Multiple myeloma

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Genomics of Multiple Myeloma

Genomics of Multiple Myeloma

Multiple myeloma (MM) is characterized by the accumulation (usually) of tumor plasma cells (PCs) within the bone marrow compartment. Clinically, MM is characterized by a wide heterogeneity both for clinical symptoms at diagnosis (bone fractures, anemia, renal failure, and extramedullary localiza- tions) and for outcome (rapid fatal evolution, long- term progression-free survival, or even cure). In the early 2000s, this clinical heterogeneity was believed to be mostly driven by chromosomal abnormalities found in the tumor PCs. On the basis of conven- tional karyotyping (rarely informative because of the low PC proliferative index) 1 - 3 or interphase fluorescence in situ hybridization (FISH) experi- ments, 4 - 8 high-risk chromosomal changes have been identified, such as the translocations t(4;14) and t(14; 16) and the loss of part of the chromosome 17 short arm (ie, del[17p]). With the use of more high- throughput technologies, such as gene expression profiling (GEP) on microarrays, molecular classifi- cations have been proposed. 9 - 13 However, these classifications have not led to the identification of several MM entities, as described with non-Hodgkin lymphomas. With the advent of next-generation sequencing (NGS) at both the DNA and the RNA levels, the goal of this review is to summarize our current knowledge of the molecular lesions of MM.
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Bone marrow mesenchymal stem cells are abnormal in multiple myeloma.

Bone marrow mesenchymal stem cells are abnormal in multiple myeloma.

Abstract Recent literature suggested that cell of the microenvironment of solid tumors could be abnormal as well. To address this hypothesis in multiple myeloma (MM), we studied bone marrow mesenchymal stem cells (BMMSCs), the only long-lived cells of the bone marrow microenvironment, by gene expression with Affymetrix arrays and phenotypic and functional study in 3 groups of individuals: patients with MM and those with monoclonal gamopathy of undefined significance (MGUS), and healthy aged-matched subjects. Gene expression profile independently classified the BMMSCs of these individuals in a normal and in a MM group. MGUS BMMSCs were interspersed between those 2 groups. Among the 145 distinct genes differentially expressed in MM and normal BMMSCs 46% were involved in tumor- microenvironment cross-talk. Known soluble factors involved in MM pathophysiologic features, (interleukin (IL)-6, IL-1ß, DKK1 and amphiregulin, were revealed and new ones found. In particular, GDF-15 was found to induce dose-dependant growth of MOLP-6, a stromal cell- dependent myeloma cell line. Functionally, MM BMMSCs induced an over-growth of MOLP-6, and their capacity to differentiate into an osteoblastic lineage was impaired. Thus, BMMSCs from MM patients could create a very efficient niche to support the survival and proliferation of the myeloma stem cells.
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In vitro expansion of gamma delta T cells with anti-myeloma cell activity by Phosphostim and IL-2 in patients with multiple myeloma.: Anti-myeloma activity of amplified gamma delta T cells

In vitro expansion of gamma delta T cells with anti-myeloma cell activity by Phosphostim and IL-2 in patients with multiple myeloma.: Anti-myeloma activity of amplified gamma delta T cells

References Alsayed, Y., Ngo, H., Runnels, J., Leleu, X., Singha, U.K., Pitsillides, C.M., Spencer, J.A., Kimlinger, T., Ghobrial, J.M., Jia, X., Lu, G., Timm, M., Kumar, A., Cote, D., Veilleux, I., Hedin, K.E., Roodman, G.D., Witzig, T.E., Kung, A.L., Hideshima, T., Anderson, K.C., Lin, C.P. & Ghobrial, I.M. (2006) Mechanisms of regulation of CXCR4/SDF-1 (CXCL12) dependent migration and homing in Multiple Myeloma. Blood, 109, 2708-2717. Attal, M., Harousseau, J.L., Stoppa, A.M., Sotto, J.J., Fuzibet, J.G., Rossi, J.F., Casassus, P.,

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Expressed fusion gene landscape and its impact in multiple myeloma

Expressed fusion gene landscape and its impact in multiple myeloma

N. Munshi 2,7 & H. Avet-Loiseau 4 Multiple myeloma is a plasma cell malignancy characterized by recurrent IgH translocations and well described genomic heterogeneity. Although transcriptome profiles in multiple myeloma has been described, landscape of expressed fusion genes and their clinical impact remains unknown. To provide a comprehensive and detailed fusion gene cartography and suggest new mechanisms of tumorigenesis in multiple myeloma, we performed RNA sequencing in a cohort of 255 newly diagnosed and homogeneously treated multiple mye- loma patients with long follow-up. Here, we report that patients have on average 5.5 expressed fusion genes. Kappa and lambda light chains and IgH genes are main partners in a third of all fusion genes. We also identify recurrent fusion genes that signi ficantly impact both progression-free and overall survival and may act as drivers of the disease. Lastly, we find a correlation between the number of fusions, the age of patients and the clinical outcome, strongly suggesting that genomic instability drives prognosis of the disease.
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Resistance to the proteasome inhibitors: Lessons from multiple myeloma and mantle cell lymphoma

Resistance to the proteasome inhibitors: Lessons from multiple myeloma and mantle cell lymphoma

2.1 Multiple myeloma MM is a plasma cell malignancy with bone marrow (BM) infiltration of clonal cells and monoclonal immunoglobulin protein in the serum and/or urine of patients. Genomic techniques have allowed a better understanding of the genetic abnormalities of MM by providing a better landscape of this collection of diseases with a common clinical phenotype [5]. Several genetic alterations including chromosomal translocations of the immunoglobulin heavy chain (IGH) gene leading to the overexpression of D-type cyclin, have been considered as primary events. Not less important are the secondary mutations and clonal evolution. The most frequent mutations occur in KRAS, NRAS, FAM46C, DIS3 and TP53, among others. These mutations affect multiple signalling pathways by altering the mRNA levels but also protein expression and stability. In the past decade, this knowledge has contributed to remarkable changes in the clinical practices, such as the implementation of more effective therapies including new classes of drugs like PIs. The combination of BTZ with immunomodulatory drugs (IMiDs) such as lenalidomide or dexamethasone are currently among the most effective treatments in MM (see section 4). The success of BTZ as a MM treatment underlies its broad impact on the stability and activity of vital cellular factors.
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Deciphering the chronology of copy number alterations in Multiple Myeloma

Deciphering the chronology of copy number alterations in Multiple Myeloma

Abstract Multiple myeloma (MM) and its precursor condition MGUS are characterized by chromosomal aberrations. Here, we comprehensively characterize the order of occurrence of these complex genomic events underlying MM development using 500 MGUS, and MM samples. We identify hyperdiploid MM (HMM) and non-HMM as genomically distinct entities with different evolution of the copy number alterations. In HMM, gains of 9,15 or 19 are the first and clonal events observed as clonal even at MGUS stage. These events are thus early and may underlie initial transformation of normal plasma cells to MGUS cells. However, CNAs may not be adequate for progression to MM except in 15% of the patients in whom the complex subclonal deletion events are observed in MM but not MGUS. In NHMM, besides the driver translocations, clonal deletion of 13 and 1q gain are early events also observed in MGUS. We combined this information to propose a timeline for copy number alteration.
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Whole-body computed tomography versus conventional skeletal survey in patients with multiple myeloma: a study of the International Myeloma Working Group.

Whole-body computed tomography versus conventional skeletal survey in patients with multiple myeloma: a study of the International Myeloma Working Group.

J Hillengass 1,2 , LA Moulopoulos 3 , S Delorme 2 , V Koutoulidis 3 , J Mosebach 2 , T Hielscher 4 , M Drake 5 , SV Rajkumar 6 , B Oestergaard 7 , N Abildgaard 7 , M Hinge 7 , T Plesner 8 , Y Suehara 9 , K Matsue 9 , N Withofs 10 , J Caers 11 , A Waage 12 , H Goldschmidt 1 , MA Dimopoulos 13 , S Lentzsch 14 , B Durie 15 and E Terpos 13 For decades, conventional skeletal survey (CSS) has been the standard imaging technique for multiple myeloma (MM). However, recently whole-body computed tomography (WBCT) has been implemented into the diagnostic criteria of MM. This analysis compares sensitivity and prognostic signi ficance of WBCT and CSS in patients with smoldering MM (SMM) and MM. Fifty-four of 212 patients (25.5%) had a negative CSS and a positive WBCT for osteolytic lesions (P o0.0001). Of 66 patients with SMM based on CSS, 12 (22.2%) had osteolytic lesions on WBCT. In comparison, WBCT failed to detect some bone destructions in the appendicular skeleton possibly due to limitations of the field of view. Presence of lytic bone lesions in WBCT was of borderline prognostic signi ficance (P = 0.051) for SMM patients, with a median time to progression of 38 versus 82 months for those without bone destructions. In conclusion, WBCT identifies significantly more sites of bone destruction than CSS. More than 20% of patients with SMM according to CSS have in fact active MM detectable with WBCT. On the basis of this and other studies, WBCT (either computed tomography (CT) alone or as part of a positron emission tomography-CT protocol) should be considered the current standard for the detection of osteolytic lesions in MM.
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A high-risk signature for patients with multiple myeloma established from the molecular classification of human myeloma cell lines.

A high-risk signature for patients with multiple myeloma established from the molecular classification of human myeloma cell lines.

These 206 patients were treated with Vincristine, Adriamicyne and Dexamethasone (VAD), high dose Melphalan (HDM) and autologous stem cell transplantation (ASCT) (27) and were termed in the following Heidelberg-Montpellier (HM) series. The .CEL files and MAS5 files have been deposited in the ArrayExpress public database, under accession number E-MTAB-362. We also used Affymetrix data of a cohort of 345 purified MMC from previously untreated patients from the Arkansas Cancer Research Center (ACRC, Little Rock, AR). The patients were treated with total therapy 2 including HDM and ASCT (28) and termed in the following ACRC-TT2 series. These data are publicly available via the online Gene Expression Omnibus (Gene Expression Profile of Multiple Myeloma, accession number GSE2658. http://www.ncbi.nlm.nih.gov/geo/). After Ficoll-density gradient centrifugation, plasma cells were purified using anti-CD138 MACS microbeads (Miltenyi Biotech, Bergisch Gladbach, Germany).
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Multiple myeloma treatment at relapse after autologous stem cell transplantation: a practical analysis

Multiple myeloma treatment at relapse after autologous stem cell transplantation: a practical analysis

Over the past decade, significant advances have been made in the field of multiple myeloma. Introduction of the so-called novel agents, proteasome inhibitors (PI) and immunomodulatory drugs (IMiD), and improved supportive care have resulted in significantly better outcome. Standard first line treatment in fit patients include PI and IMiD based induction, high dose melphalan with autologous hematopoietic stem cell transplantation (ASCT) and consolidation/maintenance. However, despite these progresses MM remains incurable for the majority of patients and most patients will relapse. Next generation PI (carfilzomib, ixazomib) and IMiD (pomalidomide) and new therapeutic classes: monoclonal antibody (elotuzumab, daratumumab) and pan- deacetylase inhibitors (panobinostat) have been successfully evaluated in relapse multiple myeloma. Some of these new agents are now approved for multiple myeloma treatment at relapse. However choosing the most appropriate treatment at relapse may be difficult. This review sum up the most important studies and provide evidence to choose the most relevant therapeutic strategy for relapse after ASCT, based on disease, patient and previous treatment related parameters.
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Cancer/Testis genes in multiple myeloma: expression patterns and prognosis value determined by microarray analysis.: Expression of cancer-testis genes in multiple myeloma

Cancer/Testis genes in multiple myeloma: expression patterns and prognosis value determined by microarray analysis.: Expression of cancer-testis genes in multiple myeloma

FIGURE 2: Gene expression of 10 CT genes measured by pan genomic Affymetrix HG-U133 Set arrays. Histograms show the expression level of 10 CT genes in five testis samples, seven normal memory B cell (MB) samples, seven normal polyclonal plasmablastic cell (PPC) samples, seven normal BM mature plasma cells (BMPC) samples, eight purified plasma cell samples from patients with monoclonal gammopathy with undetermined significance (MGUS), 64 MMC samples from patients with multiple myeloma (MMC) ordered in stages (I, II, III) and 20 HMCL samples. The signal intensity for each gene is shown on the Y axis as arbitrary units determined by the GCOS 1.2 software (Affymetrix). Empty histograms indicate an “absent” Affymetrix call and filled histograms a “present” Affymetrix call.
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Gene expression profiling and real-time PCR analyses identify novel potential cancer-testis antigens in multiple myeloma.: Novel cancer-testis genes in multiple myeloma

Gene expression profiling and real-time PCR analyses identify novel potential cancer-testis antigens in multiple myeloma.: Novel cancer-testis genes in multiple myeloma

Abstract Cancer-testis (CT) antigens are attractive targets for immunotherapeutic strategies since they are aberrantly expressed in malignant cells and not, or in limited number, in somatic tissues, except germ cells. To identify novel CT genes in multiple myeloma, we used Affymetrix HG-U133 gene expression profiles of 5 testis, 64 primary myeloma cell (MMC) and 24 normal tissue (NT) samples. A 5-filter method was developed to keep known CT genes while deleting non-CT genes. Starting from 44928 probe sets, including probe sets for 18 previously-described CT genes, we have obtained 82 genes expressed in MMC and testis and not detected in more than 6 NT. This list includes 14 of the 18 known CT genes and 68 novel putative CT genes. Real-time RT-PCR was performed for 34 genes in 12 NT, 5 MMC samples and one sample of 5 pooled testes. It has validated the CT status of 23/34 genes (67 ). We found one novel % “ testis-restricted gene (expression in testis and tumor only) ” – TEX14 – , 8 tissue-restricted (mRNA detected in 1 or 2 non-gametogenic “ ” tissues), and 7 differentially expressed (mRNA detected in three to six non-gametogenic tissues) CT genes. Further studies are “ ” warranted to determine the immunogenicity of these novel CT antigen candidates.
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Clonal hematopoiesis is associated with adverse outcomes in multiple myeloma patients undergoing transplant

Clonal hematopoiesis is associated with adverse outcomes in multiple myeloma patients undergoing transplant

investigate the interaction between CHIP, transplant and IMiDs on outcomes in multiple myeloma. Methods Cohort. Following institutional review board (IRB) approval, we collected the clinical data and all available cryopreserved products of mobilized autologous stem-cells from 629 MM patients who underwent ASCT between January 2003 and December 2011 at the Dana-Farber Cancer Institute (DFCI) in Boston, MA. The cutoff date of 2011 was used to enable enough years of follow up following stem cell transplantation and allow for the monitoring of TMNs and survival data. Clinical information was collected through November 2019. The study design complied with the Declaration of Helsinki and International Conference on Harmonization Guidelines for Good Clinical Practice. All subjects previously provided written informed consent to allow the collection of clinical information and genetic ana- lysis of PB and BM samples for research purposes (DF/HCC IRB 01 –206, 07–150 and 16 –529).
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Determining therapeutic susceptibility in multiple myeloma by single-cell mass accumulation

Determining therapeutic susceptibility in multiple myeloma by single-cell mass accumulation

Patient sample procurement and processing. Primary multiple myeloma spe- cimens were collected from patients at the Dana-Farber Cancer Institute upon provision of informed consent under a tissue banking protocol (Dana-Farber Harvard Cancer Center (DF/HCC) protocol #07-150). The protocol has been approved by the DF/HCC institutional review board (IRB), and all relevant ethical regulations were followed. Bone marrow mononuclear cells and primary MM cells are isolated using Ficoll-Hypaque density gradient sedimentation from BM aspi- rates MM patients following informed consent and IRB (Dana-Farber Cancer Institute) approval. MM patient cells are separated from BM samples by antibody- mediated positive selection using anti-CD138 magnetic-activated cell separation microbeads (Miltenyi Biotech, Gladbach, Germany). For the ex vivo drug treat- ment, aliquots are treated with 5 nM bortezomib, 200 nM dexamethasone, and 3 µM lenalidomide and assessed using the serial SMR platform. Patient samples did not allow for replicates of individual conditions on the same samples due to samples size and other practical constraints.
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Antioxidant Defenses Confer Resistance to High Dose Melphalan in Multiple Myeloma Cells

Antioxidant Defenses Confer Resistance to High Dose Melphalan in Multiple Myeloma Cells

4000 Liege, Belgium. Received: 19 February 2019; Accepted: 20 March 2019; Published: 28 March 2019    Abstract: Background: Multiple myeloma (MM) is the second most common hematological cancer after lymphoma. It is characterized by the accumulation of clonal malignant plasma cells within the bone marrow. The development of drug resistance remains a major problem for effective treatment of MM. Understand the mechanisms underlying drug resistance in MM is a focal point to improve MM treatment. Methods: In the current study, we analyzed further the role of redox imbalance induction in melphalan-induced toxicity both in human myeloma cell lines (HMCLs) and primary myeloma cells from patients. Results: We developed an in-vitro model of short-term resistance to high-dose melphalan and identified that pretreatment with physiological concentration of GSH protects HMCLs from melphalan-induced cell cycle arrest and cytotoxicity. We validated these results using primary MM cells from patients co-cultured with their bone marrow microenvironment. GSH did not affect the ability of melphalan to induce DNA damages in MM cells. Interestingly, melphalan induced reactive oxygen species, a significant decrease in GSH concentration, protein and lipd oxydation together with NRF2 (NF-E2-related factor 2) pathway activation. Conclusions: Our data demonstrate that antioxidant defenses confers resistance to high dose melphalan in MM cells, supporting that redox status in MM cells could be determinant for patients’ response to melphalan.
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Prevention and management of adverse events of novel agents in multiple myeloma: a consensus of the European Myeloma Network.

Prevention and management of adverse events of novel agents in multiple myeloma: a consensus of the European Myeloma Network.

Cytomegalovirus PIs and high-dose therapy increase the risk for cytomega- lovirus (CMV) reactivation or infection. Such infections not rarely remain unrecognized. For diagnosis of CMV infec- tion, polymerase chain reaction (PCR) technology should be used, because antibody testing may fail due to impaired antibody production. CMV prophylaxis is generally not recommended in multiple myeloma [ 71 ], but may be con- sidered in selective cases with repeated CMV reactivation. In case of active infection, therapy is typically initiated with intravenous ganciclovir. For second-line treatment or in case of poor tolerance or resistance to ganciclovir, foscarnet and cidofovir can be used [ 7 ]. Several new drugs (mar- ibavir, brincidofovir, and letermovir) are undergoing clin- ical trials. Oral valgancyclovir is convenient, usually well tolerated and an option for initial therapy in very fit patients and for prevention of recurrence of infections during peri- ods of aggressive therapy. Treatment should be continued at minimum until a negative PCR test result.
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Logic programming reveals alteration of key transcription factors in multiple myeloma

Logic programming reveals alteration of key transcription factors in multiple myeloma

Conclusion In this study, we used a specific approach to study and understand the heterogeneous gene expression profiles of approximately 600 multiple myeloma (MM) patients. Our primary goal was to provide mechanistic scenarios by identifying protein activity states of molecules that may be central to the diversity of gene expression. Our approach relies heavily on reasoning based on graphs and on changes in gene expression in the form of logical programs that combine these two types of information. The method proposed here can be summarized in the fol- lowing steps. First, we obtained a directed graph, allowing us to connect significantly up-/down-regulated genes to upstream MM-related cellular receptors. Second, we confronted this graph to transcriptomic data with IGGY, which is a tool that reasons on the logic of the graph and on shifts of expression in the data so as to predict (node, sign) assignments representing the specific states of biological entities. Using two approaches of classification, we were able to identify specific assignments for MC datasets compared to NPC datasets. Finally, taking advantage of our modeling framework, we studied the effect of performing single in silico perturbations.
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Inhibition of Aurora-kinases for tailored risk adapted treatment of multiple myeloma.

Inhibition of Aurora-kinases for tailored risk adapted treatment of multiple myeloma.

Biological implications Aurora-kinases have been associated with proliferation 7 and genetic instability 8 in different cancer entities 9-14 , including multiple myeloma 25 . Aurora-A and -B are expressed in all myeloma cell lines and proliferating 36 (non-malignant) plasmablastic cells, and are significantly higher expressed in both of these compared to memory B-cells or normal plasma cells. At the same time, expression of Aurora-A and -B correlates with the plasma cell labeling index determined by PI-staining as well as the gene expression based proliferation index. Furthermore, the percentage of primary myeloma cells of untreated patients expressing Aurora-A is in agreement with the low proliferative rate of these. The same holds true for the significant increase in Aurora-A expression from early- to late-stage plasma cell dyscrasias in both our training and validation group. Thus, Aurora-kinase expression is obviously associated with proliferation in multiple myeloma.
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Exome sequencing identifies germline variants in DIS3 in familial multiple myeloma

Exome sequencing identifies germline variants in DIS3 in familial multiple myeloma

8. Halvarsson B-M, Wihlborg A-K, Ali M, Lemonakis K, Johnsson E, Niroula A, et al. Direct evidence for a polygenic etiology in familial multiple myeloma. Blood Adv. 2017;1:619 –23. 9. Wei X, Calvo-Vidal MN, Chen S, Wu G, Revuelta MV, Sun J, et al. Germline mutations in lysine speci fic demethylase 1 (LSD1/ KDM1A) confer susceptibility to multiple myeloma. Cancer research 2018. https://doi.org/10.1158/0008-5472.CAN-17-1900 . 10. Waller RG, Darlington TM, Wei X, Madsen MJ, Thomas A, Curtin K, et al. Novel pedigree analysis implicates DNA repair and chromatin remodeling in multiple myeloma risk. PLoS Genet. 2018;14:e1007111.
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Carfilzomib with immunomodulatory drugs for the treatment of newly diagnosed multiple myeloma

Carfilzomib with immunomodulatory drugs for the treatment of newly diagnosed multiple myeloma

Abstract Car filzomib, a selective proteasome inhibitor (PI), is approved for the treatment of patients with relapsed or refractory multiple myeloma (MM). Combination regimens incorporating a PI and immunomodulatory drug (IMiD) have been associated with deep responses and extended survival in patients with newly diagnosed MM (NDMM). Car filzomib-based combinations with immunomodulators are being extensively studied in the frontline setting. The objective of this review was to describe ef ficacy and safety data for carfilzomib-based, PI/immunomodulatory combinations in NDMM. Information sources were articles indexed in PubMed and abstracts from key hematology/oncology congresses published between January 2012 and December 2018. PubMed and congresses were searched for prospective clinical studies assessing the combination of car filzomib with an IMiD for NDMM treatment. Retrospective and preclinical reports, case reports/series, reviews, and clinical studies not evaluating car filzomib–immunomodulator combinations in NDMM were excluded based on review of titles and abstracts. A total of nine articles and 72 abstracts were deemed relevant and included in the review. A total of six distinct car filzomib-based, PI/immunomodulator combination regimens have been evaluated in 12 clinical trials. Overall, treatment with these regimens has resulted in deep responses, including high rates of negativity for minimal residual disease. These deep responses have translated to long progression-free survival and overall survival rates. Ef ficacy results for these regimens have generally been consistent across subgroups de fined by age, transplant eligibility, and cytogenetic risk. The safety pro file of carfilzomib in NDMM is consistent with that observed in the relapsed-refractory MM setting. Clinical studies have found that car filzomib-based combinations with immunomodulators are highly active with a favorable safety pro file in NDMM. The carfilzomib, lenalidomide, and dexamethasone (KRd) drug backbone is a promising foundation for treatment strategies aimed at achieving long-term, deep responses (functional cures) in the frontline setting. Several ongoing studies are evaluating KRd, with or without anti-CD38 monoclonal antibodies.
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The effects of forodesine in murine and human multiple myeloma cells

The effects of forodesine in murine and human multiple myeloma cells

Copyright © 2010 Liesbeth Bieghs et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Multiple myeloma (MM) is the second most commonly diagnosed hematological malignancy, characterized by a monoclonal proliferation of malignant cells in the bone marrow. Despite recent advances in treatment strategies, MM remains incurable and new therapeutical targets are needed. Recently forodesine, a purine nucleoside phosphorylase inhibitor, was found to induce apoptosis in leukemic cells of chronic lymphocytic leukemia patients by increasing the dGTP levels. We therefore tested whether forodesine was able to inhibit proliferation and/or induce apoptosis in both murine and human MM cells through a similar pathway. We found that after 48 hours of treatment with forodesine there was a slight dGTP increase in 5T33MM and RPMI- 8226 MM cells associated with partial inhibition of proliferation and a limited induction of apoptosis. When investigating the pathways leading to cell cycle arrest and apoptosis, we observed an upregulation of p27, caspase 3, and BIM. We can conclude that forodesine has some effects on MM cells but not as impressive as the known effects in leukemic cells. Forodesine might be however potentiating towards other established cytotoxic drugs in MM.
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