, Heba A; El Nahas, Tamer; El Husseiny, Noha M; El Azeeim, Hamdy Abd

2014-06-01

Plasma cell dyscrasias (PCDs) refer to a spectrum of disorders characterized by the monoclonal proliferation of lymphoplasmacytic cells in the bone marrow and, sometimes, tissue deposition of monoclonal immunoglobulins or their components. These disorders include multiple myeloma (MM) and Waldenström's macroglobulinemia, as well as rare conditions such as light-chain deposition disease (LCDD) and heavy-chain diseases (HCDs). The worldwide annual incidence of MM is estimated at 86,000, which is approximately 0.8% of all new cancer cases. Our retrospective study aims to highlight the immunologic and epidemiological features of PCDs mainly MM in Egyptian patients and compare our results with those of other populations. Two hundred seventeen Egyptian patients with PCD were enrolled in the study. Serum, urine protein electrophoresis and immunofixation were used to demonstrate M protein. One hundred thirty-eight patients (63.6%) had IgG monoclonal band, 38 patients (17.5%) had IgA, 12 patients (5.5%) had Waldenström's macroglobulinemia (IgM monoclonal band) and 29 patients (13.4%) were light chain myeloma. One hundred fifty-one (70%) were Kappa chain positive and 66 patients (30%) were lumbda positive. Conventional cytogenetics was available for 40 patients; of them12 patients (30%) showed 13q-. Mean OS was 37.5months (1-84months). Survival analysis was statistically insignificant according to age, sex and ISS or type of treatment (P value>0.05). Long term follow up is required to further define the role of different therapeutic lines of treatment including ASCT in the various stages of PCD based on OS data. Copyright © 2013. Production and hosting by Elsevier B.V.

Synchronous Bone Metastasis From Multiple Myeloma and Prostate Adenocarcinoma as Initial Presentation of Coexistent Malignancies

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Diego Andres Adrianzen Herrera

2018-04-01

Full Text Available The radiographic appearance of bone metastases is usually determined by tumor histology and can be osteolytic, osteoblastic, or mixed. We present a patient with coexistent bone metastasis from multiple myeloma and prostate adenocarcinoma who exhibited synchronous bone involvement of both histologies within the same bone lesion, a rare phenomenon that has not been previously reported and led to atypical radiographic findings. The radiograph of a 71-year-old man with thigh swelling and pain demonstrated a lytic femoral lesion. Magnetic resonance imaging (MRI confirmed a destructive process, but showed coexistent metaphyseal sclerosis. Multiple myeloma was suspected by demonstration of monoclonal gammopathy and confirmed by computed tomography (CT-guided biopsy. Incidentally, CT demonstrated areas of sclerosis corresponding to T2 hypointensity on MRI. Further studies revealed osteoblastic spinal metastasis, prostate enhancement on CT and prostate-specific antigen (PSA level of 90 ng/mL, concerning for concomitant prostate neoplasm. After endoprosthetic reconstruction, pathology of the femur identified both plasma cell neoplasm and metastatic prostate adenocarcinoma. An association between prostate cancer and multiple myeloma is hypothesized due to tumor microenvironment similarities and possible common genetic variations, however, coexisting bone metastases have never been reported. This unusual finding explains the discrepant imaging features in our patient and is evidenced that certain clinical situations merit contemplation of atypical presentations of common malignancies even if this leads to additional testing.

Stem cell mobilization with cyclophosphamide overcomes the suppressive effect of lenalidomide therapy on stem cell collection in multiple myeloma.

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Mark, Tomer; Stern, Jessica; Furst, Jessica R; Jayabalan, David; Zafar, Faiza; LaRow, April; Pearse, Roger N; Harpel, John; Shore, Tsiporah; Schuster, Michael W; Leonard, John P; Christos, Paul J; Coleman, Morton; Niesvizky, Ruben

2008-07-01

A total of 28 treatment-naïve patients with stage II or III multiple myeloma (MM) were treated with the combination of clarithromycin, lenalidomide, and dexamethasone (BiRD). Stem cells were collected following granulocyte-colony stimulating factor (G-CSF) or cyclophosphamide (Cy) plus G-CSF mobilization at maximum response. Sufficient stem cells for 2 autologous stem cell transplants were collected from all patients mobilized with Cy plus G-CSF, versus 33% mobilized with G-CSF alone (P < .0001). The duration of prior lenalidomide therapy did not correlate with success of stem cell harvests (P = .91). In conclusion, Cy can be added to G-CSF for stem cell mobilization to successfully overcome the suppressive effect of prior treatment with lenalidomide.

Monoclonal IgG in MGUS and multiple myeloma targets infectious pathogens

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Bosseboeuf, Adrien; Feron, Delphine; Tallet, Anne; Rossi, Cédric; Charlier, Cathy; Garderet, Laurent; Caillot, Denis; Moreau, Philippe; Cardó-Vila, Marina; Pasqualini, Renata; Nelson, Alfreda Destea; Wilson, Bridget S.; Perreault, Hélène; Piver, Eric; Weigel, Pierre; Harb, Jean; Bigot-Corbel, Edith; Hermouet, Sylvie

2017-01-01

Subsets of mature B cell neoplasms are linked to infection with intracellular pathogens such as Epstein-Barr virus (EBV), hepatitis C virus (HCV), or Helicobacter pylori. However, the association between infection and the immunoglobulin-secreting (Ig-secreting) B proliferative disorders remains largely unresolved. We investigated whether the monoclonal IgG (mc IgG) produced by patients diagnosed with monoclonal gammopathy of undetermined significance (MGUS) or multiple myeloma (MM) targets infectious pathogens. Antigen specificity of purified mc IgG from a large patient cohort (n = 244) was determined using a multiplex infectious-antigen array (MIAA), which screens for reactivity to purified antigens or lysates from 9 pathogens. Purified mc IgG from 23.4% of patients (57 of 244) specifically recognized 1 pathogen in the MIAA. EBV was the most frequent target (15.6%), with 36 of 38 mc IgGs recognizing EBV nuclear antigen-1 (EBNA-1). MM patients with EBNA-1–specific mc IgG (14.0%) showed substantially greater bone marrow plasma cell infiltration and higher β2-microglobulin and inflammation/infection–linked cytokine levels compared with other smoldering myeloma/MM patients. Five other pathogens were the targets of mc IgG: herpes virus simplex-1 (2.9%), varicella zoster virus (1.6%), cytomegalovirus (0.8%), hepatitis C virus (1.2%), and H. pylori (1.2%). We conclude that a dysregulated immune response to infection may underlie disease onset and/or progression of MGUS and MM for subsets of patients. PMID:28978808

Adipokines, adiposity, and bone marrow adipocytes: Dangerous accomplices in multiple myeloma.

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Morris, Emma V; Edwards, Claire M

2018-06-26

Obesity has become a global epidemic influencing the establishment and progression of a wide range of diseases, such as diabetes, cardiovascular disease, and cancer. In 2016, International Agency for Research on Cancer reported that obesity is now associated with 13 different cancers, one of which is multiple myeloma (MM), a destructive cancer of plasma cells that predominantly reside in the bone marrow. Obesity is the accumulation of excess body fat, which causes metabolic, endocrine, immunologic, and inflammatory-like changes. Obesity is usually associated with an increase in visceral and/or subcutaneous fat; however, an additional fat depot that also responds to diet-induced changes is bone marrow adipose tissue (BMAT). There have been several studies over the past few decades that have identified BMAT as a key driver in MM progression. Adipocytes secrete numerous adipokines, such as leptin, adiponectin, resistin, adipsin, and visfatin, which when secreted at normal controlled levels have protective properties. However, in obesity these levels of secretion change, coupled with an increase in adipocyte number and size causing a profound and lasting effect on the bone microenvironment, contributing to MM cell growth, survival, and migration as well as potentially fueling bone destruction. Obesity is a modifiable risk factor making it an attractive option for targeted therapy. This review discusses the link between obesity, monoclonal gammopathy of undetermined significance (a benign condition that precedes MM), and myeloma, and the contribution of key adipokines to disease establishment and progression. © 2018 Wiley Periodicals, Inc.

One-Year Follow-Up of Natural Killer Cell Activity in Multiple Myeloma Patients Treated With Adjuvant Lenalidomide Therapy

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Laurie Besson

2018-04-01

Full Text Available Multiple myeloma (MM is a proliferation of tumoral plasma B cells that is still incurable. Natural killer (NK cells can recognize and kill MM cells in vitro and can limit MM growth in vivo. Previous reports have shown that NK cell function is impaired during MM progression and suggested that treatment with immunomodulatory drugs (IMIDs such as lenalidomide (LEN could enhance it. However, the effects of IMIDs on NK cells have been tested mostly in vitro or in preclinical models and supporting evidence of their effect in vivo in patients is lacking. Here, we monitored NK cell activity in blood samples from 10 MM patients starting after frontline induction chemotherapy (CTX consisting either of association of bortezomib–lenalidomide–dexamethasone (Velcade Revlimid Dexamethasone or autologous stem-cell transplantation (SCT. We also monitored NK cell activity longitudinally each month during 1 year, after maintenance therapy with LEN. Following frontline chemotherapy, peripheral NK cells displayed a very immature phenotype and retained poor reactivity toward target cells ex vivo. Upon maintenance treatment with LEN, we observed a progressive normalization of NK cell maturation, likely caused by discontinuation of chemotherapy. However, LEN treatment neither activated NK cells nor improved their capacity to degranulate or to secrete IFN-γ or MIP1-β following stimulation with MHC-I-deficient or antibody-coated target cells. Upon LEN discontinuation, there was no reduction of NK cell effector function either. These results caution against the use of LEN as single therapy to improve NK cell activity in patients with cancer and call for more preclinical assessments of the potential of IMIDs in NK cell activation.

Antiproliferative and Antiangiogenic Effects of Punica granatum Juice (PGJ) in Multiple Myeloma (MM).

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Tibullo, Daniele; Caporarello, Nunzia; Giallongo, Cesarina; Anfuso, Carmelina Daniela; Genovese, Claudia; Arlotta, Carmen; Puglisi, Fabrizio; Parrinello, Nunziatina L; Bramanti, Vincenzo; Romano, Alessandra; Lupo, Gabriella; Toscano, Valeria; Avola, Roberto; Brundo, Maria Violetta; Di Raimondo, Francesco; Raccuia, Salvatore Antonio

2016-10-01

Multiple myeloma (MM) is a clonal B-cell malignancy characterized by an accumulation of clonal plasma cells (PC) in the bone marrow (BM) leading to bone destruction and BM failure. Despite recent advances in pharmacological therapy, MM remains a largely incurable pathology. Therefore, novel effective and less toxic agents are urgently necessary. In the last few years, pomegranate has been studied for its potential therapeutic properties including treatment and prevention of cancer. Pomegranate juice (PGJ) contains a number of potential active compounds including organic acids, vitamins, sugars, and phenolic components that are all responsible of the pro-apoptotic effects observed in tumor cell line. The aim of present investigation is to assess the antiproliferative and antiangiogenic potential of the PGJ in human multiple myeloma cell lines. Our data demonstrate the anti-proliferative potential of PGJ in MM cells; its ability to induce G0/G1 cell cycle block and its anti-angiogenic effects. Interestingly, sequential combination of bortezomib/PGJ improved the cytotoxic effect of the proteosome inhibitor. We investigated the effect of PGJ on angiogenesis and cell migration/invasion. Interestingly, we observed an inhibitory effect on the tube formation, microvessel outgrowth aorting ring and decreased cell migration and invasion as showed by wound-healing and transwell assays, respectively. Analysis of angiogenic genes expression in endothelial cells confirmed the anti-angiogenic properties of pomegranate. Therefore, PGJ administration could represent a good tool in order to identify novel therapeutic strategies for MM treatment, exploiting its anti-proliferative and anti-angiogenic effects. Finally, the present research supports the evidence that PGJ could play a key role of a future therapeutic approach for treatment of MM in order to optimize the pharmacological effect of bortezomib, especially as adjuvant after treatment.

Antiproliferative and Antiangiogenic Effects of Punica granatum Juice (PGJ in Multiple Myeloma (MM

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Daniele Tibullo

2016-10-01

Full Text Available Multiple myeloma (MM is a clonal B-cell malignancy characterized by an accumulation of clonal plasma cells (PC in the bone marrow (BM leading to bone destruction and BM failure. Despite recent advances in pharmacological therapy, MM remains a largely incurable pathology. Therefore, novel effective and less toxic agents are urgently necessary. In the last few years, pomegranate has been studied for its potential therapeutic properties including treatment and prevention of cancer. Pomegranate juice (PGJ contains a number of potential active compounds including organic acids, vitamins, sugars, and phenolic components that are all responsible of the pro-apoptotic effects observed in tumor cell line. The aim of present investigation is to assess the antiproliferative and antiangiogenic potential of the PGJ in human multiple myeloma cell lines. Our data demonstrate the anti-proliferative potential of PGJ in MM cells; its ability to induce G0/G1 cell cycle block and its anti-angiogenic effects. Interestingly, sequential combination of bortezomib/PGJ improved the cytotoxic effect of the proteosome inhibitor. We investigated the effect of PGJ on angiogenesis and cell migration/invasion. Interestingly, we observed an inhibitory effect on the tube formation, microvessel outgrowth aorting ring and decreased cell migration and invasion as showed by wound-healing and transwell assays, respectively. Analysis of angiogenic genes expression in endothelial cells confirmed the anti-angiogenic properties of pomegranate. Therefore, PGJ administration could represent a good tool in order to identify novel therapeutic strategies for MM treatment, exploiting its anti-proliferative and anti-angiogenic effects. Finally, the present research supports the evidence that PGJ could play a key role of a future therapeutic approach for treatment of MM in order to optimize the pharmacological effect of bortezomib, especially as adjuvant after treatment.

Detection and Characterization of Circulating Tumour Cells in Multiple Myeloma

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Liangxuan Zhang

2016-06-01

Full Text Available Multiple myeloma (MM remains an incurable disease despite recent therapeutic improvements. The ability to detect and characterize MM circulating tumour cells (CTCs in peripheral blood provides an alternative to replace or augment invasive bone marrow (BM biopsies with a simple blood draw, providing real-time, clinically relevant information leading to improved disease manage‐ ment and therapy selection. Here we have developed and qualified an enrichment-free, cell-based immunofluores‐ cence MM CTC assay that utilizes an automated digital pathology algorithm to distinguish MM CTCs from white blood cells (WBCs on the basis of CD138 and CD45 expression levels, as well as a number of morphological parameters. These MM CTCs were further characterized for expression of phospho-ribosomal protein S6 (pS6 as a readout for PI3K/AKT pathway activation. Clinical feasi‐ bility of the assay was established by testing blood samples from a small cohort of patients, where we detected popu‐ lations of both CD138pos and CD138neg MM CTCs. In this study, we developed an immunofluorescent cell-based assay to detect and characterize CTCs in MM.

Detection and Characterization of Circulating Tumour Cells in Multiple Myeloma

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Liangxuan Zhang

2016-01-01

Full Text Available Multiple myeloma (MM remains an incurable disease despite recent therapeutic improvements. The ability to detect and characterize MM circulating tumour cells (CTCs in peripheral blood provides an alternative to replace or augment invasive bone marrow (BM biopsies with a simple blood draw, providing real-time, clinically relevant information leading to improved disease management and therapy selection. Here we have developed and qualified an enrichment-free, cell-based immunofluorescence MM CTC assay that utilizes an automated digital pathology algorithm to distinguish MM CTCs from white blood cells (WBCs on the basis of CD138 and CD45 expression levels, as well as a number of morphological parameters. These MM CTCs were further characterized for expression of phospho-ribosomal protein S6 (pS6 as a readout for PI3K/AKT pathway activation. Clinical feasibility of the assay was established by testing blood samples from a small cohort of patients, where we detected populations of both CD138 pos and CD138 neg MM CTCs. In this study, we developed an immunofluorescent cell-based assay to detect and characterize CTCs in MM.

Involvement of multiple myeloma cell-derived exosomes in osteoclast differentiation

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Raimondi, Lavinia; De Luca, Angela; Amodio, Nicola; Manno, Mauro; Raccosta, Samuele; Taverna, Simona; Bellavia, Daniele; Naselli, Flores; Fontana, Simona; Schillaci, Odessa; Giardino, Roberto; Fini, Milena; Tassone, Pierfrancesco; Santoro, Alessandra; De Leo, Giacomo; Giavaresi, Gianluca; Alessandro, Riccardo

2015-01-01

Bone disease is the most frequent complication in multiple myeloma (MM) resulting in osteolytic lesions, bone pain, hypercalcemia and renal failure. In MM bone disease the perfect balance between bone-resorbing osteoclasts (OCs) and bone-forming osteoblasts (OBs) activity is lost in favour of OCs, thus resulting in skeletal disorders. Since exosomes have been described for their functional role in cancer progression, we here investigate whether MM cell-derived exosomes may be involved in OCs differentiation. We show that MM cells produce exosomes which are actively internalized by Raw264.7 cell line, a cellular model of osteoclast formation. MM cell-derived exosomes positively modulate pre-osteoclast migration, through the increasing of CXCR4 expression and trigger a survival pathway. MM cell-derived exosomes play a significant pro-differentiative role in murine Raw264.7 cells and human primary osteoclasts, inducing the expression of osteoclast markers such as Cathepsin K (CTSK), Matrix Metalloproteinases 9 (MMP9) and Tartrate-resistant Acid Phosphatase (TRAP). Pre-osteoclast treated with MM cell-derived exosomes differentiate in multinuclear OCs able to excavate authentic resorption lacunae. Similar results were obtained with exosomes derived from MM patient's sera. Our data indicate that MM-exosomes modulate OCs function and differentiation. Further studies are needed to identify the OCs activating factors transported by MM cell-derived exosomes. PMID:25944696

The role of single nucleotide polymorphism of IL-6 and IL-10 cytokine on pain severity and pain relief after radiotherapy in multiple myeloma patients with painful bone destructions

OpenAIRE

Rudzianskiene Milda; Inciura Arturas; Juozaityte Elona; Gerbutavicius Rolandas; Simoliuniene Renata; Ugenskiene Rasa; Raulinaityte Danguole; Rudzianskas Viktoras; Kiavialaitis Greta Emilia

2014-01-01

Multiple myeloma (MM) cells interact with bone marrow stromal cells stimulating transcription and secretion of cytokines like IL-6 and IL-10, which are implicated in the progression and dissemination of MM. Regulation of cytokines secretion is under genetic control through genetic polymorphisms in their coding and promoter sequences. It seems that single nucleotide polymorphism (SNP) in the promoter region of various genes may regulate the plasma concentrat...

Conventional chemotherapy and long-term survival in multiple myeloma patients

International Nuclear Information System (INIS)

Kraj, M; Poglod, R.; Sokolowska, U.; Kruk, B.; Maj, S.

2010-01-01

treated, 7 patients remain without treatment. The longest follow up of a still-living patient surviving multiple myeloma is 31 years since the detection of monoclonal protein and 25 years since the beginning of antitumor treatment. The longest follow-up of a still-living patient with initially isolated bone involvement is 23 years since the detection of the first bone lesion and 19 years since the generalization of the process. In 6 cases acute myeloid leukaemia and in 5 cases solid tumors were the causes of death. In 2 patients with myeloid leukemia no plasma cell infiltrates were found at autopsy; this confirms multiple myeloma cure. Conclusions. Long-term multiple myeloma survivors are a subset of patients with the following characteristics at diagnosis: median age 55 years, small tumor burden and normal cytogenetics, normal serum calcium, creatinine and beta2M concentration, IgG M-protein iso type. In one-third of patients prolonged survival occurred despite achieving only disease stabilization on conventional treatment. Continuation of anti-tumor treatment for several years is a prerequisite for long term survival. (authors)

The Mutational Landscape of Circulating Tumor Cells in Multiple Myeloma

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Yuji Mishima

2017-04-01

Full Text Available The development of sensitive and non-invasive “liquid biopsies” presents new opportunities for longitudinal monitoring of tumor dissemination and clonal evolution. The number of circulating tumor cells (CTCs is prognostic in multiple myeloma (MM, but there is little information on their genetic features. Here, we have analyzed the genomic landscape of CTCs from 29 MM patients, including eight cases with matched/paired bone marrow (BM tumor cells. Our results show that 100% of clonal mutations in patient BM were detected in CTCs and that 99% of clonal mutations in CTCs were present in BM MM. These include typical driver mutations in MM such as in KRAS, NRAS, or BRAF. These data suggest that BM and CTC samples have similar clonal structures, as discordances between the two were restricted to subclonal mutations. Accordingly, our results pave the way for potentially less invasive mutation screening of MM patients through characterization of CTCs.

Aprepitant, Granisetron, & Dexamethasone in Preventing Nausea & Vomiting in Pts. Receiving Cyclophosphamide Before a Stem Cell Transplant

Science.gov (United States)

2016-02-12

Breast Cancer; Chronic Myeloproliferative Disorders; Gestational Trophoblastic Tumor; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasms; Nausea and Vomiting; Neuroblastoma; Ovarian Cancer; Testicular Germ Cell Tumor

Timed sequential chemotherapy of cytoxan-refractory multiple myeloma with cytoxan and adriamycin based on induced tumor proliferation.

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Karp, J E; Humphrey, R L; Burke, P J

1981-03-01

Malignant plasma cell proliferation and induced humoral stimulatory activity (HSA) occur in vivo at a predictable time following drug administration. Sequential sera from 11 patients with poor-risk multiple myeloma (MM) undergoing treatment with Cytoxan (CY) 2400 mq/sq m were assayed for their in vitro effects on malignant bone marrow plasma cell tritiated thymidine (3HTdR) incorporation. Peak HSA was detected day 9 following CY. Sequential changes in marrow malignant plasma cell 3HTdR-labeling indices (LI) paralleled changes in serum activity, with peak LI occurring at the time of peak HS. An in vitro model of chemotherapy demonstrated that malignant plasma cell proliferation was enhanced by HSA, as determined by 3HTdR incorporation assay, 3HTdR LI, and tumor cells counts, and that stimulated plasma cells were more sensitive to cytotoxic effects of adriamycin (ADR) than were cells cultured in autologous pretreatment serum. Based on these studies, we designed a clinical trial to treat 12 CY-refractory poor-risk patients with MM in which ADR (60 mg/sq m) was administered at the time of peak HSA and residual tumor cell LI (day 9) following initial CY, 2400 mg/m (CY1ADR9). Eight of 12 (67%) responded to timed sequential chemotherapy with a greater than 50% decrement in monoclonal protein marker and a median survival projected to be greater than 8 mo duration (range 4-21+ mo). These clinical results using timed sequential CY1ADR9 compare favorably with results obtained using ADR in nonsequential chemotherapeutic regimens.

Autologous Graft versus Host Disease: An Emerging Complication in Patients with Multiple Myeloma

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Anu Batra

2014-01-01

Full Text Available Autologous graft versus host disease (autoGVHD is a rare transplant complication with significant morbidity and mortality. It has been hypothesized that patients with multiple myeloma might be predisposed to autoGVHD through dysregulation of the immune response resulting from either their disease, the immunomodulatory agents (IMiDs used to treat it, or transplant conditioning regimen. Hematopoietic progenitor cell (HPC products were available from 8 multiple myeloma patients with biopsy-proven autoGVHD, 16 matched multiple myeloma patients who did not develop autoGVHD, and 7 healthy research donors. The data on number of transplants prior to developing autoGVHD, mobilization regimens, exposure to proteasome inhibitors, use of IMiDs, and class I human leukocyte antigen types (HLA A and B were collected. The HPC products were analyzed by flow cytometry for expression of CD3, CD4, CD8, CD25, CD56, and FoxP3. CD3+ cell number was significantly lower in autoGVHD patients compared to unaffected controls (P=0.047. On subset analysis of CD3+ cells, CD8+ cells (but not CD4+ cells were found to be significantly lower in patients with autoGVHD (P=0.038. HLA-B55 expression was significantly associated with development of autoGVHD (P=0.032. Lower percentages of CD3+ and CD8+ T-cells and HLA-B55 expression may be predisposing factors for developing autoGVHD in myeloma.

New treatment strategies for multiple myeloma by targeting Bcl-2 and the mevalonate pathway

NARCIS (Netherlands)

Donk, N.W.C.J. van de

2003-01-01

Multiple myeloma is a B-lineage neoplasia. Enhanced proliferation and defects in the regulation of programmed cell death account for the expansion of the malignant clone. Emergence of drug resistance is the primary cause of treatment failure in myeloma. Various studies have indicated that inhibition

European perspective on multiple myeloma treatment stratgies in 2014

DEFF Research Database (Denmark)

Ludwig, Heinz; Sonneveld, Pieter; Davies, Faith

2014-01-01

The treatment of multiple myeloma has undergone significant changes and has resulted in the achievement of molecular remissions, the prolongation of remission duration, and extended survival becoming realistic goals, with a cure being possible in a small but growing number of patients. In addition...... recommendations for the management of patients with myeloma. Treatment approaches depend on "fitness," with chronological age still being an important discriminator for selecting therapy. In younger, fit patients, a short three drug-based induction treatment followed by autologous stem cell transplantation (ASCT...

Cutaneous involvement in multiple myeloma (MM): A case series with clinicopathologic correlation.

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Malysz, Jozef; Talamo, Giampaolo; Zhu, Junjia; Clarke, Loren E; Bayerl, Michael G; Ali, Liaqat; Helm, Klaus F; Chung, Catherine G

2016-05-01

Disease-specific skin lesions are rare in patients with multiple myeloma (MM). We sought to further characterize the clinical and pathologic features of patients with cutaneous involvement with MM. We identified 13 patients with cutaneous lesions of MM. Cutaneous lesions consisted of pink, red, and violaceous papules, nodules, and/or plaques that varied in size. Histopathology revealed atypical plasma cells with occasional plasmablastic features. MM had aggressive biologic features and was at an advanced stage in the majority of patients. Despite aggressive management, including chemotherapy and stem-cell transplantation, most patients died of progressive disease within a few months after the development of cutaneous lesions. The study group was relatively small. Cutaneous involvement with MM is associated with aggressive biologic behavior and short survival. Copyright © 2015 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

Omega-3 fatty acids, EPA and DHA induce apoptosis and enhance drug sensitivity in multiple myeloma cells but not in normal peripheral mononuclear cells.

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Abdi, J; Garssen, J; Faber, J; Redegeld, F A

2014-12-01

The n-3 polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been shown to enhance the effect of chemotherapeutic drugs in clinical studies in cancer patients and to induce apoptotic tumor cell death in vitro. Until now, EPA and DHA have never been investigated in multiple myeloma (MM). Human myeloma cells (L363, OPM-1, OPM-2 and U266) and normal peripheral blood mononuclear cells were exposed to EPA and DHA, and effects on mitochondrial function and apoptosis, caspase-3 activation, gene expression and drug toxicity were measured. Exposure to EPA and DHA induced apoptosis and increased sensitivity to bortezomib in MM cells. Importantly, they did not affect viability of normal human peripheral mononuclear cells. Messenger RNA expression arrays showed that EPA and DHA modulated genes involved in multiple signaling pathways including nuclear factor (NF) κB, Notch, Hedgehog, oxidative stress and Wnt. EPA and DHA inhibited NFκB activity and induced apoptosis through mitochondrial perturbation and caspase-3 activation. Our study suggests that EPA and DHA induce selective cytotoxic effects in MM and increase sensitivity to bortezomib and calls for further exploration into a potential application of these n-3 polyunsaturated fatty acids in the therapy of MM. Copyright © 2014 Elsevier Inc. All rights reserved.

Multiple Myeloma in a Patient with Acromegaly

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Yu Mi Kang

2015-03-01

Full Text Available Acromegaly is a slowly progressing condition resulting from excess growth hormone (GH, generally caused by a GH-secreting pituitary adenoma. Cancer is the third most common cause of mortality in patients with acromegaly, and insulin-like growth factor 1 (IGF-1 is known to influence tumor formation by increasing cell proliferation and inhibiting apoptosis. Multiple myeloma (MM is a plasma cell neoplasm, and previous studies have suggested the possible role of IGF-1 in its development of MM. However, no cases of acromegaly accompanied with MM have been reported in Asia to date. We here report the case of a 58-year-old woman with acromegaly accompanied with MM who presented with longstanding acromegalic manifestations resulting from a GH-secreting pituitary adenoma and also exhibited anemia, a reversed albumin/globulin ratio, and plasmacytosis on bone marrow examination. Because IGF-1 has been suggested to play an important role in the development and progression of MM, the patient promptly underwent surgical removal of the pituitary adenoma via a transsphenoidal approach. Since there is currently no consensus on therapeutic guidelines and suggested prognosis for MM with acromegaly, long-term follow-up of such cases is needed.

Translocation t(11;14 (q13;q32 and genomic imbalances in multi-ethnic multiple myeloma patients: a Malaysian study

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Ivyna Bong Pau Ni

2012-09-01

Full Text Available More than 50% of myeloma cases have normal karyotypes under conventional cytogenetic analysis due to low mitotic activity and content of plasma cells in the bone marrow. We used a polymerase chain reaction (PCR-based translocation detection assay to detect BCL1/JH t(11;14 (q13;q32 in 105 myeloma patients, and randomly selected 8 translocation positive samples for array comparative genomic hybridization (aCGH analysis. Our findings revealed 14.3% of myeloma samples were positive for BCL1/JH t(11;14 (q13;q32 translocation (n=15 of 105. We found no significant correlation between this translocation with age (P=0.420, gender (P=0.317, ethnicity (P=0.066 or new/relapsed status of multiple myeloma (P=0.412 at 95% confidence interval level by x2 test. In addition, aCGH results showed genomic imbalances in all samples analyzed. Frequent chromosomal gains were identified at regions 1q, 2q, 3p, 3q, 4p, 4q, 5q, 7q, 9q, 11q, 13q, 15q, 21q, 22q and Xq, while chromosomal losses were detected at 4q and 14q. Copy number variations at genetic loci that contain NAMPT, IVNS1ABP and STK17B genes are new findings that have not previously been reported in myeloma patients. Besides fluorescence in situ hybridization, PCR is another rapid, sensitive and simple technique that can be used for detecting BCL1/JH t(11;14(q13;q32 translocation in multiple myeloma patients. Genes located in the chromosomal aberration regions in our study, such as NAMPT, IVNS1ABP, IRF2BP2, PICALM, STAT1, STK17B, FBXL5, ACSL1, LAMP2, SAMSN1 and ATP8B4 might be potential prognostic markers and therapeutic targets in the treatment and management of multiple myeloma patients positive for BCL1/JH t(11;14 (q13;q32 translocation.

Multiple Myeloma of the Central Nervous System: 13 Cases and Review of the Literature

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Gergely Varga

2018-01-01

Full Text Available Central nervous system involvement is a rare complication of multiple myeloma with extremely poor prognosis as it usually fails to respond to therapy. We present 13 cases diagnosed at two centers in Budapest and review the current literature. The majority of our cases presented with high-risk features initially; two had plasma cell leukemia. Repeated genetic tests showed clonal evolution in 3 cases. Treatments varied according to the era, and efficacy was poor as generally reported in the literature. Only one patient is currently alive, with 3-month follow-up, and the patient responded to daratumumab-based treatment. Recent case reports show promising effectivity of pomalidomide and marizomib.

Inhibition of STAT3 signaling and induction of SHP1 mediate antiangiogenic and antitumor activities of ergosterol peroxide in U266 multiple myeloma cells

International Nuclear Information System (INIS)

Rhee, Yun-Hee; Jeong, Soo-Jin; Lee, Hyo-Jeong; Lee, Hyo-Jung; Koh, Wonil; Jung, Ji Hoon; Kim, Sun-Hee; Sung-Hoon, Kim

2012-01-01

Ergosterol peroxide (EP) derived from edible mushroom has been shown to exert anti-tumor activity in several cancer cells. In the present study, anti-angiogenic activity of EP was investigated with the underlying molecular mechanisms in human multiple myeloma U266 cells. Despite weak cytotoxicity against U266 cells, EP suppressed phosphorylation, DNA binding activity and nuclear translocalization of signal transducer and activator of transcription 3 (STAT3) in U266 cells at nontoxic concentrations. Also, EP inhibited phosphorylation of the upstream kinases Janus kinase 2 (JAK2) and Src in a time-dependent manner. Furthermore, EP increased the expression of protein tyrosine phosphatase SHP-1 at protein and mRNA levels, and conversely silencing of the SHP-1 gene clearly blocked EP-mediated STAT3 inactivation. In addition, EP significantly decreased vascular endothelial growth factor (VEGF), one of STAT3 target genes at cellular and protein levels as well as disrupted in vitro tube formation assay. Moreover, EP significantly suppressed the growth of U266 cells inoculated in female BALB/c athymic nude mice and immunohistochemistry revealed that EP effectively reduced the expression of STAT3 and CD34 in tumor sections compared to untreated control. These findings suggest that EP can exert antitumor activity in multiple myeloma U266 cells partly with antiangiogenic activity targeting JAK2/STAT3 signaling pathway as a potent cancer preventive agent for treatment of multiple myeloma cells

Donor versus no-donor comparison of newly diagnosed myeloma patients included in the HOVON-50 multiple myeloma study

NARCIS (Netherlands)

Lokhorst, Henk M.; van der Holt, Bronno; Cornelissen, Jan J.; Kersten, Marie-José; van Oers, Marinus; Raymakers, Reinier; Minnema, Monique C.; Zweegman, Sonja; Janssen, Jeroen J.; Zijlmans, Mark; Bos, Gerard; Schaap, Nicolaas; Wittebol, Shulamiet; de Weerdt, Okke; Ammerlaan, Rianne; Sonneveld, Pieter

2012-01-01

To prospectively evaluate allogeneic stem cell transplantation (allo-SCT) for myeloma as part of first-line therapy, a donor versus no-donor analysis was performed of patients treated in the HOVON-50 study, a study that was originally designed to examine thalidomide combined with intensive therapy.

Multiple myeloma on polycythemia vera following radioactive phosphorus therapy

International Nuclear Information System (INIS)

West, W.O.

1976-01-01

A 74-year-old white man with established polycythemia vera was treated with radioactive phosphorus after phlebotomies alone failed to control his disease. About 2 3 / 4 years later he died of multiple myeloma. The mutagenic effect of radioactive phosphorus may have caused or possibly accelerated preexisting myeloma. Basic nonmalignant disease deserves careful consideration before radiation or radiomimetic agents are used. One might consider a probably less mutagenic drug such as hydroxyurea in patients with polycythemia vera when phlebotomy alone does not give good control of red cell mass and thrombocytosis

Induction of Apoptosis in Human Multiple Myeloma Cell Lines by Ebselen via Enhancing the Endogenous Reactive Oxygen Species Production

OpenAIRE

Zhang, Liang; Zhou, Liwei; Du, Jia; Li, Mengxia; Qian, Chengyuan; Cheng, Yi; Peng, Yang; Xie, Jiayin; Wang, Dong

2014-01-01

Ebselen a selenoorganic compound showing glutathione peroxidase like activity is an anti-inflammatory and antioxidative agent. Its cytoprotective activity has been investigated in recent years. However, experimental evidence also shows that ebselen causes cell death in several cancer cell types whose mechanism has not yet been elucidated. In this study, we examined the effect of ebselen on multiple myeloma (MM) cell lines in vitro. The results showed that ebselen significantly enhanced the pr...

High-dose therapy improved the bone remodelling compartment canopy and bone formation in multiple myeloma

DEFF Research Database (Denmark)

Hinge, Maja; Delaissé, Jean-Marie; Plesner, Torben

2015-01-01

transplantation, and from 20 control patients with monoclonal gammopathy of undetermined significance were histomorphometrically investigated. This investigation confirmed that MM patients exhibited uncoupled bone formation to resorption and reduced canopy coverage. More importantly, this study revealed......Bone loss in multiple myeloma (MM) is caused by an uncoupling of bone formation to resorption trigged by malignant plasma cells. Increasing evidence indicates that the bone remodelling compartment (BRC) canopy, which normally covers the remodelling sites, is important for coupled bone remodelling....... Loss of this canopy has been associated with bone loss. This study addresses whether the bone remodelling in MM is improved by high-dose therapy. Bone marrow biopsies obtained from 20 MM patients, before and after first-line treatment with high-dose melphalan followed by autologous stem cell...

G3139, a Bcl-2 antisense oligodeoxynucleotide, induces clinical responses in VAD refractory myeloma

NARCIS (Netherlands)

van de Donk, N. W. C. J.; de Weerdt, O.; Veth, G.; Eurelings, M.; van Stralen, E.; Frankel, S. R.; Hagenbeek, A.; Bloem, A. C.; Lokhorst, H. M.

2004-01-01

Expression of Bcl-2 in multiple myeloma is associated with resistance to chemotherapeutic drugs. Conversely, suppression of Bcl-2 enhanced the chemosensitivity of myeloma cells in vitro. G3139 is an antisense oligodeoxynucleotide targeted to the first six codons of the Bcl-2 mRNA open reading frame.

Emerging therapies in multiple myeloma.

Science.gov (United States)

El-Amm, Joelle; Tabbara, Imad A

2015-06-01

The treatment of multiple myeloma has evolved significantly over the past 2 decades due to the use of high-dose chemotherapy and autologous stem cell transplantation, and the subsequent introduction of the immunomodulatory agents (thalidomide and lenalidomide) and the proteasome inhibitor (bortezomib). The median overall survival of multiple myeloma patients has increased significantly with patients younger than age 50 years experiencing a 10-year survival rate of around 40%. However, despite the increased effectiveness of the first-line agents, the majority of patients will eventually relapse and become drug resistant. Promising novel therapies have recently emerged and are being used to treat relapsed and refractory patients. This review will cover the clinical data regarding these emergent therapies that include new generation of proteasome inhibitors (carfilzomib, ixazomib, oprozomib, and marizomib), immunomodulatory drugs (pomalidomide), monoclonal antibodies (elotuzumab and daratumumab), signal transduction modulator (perifosine), and histone deacetylase inhibitors (vorinostat and panobinostat).

Multiple Myeloma: Patient Handbook

Science.gov (United States)

... information about myeloma in a caring and compassionate man- ner. IMF InfoLine specialists can be reached at InfoLine@myeloma.org, or 800-452-CURE (2873) or 818-487-7455. Terms and definitions Albumin (ALB): Simple water-soluble protein that is ...

Does an NKT-cell-based immunotherapeutic approach have a future in multiple myeloma?

Science.gov (United States)

Favreau, Mérédis; Vanderkerken, Karin

2016-01-01

Natural killer T (NKT) cells constitute a unique subset of innate-like T lymphocytes which differ from conventional T cells by recognizing lipid antigens presented by the non-polymorphic major histocompatibility complex (MHC) I-like molecule CD1d. Despite being a relatively infrequent population of lymphocytes, NKT cells can respond rapidly upon activation with glycosphingolipids by production of cytokines which aim to polarize different axes of the immune system. Due to their dual effector capacities, NKT cells can play a vital role in cancer immunity, infection, inflammation and autoimmune diseases. It is believed that modulation of their activity towards immune activation can be a useful tool in anti-tumor immunotherapeutic strategies. Here we summarize the characteristics of NKT cells and discuss their involvement in immunosurveillance. Furthermore, an update is given about their role and the progress that has been made in the field of multiple myeloma (MM). Finally, some challenges are discussed that are currently hampering further progress. PMID:26895468

Osteoclasts in multiple myeloma are derived from Gr-1+CD11b+myeloid-derived suppressor cells.

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Junling Zhuang

Full Text Available Osteoclasts play a key role in the development of cancer-associated osteolytic lesions. The number and activity of osteoclasts are often enhanced by tumors. However, the origin of osteoclasts is unknown. Myeloid-derived suppressor cells (MDSCs are one of the pre-metastatic niche components that are induced to expand by tumor cells. Here we show that the MDSCs can differentiate into mature and functional osteoclasts in vitro and in vivo. Inoculation of 5TGM1-GFP myeloma cells into C57BL6/KaLwRij mice led to a significant expansion of MDSCs in blood, spleen, and bone marrow over time. When grown in osteoclastogenic media in vitro, MDSCs from tumor-challenged mice displayed 14 times greater potential to differentiate into mature and functional osteoclasts than those from non-tumor controls. Importantly, MDSCs from tumor-challenged LacZ transgenic mice differentiated into LacZ+osteoclasts in vivo. Furthermore, a significant increase in tumor burden and bone loss accompanied by increased number of osteoclasts was observed in mice co-inoculated with tumor-challenged MDSCs and 5TGM1 cells compared to the control animals received 5TGM1 cells alone. Finally, treatment of MDSCs from myeloma-challenged mice with Zoledronic acid (ZA, a potent inhibitor of bone resorption, inhibited the number of osteoclasts formed in MDSC cultures and the expansion of MDSCs and bone lesions in mice. Collectively, these data provide in vitro and in vivo evidence that tumor-induced MDSCs exacerbate cancer-associated bone destruction by directly serving as osteoclast precursors.

Effects of Voltage-Gated K+ Channel on Cell Proliferation in Multiple Myeloma

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Wei Wang

2014-01-01

Full Text Available Objective. To study the effects and underlying mechanisms of voltage-gated K+ channels on the proliferation of multiple myeloma cells. Methods. RPMI-8226 MM cell line was used for the experiments. Voltage-gated K+ currents and the resting potential were recorded by whole-cell patch-clamp technique. RT-PCR detected Kv channel mRNA expression. Cell viability was analyzed with MTT assay. Cell counting system was employed to monitor cell proliferation. DNA contents and cell volume were analyzed by flow cytometry. Results. Currents recorded in RPMI-8226 cells were confirmed to be voltage-gated K+ channels. A high level of Kv1.3 mRNA was detected but no Kv3.1 mRNA was detected in RPMI-8226 cells. Voltage-gated K+ channel blocker 4-aminopyridine (4-AP (2 mM depolarized the resting potential from −42 ± 1.7 mV to −31.8 ± 2.8 mV (P0.05. Conclusions. In RPMI-8226, voltage-gated K+ channels are involved in proliferation and cell cycle progression its influence on the resting potential and cell volume may be responsible for this process; the inhibitory effect of the voltage-gated K+ channel blocker on RPMI-8226 cell proliferation is a phase-specific event.

POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, multiple myeloma and skin changes) with cranial vault plasmocytoma and the role of surgery in its management: a case report

OpenAIRE

Plata Bello, Julio; Garcia-Marin, Victor

2013-01-01

Introduction POEMS syndrome (an acronym of polyneuropathy, organomegaly, endocrinopathy, multiple myeloma and skin changes) is a paraneoplastic disorder related to an underlying plasma cell dyscrasia. The development of such a syndrome is rare and its association with calvarial plasmocytoma is even less common, with only two previous reported cases. We describe, in detail, an unusual presentation of cranial plasmocytoma associated with POEMS syndrome and briefly discuss the possible role of s...

Pleural Effusion in Multiple Myeloma.

Science.gov (United States)

Wang, Zhuo; Xia, Guoguang; Lan, Ling; Liu, Fayong; Wang, Yanxun; Liu, Baoyue; Ding, Yi; Dai, Li; Zhang, Yunjian

2016-01-01

Pleural effusion is rarely observed in patients with multiple myeloma (MM). Myeloma cell infiltration or invasion to the pleura is very rare. This study aimed to investigate the clinical characteristics of pleural effusion in patients with MM. We retrospectively reviewed the medical records of patients diagnosed with pleural effusion, MM, and pleural effusion with MM between 2004 and 2014 at Beijing Jishuitan Hospital. The present study included patients with pleural effusion who underwent cytological, bacteriological, biochemical and other testing. The cytopathology of abnormal pleural effusion cells was not diagnostic, thus flow cytometry was performed. MM was defined using the diagnosis standard of NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) 2014 for MM. This study included 3,480 pleural effusion patients and 319 MM patients. There were 34 patients with both MM and pleural effusion (17 men and 17 women). The average age was 63 years (range, 48-84 years). Pleural effusion with MM was caused by congestive heart disease, chronic renal failure, hypoalbuminemia, pulmonary infarctions, cirrhosis, pulmonary arterial hypertension, parapneumonic effusion, tuberculous pleural effusion, and myelomatous pleural effusion (MPE). The diagnosis of MPE was confirmed by the detection of myeloma cells in the pleural fluid using flow cytometric analyses. There were only 2 MPE cases in our study. The first MPE case was a woman. The first clinical manifestation was pleural effusion, and the diagnosis was non-secretory MM, DSS stage IIIA (Durie-Salmon staging system); ISS stage I (the International Staging System). The second MPE case was a man who was diagnosed with MM IgA-κ, DSS stage IIIA; ISS stage II. The detection rate of MPE was very low. MPE tended to present with yellow exudates and the lack of physical and chemical characteristics. Furthermore, patients with MPE exhibited many yellow nodules on the pleura. These nodules were lobulated and had abundant

Combined autophagy and proteasome inhibition: a phase 1 trial of hydroxychloroquine and bortezomib in patients with relapsed/refractory myeloma.

Science.gov (United States)

Vogl, Dan T; Stadtmauer, Edward A; Tan, Kay-See; Heitjan, Daniel F; Davis, Lisa E; Pontiggia, Laura; Rangwala, Reshma; Piao, Shengfu; Chang, Yunyoung C; Scott, Emma C; Paul, Thomas M; Nichols, Charles W; Porter, David L; Kaplan, Janeen; Mallon, Gayle; Bradner, James E; Amaravadi, Ravi K

2014-08-01

The efficacy of proteasome inhibition for myeloma is limited by therapeutic resistance, which may be mediated by activation of the autophagy pathway as an alternative mechanism of protein degradation. Preclinical studies demonstrate that autophagy inhibition with hydroxychloroquine augments the antimyeloma efficacy of the proteasome inhibitor bortezomib. We conducted a phase I trial combining bortezomib and hydroxychloroquine for relapsed or refractory myeloma. We enrolled 25 patients, including 11 (44%) refractory to prior bortezomib. No protocol-defined dose-limiting toxicities occurred, and we identified a recommended phase 2 dose of hydroxychloroquine 600 mg twice daily with standard doses of bortezomib, at which we observed dose-related gastrointestinal toxicity and cytopenias. Of 22 patients evaluable for response, 3 (14%) had very good partial responses, 3 (14%) had minor responses, and 10 (45%) had a period of stable disease. Electron micrographs of bone marrow plasma cells collected at baseline, after a hydroxychloroquine run-in, and after combined therapy showed therapy-associated increases in autophagic vacuoles, consistent with the combined effects of increased trafficking of misfolded proteins to autophagic vacuoles and inhibition of their degradative capacity. Combined targeting of proteasomal and autophagic protein degradation using bortezomib and hydroxychloroquine is therefore feasible and a potentially useful strategy for improving outcomes in myeloma therapy.

Genetic variants and multiple myeloma risk

DEFF Research Database (Denmark)

Martino, Alessandro; Campa, Daniele; Jurczyszyn, Artur

2014-01-01

BACKGROUND: Genetic background plays a role in multiple myeloma susceptibility. Several single-nucleotide polymorphisms (SNP) associated with genetic susceptibility to multiple myeloma were identified in the last years, but only a few of them were validated in independent studies. METHODS...... with multiple myeloma risk (P value range, 0.055-0.981), possibly with the exception of the SNP rs2227667 (SERPINE1) in women. CONCLUSIONS: We can exclude that the selected polymorphisms are major multiple myeloma risk factors. IMPACT: Independent validation studies are crucial to identify true genetic risk...

Safety of Outpatient Autologous Hematopoietic Cell Transplantation for Multiple Myeloma and Lymphoma

Science.gov (United States)

Graff, Tara M.; Singavi, Arun K.; Schmidt, William; Eastwood, Daniel; Drobyski, William R.; Horowitz, Mary; Palmer, Jeanne; Pasquini, Marcelo; Rizzo, Douglas J.; Saber, Wael; Hari, Parmeswaran; Fenske, Timothy S.

2015-01-01

Autologous peripheral stem cell transplantation (AutoHCT) is commonly an inpatient procedure. However, AutoHCT is increasingly being offered on an outpatient basis. To better characterize the safety of outpatient AutoHCT, we compared the outcome of 230 patients who underwent AutoHCT on an inpatient (IP) versus outpatient (OP) basis for myeloma or lymphoma within a single transplant program. All OP transplants occurred in a cancer center day hospital. Hematopoietic recovery occurred earlier in the OP cohort, with median time to neutrophil recovery of 10 vs. 11 days (p<0.001) and median time to platelet recovery of 19 vs. 20 days (p=0.053). 51% of the OP cohort never required admission, with this percentage increasing in later years. Grade 3–4 non-hematologic toxicities occurred in 29% of both cohorts. Non-relapse mortality at one year was 0% in the OP cohort and 1.5% in the IP cohort (p=0.327). Two year progression-free survival was 62% for OP vs. 54% for IP (p=0.155). One and two year overall survival was 97% and 83% for OP vs. 91% and 80% for IP, respectively (p=0.271). We conclude that, with daily outpatient evaluation and aggressive supportive care, outpatient AutoHCT can result in excellent outcomes for myeloma and lymphoma patients. PMID:25867651

Game Theory of Tumor–Stroma Interactions in Multiple Myeloma: Effect of Nonlinear Benefits

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Javad Salimi Sartakhti

2018-05-01

Full Text Available Cancer cells and stromal cells often exchange growth factors with paracrine effects that promote cell growth: a form of cooperation that can be studied by evolutionary game theory. Previous models have assumed that interactions between cells are pairwise or that the benefit of a growth factor is a linear function of its concentration. Diffusible factors, however, affect multiple cells and generally have nonlinear effects, and these differences are known to have important consequences for evolutionary dynamics. Here, we study tumor–stroma paracrine signaling using a model with multiplayer collective interactions in which growth factors have nonlinear effects. We use multiple myeloma as an example, modelling interactions between malignant plasma cells, osteoblasts, and osteoclasts. Nonlinear benefits can lead to results not observed in linear models, including internal mixed stable equilibria and cyclical dynamics. Models with linear effects, therefore, do not lead to a meaningful characterization of the dynamics of tumor–stroma interactions. To understand the dynamics and the effect of therapies it is necessary to estimate the shape of the benefit functions experimentally and parametrize models based on these functions.

Flow Cytometry Method as a Diagnostic Tool for Pleural Fluid Involvement in a Patient with Multiple Myeloma

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MUZAFFER KEKLIK

2012-01-01

Full Text Available

Multiple myeloma is a malignant proliferation of plasma cells that mainly affects bone marrow. Pleural effusions secondary to pleural myelomatous involvement have rarely been reported in the literature. As it is rarely detected, we aimed to report a case in which pleural effusion of a multiple myeloma was confirmed as true myelomatous involvement by flow cytometry method. A 52-years old man presented to our clinic with chest and back pain lasting for 3 months. On the chest radiography, pleural fluid was detected in left hemithorax. Pleural fluid flow cytometry was performed. In the flow cytometry, CD56, CD38 and CD138 found to be positive, while CD19 was negative. True myelomatous pleural effusions are very uncommon, with fewer than 100 cases reported worldwide. Flow cytometry is a potentially useful diagnostic tool for clinical practice. We presented our case; as it has been rarely reported, although flow cytometer is a simple method for detection of pleural fluid involvement in multiple myeloma.

Nucleotide excision repair is a potential therapeutic target in multiple myeloma

Science.gov (United States)

Szalat, R; Samur, M K; Fulciniti, M; Lopez, M; Nanjappa, P; Cleynen, A; Wen, K; Kumar, S; Perini, T; Calkins, A S; Reznichenko, E; Chauhan, D; Tai, Y-T; Shammas, M A; Anderson, K C; Fermand, J-P; Arnulf, B; Avet-Loiseau, H; Lazaro, J-B; Munshi, N C

2018-01-01

Despite the development of novel drugs, alkylating agents remain an important component of therapy in multiple myeloma (MM). DNA repair processes contribute towards sensitivity to alkylating agents and therefore we here evaluate the role of nucleotide excision repair (NER), which is involved in the removal of bulky adducts and DNA crosslinks in MM. We first evaluated NER activity using a novel functional assay and observed a heterogeneous NER efficiency in MM cell lines and patient samples. Using next-generation sequencing data, we identified that expression of the canonical NER gene, excision repair cross-complementation group 3 (ERCC3), significantly impacted the outcome in newly diagnosed MM patients treated with alkylating agents. Next, using small RNA interference, stable knockdown and overexpression, and small-molecule inhibitors targeting xeroderma pigmentosum complementation group B (XPB), the DNA helicase encoded by ERCC3, we demonstrate that NER inhibition significantly increases sensitivity and overcomes resistance to alkylating agents in MM. Moreover, inhibiting XPB leads to the dual inhibition of NER and transcription and is particularly efficient in myeloma cells. Altogether, we show that NER impacts alkylating agents sensitivity in myeloma cells and identify ERCC3 as a potential therapeutic target in MM. PMID:28588253

Auger electron emitter against multiple myeloma - targeted endo-radio-therapy with {sup 125}I-labeled thymidine analogue 5-iodo-4'-thio-2'-deoxyuridine

Energy Technology Data Exchange (ETDEWEB)

Morgenroth, Agnieszka, E-mail: amorgenroth@ukaachen.de [Nuclear Medicine Clinic, University Ulm, Albert-Einstein-Allee 23, D-89081 Ulm (Germany); Nuclear Medicine Clinic, University Aachen, RWTH, Pauwelsstrasse 30, D-52074 Aachen (Germany); Dinger, Cornelia; Zlatopolskiy, Boris D.; Al-Momani, Ehab; Glatting, Gerhard [Nuclear Medicine Clinic, University Ulm, Albert-Einstein-Allee 23, D-89081 Ulm (Germany); Mottaghy, Felix M. [Nuclear Medicine Clinic, University Aachen, RWTH, Pauwelsstrasse 30, D-52074 Aachen (Germany); Reske, Sven N. [Nuclear Medicine Clinic, University Ulm, Albert-Einstein-Allee 23, D-89081 Ulm (Germany)

2011-10-15

Introduction: Multiple myeloma (MM) is a plasma cell malignancy characterized by accumulation of malignant, terminally differentiated B cells in the bone marrow. Despite advances in therapy, MM remains an incurable disease. Novel therapeutic approaches are, therefore, urgently needed. Auger electron-emitting radiopharmaceuticals are attractive for targeted nano-irradiation therapy, given that DNA of malignant cells is selectively addressed. Here we evaluated the antimyeloma potential of the Auger electron-emitting thymidine analogue {sup 125}I-labeled 5-iodo-4'-thio-2'-deoxyuridine ([{sup 125}I]ITdU). Methods: Cellular uptake and DNA incorporation of [{sup 125}I]ITdU were determined in fluorodeoxyuridine-pretreated KMS12BM, U266, dexamethasone-sensitive MM1.S and -resistant MM1.R cell lines. The effect of stimulation with interleukin 6 (IL6) or insulin-like growth factor 1 (IGF1) on the intracellular incorporation of [{sup 125}I]ITdU was investigated in cytokine-sensitive MM1.S and MM1.R cell lines. Apoptotic cells were identified using Annexin V. Cleavage of caspase 3 and PARP was visualized by Western blot. DNA fragmentation was investigated using laddering assay. Therapeutic efficiency of [{sup 125}I]ITdU was proven by clonogenic assay. Results: [{sup 125}I]ITdU was shown to be efficiently incorporated into DNA of malignant cells, providing a promising mechanism for delivering highly toxic Auger radiation emitters into tumor DNA. [{sup 125}I]ITdU had a potent antimyeloma effect in cell lines representing distinct disease stages and, importantly, in cell lines sensitive or resistant to the conventional therapeutic agent, but was not toxic for normal plasma and bone marrow stromal cells. Furthermore, [{sup 125}I]ITdU abrogated the protective actions of IL6 and IGF1 on MM cells. [{sup 125}I]ITdU induced massive damage in the DNA of malignant plasma cells, which resulted in efficient inhibition of clonogenic growth. Conclusion: These studies may provide a

PI3K/Akt inhibitor LY294002 potentiates homoharringtonine antimyeloma activity in myeloma cells adhered to stromal cells and in SCID mouse xenograft.

Science.gov (United States)

Chen, Ping; Wen, Xiaofang; Wang, Bin; Hou, Diyu; Zou, Hong; Yuan, Qin; Yang, Hui; Xie, Jieqiong; Huang, Huifang

2018-05-01

Homoharringtonine (HHT) is a known anti-leukemia drug that inhibits multiple myeloma (MM) cells both in vitro and in vivo. Our prior study demonstrated that the potency of HHT in MM cells was compromised significantly when myeloma cells were co-cultured with BM stromal cells. This study aimed to investigate whether PI3K/Akt inhibitor LY294002 could potentiate the antimyeloma activity of HHT against MM cells adhered to BM stromal cells and in vivo xenograft models. A co-culture system composed of MM cells and human stromal cells was employed to mimic MM cells in bone marrow niche. The inhibitory and pro-apoptotic effect of HHT and LY294002 was determined by CCK-8 assay or flow cytometry. Expression of PI3K/Akt signaling molecules and anti-apoptotic protein myeloid cell leukemia-1 (Mcl-1) was assessed by western blot analysis and/or reverse transcription real-time quantitative PCR (RT-qPCR). MM xenografts were used to evaluate antitumor effect of combined therapy with HHT and LY294002. Adhesion to BM stromal cells rendered MM cells resistant to HHT whereas silencing Mcl-1 partly reversed the resistance. LY294002 induced apoptosis in MM cells and potentiated the antimyeloma effects of HHT by inhibiting the PI3K/Akt signal pathway which was abnormally activated during adhesion. LY294002 also enhanced the antimyeloma effect of HHT in in vivo xenograft models. These findings suggest that activation of PI3K/Akt signal pathway was responsible for the resistance to HHT in MM cells adhered to stromal cells. LY294002 can potentiate the antimyeloma activity of HHT both in vitro and in vivo, which may represent a new clinical treatment in MM.

GWAS of 972 autologous stem cell recipients with multiple myeloma identifies 11 genetic variants associated with chemotherapy-induced oral mucositis

DEFF Research Database (Denmark)

Coleman, Elizabeth Ann; Lee, Jeannette Y; Erickson, Stephen W

2015-01-01

PURPOSE: High-dose chemotherapy and autologous stem cell transplant (ASCT) to treat multiple myeloma (MM) and other cancers carries the risk of oral mucositis (OM) with sequelae including impaired nutritional and fluid intake, pain, and infectious complications. As a result of these problems, can...

Value of the free light chain analysis in the clinical evaluation of response in multiple myeloma patients receiving anti-myeloma therapy

DEFF Research Database (Denmark)

Toftmann Hansen, Charlotte; Pedersen, Per T.; Jensen, Bo Amdi

Value of the free light chain analysis in the clinical evaluation of response in multiple myeloma patients receiving anti-myeloma therapy.......Value of the free light chain analysis in the clinical evaluation of response in multiple myeloma patients receiving anti-myeloma therapy....

Lack of survival improvement with novel anti-myeloma agents for patients with multiple myeloma and central nervous system involvement: the Greek Myeloma Study Group experience.

Science.gov (United States)

Katodritou, Eirini; Terpos, Evangelos; Kastritis, Efstathios; Delimpasis, Sossana; Symeonidis, Argiris S; Repousis, Panagiotis; Kyrtsonis, Marie-Christine; Vadikolia, Chrysa; Michalis, Eurydiki; Polychronidou, Genovefa; Michael, Michael; Papadaki, Sofia; Papathanasiou, Maria; Kokoviadou, Kyriaki; Kioumi, Anna; Vlachaki, Eythimia; Hadjiaggelidou, Christina; Kouraklis, Alexandra; Patsias, Ioannis; Gavriatopoulou, Maria; Kotsopoulou, Maria; Verrou, Evgenia; Gastari, Vasiliki; Christoulas, Dimitrios; Giannopoulou, Evlambia; Pouli, Anastasia; Konstantinidou, Pavlina; Anagnostopoulos, Achilles; Dimopoulos, Meletios-Athanasios

2015-12-01

Involvement of the central nervous system (CNS) is a rare complication of multiple myeloma (MM). Herein, we have described the incidence, characteristics, prognostic factors for post CNS-MM survival, and outcome of CNS-MM and explored the efficacy of novel agents (NA) (thalidomide, bortezomib, lenalidomide) in this setting. Between 2000 and 2013, 31 (0.9 %) out of 3408 newly diagnosed symptomatic MM patients, consecutively diagnosed and treated during the same period in 12 Greek centers, developed CNS-MM (M/F 15/16, median age 59 years, range 20-96 years; newly diagnosed/relapsed-refractory 2/29; median time to CNS-MM diagnosis 29 months). Clinical and laboratory characteristics were retrospectively recorded. Twenty-six percent of patients had circulating plasma cells (PCs) or plasma cell leukemia (PCL) at CNS-MM and 39 % had skull-derived plasmacytomas, suggesting hematological and contiguous spread. Treatment for CNS-MM was offered in 29/31 patients and 11/29 responded (NA 18/29, additional radiotherapy 9/28, intrathecal chemotherapy 13/29). The median post CNS-MM survival was 3 months (95 % CI 1.9-4.1) and did not differ between patients treated with NA and/or radiotherapy vs. others. In the multivariate analysis, prior treatment of MM with NA, extramedullary disease (EMD) during MM course (i.e., plasmacytomas, circulating PCs, or documented PCL) and abnormally high LDH at MM diagnosis were independent prognostic factors, whereas treatment of CNS-MM with NA did not predict for post CNS-MM survival. Despite the relatively limited number of patients due to the rarity of CNS-MM, our results suggest that NA do not seem to improve post CNS-MM survival. Patients with EMD display shortened post CNS-MM survival and should be followed thoroughly.

Treatment of aggressive multiple myeloma by high-dose chemotherapy and total body irradiation followed by blood stem cells autologous graft

International Nuclear Information System (INIS)

Fermand, J.P.; Levy, Y.; Gerota, J.; Benbunan, M.; Cosset, J.M.; Castaigne, S.; Seligmann, M.; Brouet, J.C.

1989-01-01

Eight patients with stage III aggressive multiple myeloma, refractory to current chemotherapy in six cases, were treated by high-dose chemotherapy (nitrosourea, etoposide, and melphalan) (HDC) and total body irradiation (TBI), followed by autografting with blood stem cells. These cells were previously collected by leukapheresis performed during hematologic recovery following cytotoxic drug-induced bone marrow aplasia. Seven patients were alive 9 to 17 months after HDC-TBI and graft. One died at day 40 from cerebral bleeding. All living patients achieved a 90% or greater reduction in tumor mass. In two cases, a complete remission (CR) has persisted at a follow-up of 15 and 16 months. Three patients have been well and off therapy with stable minimal residual disease (RD) since 10, 11, and 17 months, respectively. A patient in apparent CR and another with RD have relapsed 9 to 12 months posttreatment. Autologous blood-derived hematopoietic stem cells induced successful and sustained engraftment in all living patients. These results, although still preliminary, indicate that HDC and TBI, followed by blood stem cells autograft, which has both practical and theoretical interest over allogeneic or autologous bone marrow transplantation, deserve consideration in selected patients with multiple myeloma

Benefit from autologous stem cell transplantation in primary refractory myeloma? Different outcomes in progressive versus stable disease

Science.gov (United States)

Rosiñol, Laura; García-Sanz, Ramón; Lahuerta, Juan José; Hernández-García, Miguel; Granell, Miquel; de la Rubia, Javier; Oriol, Albert; Hernández-Ruiz, Belén; Rayón, Consuelo; Navarro, Isabel; García-Ruiz, Juan Carlos; Besalduch, Joan; Gardella, Santiago; Jiménez, Javier López; Díaz-Mediavilla, Joaquín; Alegre, Adrián; Miguel, Jesús San; Bladé, Joan

2012-01-01

Background Several studies of autologous stem cell transplantation in primary refractory myeloma have produced encouraging results. However, the outcome of primary refractory patients with stable disease has not been analyzed separately from the outcome of patients with progressive disease. Design and Methods In the Spanish Myeloma Group 2000 trial, 80 patients with primary refractory myeloma (49 with stable disease and 31 with progressive disease), i.e. who were refractory to initial chemotherapy, were scheduled for tandem transplants (double autologous transplant or a single autologous transplant followed by an allogeneic transplant). Patients with primary refractory disease included those who never achieved a minimal response (≥25% M-protein decrease) or better. Responses were assessed using the European Bone Marrow Transplant criteria. Results There were no significant differences in the rates of partial response or better between patients with stable or progressive disease. However, 38% of the patients with stable disease at the time of transplantation remained in a stable condition or achieved a minimal response after transplantation versus 7% in the group with progressive disease (P=0.0017) and the rate of early progression after transplantation was significantly higher among the group with progressive disease at the time of transplantation (22% versus 2%; P=0.0043). After a median follow-up of 6.6 years, the median survival after first transplant of the whole series was 2.3 years. Progression-free and overall survival from the first transplant were shorter in patients with progressive disease (0.6 versus 2.3 years, P=0.00004 and 1.1 versus 6 years, P=0.00002, respectively). Conclusions Our results show that patients with progressive refractory myeloma do not benefit from autologous transplantation, while patients with stable disease have an outcome comparable to those with chemosensitive disease. (ClinicalTrials.gov:NCT00560053) PMID:22058223

The diagnostic value of SE MRI and DWI of the spine in patients with monoclonal gammopathy of undetermined significance, smouldering myeloma and multiple myeloma

Energy Technology Data Exchange (ETDEWEB)

Dutoit, Julie C.; Vanderkerken, Matthias A.; Dochy, Frederick; Verstraete, Koenraad L. [Ghent University Hospital, Department of Radiology, Ghent (Belgium); Anthonissen, Joris [Ghent University, Ghent (Belgium)

2014-11-15

To evaluate DWI of the bone marrow in the differentiation of monoclonal gammopathy of undetermined significance (MGUS), smouldering myeloma (SMM) and multiple myeloma (MM). The retrospective study includes 64 patients with MGUS, 27 with SMM, 64 with new MM and 12 controls. Signal intensity (SI) of spinal SE-MRI and DWI (b0-1000) as well as apparent diffusion coefficients (ADC) were measured in the T10 and L3. Qualitative assessment of b-images was performed by one experienced radiologist. ADC600 and ADC1000 are the best ADC values in differentiating patient groups (p < 0.030). SIT2, SIb1000 and ADC1000 are higher and SIT1 lower in L3 compared to T10 (p < 0.050). All quantitative parameters of L3 can differentiate significantly between MGUS and MM (p < 0.050) and between patients with percentage plasma cells (PC%) between 0-10 % compared to >50 % (p = 0.001). Only SIT2 for L3 can differentiate MGUS from SMM (p = 0.044) and PC%0-10 from PC%10-25 (p = 0.033). Qualitative interpretation of b1000 images allows differentiating MM patients from those with MGUS or SMM (p < 0.001). Spinal SE-MRI can differentiate among MGUS, SMM, MM and control subjects. DWI based on the SI on b1000 images and ADC values is increased in MM compared to MGUS and SMM. Qualitative assessment of b-images can differentiate MM from MGUS or SMM. (orig.)

Daratumumab: a first-in-class CD38 monoclonal antibody for the treatment of multiple myeloma

Directory of Open Access Journals (Sweden)

Larysa Sanchez

2016-06-01

Full Text Available Abstract Daratumumab is a human monoclonal antibody that targets CD38, a cell surface protein that is overexpressed on multiple myeloma (MM cells. Preclinical studies have shown that daratumumab induces MM cell death through several mechanisms, including complement-dependent cytotoxicity (CDC, antibody-dependent cell-mediated cytotoxicity (ADCC, antibody-dependent cellular phagocytosis (ADCP, and apoptosis. Given the encouraging efficacy and acceptable safety profile of daratumumab demonstrated in clinical trials, daratumumab has emerged as a novel treatment option for myeloma and became the first monoclonal antibody approved by the FDA for the treatment of MM.