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: Due to recent treatment advances, MM patients (pts) are living longer (Kumar et al, Blood 2008), underscoring the importance of patient quality of life and management of adverse events (AEs) related to MM therapy. MM pts are at risk of cardiac events due to age and disease-related factors, as well as cardiotoxicity from treatments including anthracyclines, proteasome inhibitors (PIs), and high-dose therapy. Both of the US FDA-approved PIs, Btz and carfilzomib, have been associated with cardiac events in MM pts, with cardiac toxicity and cardiac adverse reactions included under ‘Warnings and Precautions’ in the respective US labels. The development of Btz, a reversible boronate peptide PI, involved numerous large, controlled clinical trials, providing a benchmark for the expected incidence of heart failure with PIs. Here, we report a retrospective analysis of the risk of heart failure associated with Btz in phase 2 and 3 MM studies leading to regulatory approvals in the US and EU. Methods Study databases were retrospectively analyzed for AEs of grade ≥3 heart failure. In the relapsed/refractory setting, the following studies were included: the phase 2 SUMMIT trial (Btz ± dexamethasone; Richardson et al, NEJM 2003), and the phase 3 APEX (Btz vs dexamethasone; Richardson et al, NEJM 2005), MMY-3001 (Btz + liposomal doxorubicin vs Btz; Orlowski et al, J Clin Oncol 2007), and MMY-3021 (subcutaneous [SC] vs intravenous [IV] Btz; Moreau et al, Lancet Oncol 2011) trials. In the upfront setting, the phase 3 VISTA trial (Btz-melphalan-prednisone [VMP] vs MP; San Miguel et al, NEJM 2008) in transplant-ineligible pts and a pooled analysis of three phase 3 trials (IFM 2005-01, HOVON-65/GMMG-HD4, PETHEMA GEM2005MENOS65) of Btz-based vs non-Btz-based induction (N=779 vs 776; Sonneveld et al, IMW 2013) in transplant-eligible pts were included. Cardiac exclusion criteria typically included NYHA class III/IV (≥II in MMY-3001), myocardial infarction within 6 mos, and ECG evidence of acute ischemia. Heart function tests (primarily ECG) were incorporated in study designs. Heart failure events were analyzed and re-coded for consistency across studies, using standardized MedDRA (v4.0, 8.0, 8.1, 9.0, 9.1, and 10.0) query preferred terms with grouping of clinically related events. Results 2509 pts treated with Btz in the specified phase 2 and 3 trials and an additional 1445 pts treated with non-Btz-based therapies in the control arms of the phase 3 studies were included in this analysis. Pt characteristics and rates of grade ≥3 heart failure by study arm are shown in the table. Among all Btz-treated pts, the rate of grade ≥3 heart failure was 2.0%; the rate was 2.0% in newly diagnosed pts and 1.9% in relapsed and/or refractory pts. In the comparative studies (APEX, VISTA) and pooled pre-ASCT induction analysis, the overall rates across the Btz and non-Btz arms were 2.0% and 1.6%, respectively (p=0.41). Risk factors, including prior anthracycline exposure and history of cardiac complications, were balanced between Btz and non-Btz arms. Conclusions In this retrospective analysis of data from key phase 2 and 3 studies, Btz was associated with a low rate of grade ≥3 heart failure in both the newly diagnosed (2.0%) and relapsed and/or refractory (1.9%) settings. Importantly, across comparative studies, the rate was only marginally higher and not statistically different from the background rate in non-Btz comparator arms. Data from ongoing prospective and comparative studies are necessary to determine whether PIs – including Btz, carfilzomib, and PIs at earlier stages of clinical development – have different cardiotoxicity profiles. Disclosures: San Miguel: Millennium: The Takeda Oncology Company: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Sonneveld:Jansssen: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Onyx: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Orlowski: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; Millennium: The Takeda Oncology Company: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Resverlogix: Research Funding; Array Biopharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Merck: Membership on an entity’s Board of Directors or advisory committees. Moreau:Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Millennium: The Takeda Oncology Company: Membership on an entity’s Board of Directors or advisory committees; Onyx: Membership on an entity’s Board of Directors or advisory committees. Rosiñol:Janssen: Honoraria; Celgene: Honoraria. Moslehi:Alnylam: Consultancy; Novartis: Consultancy; Millennium: The Takeda Oncology Company: Consultancy; Forest Laboratories: Research Funding. Faber:Celgene: Consultancy, Honoraria; Millennium: The Takeda Oncology Company: Consultancy, Honoraria; Onyx: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria. Voorhees:Acetylon: Research Funding; Millennium: The Takeda Oncology Company: Research Funding; Merck: Research Funding; Janssen: Research Funding; Prolexys Pharmaceuticals: Research Funding; GlaxoSmithKline: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Abbott Laboratories: Consultancy. Marquez:Johnson & Johnson: Equity Ownership; Janssen: Employment. Desai:Janssen: Employment; Johnson & Johnson: Equity Ownership. van de Velde:Janssen: Employment; Johnson & Johnson: Equity Ownership. Elliott:Millennium: The Takeda Oncology Company: Employment. Shi:Millennium: The Takeda Oncology Company: Employment. Dow:Millennium: The Takeda Oncology Company: Employment. Jobanputra:Millennium: The Takeda Oncology Company: Employment. Esseltine:Millennium: The Takeda Oncology Company: Employment; The Takeda Pharmaceutical Company: Equity Ownership. Niculescu:Millennium: The Takeda Oncology Company: Employment. Anderson:Celgene: Consultancy; Onyx Pharmaceuticals: Consultancy; Sanofi-Aventis: Consultancy; Gilead: Consultancy; Acetylon Pharmaceuticals: Equity Ownership; Oncopep: Equity Ownership. Lonial:Merck: Consultancy; Onyx Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Millennium: The Takeda Oncology Company: Consultancy. Richardson:Millennium: The Takeda Oncology Company: Membership on an entity’s Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees.

Abstract: A high frequency of RAS/RAF mutations and recurrent mutations in PDGFRA and JAK3 were found in relapsed multiple myeloma patients. Patients with NRAS, but not KRAS, mutation exhibited significantly reduced sensitivity to bortezomib but not high-dose dexamethasone.

Abstract: Persons of African ancestry (AA) have a twofold higher risk for multiple myeloma (MM) compared with persons of European ancestry (EA). Genome-wide association studies (GWASs) support a genetic contribution to MM etiology in individuals of EA. Little is known about genetic risk factors for MM in individuals of AA. We performed a meta-analysis of 2 GWASs of MM in 1813 cases and 8871 controls and conducted an admixture mapping scan to identify risk alleles. We fine-mapped the 23 known susceptibility loci to find markers that could better capture MM risk in individuals of AA and constructed a polygenic risk score (PRS) to assess the aggregated effect of known MM risk alleles. In GWAS meta-analysis, we identified 2 suggestive novel loci located at 9p24.3 and 9p13.1 at P & lt; 1 × 10−6; however, no genome-wide significant association was noted. In admixture mapping, we observed a genome-wide significant inverse association between local AA at 2p24.1-23.1 and MM risk in AA individuals. Of the 23 known EA risk variants, 20 showed directional consistency, and 9 replicated at P & lt; .05 in AA individuals. In 8 regions, we identified markers that better capture MM risk in persons with AA. AA individuals with a PRS in the top 10% had a 1.82-fold (95% confidence interval, 1.56-2.11) increased MM risk compared with those with average risk (25%-75%). The strongest functional association was between the risk allele for variant rs56219066 at 5q15 and lower ELL2 expression (P = 5.1 × 10−12). Our study shows that common genetic variation contributes to MM risk in individuals with AA.