Citations

Background: Multiple myeloma (MM) is a heterogeneous disease with varying survival outcomes depending on the presence of certain genetic abnormalities. Common abnormalities include trisomies, translocations involving the chromosome 14, and amplifications or deletions of chromosomes 1, 13, and 17. t(11;14), occurring in 15% of patients with myeloma, had been considered a standard risk abnormality, but recent data suggest inferior outcome. This is important as new therapeutic options such as the BCL-2 inhibitor venetoclax has been shown to be particularly effective in t(11;14) patients. Methods: This was a multicenter study to identify the outcomes of patients with t(11;14), using a retrospectively assembled cohort. Patients with MM diagnosed between 2005 and 2015 with t(11;14) identified on FISH performed within six months of diagnosis, and with treatment details available and if alive, a minimum of 12 months of follow up, were enrolled. Results: The current analysis includes 1216 patients; median age of 62.56 years; 58.7% male. The median follow-up from diagnosis for the entire cohort was 51.9 months; 69.1% of the patients were alive at the last follow up. ISS stage distribution included: Stage I (35.7%), Stage II (34.0%) and Stage III (15.1%), data was missing for the rest. The distribution of concurrent FISH abnormalities included: trisomies (3.5%), del 13q (13.3%), 1q amp (8.8%), and del 17p or monosomy 17 (5.8%). Initial regimen included: 27.2% had an immunomodulatory (IMiD), 45.9% had a proteasome inhibitor (PI), 17.7% had both, and 9.0% had no novel agent. The drug classes by line of therapy are shown in Table 1. An early stem cell transplant (defined as within 12 months of start of first line treatment) was used in 49.4% of patients. The median time to next treatment (TTNT) after starting initial treatment was 26.6 (95% CI: 23.9 to 29.2) months. The median overall survival (OS) from diagnosis for the entire cohort was 95.1 (95% CI: 85.9 to 105.9) months; 4-year estimates for those diagnosed from January 2005 to December 2009, and from January 2010 to December 2014 were 77.5% and 78.6%, respectively. The median OS for those with any one high risk FISH lesion (del 17p/ 1q amp) was 67.5 (55.2, 97.1) versus 101.7 (89.7, 107.3) months. Patients with early SCT (within 12 months of diagnosis) had better OS: 108.3 (103.8, 133.0) vs. 69.8 (61.5, 80.3) months. Conclusion: Patients with t(11;14) without high risk FISH abnormalities have an excellent survival. Patients receiving a PI + IMiD combination and those receiving autologous SCT as part of initial therapy had best survival. Though numbers are limited, patients in the later lines receiving newer drugs such as venetoclax and daratumumab had high response rates and durable responses. Disclosures Kumar: Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding. Bittrich:Celgene: Other: Travel Funding, Research Funding; Else Kröner Fresenius Foundation: Research Funding; Otsuka Pharmaceuticals Europe: Other: N/A; SANOFI Aventis: Membership on an entity's Board of Directors or advisory committees, N/A, Research Funding; University Hospital Wuerzburg: Employment; Bristol Myers Squibb: Research Funding; Pfizer: Other: Travel Funding; AMGEN: Other: Travel Funding; JAZZ Pharmaceuticals: Other: Travel Funding; Wilhelm Sander Foundation: Research Funding; German Research Foundation (DFG): Other: N/A; University of Würzburg: Other: N/A. Goldschmidt:Mundipharma: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; John-Hopkins University: Research Funding; Dietmar-Hopp-Stiftung: Research Funding; Janssen: Consultancy, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Research Funding; Molecular Partners: Research Funding; John-Hopkins University: Research Funding; Amgen: Consultancy, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Honoraria, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Reece:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Otsuka: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; BMS: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Merck: Research Funding. Mateos:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmamar: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria; EDO: Membership on an entity's Board of Directors or advisory committees. Ludwig:Celgene: Speakers Bureau; Amgen: Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau; PharmaMar: Consultancy; Janssen: Speakers Bureau; BMS: Speakers Bureau. Mangiacavalli:celgene: Consultancy; Amgen: Consultancy; Janssen cilag: Consultancy. Dimopoulos:Sanofi Oncology: Research Funding. Kastritis:Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Honoraria; Prothena: Honoraria; Genesis: Honoraria. Yee:Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Karyopharm: Consultancy; Adaptive: Consultancy. Raje:Amgen Inc.: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene Corporation: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Merck: Consultancy. Rosta:Cornerstone Research Group: Employment. Haltner:Cornerstone Research Group: Employment. Cameron:Cornerstone Research Group: Employment, Equity Ownership. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy.

Abstract Introduction: Renal impairment (RI) is a classic clinicopathological feature of MM, is associated with poor prognosis and shorter survival (Eleutherakis-Papaiakovou Leuk Lymphoma 2007), and can complicate drug dosing and limit treatment options. In clinical trials, the proteasome inhibitors K and V have demonstrated efficacy in RRMM pts with RI, with superior efficacy observed in K-treated pts (Dimopoulos Blood 2017). K and V have also been observed to improve renal function in RRMM pts (Dimopoulos Clin Lymphoma Myeloma 2009; Dimopoulos Blood Advances 2017). However, few studies have investigated the real-world effectiveness of K- and V-based regimens in renal rescue. This study aimed to describe and compare renal response rates in RRMM pts treated with K + dexamethasone (Kd) and V + dexamethasone (Vd) in oncology clinics. Methods: The Oncology Services Comprehensive Electronic Records (OSCER) database (Lau Clin Epidemiol 2011) contains electronic medical records (EMR) from community- and hospital-affiliated oncology clinics in the United States. MM pts aged ≥18 who entered an OSCER clinic Jan 2012‒Feb 2018; initiated Kd or Vd treatment as line 2 (2L), 3L, or 4L; and had baseline renal impairment (Modification of Diet in Renal Disease Study estimated glomerular filtration rate [eGFR] <50 mL/min from the most recent baseline serum creatinine measurement) were included. Index date was the date of Kd or Vd initiation. The baseline period was 60 d prior to index to 30 d post-index. Follow-up was 30 d after index date to 60 d after completion of the same line. Primary outcome was renal response during follow-up. Renal response was defined according to the International Myeloma Working Group criteria (Dimopoulos J Clin Oncol 2016): complete response (RCR; baseline eGFR <50 mL/min and best post-treatment eGFR ≥60 mL/min), partial response (baseline eGFR <15 mL/min and best post-treatment eGFR 30‒59 mL/min), minor response (baseline eGFR <15 mL/min and best post-treatment eGFR 15‒29 mL/min, or baseline eGFR 15‒29 mL/min and best post-treatment eGFR 30‒59 mL/min). Renal response rates in Kd- and Vd-treated pts were evaluated using the Kaplan-Meier method and log-rank test. Incidence rate ratios (IRR) and 95% confidence intervals (CIs) were calculated for renal overall response (ROR) and RCR using multivariate Cox proportional hazard models adjusted for baseline covariates (demographics, Eastern Cooperative Oncology Group Performance Status, International Staging System stage, baseline renal function, V use in 1L, time from MM diagnosis to line initiation, use of intravenous bisphosphonates, and baseline serum calcium, serum free light chain ratio, lactate dehydrogenase, and whole blood hemoglobin measurements). Missing baseline values were estimated by multiple imputations. Results: 543 Kd-treated and 1005 Vd-treated pts were included. Baseline characteristics were similar between cohorts, with no difference in baseline eGFR stages. More Kd pts were <65 yrs of age at MM diagnosis. Median time from diagnosis to line initiation was longer in Kd pts (Kd: 17.1 mos; Vd 16.1 mos). V-based regimens were the most common therapies in 1L. Median (interquartile range) treatment duration was 4.4 (2.3-8.3) mos for Kd and 4.3 (2.1-8.3) mos for Vd. Pts treated with Kd at 2L were more likely than those treated with Vd to achieve both ROR (51.4% [178/346] vs 39.6% [327/825]; log-rank test p<0.0001) and RCR (26.6% [92/346] vs 22.2% [183/825]; log-rank test p=0.0229). This pattern persisted when 3L and 4L pts were included, (ROR: 48.4% [263/543] vs 39.8% [400/1005]; log-rank p<0.0001; RCR: 26% [141/543] vs 22.1% [222/1005]; log-rank p=0.0084) (Figures 1A and 1B). Following adjustment for potential baseline confounders, 2L Kd pts were 45% more likely to achieve ROR (IRR, 95% CI: 1.45, 1.18‒1.78) and 68% more likely to achieve RCR (1.68, 1.24‒2.28) vs 2L Vd pts (Figure 2). Kd pts in 2‒4L were 36% more likely to achieve ROR (1.36, 1.15‒1.62) and 52% more likely to achieve RCR (1.52, 1.19‒1.94). Conclusions: Using one of the most complete oncology EMR databases available, we found that RRMM pts with baseline RI treated with Kd had higher rates of overall and complete renal response, and were more likely to have a renal response, compared with pts treated with Vd. A limitation of the study is that we could not account for all concomitant medications or comorbidities that affect renal function, as some may not be captured in OSCER. Disclosures Kumar: AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding. Fu:Amgen: Employment, Equity Ownership. Mezzi:Amgen: Employment, Equity Ownership. Braunlin:Amgen: Employment. Kim:Amgen: Employment, Equity Ownership. Iskander:Amgen: Employment, Equity Ownership. Niesvizky:Amgen Inc.: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Jagannath:Celgene: Consultancy; Novartis: Consultancy; Merck: Consultancy; Medicom: Speakers Bureau; Multiple Myeloma Research Foundation: Speakers Bureau; Bristol-Myers Squibb: Consultancy. Boccia:Sandoz: Consultancy; Celgene: Speakers Bureau; Abbvie: Speakers Bureau; Genentech: Research Funding, Speakers Bureau; Amgen: Research Funding, Speakers Bureau; BMS: Research Funding; Pfizer: Consultancy; AstraZeneca: Research Funding, Speakers Bureau. Raje:Celgene: Consultancy; Janssen: Consultancy; Merck: Consultancy; Takeda: Consultancy; AstraZeneca: Research Funding; Research to Practice: Honoraria; Medscape: Honoraria; BMS: Consultancy; Amgen Inc.: Consultancy.

Abstract From 2013-2017, numerous new approvals and expanded indications have dramatically changed the treatment (tx) landscape for MM. Since that time, experienced MM physicians from leading academic institutions and cancer centers (experts) have annually updated and contributed tx recommendations for an online decision support tool designed to provide healthcare providers (HCPs) with patient-specific tx guidance. This MM tool is freely available online at www.clinicaloptions.com/myelomatool and HCPs can use the tool to enter details of a patient case, indicate their intended tx plan, and then expert tx recommendations for that case are provided. Methods This study includes analysis of tx recommendations from 5 MM experts for 270 unique MM case scenarios made during development of the 2018 update to this tool. We also aim to compare the evolving tx recommendations among the experts over time, from 2013-2017, and to determine practice patterns of HCPs using the tool over the same time span. Results Based on analysis of these annually updated MM tools, consensus (≥ 3 of 5 experts choosing the same tx for the same case) among experts has been increasing for induction tx since 2013. In ASCT-eligible patients with no specific comorbidities, experts recommended bortezomib/lenalidomide/dexamethasone (VRd) in 100% and 90% of tool cases in 2018 and 2017, respectively, which increased from 65% to 75% consensus in 2013-2015. In previous analyses, the percentage of HCPs using VRd has also increased, albeit more slowly than with experts. In 2017, 42% of HCPs indicated that they are using VRd as induction in this setting compared with 22% in 2015-2016 and 9% in 2014-2015. For ASCT-ineligible patients with ECOG > 2 but no specific comorbidities, all 5 experts recommend triplet therapy for all cases regardless of risk in 2018, but in 2017, 3 of 5 recommended triplet therapy and 2 of 5 recommended doublets for normal-risk disease. Expert recommendations for induction change, however, based on specific patient comorbidities. For patients with peripheral neuropathy, 4 of 5 experts recommended carfilzomib/lenalidomide/dexamethasone instead of VRd. For patients with renal insufficiency, 4 of 5 experts recommended bortezomib/cyclophosphamide/dexamethasone. For patients with cardiac dysfunction, all 5 experts continue to recommend VRd for patients with ECOG ≤ 2 while 2 of 5 change from VRd to Rd for patients with ECOG > 2. For patients who achieve VGPR or better to induction, all 5 experts recommend lenalidomide maintenance for standard risk disease. But for patients with high risk disease who achieve VGPR or better to induction, 3 of 5 experts recommend bortezomib/lenalidomide combination maintenance therapy regardless of induction regimen, 1 expert recommends single-agent bortezomib regardless of induction regimen, and 1 expert recommends bortezomib after a PI-based induction regimen or lenalidomide for an IMiD or IMiD/PI-based induction regimen. In the 2018 tool update, the number of R/R case scenarios with 100% expert consensus increased over previous years: 20% of cases had all 5 experts agreeing on tx vs 12% in 2017. In addition, 29% of cases had 3 of 5 experts agreeing and 8% had 2 pairs of experts agreeing in 2018 vs none with 3 of 5 experts agreeing and 21% with 2 pairs of experts agreeing in 2017. In 2018, experts recommended daratumumab/pomalidomide/dexamethasone all cases with 100% consensus, which comprises patients who are refractory to multiple agents including lenalidomide, bortezomib, and/or carfilzomib. Overall, 23 different regimens were recommended for R/R MM; and additional majority expert consensus included daratumumab/lenalidomide/dexamethasone, daratumumab/carfilzomib/dexamethasone, and carfilzomib/pomalidomide/dexamethasone (Table 1). Conclusions Practice patterns are changing rapidly and are more complex, particularly in the R/R setting, in response to the evolving tx landscape for MM. This analysis highlights several areas of expert consensus, but disparities remain for select cases. The newest approved therapies continue to have a strong impact on experts' recommendations as they have been fully integrated into their tx approaches. These analyses provide a real-time assessment of changing tx patterns among experts as well as HCPs. We will present analyses of cases entered in the 2018 online tool by HCPs and detailed comparisons of expert and the intended tx of clinicians using the tool. Disclosures Ghobrial: Takeda: Consultancy; Janssen: Consultancy; Celgene: Consultancy; BMS: Consultancy. Lonial:Amgen: Research Funding. Raje:Research to Practice: Honoraria; Takeda: Consultancy; AstraZeneca: Research Funding; Celgene: Consultancy; BMS: Consultancy; Merck: Consultancy; Janssen: Consultancy; Amgen Inc.: Consultancy; Medscape: Honoraria. Kumar:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding.

Abstract Abstract 1024 Background: The MMRC is a non-profit, disease-focused consortium founded in 2004. Sixteen North American member institutions with expertise in multiple myeloma (MM) work collaboratively with the MMRC Inc. (Norwalk, CT) and numerous pharmaceutical partners to speed development of new treatment options to MM patients. In December 2007, MMRC Inc. implemented business solutions to address barriers to rapid activation of phase I-II trials and established benchmarks for initiating and conducting these studies. In December 2010, we reported significantly faster trial start up and accrual data from previous years1,2. Today, we update and expand on MMRC performance data and analysis of progress. Methods: Twenty-five (25) trials conducted within the Consortium from May 2006 to July 2011 had sufficient start up trial data for review. FPFD was defined as the time from the member institutions' receipt of the final protocol (FP) from the trial sponsor, to the time the first patient was dosed on the trial at any participating MMRC member institution. With respect to enrollment, pre-study enrollment commitment (EC) established between MMRC and the study sponsor was defined as the total number of subjects committed to receive at least one dose of study drug across all participating MMRC centers on a trial; baseline enrollment timeline (BET) was prospectively defined as the target time period to attain EC. Results: Mean time to FPFD in the recent group of trials (RG; n=18; Sept 08-Jul 11) held steady at 131 calendar days from receipt of FP as compared to 181 days for the early group of trials (EG; n=7; Jun06-Sept08) representing a 28% reduction in time to FPFD. More importantly, there was a 20% decrease in time to FPFD by all participating MMRC centers on any MMRC trial from 189 days in the RG compared to 236 days in the EG representing an important achievement especially in the Phase I/II arena. MMRC trial accrual data was available for 17/25 trials (2 EG trials were missing data and 6 RG trials continue enrolling). The pre-study mean MMRC EC was 44 subjects per trial (n=19 trials; 849 patients); the mean actual MMRC enrollment was 49 subjects per trial (n=19; 935 patients through July 11) representing a 10% over enrollment versus committed enrollment. A total of 17/19 evaluable trials (89%) met their EC; 12/19 trials met EC within BET (71%) of which 8/12 trials (67%) reached EC 34% faster than their BET (representing a mean reduction of 4.5 months). The overall pre-study mean BET for 19 trials was 13.6 months. MMRC's actual mean enrollment timeline was 12.8 months for the group of 17 evaluable trials representing improvement over the original BET by a mean of 10%. Discussion: MMRC's acceleration of clinical trials provides physicians and patients with rapid access to novel compounds; industry with data for important drug development decisions; and academic institutions with more trials of high scientific interest. Even so, our data uncovered opportunities for improvement. The submission time from receipt of the final protocol from the trial sponsor to Scientific Review Committee (SRC) took an average 30 calendar days across all trials. A reduction to half this time could make a difference to patients and therefore warrants further exploration. Conclusion: Today, drug development in multiple myeloma is fast-paced and highly competitive. MMRC's frequent review of trial metrics provides valuable insight to continually speed answers to physicians, patients and industry. Disclosures: Richardson: Multiple Myeloma Research Consortium: Annual grant in support Clinical Trial Project Management. Vij:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Lonial:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Siegel:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Jakubowiak:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Reece:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Jagannath:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Hofmeister:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Stewart:Multiple Myeloma Research Consortium: Annual Grant in support of clinical trial Project Management. Wolf:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Krishnan:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Zimmerman:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Kumar:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Roy:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Fay:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management. Anderson:Multiple Myeloma Research Consortium: Annual grant in support of clinical trial Project Management.

Abstract NF-κB is a transcriptional factor promoting tumor cell growth and inhibition of apoptosis via regulating expression of proteins modulating cell cycle and anti-apoptosis. NF-κB is constitutively associated with an inhibitor (IκB), which is phosphorylated by IκB kinase (IKK) upon cell stimulation (ie, TNFα) and subsequently degraded by ubiquitin-proteasome pathway, thereby allowing NF-κB to translocate to nucleus. We have previously shown that an IKK inhibitor PS-1145 partially (20–50%) inhibits MM cell proliferation; however, it inhibits both IL-6 secretion from BMSCs triggered by MM cell adhesion and proliferation of MM cells adherent to BMSCs. Targeting IKKβ is therefore a possible therapeutic option for inhibition of MM cell growth in the bone marrow microenvironment by downregulating NF-κB activity. In this study, we further delineated the biologic significance of IKK inhibition in MM cells using IKKβ specific inhibitor MLN120B (Millennium Pharmaceuticals, Cambridge, MA). MLN120B induced 60–90% growth inhibition in cells from the MM cell lines RPMI8226, RPMI/Dox40, RPMI/LR5, U266, and INA-6; on the other hand, it induced only 25–30% inhibition in MM.1S and MM.1R cells, assessed by 72 h tritiated-thymidine uptake. Importantly, neither IL-6 nor IGF-1 overcomes the growth inhibitory effect of MLN120B in both MM.1S and U266 cells. Interestingly, MLN120B significantly augmented TNFα-induced cytotoxicity in MM.1S cells. We next examined whether MLN120B could enhance the cytotoxicity of other agents. MLN120B augmented growth inhibition triggered by doxorubicin and melphalan in RPMI8226 and IL-6 dependent INA-6 cell line. We therefore studied growth inhibitory effect of MLN120B in the presence of bone marrow stromal cells (BMSCs). MLN120B inhibited 70–80% of constitutive IL-6 secretion from BMSCs, without toxicity. Importantly, MLN120B almost completely blocked stimulation of MM.1S, U266 and INA-4 cell growth and IL-6 secretion from BMSCs induced by binding of tumor cells to BMSCs. Finally, MLN120B overcame the protective effect of BMSCs, cell adhesion mediated drug resistance, against dexamethasone in MM.1S cells. Taken together, our data demonstrate that an IKKβ inhibitor induces cytotoxicity in MM cells in the BM milieu, providing the framework for clinical trials of these novel agents to improve patient outcome in MM.

Abstract Angiogenesis or formation of new blood vessels from existing blood vessels, in contrast to vasculogenesis or de novo formation of new vessels, plays an important role in the progression and spread of most cancers. Multiple myeloma (MM) is characterized by increased microvessel density (MVD), a quantitative estimate of angiogenesis, which correlates with stage of disease. MVD increases with progression from MGUS to smoldering MM to newly diagnosed MM and relapsed MM. It is a powerful prognostic factor, predicting for overall survival. To further elucidate the biological basis for the prognostic value of increased angiogenesis in MM, we studied the interactions of MM cells with endothelial cells using HUVECS as a model system. Co-culture of MM cells (MM1.S, OPM2, U266) with HUVECS induced tumor cell proliferation. Enhanced tumor cell proliferation correlated with the number of HUVECs and was greater than that triggered by co-culture with patient bone marrow stromal cells. When HUVECs were fixed prior to co-culture there was a significant decrease in the tumor cell proliferation. Addition of HUVEC conditioned media to the MM cell lines also induced proliferation. Importantly, HUVECS protected against anti-MM agents including conventional agents (Dexamethasone, Doxorubicin, Melphalan) and novel drugs (Revlimid™). The protective effect afforded by co-culture was lost on HUVEC fixation. Intracellular signaling events following MM cell-endothelial cell contact were studied to understand the mechanisms of the proliferative and protective effects. Western blotting demonstrated activation of the JAK/STAT, PI3K/Akt and the MAPK pathways, mediating proliferation and survival. Ongoing studies focused on understanding cytokine as well as adhesion-mediated interactions between the endothelial cells and the MM cells will identify targets for new therapeutic approaches in MM.

Abstract Abstract 127 Two- and three-drug regimens incorporating bortezomib (Velcade®, Vc), lenalidomide (Revlimid®, Rev), dexamethasone (Dex), and cyclophosphamide (Cy) (Vc–Dex, Rev–Dex, Vc–Dex–Rev [VDR], and Vc–Dex–Cy [VDC]), have been shown to be effective and well tolerated in previously untreated multiple myeloma (MM). Combining Vc and Dex with Rev and Cy in a novel four-drug regimen (VDCR) may result in even greater activity with improved quality and duration of response. Results from the phase 1 dose-escalation portion of the multi-center EVOLUTION study showed that the VDCR regimen is a highly active and generally well-tolerated induction therapy in previously untreated MM patients (pts). Here we report the efficacy and safety of VDR, VDC, and VDCR from the non-comparative phase 2 portion of the study. Methods: Pts were randomized to receive up to eight 21-d cycles of VDR (Vc 1.3 mg/m2 d 1, 4, 8, 11; Dex 40 mg d 1, 8, 15; Rev 25 mg d 1–14) or VDC (VD as in VDR, plus Cy 500 mg/m2 d 1, 8) or VDCR (VDC plus Rev 15 mg d 1–14) as induction therapy, followed by Vc 1.3 mg/m2 (d 1, 8, 15, 22) for four 42-d maintenance cycles in all treatment arms. Pts received prophylactic antibiotics, acyclovir, transfusion support, and anticoagulants as required. Eligible pts wishing to undergo autologous stem cell transplant (ASCT) could undergo stem cell mobilization any time after cycle 2, and undergo ASCT any time after cycle 4. Response categories were based on the IMWG Criteria with the addition of near complete response (nCR). Adverse events (AEs) were graded using the CTCAE v3.0. Results: In the VDR, VDC, and VDCR arms 42, 32, and 43 pts (including 6 pts treated at the maximum planned dose of Cy (500 mg/m2) from phase 1) have been treated, and 42, 31, and 33 are evaluable for response, respectively, as of data cut-off (31 July 2009). Median ages in the VDR, VDC, and VDCR arms were 60, 62, and 62 years, respectively; 62%, 63%, and 66% had International Staging System stage lI/III disease, and 38%, 25%, and 33% had Karnofsky Performance Status ≤80%, respectively. The median number of VDR, VDC, and VDCR cycles received is 4.5, 6, and 4, respectively (range 1–12). Best unconfirmed response rates are shown in the Table; patients categorized as very good partial response (VGPR) include those who have no measurable M-protein but have not yet had bone marrow assessments to confirm CR/nCR status. The overall rates of treatment-emergent AEs were 95%, 97%, and 88% for the VDR, VDC, and VDCR arms, respectively, with ≥grade 3 reported in 67%, 59%, and 65%. Peripheral neuropathy (PN) was reported as grade 2/3 in 12%/12% in the VDR, 31%/3% in the VDC, and 12%/9% in the VDCR arms; there was no grade 4 PN reported. Grade 3/4 neutropenia was reported in 5%/5%, 28%/13%, and 23%/9% of pts in the VDR, VDC, and VDCR arms, and grade 3/4 thrombocytopenia in 5%/2%, 9%/0%, and 5%/0% of pts, respectively. One case of grade 3 deep-vein thrombosis was reported in the VDCR arm. Overall rates of serious AEs were 24%, 13%, and 37% in the VDR, VDC, and VDCR arms, respectively. Two pts have died in the VDCR arm, both due to renal failure, considered possibly treatment-related. To date, 6 pts have undergone ASCT in the VDR arm, 5 in the VDC arm, and 3 in the VDCR arm. Median CD34+ yield was 4.7, 6.3, and 6.8 × 106/kg in the VDR, VDC, and VDCR arms, respectively. Conclusions: VDR, VDC, and VDCR are highly active and generally well-tolerated regimens in previously untreated MM. Response rates in the VDCR arm appeared somewhat higher than in the VDR and VDC arms at this early time point, although there also appeared to be higher rates of serious AEs, including possible treatment-related mortality in the VDCR arm. Following an interim analysis, dosing in the VDC arm was modified to include Cy on day 15 to examine if this will improve CR rates. Ten pts have been enrolled to date. Disclosures: Kumar: CELGENE: Research Funding; MILLENNIUM: Research Funding; BAYER: Research Funding; GENZYME: Research Funding; NOVARTIS: Research Funding. Flinn:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hari:Milennium Pharmaceuticals Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Callander:Millenium: Research Funding. Noga:Millennium Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Stewart:Takeda-Millenium, Celgene, Novartis, Amgen: Consultancy; Takeda, Millenium: Research Funding; Genzyme, Celgene, Millenium, Proteolix: Honoraria. Raje:Celgene: Research Funding; Novartis: Research Funding; AstraZeneca: Research Funding. Rifkin:Millennium Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Cephalon: Speakers Bureau. Shi:Millennium Pharmaceutical Inc.: Employment. Webb:Millennium: Employment, Equity Ownership. Richardson:Keryx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Abstract Background: Isatuximab (ISA) is an anti-CD38 monoclonal antibody with multiple modes of action for killing tumor cells through immune cell engagement and direct tumor targeting. In preclinical studies, pomalidomide (Pom) enhanced both the direct and indirect anti-tumor activity of ISA to a greater degree than lenalidomide (Len) (Jiang et al. Leukemia 2016). Here, we report the preliminary results of an ongoing Phase Ib dose-escalation study of ISA plus Pom and dexamethasone (Dex) in patients with relapsed and refractory multiple myeloma (RRMM) (NCT02283775). Methods: Patients with RRMM (≥2 prior MM therapies, including Len and a proteasome inhibitor) with adequate bone marrow reserve/organ function were sequentially enrolled to receive ISA 5, 10 or 20 mg/kg (weekly × 4 doses, then every 2 weeks until disease progression or intolerable toxicity) in combination with Pom 4 mg (days 1-21) and Dex 40 mg (days 1, 8, 15, and 22; 20 mg if ≥75 years old), in 28-day cycles. Pom or Dex dose reductions were permitted after Cycle 1, or during Cycle 1 in response to dose-limiting toxicities (DLTs). The primary objective was to determine the maximum tolerated dose (MTD) or recommended dose, based on the occurrence of treatment-related DLTs. Secondary objectives included evaluation of efficacy (by objective response assessment according to IMWG criteria), safety, and pharmacokinetics (PK). Results: At data cut-off (May 11, 2016), 14 patients had been treated in the first 2 dose-escalation cohorts: 8 patients at 5 mg/kg and 6 patients at 10 mg/kg. Overall, median age was 65.5 (range, 42-77) years and median time from diagnosis was 4.25 (1.0-12.5) years. Half of the patients (7/14) had received at least 5 prior regimens (median 4.5 [2-11]; prior carfilzomib in 50% of patients). Ten patients (71%) had received at least one prior stem cell transplant. Median duration of dosing was 21.2 (4-42) and 8.1 (4-12) weeks in the 5 mg/kg and 10 mg/kg cohorts, respectively, with the latter cohort also having the shortest follow-up. Three patients discontinued treatment, all in the 5 mg/kg cohort: 2 due to confirmed disease progression (discontinuation after 2 and 4 treatment cycles, respectively) and 1 due to patient withdrawal (discontinuation in Cycle 1 and patient not evaluable for response). There were no discontinuations due to treatment-emergent adverse events (TEAEs) in either cohort. Two DLTs were reported: one in the 5 mg/kg cohort (prolonged grade [Gr] 4 neutropenia), and the other in the 10 mg/kg cohort (Gr 4 neutropenic infection); both DLTs resolved with Pom dose delay/reduction. MTD has not yet been reached; the 20 mg/kg dose level is under enrollment. Overall, Gr 3/4 TEAEs were reported in 10 (71%) patients; serious TEAEs in 6 (43%) patients. The most frequent TEAEs were fatigue (64%), upper respiratory tract infection, tremor, dyspnea, and cough (29% each). The most common Gr 3/4 hematologic abnormality (laboratory assessment) was neutropenia (Gr 1, 0%; Gr 2, 7%; Gr 3, 43%; Gr 4, 43%). Gr 3/4 thrombocytopenia was reported in 4 (29%) patients (Gr 3, n=2; Gr 4, n=2). Infusion-associated reactions (IARs) occurred in 8 (57%) patients, with all cases Gr 1/2 in severity. IARs occurred during the first infusion in most patients; 3/14 (21%) patients experienced IARs at a subsequent infusion, of whom only one had IARs after Cycle 1. Of the patients evaluable for confirmed response, 8/13 (62%) achieved at least partial response (PR), and 10/13 (77%) at least minimal response (MR). At 5 mg/kg, 1 patient achieved complete response (CR), 2 very good partial response (VGPR) and 2 PR. At 10 mg/kg, 2 patients achieved VGPR, 1 PR, and 2 MR. Of the eight patients who achieved at least PR, all continued to respond without confirmed disease progression at data cut-off. The PK parameters of ISA were not affected by co-administration with Pom/Dex. Conclusions: These preliminary data suggest that the combination of ISA and Pom/Dex is generally well tolerated and clinically active in patients with heavily pre-treated RRMM. Enrollment continues and longer term follow-up from this study, including data from the 20 mg/kg cohort, will be presented. A Phase III trial to evaluate ISA plus Pom/Dex is planned. Disclosures Richardson: Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mikhael:Sanofi: Research Funding; Celgene: Research Funding; Abbvie: Research Funding; Onyx: Research Funding. Usmani:Pharmacyclics: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Skyline: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Britsol-Myers Squibb: Consultancy, Research Funding; BioPharma: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Array: Research Funding; Novartis: Speakers Bureau. Raje:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Eli Lilly: Research Funding. Bensinger:Takeda: Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; Acetylon: Research Funding; Bayer: Research Funding. Campana:Sanofi: Employment. Gao:Sanofi: Employment. Dubin:Sanofi Oncology: Employment. Wack:Sanofi: Employment. Anderson:Gilead: Membership on an entity's Board of Directors or advisory committees; Oncoprep: Equity Ownership; Oncoprep: Equity Ownership; Millennuim: Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Equity Ownership; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Acetylon: Equity Ownership; Acetylon: Equity Ownership; Millennuim: Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Equity Ownership; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees.

Abstract Interleukin-6 (IL-6) and insulin-like growth factor-1 (IGF-1) mediate growth of MM cells via activation of the mitogen-activated protein kinase (MAPK), JAK2/STAT3, and phosphatidylinositol 3′-kinase/Akt kinase (PI3-K/Akt) signaling cascades. We have previously demonstrated the in vitro and in vivo activity of Revlimid™ (CC-5013), an immunomodulatory analog (IMiD) of thalidomide, in MM. In the present study, we have examined the anti-MM activity of rapamycin, a specific mTOR inhibitor, combined with Revlimid™. This combination was highly synergistic at 0.1nmol/L of rapamycin with 0.1mmol/L of Revlimid™, and remained synergistic at higher concentrations. Based on the Chou-Talalay method, combination indices of < 1 were noted for all dose ranges of Revlimid™ and rapamycin, suggesting strong synergism. Importantly, this combination was able to overcome drug resistance when tested against MM cell lines resistant to conventional (doxorubicin, melphalan, dexamethasone) chemotherapy. Moreover, the combination, but not rapamycin alone, was able to overcome the growth advantage conferred on MM cells by IL-6, IGF-1, or adherence to bone marrow stromal cells (BMSCs). Cytotoxicity triggered by a combination of rapamycin with Revlimid™ resulted in apoptosis of MM cells. Furthermore, differential signaling cascades, including the MAPK and PI3-K/Akt pathways, were targeted by these drugs individually and in combination, suggesting the molecular mechanism by which they interfere with MM growth and survival. These studies therefore provide the framework for the clinical evaluation of targeted agents like mTOR inhibitors combined with immunomodulatory agents like Revlimid™ to improve patient outcome in MM.

Abstract Background: Oprozomib (OPZ) is an oral epoxyketone proteasome inhibitor that has shown promising antitumor activity in patients (pts) with hematologic malignancies (HM), including WM (Kaufman, EHA 2013, P223; Ghobrial, ASH 2013, 3184). Updated safety and efficacy results from the subset of pts with WM enrolled in this ongoing phase 1b/2 study in pts with HM are presented. Methods: This open-label, multicenter, phase 1b/2 study (NCT01416428) is enrolling adult pts with HM who have relapsed after receiving ≥1 line of therapy. The primary objectives of the phase 1b portion of the study are to determine the maximum tolerated dose (MTD) and the safety and tolerability profile of OPZ. The primary objective of the phase 2 portion of the study is to determine the best overall response rate (ORR; ≥minimal response [MR]). In the phase 1b portion, single-agent OPZ is being administered once daily on days 1, 2, 8, and 9 of a 14-day cycle (2/7 schedule) or on days 1–5 of a 14-day cycle (5/14 schedule). The starting dose was 150 mg/day (mg/d); doses were escalated in 30-mg increments. In the phase 2 study, pts have received 240 mg/d on the 5/14 schedule, which was the initial phase 2 schedule opened to enrollment. For this report, all enrolled patients with HM are included in the description of the MTD while only the subset of patients with WM is included in the safety and efficacy results. Results: As of July 21, 2014, 106 pts with HM (including 36 pts with WM) were enrolled and treated with the OPZ tablet. Enrollment and baseline demographic information for pts with WM are presented in Table 1. For WM patients in the phase 1b portion, median treatment duration was 17.1 weeks (range, 3.1–51.4; 2/7 schedule) and 51.7 weeks (range, 3.9–74.9; 5/14 schedule); preliminary median treatment duration in the ongoing phase 2 portion was 8.1 weeks (range, 0.7–22.0). In all pts with HM, the MTD for the 2/7 schedule was 300 mg/d and 240 mg/d for the 5/14 schedule. None of 3 dose-limiting toxicities (DLTs) on the 2/7 schedule occurred in patients with WM. Two of the 4 DLTs observed on the 5/14 schedule occurred in pts with WM (grade 4 tumor lysis syndrome [240 mg/d, n=1] and grade 3 vomiting [270 mg/d, n=1]). The most common adverse events (AEs) in pts with WM are shown in Table 2. Grade 4 AEs were thrombocytopenia (n=1; phase 1b; 2/7 schedule) and influenza and tumor lysis syndrome (n=1 each; phase 1b; 5/14 schedule). No on-study deaths occurred in pts with WM. In the phase 1b portion, two pts (25%) in the 2/7 schedule and 1 pt (9%) in the 5/14 schedule discontinued treatment due to an AE; 6 pts (35%) discontinued treatment due to an AE in the phase 2 portion. In the phase 1b portion, 3 pts (38%) (2/7 schedule) and 6 pts (55%) (5/14 schedule) had their dosage reduced at least once due to an AE; 10 pts (59%) in the phase 2 portion had their dosage reduced at least once due to an AE. In the phase 1b portion, all 19 pts were eligible for response and were carfilzomib (CFZ)-naïve. The ORR in 8 pts enrolled on the 2/7 schedule was 38% (3 pts had a partial response [PR]). Among 11 pts enrolled on the 5/14 schedule, the ORR was 73% (1 complete response, 1 very good partial response, 5 PRs, and 1 MR); the ORR for BTZ-refractory pts (n=4) was 75%. All 17 pts enrolled on the phase 2 portion were response-eligible. The ORR in the phase 2 portion was 59% (there were 5 PRs and 5 MRs). The ORR among CFZ-naïve pts (n=16) in the phase 2 portion was 56; the ORR among BTZ-refractory pts (n=3) was 67%. Conclusions: The MTD of OPZ was 300 mg/d in the 2/7 schedule and 240 mg/d in the 5/14 schedule; these MTDs were determined from all pts with HM. In pts with WM who received single-agent OPZ, the most common grade 3 AEs were neutropenia and diarrhea; grade 4 AEs were infrequent. Additional measures will be taken to improve gastrointestinal tolerability. Single-agent OPZ continues to have promising antitumor activity in pts with WM. Enrollment of patients on the 2/7 schedule is continuing; the target enrollment for the phase 2 portion of the study is 66 patients. Extended-release OPZ tablets will be introduced and assessed for safety, activity, and pharmacokinetics. Updated results will be presented at the meeting. Disclosures Siegel: Celgene: Honoraria, Speakers Bureau; Onyx: Honoraria, Speakers Bureau; Millennium: Honoraria, Speakers Bureau. Off Label Use: Monoclonal antibody/toxin fusion protein. For treatment of multiple myeloma. Kaufman:Millennium: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Onyx: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Spectrum: Consultancy, Honoraria; Merck: Research Funding. Raje:Celgene: Consultancy; Millennium: Consultancy; Novartis: Consultancy; Amgen: Consultancy; Onyx: Consultancy; Acetylon: Research Funding; Ely Lilly: Research Funding. Mikhael:Onyx: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Novartis: Research Funding. Kapoor:Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding. Treon:Onyx: Consultancy, Research Funding. Neuman:Onyx: Employment. Lee:Onyx Pharmaceuticals, an Amgen subsidiary: Employment. Ghobrial:BMS: Advisory Board Other; Celgene: Advisory Board, Advisory Board Other; Millennium: Advisory Board, Advisory Board Other; Onyx: Advisory Board, Advisory Board Other.