Anderson, Kenneth C.

8108 Background: 2-methoxyestradiol (2ME2) is a natural endogenous product of estradiol metabolism with anti-angiogenic and anti-neoplastic properties that has demonstrated activity against multiple myeloma cell lines and xenografts in immunocompromised mice. We report results of the first phase II clinical trial of 2ME2 in pts with relapsed and plateau phase myeloma. Methods: This trial was designed with a one-stage design to accrue 60 pts in the setting of relapsed and plateau phase myeloma. 2ME2 was administered orally at a dose of 1000 mg daily. After the first 39 pts were accrued, based on the results of ongoing phase I trials, the dose of 2ME2 was increased to 800 mg twice daily for the remaining patients. Pts who were already on study at that point were also allowed to escalate their dose to 800 mg twice daily. The primary endpoint was overall response rate. Responses were assessed using Eastern Cooperative Oncology Group criteria. Results: Sixty patients were treated at Mayo Clinic and Dana Farber Cancer Institute. Median age was 60 years (range, 28–99). Thirty-one patients had relapsed/refractory myeloma and 29 patients had plateau phase myeloma. Median number of prior therapies was 4 including stem cell transplant (48%), thalidomide (62%), bortezomib (6%) and lenalidomide (3%). Therapy was well tolerated. Adverse events were anemia (35%), fatigue (35%), nausea (25%), diarrhea (20%), hot flashes (20%), headache (17%), muscle cramps (15%), and upper respiratory tract infection (15%). Most toxicities were mild (grade 1–2). Estimated progression-free survival rates for all pts at one, two, and three years are 24%, 16%, and 9% respectively. Three pts with plateau phase disease, have been on study for over 4 years without progression at 50, 60, and 63 months. Response assessment is ongoing; so far, whilst no partial responses have been seen, prolonged stable disease has been observed in 3 pts (5%). Conclusions: 2ME2 is a novel agent that appears to be safe and well tolerated. Although no responses have been seen, prolonged stable disease in some pts is promising. Preliminary pharmacokinetic data indicate that the dose of 2ME2 used in this study may be inadequate, and a new formulation with significantly better bioavailability will be tested soon in this patient population. No significant financial relationships to disclose.

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 < 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 < .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.

Abstract INTRODUCTION: mTOR inhibitors have been associated with responses in Mantle cell lymphoma and other lymphomas (J Clin Oncol23; 5347, 2005). Phase I and II trials with the oral everolimus (RAD001, Novartis Pharmaceuticals) have demonstrated a favorable side effect profile. This phase II study tested everolimus in patients with relapsed/refractory Waldenstrom Macroglobulinemia (WM). METHODS: Patients who had at least one previous therapy for WM and who had relapsed or refractory disease were eligible. Other eligibility criteria included symptomatic disease, > 2 weeks from last therapeutic agent used, >10% involvement with lymphoplasmacytic cells in the bone marrow, IgM paraprotein > 2x upper limit of normal, absolute neutrophil count >1000/mm3 and platelet count >75,000/mm3, serum creatinine of < 2 x upper limit of normal. NCI CTCAE v3.0 was used for toxicity assessment. Response was assessed by criteria established at the second consensus panel for WM. All patients received 10mg RAD001 daily for 28 days per cycle for 6 cycles; response was assessed after 2 cycles. RESULTS: 10pts (8 men and 2 women, median age is 62 years, range 52–71) have been treated to date. The median number of lines of prior treatment was 3 (range 1 – 5). The median IgM at baseline was 3970 mg/dL (range 3120– 7410); median M-spike at baseline was 2.07 gm/dL (range 1.41 – 4.02); and median hemoglobin was 11.3 g/dL (9.4–13.3). The median follow up was 4 months (range 1 – 7 months). Prior therapy included rituximab, nucleoside analogues (fludarabine and 2-CDA), combination chemotherapy (e.g CHOP, CVP), chlorambucil. and bortezomib. Seven patients are currently evaluable for response. The best response to single agent RAD001 after 2 cycles is presented in Table 1. Median duration of response has not been reached. Patients tolerated RAD001 well without significant toxicities. The main toxicities observed were apthous ulcers in 4 patients. One patient required dose reduction due to mucositis. One patient stopped therapy within the first month of treatment and went on to hospice care before succumbing to his disease after one month. Attributable toxicities otherwise proved manageable with appropriate supportive care and RAD001 was generally well tolerated, with no peripheral neuropathy. CONCLUSIONS: Oral RAD001 as monotherapy has been well tolerated and demonstrates exciting activity achieving PR + MR in 57%, and/or stabilization of disease in 43% of evaluable patients with relapsed WM. Accrual of a total of 30 patients is rapidly ongoing. Updated data will be presented at the meeting. Table 1 Response N=7; ORR (CR+PR+MR)= 57% Median time to best response (months) Partial Response 1 (14%) 5 Minimal Response 3 (43%) 4 (3–6) Stable Disease (SD) 3 (43%) NA Progressive Disease 0

Multiple myeloma (MM) is a neoplasm thought to arise from a damaged germinal center B-cell that progresses to a plasma cell clone arising in bone marrow. MM comprises 20% of all hematologic cancer deaths. Persons of African ancestry (AA) have a 1.5 to 2-fold higher risk compared to individuals of European ancestry (EA). Genetically driven differences in hematopoiesis may lead to variation in the levels white blood cell (WBC) subsets which could, in turn, be associated with MM etiology. There are differences in genetic determinants of WBC traits between EA and AA populations, with possible implications for the racial disparity in risk. We tested the above hypothesis using Mendelian randomization (MR), an approach that leverages genetic determinants of specific traits (i.e. WBC counts) to estimate their effects on the risk of an outcome; and a transcriptome-wide association study (TWAS), which utilizes genetic predictors of gene expression to identify susceptibility genes. These analytic approaches were applied to data from the African American Multiple Myeloma Study (AAMMS) consisting of 1813 cases and 8871 AA cancer-free controls to examine how differences in heritable WBC gene expression profiles influence MM risk. Genetic determinants of variation in WBC subsets in AA were obtained from the literature and supplemented with new genome-wide association findings in AA subjects from the UK Biobank cohort (n=6108). Odds ratios (OR) for MM per 1 standard deviation (SD) increase in each WBC phenotype were estimated using independent (linkage disequilibrium (LD) r2<0.10) variants with P<10-6 as genetic instruments. Analyses based on variants associated with WBC traits in AA populations did not identify any statistically-significant associations between MM risk and WBC overall (p=0.81, using 15 SNPs) or subsets (lymphocytes, monocytes, eosinophils, neutrophils and basophils, p>0.05 for each). However, when we applied genetic determinants of WBC identified in 330,000 cancer-free EA UK Biobank participants (P<10-8, replication P<0.05, LD r2<0.05), a statistically significant inverse relationship emerged between increasing lymphocyte counts and MM risk (OR=0.80, 95% CI: 0.66-0.97, p=0.02, using 385 SNPs), as well as increasing basophil counts (OR=0.63, 95% CI: 0.41-0.96, p=0.03, using 140 SNPs). Next, we examined the association between WBC gene expression profiles and MM risk in AAMMS data. We applied published and validated ancestry-specific models developed using the PrediXcan approach, which leverage germline genetic and transcriptomic data from the Multi-Ethnic Study of Atherosclerosis (MESA) (Mogil et al. PMID: 30096133). The primary TWAS used gene expression models trained in AA subjects (n=233), with sensitivity analyses using models developed in AA and Hispanic subjects (n=585). The TWAS significance threshold was based on the number of genes with significant germline prediction models (p<0.05 and R2 ≥0.05) in AA, corresponding to P < 0.05/2700 = 1.85×10-5. The expression of two genes was significantly associated with MM risk: KANK1at 9p24.3 (P = 1.01×10-5) and DNAJC27at 2p23.3 (P = 1.56×10-5). KANK1is a candidate tumor suppressor gene for renal cell carcinoma and has recently been associated with MM risk in AA [Du, Blood 2017 130:3058]. Here we provide additional evidence for its role in MM etiology via gene expression-mediated mechanisms. DNAJC27 (previously known as RBJ) is a novel MM risk gene linked to constitutive activation of ERK in solid tumors. We also identified two suggestively associated genes: PRR14 (P = 1.34×10-4; combined AA-Hispanic sample: P = 1.56×10-6), which has been linked to MM risk in EA populations, and PARP16 (P = 9.46×10-5). To our knowledge this is the first study to comprehensively examine variation in WBC traits and gene expression profiles with respect to MM risk in AA. Our TWAS analysis leveraged data from the largest collection of genetic and gene expression data in AA, enabling ancestry-matched inference and identification of two novel risk genes. Although the limited availability of genetic instruments for WBC limited the power of MR analysis, findings using variants identified in European populations may offer some insight into trans-ethnic etiologic pathways and contribute to risk stratification strategies using genetic and blood cell count biomarkers. Future studies, particularly with MGUS-free controls, are needed to validate these results. Disclosures Song: Millennium Pharmaceuticals Inc: Employment. Rand:Ancestry.com: Employment. Ailawadhi:Cellectar: Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy; Pharmacyclics: Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy. Nooka:Takeda: Honoraria, Other: advisory board participation; Janssen: Honoraria, Other: advisory board participation; GSK: Honoraria, Other: advisory board participation; Spectrum pharmaceuticals: Honoraria, Other: advisory board participation; Adaptive technologies: Honoraria, Other: advisory board participation; Amgen: Honoraria, Other: advisory board participation; Celgene: Honoraria, Other: advisory board participation; BMS: Honoraria, Other: advisory board participation. Singhal:Bureau of Millennium/Takeda, Celgene, Janssen, Celgene, Bristol-Myers Squibb and Bluebird: Speakers Bureau. van Rhee:Takeda: Consultancy; Sanofi Genzyme: Consultancy; Castleman Disease Collaborative Network: Consultancy; EUSA: Consultancy; Adicet Bio: Consultancy; Kite Pharma: Consultancy; Karyopharm Therapeutics: Consultancy. Mehta:Millennium/Takeda, Celgene; stock in Celgene, Bristol-Myers Squibb and Bluebird: Speakers Bureau. Wolf:Takeda: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Amgen: Consultancy. Martin:Roche and Juno: Consultancy; Amgen, Sanofi, Seattle Genetics: Research Funding. Fiala:Incyte: Research Funding. Terebelo:Jannsen: Speakers Bureau; Celgene: Honoraria; Newland Medical Asociates: Employment. Anderson:Bristol-Myers Squibb: Other: Scientific Founder; Oncopep: Other: Scientific Founder; Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Sanofi-Aventis: Other: Advisory Board. Vij:Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Genentech: Honoraria; Janssen: Honoraria; Karyopharm: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Research Funding. Bernal-Mizrachi:TAKEDA: Research Funding; Kodikas Therapeutic Solutions, Inc: Equity Ownership; Winship Cancer Institute: Employment, Patents & Royalties. Morgan:Amgen, Roche, Abbvie, Takeda, Celgene, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Other: research grant, Research Funding. Zonder:Celgene Corporation: Consultancy, Honoraria, 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; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Intellia: Consultancy, Membership on an entity's Board of Directors or advisory committees; Caelum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alnylam: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees. Huff:Member of Safety Monitoring Board for Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees; Karyopharm, Sanofi, MiDiagnostics: Consultancy. Lonial:Karyopharm: Consultancy; Takeda: Consultancy, Research Funding; Amgen: Consultancy; BMS: Consultancy; Janssen: Consultancy, Research Funding; GSK: Consultancy; Celgene Corporation: Consultancy, Research Funding; Genentech: Consultancy. Orlowski:Poseida Therapeutics, Inc.: Research Funding.

Abstract Background: The phase 3 double-blind, CALGB/Alliance 100104 study assessed the efficacy and safety of lenalidomide (LEN) or placebo maintenance therapy until relapse in post-autologous stem cell transplantation (ASCT) patients with newly-diagnosed multiple myeloma (NDMM). Interim analyses demonstrated superiority for LEN versus placebo for time to progression (TTP), thus meeting the primary TTP endpoint of the trial. The study was unblinded in December 2009 and, based on the TTP and overall survival (OS) benefit observed with LEN, patients in the placebo arm (who had not yet progressed) at the time of unblinding were given the option of crossing over to receive LEN. Data have been reported for a follow-up of 91 months based on the planned intention to treat (ITT) analysis, yielding a TTP hazard ratio (HR) 0.57 and an OS difference of HR 0.61 (Holstein SA, et al. Lancet Haematol. 2017;4:e431-42). Crossover to active treatment enabled patients to benefit from LEN maintenance and collection of additional efficacy and safety data; however, crossover can confound the estimates of OS for longer follow-up. We report the results of an analysis adjusted for crossover, thus aiming to provide a more accurate estimate of the survival benefit achieved with LEN maintenance therapy. Methods: Results are reported for an analysis based on an updated data cutoff, post-October 2016. The rank-preserving structural failure time model (RPSFTM) was considered the most appropriate method to adjust for crossover (Robins JM, Tsiatis AA. Commun Stat Theory Methods. 1991;20:2609-31). This method requires that the assumption that the treatment effect is the same for patients who receive LEN at randomization as those who receive LEN as crossover treatment is not violated; a landmark analysis was performed to explore this. The iterative parameter estimation (IPE; Branson M, Whitehead J. Stat Med. 2002;21:2449-63) algorithm was used as validation. Both the RPSFTM and IPE analyses assume a residual LEN effect after discontinuation (base case). Results: A total of 76 NDMM patients who had not progressed, as determined by central adjudication, crossed over from placebo to LEN and were included in the analysis. The landmark analysis of OS from the date of unblinding indicated that the treatment effect for the crossover versus the non-crossover placebo group was HR 0.57 (95% confidence interval [CI] 0.29-1.15) (Figure). This also provided a measure of the benefit of LEN maintenance in patients who started maintenance therapy after the trial-specified 90-100 day window post-ASCT (median 11.5 months post-randomization; range 3.2-51.0 months). Adjustment for crossover using the RPSFTM or IPE resulted in an increase in the relative treatment effect of LEN maintenance (vs placebo) on OS from 30.8 months for the ITT analysis (HR 0.61; 95% CI 0.47-0.81) to 40.1 months (HR 0.52; 95% CI 0.36-0.73) for the RPSFTM analysis and 38.8 months (HR 0.52; 95% CI 0.37-0.74) for the IPE analysis (Table). Results were consistent across the two methods. Discussion: This analysis was performed on an updated version of the data set reported in the Holstein article. Once we adjusted for crossover, depending on the methodology used, there was an additional gain of ~40 months of OS. Previously, a pre-planned, pooled meta-analysis of 3 studies that included CALGB/Alliance (McCarthy PL, et al J Clin Oncol. 2017;35:3279-89) indicated that the OS gain was 2.5 years; however, our analysis from the CALGB study alone shows that LEN maintenance may provide a survival benefit of > 3 years. In diseases where prolonged follow-up is required to demonstrate survival benefits, allowing patients to crossover to active treatment may be important to facilitate this. However, the results should be analyzed appropriately to enable assessment of the value of the therapy. As this analysis indicates, the value of active treatment may be underestimated if adjustment for crossover is not performed. In conclusion, the data reported here provide further insight into the survival benefits of LEN maintenance therapy post-ASCT and support guideline recommendations to offer LEN maintenance therapy to all patients post-ASCT. Support: U10CA180821, U10CA180882, U10CA180820; ClinicalTrials.gov Identifier: NCT00114101. Disclosures McCarthy: Bristol Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Richardson:Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: 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; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Cooper:Celgene: Consultancy; BresMed Health Solutions Ltd: Employment. Saunders:Celgene: Consultancy; BresMed Health Solutions Ltd: Employment. Dhanasiri:Celgene: Employment, Equity Ownership. Anderson:Bristol Myers Squibb: Consultancy; Millennium Takeda: Consultancy; C4 Therapeutics: Equity Ownership, Other: Scientific founder; Celgene: Consultancy; OncoPep: Equity Ownership, Other: Scientific founder; Gilead: Membership on an entity's Board of Directors or advisory committees. Stadtmauer:Celgene: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Takeda: Consultancy. Holstein:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Abstract Abstract 3165 Background: Accrual to large oncology group studies in the United States is often slower than planned, especially in less common malignancies such as Multiple Myeloma (MM). To improve the treatment of patients with MM, it is essential that we address the barriers to accrual (BtA) to national clinical trials. The NCI Myeloma Steering Committee (MYSC) formed the Accrual Working Group (AWG), charged to analyze this problem. Methods: The members of the MYSC have developed a list of 10 potential BtA to NCI MM-CT under the leadership of the AWG at meetings conducted in person and by monthly telephone conference. This list was distributed via Survey Monkey among investigators and research staff of the SWOG, ECOG/ACRIN and Alliance research bases for the purpose of ranking the perceived importance of the 10 selected BtA. Responses based on a 0–5 Likert Scale were analyzed as continuous and categorical. For the latter, responses were grouped: Impedes Accrual – No (0,1), Yes (2–5); Significantly Impedes Accrual – No (0–3), Yes (4,5). Results: 246 survey responses were received. 50 participants who indicated that they had never attempted to or actually never enrolled a patient into a MM-CT were excluded. Of 196 responders, 61% had enrolled at least 5 patients, 43% practiced in academic centers (A) and 57% in community centers (C). 26% identified themselves as research staff, 74% as primarily physician investigators including Principal Investigators (12%). 78% have current access to NCI MM-CT. 46% identified their research base affiliation with SWOG, 20% with ECOG/ACRIN, 17% with Alliance, 17% as CTSU, NRG and other. The majority of survey responders confirmed agreement in the perception that all 10 identified BtA impede accrual, ranging from 60–84% depending on the specific barrier identified, while significant impediment to accrual ascribed to these BtA ranged from 22–47%. The perceived barriers most often cited as impeding accrual were (1) spectrum of available treatment options, (2) level of reimbursement for clinical trial related expenses and (3) patient‘s need for prompt treatment intervention (84%, 80%, 76% respectively). The first two barriers along with the requirement that patients receive their treatment exclusively at the NCI designated treatment site were rated most often as significantly impeding accrual (37%, 47%, 34% respectively). The first two were also identified most often as perceived BtA independent of practice setting (A, C), type of research engagement (physician investigator, research staff) and level of experience with MM-CT. Interestingly, the perception that patients must receive their treatment at the NCI designated treatment site and competing industry sponsored clinical trials were substantially more often cited as impeding accrual in academic centers compared to community centers and by physician investigators compared to research staff. The complexity of required diagnostic work up and the complexity of the treatment protocol and follow up testing were substantially more often cited as BtA in the community setting and by research staff compared to their peers in the academic setting and by physician investigators. The NCI MYSC AWG has proposed specific solutions to potentially lower perceived BtA. These include guidelines to allow protocol specific administration of commercially available agents by the patient‘s local oncologist, a simplified diagnostic work up and treatment plan and eligibility inclusion of patients who have received up to one cycle of specified urgent therapy prior to enrollment in MM-CT. Conclusions: We have queried experienced clinical investigators and research staff on 10 potential MM-CT specific BtA and found substantial consensus among responding participants in this survey. There are apparent differences in perceived BtA between the respondents from academic and community centers as well as between research staff and physician investigators. These data suggest that a structured approach to identification of BtA to clinical trials is feasible and creates opportunities to overcome them. This may have application to clinical trials across other diseases and may also lead to improvements in accrual. Disclosures: Barlogie: Celgene, IMF, MMRF, Millennium, Genzyme: Consultancy; Celgene, IMF, Millennium: Honoraria; Celgene, Novartis, NCI, Millennium, Onyx, Icon: Research Funding; GEP: Patents & Royalties.

Abstract Introduction The 2-3 fold excess risk of multiple myeloma (MM) among family members of cases suggests a heritable contribution to risk. Recently, a genome-wide association study (GWAS) identified two genome-wide significant and one promising novel loci associated with multiple myeloma risk. To confirm these associations and identify additional novel risk loci, we performed a four-center, genome-wide association meta-analysis. Methods A fixed effects model was used for the meta-analysis which included a total of 1248 cases and 1485 controls, all of European descent, genotyped and analyzed at four separate centers with samples contributed by 10 studies. After quality control and imputation using the 1000 Genomes Project, the analysis included ∼9.5 million variants (λ=1.024). Associations between (single nucleotide polymorphisms) SNP genotypes and MM risk were evaluated under a log-additive model of inheritance, with each study adjusting for age, sex, and up to 10 principal components to control for population stratification. Promising results were replicated in an independent set of 1587 cases and 1770 controls using TaqMan, for a total of 2835 and 3255 cases and controls, respectively, in a combined meta-analysis. Results The discovery meta-analysis did not reveal any genome-wide significant associations (defined as p<5 x 10-8). We used a novel pruning algorithm to identify the top 35 most promising single nucleotide polymorphisms (SNPs) to advance to replication. We successfully genotyped 22 SNPs in the replication set. In the combined discovery and replication meta-analysis, rs1345359 at 12q23.1 was the most strongly associated SNP (P=9 x 10-8, Table 1). The variant allele C was associated with reduced risk (odds ratio discovery set [OR]= 0.69, OR replication set = 0.78, OR combined = 0.74). A second locus at 20q13.2 (rs150220835), was associated with a two-fold increased risk (P=1.22 x 10-6), a borderline increased risk (P=0.0900) and 45% increased risk (P=2.44 X 10-5) in the discovery, replication, and combined analysis sets respectively (Table 1). We also confirmed the association between MM risk and two previously published SNPs (rs4487645, p=0.0007and rs105251, p=0.0044) (Broderick et al., Nat. Genet., 2011). The third previously suggested SNP (rs6746082) was of nominal significance (p=0.0517) in the meta-analysis. Discussion We confirmed the association between MM risk and two previously published SNPs and identified a possible association with a novel SNP in chromosome 12q23.1 (rs1345359). This SNP is not located in a gene nor associated with biofeatures in ENCODE, thus further examination of correlated SNPs is necessary to identify a functional SNP linked to this locus. We also found suggestive evidence for a second locus at 20q13.2 requiring additional replication. Larger studies would improve risk variant discovery for this rare hematologic malignancy. Disclosures: Wolf: Celgene: Honoraria, Research Funding; Millenium: Honoraria; Onyx: Honoraria. Anderson:Celgene, Millennium, BMS, Onyx: Membership on an entity’s Board of Directors or advisory committees; Acetylon, Oncopep: Scientific Founder , Scientific Founder Other.

Abstract Background Melphalan, prednisone and thalidomide (MPT) is a standard therapy for NDMM recognized worldwide based on a statistically significant advantage in overall survival (OS) and progression-free survival (PFS) vs. MP (Facon Lancet 2007; Fayers Blood 2011; NCCN 2013). The combination of lenalidomide and low-dose dexamethasone (Rd) increased OS with fewer adverse events (AEs) than treatment with lenalidomide and high-dose dexamethasone in NDMM pts (ECOG E4A03) (Rajkumar Lancet Oncol 2010). The FIRST trial is a multicenter, open-label, phase III trial comparing the efficacy and safety of Rd versus MPT in transplant-ineligible NDMM pts. Methods NDMM pts either ≥ 65 years of age, or not candidates for SCT were randomized to one of three arms: Rd in 28-day cycles until disease progression (Arm A), Rd in 28-day cycles for 72 weeks (18 cycles, Arm B), or MPT in 42-day cycles for 72 weeks (12 cycles, Arm C). Assessments by International Myeloma Working Group criteria were done after each cycle. Pts with renal impairment were enrolled; however, pts on dialysis were excluded. Starting doses of lenalidomide and dexamethasone were adjusted based on renal function and age, respectively. Melphalan starting dose was adjusted based on age, absolute neutrophil count, platelet count, and renal function; and thalidomide was adjusted for age. Dose adjustments were permitted for AEs. All pts were required to receive anti-thrombotic prophylaxis. Stratification factors included age, International Stage System, and country. The primary endpoint was a comparison of PFS in Arm A vs. Arm C. Secondary endpoints included OS, overall response rate (ORR), time to response, duration of response (DOR), safety, and quality of life (QOL). A preplanned additional analysis included time from randomization to second progression event or death (PFS2). The final preplanned analysis of independently adjudicated progressive disease (PD) events in Arm A vs. Arm C conducted after 960 events of death or PD, and an interim of OS in 64% of survival events (574/896 events) are presented in this abstract. Comparisons of PFS and all secondary endpoints, including OS for all three arms, will be presented at the meeting. Results A total of 1,623 pts were randomized 1:1:1 in three arms. As of today, 121 pts continue to receive lenalidomide on study (Arm A). The median age was 73 (40.0–92.0) years; 35% pts were aged ≥ 75 years; and 41% of pts had ISS stage 3 disease. After a median follow-up of 37 months, the trial met its primary endpoint (PFS), demonstrating a 28% reduction in risk of progression or death (HR=0.72; p= 0.00006). The preplanned interim analysis of OS demonstrated a 22% reduction in risk of death in favor of Arm A vs. Arm C (HR=0.78, p=0.01685); however, the pre-specified boundary (p<0.0096) was not crossed. All other secondary endpoints consistently showed improvement in favor of Arm A vs. Arm C; ORR (PR or better) 75% vs. 62% (p < 0.00001), DOR (HR=0.63; p<0.00001), and PFS2 (HR=0.78, p=0.0051). Relevant Grade 3/4 adverse events in Arm A vs. Arm C were neutropenia (28% vs. 45%), thrombocytopenia (8% vs. 11%), febrile neutropenia (1% vs. 3%), infection (29% vs. 17%), neuropathy (5% vs. 15%), and deep-vein thrombosis (5% vs. 3%). The incidence of secondary primary malignancies (SPM) was evaluated. Hematologic malignancies were 0.4% in Arm A vs. 2.2% in Arm C; the overall incidence of solid tumors was identical (2.8%). Conclusion Continuous treatment with the all oral doublet Rd significantly improved the primary endpoint of PFS compared with the standard triplet, MPT. All secondary endpoints support the clinical benefit of continuous Rd treatment. The safety profile of Rd was manageable, with reduced hematologic SPM compared to MPT. Disclosures: Facon: Celgene: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Off Label Use: Lenalidomide as treatment for NDMM. Dimopoulos:Celgene, Orthobiotech: Honoraria. Dispenzieri:Celgene, Millenium, Jansenn, Pfizer: Research Funding. Catalano:Celgene, Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Hulin:Janssen: Honoraria; Celgene: Honoraria. Cavo:Celgene, Janssen, Millennium, Onyx, Brystol Myers Squibb: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Pinto:Mundipharma: Consultancy, Honoraria; Roche: Honoraria; Celgene: Consultancy, Honoraria. Weisel:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Ludwig:Celgene: Honoraria, Research Funding, Speakers Bureau. Bahlis:Celgene: Consultancy, Honoraria. Delforge:Celgene: Honoraria. Chen:Celgene: Consultancy, Research Funding; Lundbeck: Consultancy; Johnson & Johnson: Consultancy, Research Funding; Roche: Honoraria; GlaxoSmithKline: Research Funding. Oriol:Celgen: Consultancy. White:Celgene: Honoraria, Research Funding. Binder:Celgene: Research Funding. Anderson:Acetylon, OncoPep: Equity Ownership; Celgene, Onyx, Sanofi Aventis, Gileod: Consultancy. Moreau:Celgene Corporation: Honoraria, Speakers Bureau. Attal:Janssen: Lectures, Lectures Other, Membership on an entity’s Board of Directors or advisory committees; Celgene Corporation: Lectures Other, Membership on an entity’s Board of Directors or advisory committees. Knight:Celgene: Employment, Equity Ownership. Chen:Celgene: Employment. Van Oostendorp:Celgene: Employment. Jacques:Celgene: Employment. Ervin-Haynes:Celgene: Employment, Patents & Royalties. Benboubker:Celgene: Consultancy.

Abstract Introduction Few treatments options are available for patients (pts) with relapsed/refractory multiple myeloma (RRMM) who have previously been treated with lenalidomide (LEN) and bortezomib (BORT), and their prognosis is poor. Pomalidomide (POM) is a distinct IMiD® immunomodulatory agent with a mechanism of action consisting of direct anti-myeloma, stromal-support inhibitory, and immunomodulatory effects. In randomized phase 2 and 3 trials (MM-002 and MM-003), POM plus low-dose dexamethasone (POM+LoDEX) demonstrated marked efficacy in RRMM pts who had received multiple prior therapies, including LEN and BORT. This side-by-side analysis presents the most recent survival and safety data from these trials. Methods The MM-002 and MM-003 trials enrolled pts with ≥ 2 prior therapies, including LEN and BORT. In MM-002, pts received POM (4 mg/day on days 1–21 of each 28-day cycle) alone or in combination with LoDEX (40 mg/week). In MM-003, pts were randomized 2:1 to receive POM+LoDEX or high-dose DEX alone (HiDEX) (40 mg/days 1–4, 9–12, 17–20 in a 28-day cycle); HiDEX was chosen as the comparator to isolate the effects of POM, as at the time of trial design it was the standard salvage therapy for heavily pretreated pts. Thromboprophylaxis was required for all pts treated with POM and pts at high risk of developing venous thromboembolism. Data cutoff was February 1, 2013 for MM-002 and March 1, 2013 for MM-003. The primary endpoint in both trials was progression-free survival (PFS). Secondary endpoints included overall survival (OS), response rates, duration of response, and safety. Results In each study, pts had received a median of 5 prior therapies (range 1-17), and all pts had received prior LEN and BORT. In MM-002, 113 pts were treated with POM+LoDEX and 108 were treated with POM alone (60% of POM alone pts subsequently received DEX). A total of 79% of pts were LEN refractory; 62% were refractory to both LEN and BORT; and 35% had received LEN as their last prior therapy. With a median follow-up of 14.2 months (mos), median PFS was 4.2 mos, OS was 16.5 mos, and overall response rate (ORR, defined as at least a partial response) was 33% with POM+LoDEX (Table 1). In MM-003, 302 pts were treated with POM+LoDEX and 153 pts were treated with HiDEX (50% of HiDEX pts subsequently received POM). A total of 94% of pts were LEN refractory; 74% were both LEN and BORT refractory; and 29% had received LEN as their last prior therapy. Survival outcomes were similar in MM-003; with a median follow-up of 10 mos, median PFS was 4.0 mos, OS was 12.7 mos, and ORR was 31% with POM+LoDEX. In both trials, LEN as last prior therapy did not impact response, PFS, or OS vs the overall population. Commonly observed adverse events (AEs) are presented in Table 2 for pts treated with POM+LoDEX. Grade 3 and 4 neutropenia was 28% and 13% in MM-002, and 26% and 22% in MM-003 for the POM+LoDEX arms, respectively. AEs were generally manageable for POM+LoDEX in MM-002 and MM-003 with dose interruptions (67% for both) and reductions (29% and 26%, respectively), and standard supportive care, including growth factor support (46% and 43%), red blood cell transfusions (45% and 49%), platelet transfusions (14% and 20%), and anti-infective agents (89% in both trials). Rates of POM discontinuation due to treatment-related AEs were low (2–4% with POM+LoDEX). In MM-002 and MM-003, 49% and 51% of pts in the POM+LoDEX arms experienced neutropenia of any grade. With appropriate AE management, 9% and 23% had dose interruptions, 4% and 8% had dose reductions, and 1 pt in both MM-002 and MM-003 discontinued due to neutropenia. Febrile neutropenia developed in 3% and 10% of pts; 1% and 4% had dose interruptions, 0% and 2% had dose reductions, and no pts discontinued due to febrile neutropenia in the MM-002 and MM-003 studies, respectively. The majority of infections occurred in the absence of neutropenia of any grade (54% in MM-002 and 66% in MM-003). The rate of POM discontinuation due to infection was low (1% in MM-002 and 2% in MM-003). Conclusion In both the MM-002 and MM-003 trials, POM+LoDEX consistently extended PFS in advanced RRMM pts. PFS, OS, and ORR were not negatively impacted in patients who were refractory to LEN or BORT, even as last prior therapy. Both trials demonstrated that with dose modifications and supportive care POM was well tolerated, leading to few discontinuations. POM+LoDEX should be considered a standard of care for pts with advanced RRMM who have exhausted LEN and BORT. Disclosures: Siegel: Celgene Corporation: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Onyx: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Richardson:Millennium: 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 Corporation: Membership on an entity’s Board of Directors or advisory committees. Dimopoulos:Celgene Corporation: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Chen:Celgene Corporation: Consultancy, Honoraria, Research Funding. Song:Celgene Corporation: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Vij:Onyx: Consultancy, Research Funding; Millenium: Speakers Bureau; Celgene Corporation: Consultancy, Research Funding, Speakers Bureau. Bahlis:Celgene Corporation: Consultancy, Honoraria, Research Funding. Baz:Millenium: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Celgene Corporation: Research Funding. Hofmeister:Celgene Corporation: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Weisel:Celgene Corporation: Consultancy, Honoraria, Research Funding. Jagannath:Millennium: Honoraria; Celgene Corporation: Honoraria. Lonial:Millennium: Consultancy; Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Sanofi: Consultancy; Onyx: Consultancy; Celgene Corporation: Consultancy. Delforge:Celgene Corporation: Honoraria. Talpaz:Ariad, Sanofi, Novartis: Membership on an entity’s Board of Directors or advisory committees; Ariad, Novartis, BMS, Pfizer: Speakers Bureau; Ariad, BMS, Sanofi, INCYTE: Research Funding. Moreau:Celgene Corporation: Honoraria, Speakers Bureau. San Miguel:Jansen, Celgene Corporation, Onyx, Novartis, Millenium: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Karlin:Janssen: Honoraria; Celgene Corporation: Consultancy, Expert board committee Other, Honoraria. Goldschmidt:Celgene Corporation, Janssen, Novartis: Consultancy, Honoraria, Research Funding. Oriol:Celgene Corporation: Consultancy. Alegre:Janssen: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene Corporation: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Cavo:Millennium: 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; 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; Celgene Corporation: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Martinez-Lopez:Celgene Corporation: Honoraria, Research Funding. Lacy:Celgene Corporation: Research Funding. Chen:Celgene Corporation: Employment, Equity Ownership. Casey:Celgene Corporation: Employment, Equity Ownership. Sternas:Celgene Corporation: Employment, Equity Ownership. Zaki:Celgene Corporation: Employment, Equity Ownership. Jacques:Celgene Corporation: Employment, Equity Ownership. Anderson:Onyx: Consultancy, Equity Ownership; Gilead: Consultancy, Equity Ownership; sanofi aventis: Consultancy, Equity Ownership; Oncopep: Consultancy, Equity Ownership; Acetylon: Consultancy, Equity Ownership; Celgene Corporation: Consultancy, Equity Ownership.

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.