Strategy For Treatment Of Multiple Myeloma Research Articles

No decrease in fracture risk despite 15 years of treatment evolution for multiple myeloma patients: A Danish nationwide case-control study.

While treatment strategies for multiple myeloma have evolved radically over the last decades, little is known about the risk of fractures for symptomatic multiple myeloma patients over time. To determine the effect of different treatment periods (1996-2000, 2001-2006 and 2007-2011) on the risk of fractures in patients with multiple myeloma. This retrospective case-control study included patients with multiple myeloma in Denmark, using the Danish National Health Service. Cases were defined as patients who had sustained a fracture between 1996 and 2011, and controls were those without a fracture. Exposure was defined as an ICD code for multiple myeloma. Vertebral fractures, gender, and age were considered in secondary analyses. Conditional logistic regression was used to estimate odd ratios (ORs) of fracture risk, and the analyses were adjusted for comorbidities and recent drug use. The study population consisted of 925,341 cases, and the same number of matched controls, of whom 1334 patients with multiple myeloma. Among cases, the risk of any fracture was higher in multiple myeloma patients compared to patients without multiple myeloma (any fracture: ORadj[95% CI] 1996-2000: 1.7[1.3-2.3]; 2001-2006: 1.3[1.1-1.6]; 2007-2011: 1.7[1.4-2.2]). Although fractures were mainly non-vertebral, the risk of vertebral fractures in particular was higher in multiple myeloma patients (vertebral fracture: ORadj[95% CI] 1996-2000: 3.5[1.4-8.6]; 2001-2006: 4.0[1.9-8.2]; 2007-2011: 3.0[1.6-5.7]). Despite new treatment strategies and improved supportive care, this study showed no decreased fracture risk for multiple myeloma patients over time. New treatment strategies, even if they have a positive impact on overall survival, offer no guarantee for a corresponding reduction in bone lesions.

Current Treatment Strategies for Multiple Myeloma.

The treatment of multiple myeloma (MM) continues to evolve with the approval of numerous agents over the past decade. Advances in treatment have led to the incorporation of these newer therapies into the treatment paradigm, with improvements in overall survival and the possibility of deep responses including a minimal residual disease-negative state. The strategy of triplet therapies for patients with newly diagnosed MM, followed by high-dose chemotherapy and autologous stem-cell transplantation for eligible patients, and subsequently consolidation and maintenance therapy, is the current treatment roadmap for patients. However, patients with MM will ultimately develop refractoriness to antimyeloma therapies. In this article, we summarize our current practice of managing patients with MM. We highlight our approach to patients with newly diagnosed MM who are transplantation eligible and ineligible and highlight risk-adapted strategies for these patients. In addition, we discuss our approach to the management of patients with relapsed or refractory MM. Last, we review standard therapies and emerging strategies such as targeted approaches, immune-based therapies, and drugs with novel mechanisms of action. Trials evaluating chimeric antigen receptor T cells targeting B-cell maturation antigen are ongoing and are only one of several novel approaches targeting cell maturation antigen, which include the use of bispecific T-cell engager antibodies and antibody drug conjugates. Emerging therapies offer the promise of more individualized approaches in the management of patients with MM and ultimately may result in the possibility of being one step closer to curing patients with MM.

The MP0250-CP201 Mirror Study: A Phase 2 Study Update of MP0250 Plus Bortezomib and Dexamethasone in Relapse/Refractory Multiple Myeloma (RRMM) Patients Previously Exposed to Proteasome Inhibitors and Immunomodulatory Drugs

The MP0250-CP201 Mirror Study: A Phase 2 Study Update of MP0250 Plus Bortezomib and Dexamethasone in Relapse/Refractory Multiple Myeloma (RRMM) Patients Previously Exposed to Proteasome Inhibitors and Immunomodulatory Drugs

RNA-Sequencing Based Assessment of Targets, Risk and Long Term Survival for Personalized Treatment of Multiple Myeloma

Aim of our study is to implement RNA-sequencing as basis for risk adapted and targeted treatment-strategies in multiple myeloma. We establish assessment of malignant plasma cell proliferation and risk-stratification de novo (HDHRS) by RNA-sequencing, transfer microarray-based risk scores to RNA-sequencing, and report expression of actionable including immune-oncological targets. Methods. Transcriptome profiling was performed on CD138 purified malignant plasma cell samples from previously untreated symptomatic multiple myeloma patients undergoing high-dose melphalan treatment and autologous stem cell transplantation. RNA-sequencing was performed on an Illumina NextSeq500-platform using 5ng of total RNA (n=535), and, in the same cohort, by gene expression profiling using Affymetrix U133 2.0 DNA-microarrays (n=534). iFISH was performed using a ten-probe panel (n=535). Clinical data and survival of patients treated with high-dose therapy and autologous stem cell transplantation were assessed (n=534/533/534 for RNA-seq/GEP/iFISH) with median follow up of 64 months. Data were validated using the independent COMPASS cohort (n=767 pts., median follow up of 31 months). Results. RNA-sequencing is feasible in more than 90% of myeloma patients. It allows assessment of proliferation (RPI) and risk, both de novo (HDHRS) and regarding microarray-based scores (UAMS GEP70-, EMC92-, Rs-score). All scores are significantly predictive for overall and event-free survival in GEP are likewise in RNA-seq with hazard ratio for high risk to low risk group of 3.06, 4.3, 2.84, 3.93 and 3.30 in overall survival of test group. (See as example gene expression based proliferation index / RNA-seq based proliferation index, Fig. 1). The de novo RNA-seq risk stratification (HDHRS) superiorly delineates three significantly different groups of 40%, 38%, and 22% of patients with 5-year survival rates of 84%, 67%, and 32%, respectively (Fig.2). It likewise discerns a group of long term surviving patients with a survival rate of 57% and 49%, at 10 and 12 years, respectively. Targets expressed in normal plasma cells with varying expression height in malignant include BCMA and CD38, those aberrantly expressed CSF1, CD20 and HGF. Mutated actionable transcripts include BRAF V600E/K (target), the proteasome and cereblon (resistance). In conclusion, RNA-seq allows assessment of risk, long term survival and targets in multiple myeloma both in phase III multicenter trials as well as in clinical Routine. Disclosures Moreaux: Diag2Tec: Other: Co-founder of Diag2Tec company.

Current management and emerging treatment strategies for multiple myeloma.

Multiple myeloma is a malignant plasma cell neoplasm that is incurable despite significant progress in treatment over the past several decades. The incorporation of novel agents and combinations into the MM treatment paradigm has resulted in improved survival and tolerability, as well as deeper responses including achieving a minimal residual disease negative state. The addition of new treatment options and combinations has added complexity in treatment selection for myeloma patients. The current strategy for newly diagnosed myeloma involves induction, consolidation, and maintenance therapy. However, nearly all myeloma patients will develop refractory disease. This highlights the need for more effective therapies targeting the myeloma cells and their microenvironment. In this article, we summarize current management of transplant eligible and ineligible newly diagnosed patients in both the upfront and relapsed refractory setting, highlighting risk adapted strategies. We also summarize emerging therapies, such as immune and targeted approaches, as well as drugs with novel mechanisms of action. Emerging strategies offer individualized treatment options and may ultimately offer the possibility of a cure for myeloma patients.

Prospective target assessment and multimodal prediction of survival for personalized and risk-adapted treatment strategies in multiple myeloma in the GMMG-MM5 multicenter trial

BackgroundPersonalized and risk-adapted treatment strategies in multiple myeloma prerequisite feasibility of prospective assessment, reporting of targets, and prediction of survival probability in clinical routine. Our aim was first to set up and prospectively test our experimental and analysis strategy to perform advanced molecular diagnostics, i.e., interphase fluorescence in-situ hybridization (iFISH) in ≥ 90% and gene expression profiling (GEP) in ≥ 80% of patients within the first cycle of induction chemotherapy in a phase III trial, seen as prerequisite for target expression-based personalized treatment strategies. Secondly, whether the assessment of risk based on the integration of clinical, cytogenetic, and expression-based parameters (“metascoring”) is possible in this setting and superior to the use of single prognostic factors.MethodsWe prospectively performed plasma cell purification, GEP using DNA-microarrays, and iFISH within our randomized multicenter GMMG-MM5-trial recruiting 604 patients between July 2010 and November 2013. Patient data were analyzed using our published gene expression report (GEP-R): after quality and identity control, integrated risk assessment (HM metascore) and targets were reported in clinical routine as pdf-document.ResultsBone marrow aspirates were obtained from 573/604 patients (95%) and could be CD138-purified in 559/573 (97.6%). Of these, iFISH-analysis was possible in 556 (99.5%), GEP in 458 (82%). Identity control using predictors for sex, light and heavy chain type allowed the exclusion of potential sample interchanges (none occurred). All samples passed quality control. As exemplary targets, IGF1R-expression was reported expressed in 33.1%, AURKA in 43.2% of patients. Risk stratification using an integrated approach, i.e., HM metascore, delineated 10/77/13% of patients as high/medium/low risk, transmitting into significantly different median progression-free survival (PFS) of 15 vs. 39 months vs. not reached (NR; P < 0.001) and median overall survival (OS) of 41 months vs. NR vs. NR (P < 0.001). Five-year PFS and OS-rates were 5/31/54% and 25/68/98%, respectively. Survival prediction by HM metascore (Brier score 0.132, P < 0.001) is superior compared with the current gold standard, i.e., revised ISS score (0.137, P = 0.005).ConclusionsProspective assessment and reporting of targets and risk by GEP-R in clinical routine are feasible in ≥ 80% of patients within the first cycle of induction chemotherapy, simultaneously allowing superior survival prediction.

Insights on Multiple Myeloma Treatment Strategies.

The introduction of new agents and management strategies over the past decade has resulted in a major step change in treatment outcomes with deepening responses and increased survival for patients with multiple myeloma. In daily clinical practice, healthcare professionals are now faced with challenges including, optimal treatment sequencing and changing treatment goals. In light of this, a group of experts met to discuss diagnostic and treatment guidelines, examine current clinical practice, and consider how new clinical trial data may be integrated into the management of multiple myeloma in the future.

Design, synthesis and evaluation of anti-CD38 antibody drug conjugate based on Daratumumab and maytansinoid.

Daratumumab, an FDA approved antibody drug, displays specific targeting ability to abnormal white blood cells overexpressing CD38 and provides efficacious therapy for multiple myeloma. Here, in order to achieve enhanced remission of multiple myeloma, we designed Dara-DM4, antibody drug conjugates (ADCs) by conjugating Daratumumab and DM4 via a disulfide linker. Dara-DM4 showed significantly higher cellular uptake and inhibitory efficacy on MM1S cells that overexpressing CD38 with an IC50 of 0.88 µg/mL post 72 hr treatment. These results support a promising ADCs strategy for multiple myeloma treatment.

PGC1β regulates multiple myeloma tumor growth through LDHA-mediated glycolytic metabolism.

Multiple myeloma (MM) is an incurable hematologic malignancy due to inevitable relapse and chemoresistance development. Our preliminary data show that MM cells express high levels of PGC1β and LDHA. In this study, we investigated the mechanism behind PGC1β‐mediated LDHA expression and its contribution to tumorigenesis, to aid in the development of novel therapeutic approaches for MM. Real‐time PCR and western blotting were first used to evaluate gene expression of PGC1β and LDHA in different MM cells, and then, luciferase reporter assay, chromatin immunoprecipitation, LDHA deletion report vectors, and siRNA techniques were used to investigate the mechanism underlying PGC1β‐induced LDHA expression. Furthermore, knockdown cell lines and lines stably overexpressing PGC1β or LDHA lentivirus were established to evaluate in vitro glycolysis metabolism, mitochondrial function, reactive oxygen species (ROS) formation, and cell proliferation. In addition, in vivo xenograft tumor development studies were performed to investigate the effect of PGC1β or LDHA expression on tumor growth and mouse survival. We found that PGC1β and LDHA are highly expressed in different MM cells and LDHA is upregulated by PGC1β through the PGC1β/RXRβ axis acting on the LDHA promoter. Overexpression of PGC1β or LDHA significantly potentiated glycolysis metabolism with increased cell proliferation and tumor growth. On the other hand, knockdown of PGC1β or LDHA largely suppressed glycolysis metabolism with increased ROS formation and apoptosis rate, in addition to suppressing tumor growth and enhancing mouse survival. This is the first time the mechanism underlying PGC1β‐mediated LDHA expression in multiple myeloma has been identified. We conclude that PGC1β regulates multiple myeloma tumor growth through LDHA‐mediated glycolytic metabolism. Targeting the PGC1β/LDHA pathway may be a novel therapeutic strategy for multiple myeloma treatment.

ClC5 Decreases the Sensitivity of Multiple Myeloma Cells to Bortezomib via Promoting Prosurvival Autophagy.

Resistance to bortezomib (BZ) is the major problem that largely limits its clinical application in multiple myeloma treatment. In the current study, we investigated whether ClC5, a member of the chloride channel family, is involved in this process. The MTT assay showed that BZ treatment decreased cell viability in three multiple myeloma cell lines (ARH77, U266, and SKO-007), with IC50 values of 2.83, 4.37, and 1.91 nM, respectively. Moreover, BZ increased the conversion of LC3B-I to LC3B-II and expressions of beclin-1 and ATG5, concomitantly with a decreased p62 expression. Pharmacological inhibition of autophagy with 3-MA facilitated cell death in response to BZ treatment. Additionally, BZ increased ClC5 protein expression in ARH77, U266, and SKO-007 cells. Knockdown of ClC5 with small interfering RNA sensitized cells to BZ treatment, and upregulation of ClC5 induced chemoresistance to BZ. Furthermore, ClC5 downregulation promoted BZ-induced LC3B-I to LC3B-II conversion and beclin-1 expression, whereas overexpression of ClC5 showed the opposite results in ARH77 cells. Finally, BZ induced dephosphorylation of AKT and mTOR, which was significantly attenuated by ClC5 inhibition. However, ClC5 upregulation further enhanced AKT and mTOR dephosphorylation induced by BZ. Our study demonstrates that ClC5 induces chemoresistance of multiple myeloma cells to BZ via increasing prosurvival autophagy by inhibiting the AKT–mTOR pathway. These data suggest that ClC5 may play a critical role in future multiple myeloma treatment strategies.

Combination of a Novel HDAC 6 Inhibitor ACY-241 with Anti-PD-L1 Antibody Enhances Anti-Tumor Immunity and Cytotoxicity in Multiple Myeloma

Introduction Histone deacetylases (HDACs) are attractive therapeutic targets, and selective HDAC inhibitors (HDACi), alone or in combination with other anti-cancer agents are useful treatment strategies in multiple myeloma (MM). HDACs are also involved in immune regulation in hematological malignancies. For example, blockade of HDACs upregulate immunecheckpoints such as PD-1 ligand (PD-L1). Furthermore, combination of HDACi with PD-1/PD-L1 checkpoint blockade significantly improves immunotherapy in a murine B16F10 model [Woods et al, Cancer Immunol Res. 2015; 3:1375-85]. Here we utilized an orally bioavalable HDAC6 selective inhibitor ACY-241 currently under clinical trials to examine whether combination of ACY-241 with anti-PD-L1 antibody enhances anti-MM immunity. For these studies, we utilized our previously published co-culture models of immune effector cells (plasmacytoid dendritic cells, pDCs, T cells, NK cells) and MM cells (Chauhan et al, Cancer Cell 2009, 16:309-323; Ray et al, Leukemia 2015, 29:1441-1444). Specifically, in MM we have shown that: 1) PD-1 is highly expressed on T and NK cells, and both pDCs and MM cells express PD-L1; 2) MM-pDCs confer T- and NK cell immune suppression via PD-L1/PD-1 immune checkpoints and 3) blockade of PD-L1-PD-1 signaling axis by anti-PD-L1 Ab generates MM-specific CD8+ CTL activity, as well as enhances NK-cell-mediated MM cell cytolytic activity. We here examined whether combination of ACY-241 with anti-PD-L1 Ab increases anti-tumor immunity and cytotoxicity in MM.Methods Minimally cytotoxic concentrations of ACY-241 (0.1-0.2 µM) or anti-PD-L1 Ab (5 µg/ml) were utilized to assess immune function. In T cell proliferation assay, MM patient pDCs were co-cultured with autologous T cells (pDC:T ratio; 1:10) in the presence of ACY-241, anti-PD-L1 Ab, or a combination of ACY-241 and anti-PD-L1 Ab for 5 days; proliferation was then quantified using CellTrace Violet proliferation kit for flow cytometry. CTL activity assays MM CD8+ T cells were cultured with autologous pDCs (1:10 pDC/T ratio) with ACY-241, anti-PD-L1 Ab, or both for 5 days; cells were then washed to remove drug, and pre-stained target MM cells (20:1 E/T ratio) were then added for another 2-3 days, followed by quantification of viable MM cells using FACS. NK-cell mediated cytotoxicity was assessed using flow-based CFSE-stained target lysis assays, as well as degranulation assay quantifying cell surface CD107a. Statistical parameters were calculated using GraphPad Prism.Results. 1) Treatment of RPMI-8226, U266, and MM.1S cells with ACY-241 increases PD-L1 expression; and blockade of PD-L1 using anti-PD-L1 Ab increases the anti-MM activity of ACY-241. 2) Combination of ACY-241 and anti-PDL1 Ab enhances MM-patient pDC-induced NK cell-mediated cytolytic activities against allogenic MM cells (p < 0.008; 2-5 fold increase for combination versus anti-PD-L1 Ab alone). NK cell mediated lysis was insignificant in the absence of pDCs. 3) ACY-241, anti-PD-L1 Ab or their combination, activates patient BM-CD8+T cells in autologous pDCs/T cell co-cultures. Importantly, combination of ACY-241 and anti-PD-L1 Ab triggers a more robust allogenic and autologous MM-specific CD8+ CTL activity than anti-PD-L1 Ab alone (1.5-2.0 fold increase in combination regimen vs anti-PD-L1 Ab; p = 0.01). 4) Treatment of pDC-T cell cocultures with ACY-241 plus anti-PD-L1 Ab enhanced cytotoxic activity of CD8+ T cells against HLA-A2+ U266 cells (1.5-2 fold in combinations vs anti-PD-L1 Ab; p = 0.003). 5) In concert with above findings, ACY-241 plus anti-PD-L1 Ab increases CD107a expression in NK and CD8+T cells (CD107a+ NK: 5 fold; p = 0.003; CD107a+ CD8+T: 5 fold; p= 0.001; vs anti-PD-L1 Ab alone). Finally, 6) pDC-mediated CD8+ CTL activity was also confirmed using HLA-A2+ HCT116 colon cancer cells (~2 fold loss in viability in combination vs anti-PD-L1 Ab; p = 0.006)Conclusions The combination of HDAC6 inhibitor ACY-241 and anti-PD-L1 Ab enhances pDC-induced T and NK cell-mediated cytolytic acitvities in MM. Our study provides the basis for combining ACY-241 with anti-PD-L1 Ab to restore immune function, and enhance MM cytotoxicity, and improve patient outcome in MM. DisclosuresHideshima:Acetylon: Consultancy; C4 Therapeutics: Equity Ownership. Chauhan:C4 Therapeutics: Equity Ownership; Epicent Rx: Consultancy; Oncopeptide AB: Consultancy; Stemline Therapeutics, Inc.: Consultancy. Anderson:Celgene Corporation: Consultancy; Millennium Pharmaceuticals: Consultancy; Novartis AG: Consultancy; Bristol-Myers Squibb:: Consultancy; Oncopep: Other: Scientific Founder; Acetylon: Other: Scientific Founder.

PCN14 - Comparative Effectiveness of Treatment Strategies For Multiple Myeloma in Elderly Patients: A Network Meta-Analysis

PCN14 - Comparative Effectiveness of Treatment Strategies For Multiple Myeloma in Elderly Patients: A Network Meta-Analysis

Bidirectional Notch Signaling and Osteocyte-Derived Factors in the Bone Marrow Microenvironment Promote Tumor Cell Proliferation and Bone Destruction in Multiple Myeloma.

In multiple myeloma, an overabundance of monoclonal plasma cells in the bone marrow induces localized osteolytic lesions that rarely heal due to increased bone resorption and suppressed bone formation. Matrix-embedded osteocytes comprise more than 95% of bone cells and are major regulators of osteoclast and osteoblast activity, but their contribution to multiple myeloma growth and bone disease is unknown. Here, we report that osteocytes in a mouse model of human MM physically interact with multiple myeloma cells in vivo, undergo caspase-3-dependent apoptosis, and express higher RANKL (TNFSF11) and sclerostin levels than osteocytes in control mice. Mechanistic studies revealed that osteocyte apoptosis was initiated by multiple myeloma cell-mediated activation of Notch signaling and was further amplified by multiple myeloma cell-secreted TNF. The induction of apoptosis increased osteocytic Rankl expression, the osteocytic Rankl/Opg (TNFRSF11B) ratio, and the ability of osteocytes to attract osteoclast precursors to induce local bone resorption. Furthermore, osteocytes in contact with multiple myeloma cells expressed high levels of Sost/sclerostin, leading to a reduction in Wnt signaling and subsequent inhibition of osteoblast differentiation. Importantly, direct contact between osteocytes and multiple myeloma cells reciprocally activated Notch signaling and increased Notch receptor expression, particularly Notch3 and 4, stimulating multiple myeloma cell growth. These studies reveal a previously unknown role for bidirectional Notch signaling that enhances MM growth and bone disease, suggesting that targeting osteocyte-multiple myeloma cell interactions through specific Notch receptor blockade may represent a promising treatment strategy in multiple myeloma.

Interfering with Arginine Metabolism As a New Treatment Strategy for Multiple Myeloma

IntroductionStarvation of tumor cells from the amino acid arginine has recently gained particular interest because of the downregulation of the rate-limiting enzyme argininosuccinate synthethase 1 (ASS1) in various cancer entities. ASS1-deficient cells cannot resynthesize arginine from citrulline and are therefore considered arginine auxotrophic. The arginine depleting enzyme arginine deiminase (ADI-PEG20, Polaris Pharmaceuticals) is currently tested in phase I-III clinical trials for different arginine auxotrophic cancers. The natural arginine analogue canavanine can compete with arginine for arginyl-tRNA-binding sites and consequently be incorporated into nascent proteins instead of arginine. Canavanine could therefore potentially further disturb intracellular protein homeostasis, especially under arginine deprivation. The sensitivity of myeloma cells towards arginine depletion strategies has not been analyzed so far.MethodsHuman myeloma cell lines and CD138-sorted primary human myeloma cells from patient bone marrow were screened for ASS1 expression by western blotting (WB). The cells were cultured in arginine free medium and assessed for proliferation and metabolic activity (CFSE/MTT assays), apoptosis (caspase-3 cleavage) and cell death (annexinV/propidium iodide). Canavanine was supplied in both arginine-sufficient and -deficient conditions. The level of intracellular protein stress was determined by WB and/or flow cytometry analysis for ubiquitinated proteins, phosphorylated eukaryotic initiation factor 2α (peIF2α) and the spliced isoform of the X-Box binding protein 1 (Xbp1s). Repetitive ADI-PEG20 ± canavanine application i.p. were tested in vivo in an U266 myeloma xenograft model in NOD/SCID/IL2Rcg-/- (NSG) mice. Arginine and canavanine levels in plasma were determined by HPLC. Tumor growth was measured, mice were assessed for survival, weight and side effects. Tumor tissues were analyzed for caspase-3 cleavage and Ki67 expression by immunohistochemistry.Results5 of 6 myeloma cell lines were negative for ASS1. Also, ASS1 was either not or only weakly expressed in the majority of primary CD138+ myeloma patient samples. Arginine starvation induced an arrest of cell proliferation and/or metabolic activity of primary myeloma cells and myeloma cell lines after 18-24 h. Addition of citrulline could only rescue ASS1 positive myeloma cells due to the intracellular resynthesis of arginine. Arginine starvation alone led to delayed induction of apoptosis (e.g. 35% cell death of NCI-H929 cells after 72 h of treatment). Addition of 100 mM canavanine strongly increased cell death specifically in the context of arginine deficiency (e.g. cell death in NCI-H929 cells: 87% after 24 h, 100 % after 48h) while it was non-toxic and had no effect on cell viability under physiological arginine conditions. Co-application of canavanine induced ubiquitination of cellular proteins and led to the prolongation of a fatal unfolded protein response (UPR) as measured by markedly elevated Xbp1s levels. Prolonged UPR ultimately led to the induction of apoptosis as reflected by annexin V binding and caspase-3 cleavage. In an U266 myeloma NSG xenograft model, systemic arginine depletion by ADI-PEG20 suppressed tumor growth in vivo and significantly prolonged median survival of mice when compared with the control group (22±3 vs. 15±3 days). Canavanine treatment alone had no influence on viability (13±0 days). However, the combination of ADI-PEG20 and canavanine demonstrated the longest median survival (27±7 days). Histological examination of explanted tumors showed the highest rates of caspase-3 cleavage in the ADI-PEG20/canavanine group.ConclusionMyeloma cells are mostly arginine auxotrophic and can be selectively targeted by arginine starvation. Combination of arginine depletion with the arginine analogue canavanine leads to a highly efficient and specific tumor cell eradication and should be further optimized in multiple myeloma preclinical models. DisclosuresBomalaski:Polaris Pharmaceuticals Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Occurrence and Prognostic Significance of Cytogenetic Evolution in Patients with Multiple Myeloma

Abstract Background: Cytogenetic evaluation, especially using fluorescence in situ hybridization (FISH), at the time of diagnosis is essential for initial risk stratification and the employment of risk-adapted treatment strategies in multiple myeloma. Little is known about the occurrence and prognostic significance of cytogenetic evolution during follow up. Methods: We studied 433 patients who were diagnosed with multiple myeloma between January 2000 and December 2011 and had at least two FISH evaluations at Mayo Clinic Rochester, including the diagnostic specimen. Bone marrow aspirates were evaluated for deletions, monosomies, trisomies, and tetrasomies using chromosome- or centromere-specific FISH probes. IGH rearrangements were evaluated using an IGH break-apart probe and up to five potential partners (FGFR3, CCND1, CCND3, MAF, and MAFB). Cytogenetic evolution was defined as a new deletion, monosomy, trisomy, tetrasomy, or translocation during follow up. Multivariable-adjusted logistic regression models were used to assess the associations between the parameters of interest and the presence of cytogenetic evolution in follow-up specimens. Multivariable-adjusted Cox proportional hazards models were used to assess the effect of cytogenetic evolution on overall survival. All models were adjusted for sex, age, the presence of high-risk FISH abnormalities, and the number of abnormalities at the time of diagnosis. Likelihood ratio tests were used to assess the goodness of fit of nested models. The χ2 or Fisher's exact test was used to assess the distribution of cytogenetic abnormalities in subgroups. Results: The median age at diagnosis was 60 years (32 - 82), 264 (61%) of the patients were male. The median overall survival for the entire cohort was 7.0 years (6.2 - 7.8). At the time of diagnosis, 150 (35%) and 57 (13%) of the 433 patients presented with a hyperdiploid karyotype and cytogenetic high-risk abnormalities, respectively. Independent of each other, the presence of a translocation at the time of diagnosis was associated with decreased odds of cytogenetic evolution during follow up (OR 0.39, 95% CI 0.24 - 0.63, p &lt; 0.001) while the presence of at least one trisomy or tetrasomy at the time of diagnosis was associated with increased odds (OR 2.53, 95% CI 1.37 - 4.70, p = 0.003). A greater proportion of patients presenting with a hyperdiploid karyotype experienced cytogenetic evolution during follow up. Those patients more frequently evolved additional trisomies and tetrasomies, while translocations were more common in those presenting with a non-hyperdiploid karyotype (Table 1). The development of additional abnormalities during the three years following diagnosis (compared to no new abnormalities) was associated with increased subsequent mortality in those who survived at least three years (HR 3.22, 95% CI 1.82 - 5.68, p &lt; 0.001). Including the time between first and last cytogenetic evaluation as a covariate did not significantly change the parameter estimates or improve model fit (p = 0.727). Conclusions: Demographics, risk profile, and overall survival of this cohort reflect the fact that patients had to survive long enough to undergo repeated cytogenetic evaluation. Hyperdiploid and non-hyperdiploid genotypes were associated with distinct behavior regarding cytogenetic evolution during follow up. The identification of cytogenetic evolution was an adverse prognostic factor in those who survived at least three years after diagnosis. These findings emphasize the importance of the dynamics of the underlying clonal disease process for accurate risk assessment and suggest that selected subgroups of patients may benefit from risk stratification during follow up. Table 1. Cytogenetic evolution during follow up in 433 patients with multiple myeloma stratified by karyotype at the time of diagnosis Hyperdiploid (n = 150) Non-hyperdiploid (n = 283) p New abnormality 76 (51%) 108 (38%) 0.012 New monosomy 8 (5%) 24 (8%) 0.243 New trisomy 48 (32%) 55 (19%) 0.004 New tetrasomy 37 (25%) 27 (10%) &lt; 0.001 New deletion 17 (11%) 27 (10%) 0.557 New translocation 1 (1%) 11 (4%) 0.065 Most common new abnormality [type (percent of type in each group)] Monosomy mono(13) (75%) mono(13) (62%) Trisomy tri(11) (22%) tri(3) (22%) Tetrasomy tetra(15) (48%) tetra(15) (30%) Deletion del(17p) (79%) del(17p) (63%) Translocation t(11;14) (100%) t(11;14) (36%) Data are given as count (percent) unless denoted otherwise. Disclosures Binder: American Society of Hematology: Research Funding. Kumar:AbbVie: Research Funding; Onyx: Research Funding; Sanofi: Research Funding; Celgene, Millenium, Sanofi, Skyline, BMS, Onyx, Noxxon,: Other: Consultant, no compensation,; Skyline, Noxxon: Honoraria; Millenium/Takeda: Research Funding; Janssen: Research Funding; Celgene: Research Funding.

Characterization of Heat Shock Factor 1 in Response to Proteasome Inhibition Unveils a Novel Therapeutic Strategy for Multiple Myeloma Treatment

e244 The percentage of CD3+HLA-DR+ T lymphocytes in the peripheral blood of the patients suffering from MM was 3.85 3.64% (median, 2.73%) and it was significantly statistically lower (p1⁄40.01) in comparison to the control group where an average percentage of these cells was 6.01 2.84% (median, 7.01%). The percentage of CD3+CD56+16+ NKT cells in the peripheral blood of the patients with MM was 10.93 11.02% (median, 8.59%) and it was significantly statistically lower (p1⁄40.0005) in comparison to the control group (21.15 9.08%; median, 22.8%). A positive correlation between the percentage of CD3+HLA-DR+ T lymphocytes and the percentage of BDCA2+CD123+ lymphoid DCs in bone marrow was demonstrated. The relation was statistically significant p1⁄40.001. Furthermore, a significant, positive correlation was found between the percentage of CD3+CD56+CD16+ NKT cells and the percentage of BDCA2+CD123+ lymphoid DCs in bone marrow (p1⁄40.04). Obtained results revealed the relations between the percentage of DCs subpopulations and lymphocytes subsets, especially the activated ones, in the peripheral blood and bone marrow. The previously described role of DCs in the process of an immunological response, either adaptive or innate, lets us think that the decrease of the number or percentage of these cells may have a negative influence on the process of an activation of effector cells and, consequently, on the effectiveness of a response to foreign as well as neoplastic antigens in patients suffering from MM.

Cereblon binding molecules in multiple myeloma

Immunomodulation is an established treatment strategy in multiple myeloma with thalidomide and its derivatives lenalidomide and pomalidomide as its FDA approved representatives. Just recently the method of action of these cereblon binding molecules was deciphered and results from large phase 3 trials confirmed the backbone function of this drug family in various combination therapies. This review details the to-date knowledge concerning mechanism of IMiD action, clinical applications and plausible escape mechanisms in which cells may become resistant/refractory to cereblon binding molecule based treatment.

Phase 1 study of weekly dosing with the investigational oral proteasome inhibitor ixazomib in relapsed/refractory multiple myeloma

AbstractProteasome inhibition is an effective treatment strategy for multiple myeloma. With improving survival, attention is increasingly focusing on ease of administration and toxicity profile. Ixazomib is an investigational, orally bioavailable 20S proteasome inhibitor. Sixty patients with relapsed and/or refractory multiple myeloma were enrolled on this phase 1 trial to evaluate safety and tolerability and determine the maximum tolerated dose (MTD) of single-agent, oral ixazomib given weekly for 3 of 4 weeks. Upon MTD determination, patients were enrolled to 4 different cohorts based on relapsed/refractory status and prior bortezomib and carfilzomib exposure. The MTD was determined to be 2.97 mg/m2. Dose-limiting toxicities were grade 3 nausea, vomiting, and diarrhea in 2 patients, and grade 3 skin rash in 1 patient. Common drug-related adverse events were thrombocytopenia (43%), diarrhea (38%), nausea (38%), fatigue (37%), and vomiting (35%). The observed rate of peripheral neuropathy was 20%, with only 1 grade 3 event reported. Nine (18%) patients achieved a partial response or better, including 8 of 30 (27%) evaluable patients treated at the MTD. Pharmacokinetic studies suggested a long terminal half-life of 3.6 to 11.3 days, supporting once-weekly dosing. This trial was registered at www.clinicaltrials.gov as #NCT00963820.

European perspective on multiple myeloma treatment strategies in 2014.

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, nowadays it is possible to categorize patients more precisely into different risk groups, thus allowing the evaluation of therapies in different settings and enabling a better comparison of results across trials. Here, we review the evidence from clinical studies, which forms the basis for our 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) remains the preferred option. Consolidation and maintenance therapy are attractive strategies not yet approved by the European Medicines Agency, and a decision regarding post-ASCT therapy should only be made after detailed discussion of the pros and cons with the individual patient. Two- and three-drug combinations are recommended for patients not eligible for transplantation. Treatment should be administered for at least nine cycles, although different durations of initial therapy have only rarely been compared so far. Comorbidity and frailty should be thoroughly assessed in elderly patients, and treatment must be adapted to individual needs, carefully selecting appropriate drugs and doses. A substantial number of new drugs and novel drug classes in early clinical development have shown promising activity. Their introduction into clinical practice will most likely further improve treatment results.

The evolution of multiple myeloma treatment strategies based on changes in effect judgment

The evolution of multiple myeloma treatment strategies based on changes in effect judgment