Citations

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 Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of non-Hodgkin’s lymphomas (NHL) characterized by poor treatment outcomes with conventional chemotherapy, including CHOP [complete remission (CR) ∼40%]. Retrospective studies suggest that the incorporation of etoposide into chemotherapy regimens may improve outcomes compared to CHOP. In contrast, anthracyclines appear to have a limited role in PTCL, largely attributed to p-glycoprotein related resistance. Pralatrexate was the first drug approved for patients (pts) with relapsed PTCL, providing a rationale to evaluate it in the front-line setting. Herein, we evaluated the efficacy of a novel combination for the primary therapy of pts with PTCL whereby the anthracycline in CHOP backbone was replaced with etoposide (CEOP) alternating with pralatrexate (P). Methods Pts > 18 years (yrs) with PTCL stages II-IV with no prior therapy and adequate end organ function were eligible. Eligible histologies included, PTCL-NOS, AILT, ALCL (ALK positive pts only allowed if IPI >3). CEOP (Cycle A) was administered as: cyclophosphamide 750 mg/m2 IV d1, etoposide 100 mg/m2 IV d1-3 (or 100 mg/m2 IV d1 and 200 mg/m2 PO days 2-3), vincristine 2 mg IV day 1 and prednisone 100 mg/day X 5 alternating with P (cycle B) 30 mg/m2 IV d 15, 22 and 29 (with vitamin B12 and folate supplementation). Growth factors were used to support both cycles of therapy. Imaging to assess response was done after cycle 2B, 4B and 6B. Pts achieving a remission were eligible for consolidative autologous stem cell transplant (ASCT) after cycle 4B at physician discretion. The primary statistical aim was to improve the CR rate from 40 to 63% with CEOP-P and optional transplant. Secondary objectives included assessment of event free survival (EFS), overall survival (OS) and toxicity of the regimen. A two-stage Simon design (alpha=0.10, 90% power) tested the null hypothesis that the CR rate would be </= to 40%. For the first stage of 20 evaluable pts, the trial would be terminated if 8 or fewer pts experienced a CR after course 2B of chemotherapy. For the second stage, a total of 34 pts were required with at least 17 achieving a CR at the end of therapy to consider the regimen useful. Results 34 pts were enrolled and one withdrew consent before starting therapy, leaving 33 pts enrolled between 7/2011 and 1/2013. Characteristics are shown in Table 1. 27 pts received at least 2 cycles of therapy. 6 pts received only 1 cycle due to early disease progression in 4 and adverse events in 2. Grade 3-4 toxicities attributed to therapy included, anemia (27%), thrombocytopenia (12%), febrile neutropenia (18%), mucositis (18%), sepsis (15%), increased creatinine (12%) and liver transaminases (12%). At the end of stage 1, 10 of 20 pts (50%) achieved a CR; therefore accrual proceeded to stage 2. At the time of this initial analysis, the overall response rate is 70%. To date 15 pts (45%) have achieved a CR with two additional pts pending evaluation. Overall, the 1-yr EFS is 48% (95% CI 28-64), and 1-yr OS 70% (95% CI 47-84) (Figures 1 and 2). 6 pts (18%) to date (n=3 CR, n=2 PR and 1 with stable disease) have received consolidation with ASCT and all are in CR post-transplant. Pts who proceeded to ASCT were younger than the non-transplant cohort (median age 58 versus 64 yrs) with other clinical characteristics being similar. On exploratory bivariate analyses, age <60 yrs, absence of B symptoms, low IPI score (0,1), achieving a CR, and receiving a ASCT were associated with better EFS. Attaining a CR was the only factor associated with better OS and was highest in patients with low IPI (78%) and those with ALCL histology (75%). Conclusions CEOP-P met the pre-defined stage 1 response criteria. Longer follow-up is needed to assess the impact on the final CR rate and secondary objectives of EFS and OS. Defining optimal front line therapy in PTCL continues to be a challenge and an unmet need. Disclosures: Advani: Seattle Genetics: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Spectrum Pharmaceuticals: Research Funding. Off Label Use: Pralatrexate is currently only approved for relapsed/refractory PTCL. Lechowicz:Allos Therapeutics: 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; Millennium: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Carson:Spectrum Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau. Foss:merck: Research Funding; spectrum: Research Funding; eisai: Membership on an entity’s Board of Directors or advisory committees; millenium: Honoraria, Membership on an entity’s Board of Directors or advisory committees; celgene: Honoraria, Research Funding; seattle genetics: Research Funding. Horwitz:Celgene : Consultancy, Research Funding; Spectrum Pharamaceuticals: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Infinity Pharmaceuticals: Consultancy; Kyowa Hakko Kirn Pharma: Consultancy; Genzyme : Research Funding; Janssen: Research Funding; Millennium: Consultancy, Research Funding. Pro:Spectrum Pharmaceuticals: Honoraria. Pinter-Brown:Spectrum Pharmaceuticals: Consultancy, Honoraria. Smith:Micromet: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy; Allos: Consultancy; Genentech: Consultancy; Onyx: Consultancy. Shustov:Spectrum Pharmaceuticals: Consultancy, Honoraria. Savage:Spectrum Pharmaceuticals: Research Funding. Vose:Spectrum Pharmaceuticals: Research Funding.

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 Myeloproliferative disorders (MPDs), diagnosed in 15,000 individuals annually, are characterized by overproduction of lineage-committed blood cells, thrombotic events, occasionally marrow fibrosis or progression to acute myelogenous leukemia and frequently a point mutation (V617F) in the JAK2 kinase. Mutant JAK2 expression results in erythrocyte overproduction in almost all cases of polycythemia Vera (PV). We investigated the molecular mechanisms driving erythroid skewed differentiation and the capacity of a selective JAK2 inhibitor (TG101348) to normalize PV progenitor differentiation. Both JAK2 V617F+ transduced cord blood and PV progenitor erythroid colony formation was potently inhibited by TG101348 (300 nM). Bioluminescent immunocompromised mouse transplantation studies revealed that TG101348 (150 mg/kg) treatment significantly reduced human erythroid engraftment by both PV and JAK2 V617F+ cord blood progenitors. Moreover, the imbalance between GATA-1 and PU.1 transcripts typical of JAK2 V617F+ progenitors normalized after treatment with TG101348. In addition, TG101348 inhibited both JAK2-mediated STAT5 phosphorylation and AKT-regulated GATA-1 phosphorylation in an erythropoietin responsive cell line suggesting a dual mechanism for the erythroid inhibitory effects of TG101348. Because of selective inhibition of JAK2 V617F+ progenitors both in vitro and in vivo, TG101348 may be an effective molecularly targeted inhibitor of JAK2 V617F+ driven MPDs in clinical trials.

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 Introduction Multiple Myeloma is not a single disease. There is increasing support for risk classification in combination with treatment decision making because of its impact on clinical outcomes. Here we demonstrate additional evidence of the prognostic value of SKY92, an established genetic marker of high risk Multiple Myeloma in a multicenter collection of samples with undisclosed treatments. Materials Methods A public GEP dataset (MMRC, MMGI portal) contained 114 cases of untreated Multiple Myeloma and was used for SKY92 high risk OS prediction (Kuiper et al. Leukemia 2012). In collaboration with MMRC, OS (with a minimum of at least 2 year follow-up) was collected for 91 of 114 cases for the purpose of this analysis. Briefly, CD138-positive plasma cells had been purified prior to total RNA extraction and subsequent gene expression profiling on Affymetrix U133Plus2.0 GeneChips. The 91 cases represented 9 different clinical sites and their CEL files were normalized as a single batch against a reference cohort of 329 cases after which the SKY92 risk scores were determined as either standard risk or high risk. Results SKY92 resulted in 19 high risk (20.9%) versus 72 standard risk (79.1%) cases in the unselected 91 case-cohort. Comparisons with other high risk GEP signatures will be performed. The OS analysis (Figure 1) shows that the HR cases have significantly shorter survival (Hazard Ratio 11, p = 7 x 10-5). Table 1 shows that high risk patients had more elevated B2M (26.3% vs 13.9%), more low albumin (26.3% vs 16.7%) and more high creatinine (26.3% vs 11.0%). There was no difference between high and standard groups in diagnosis dates (not shown). Cause of the 16 (84.2%) deaths among the high risk cases, and 21 (29.1%) deaths among the standard risk cases indicates that high risk contains less disease progression deaths (57.1% vs 31.3%), and more unknown deaths (56.3% vs 23.8%). Conclusions The SKY92 classifier identified 19 of 91 cases (21%) as high risk, recapitulating the percentage of high risk in previously studied cohorts (Kuiper et al. 2012). Moreover the hazard ratio of 11 when events up to 24 months or 8.18 when all events are considered, emphasizes the unmet medical need of high risk cases identified with SKY92 as 69% of all deaths within 2 years (9/13 death events) were in this category. Acknowledgments This research was performed within the framework of CTMM, the Center for Translational Molecular Medicine, project BioCHIP grant 03O-102. Rafael Fonseca is a Clinical Investigator of the Damon Runyon Cancer Research Fund. This work is supported by grants R01 CA83724, ECOG CA 21115T, Predolin Foundation, Mayo Clinic Cancer Center and the Mayo Foundation. Disclosures: van Beers: Skyline Diagnostics: Employment. Van Vliet:Skyline Diagnostics: Employment. Anderson:celgene: Consultancy; onyx: Consultancy; gilead: Consultancy; sanofi aventis: Consultancy; oncopep: Equity Ownership; acetylon: Equity Ownership. Jagannath:Celgene: Honoraria; Millennium: Honoraria. Jakubowiak:BMS: Consultancy, 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, Speakers Bureau; Millennium: Consultancy, 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, Speakers Bureau. Kumar:Celgene: Clinical Trial Support Other, Membership on an entity’s Board of Directors or advisory committees; Cephalon: Clinical Trial Support, Clinical Trial Support Other; Millennium: Clinical Trial Support, Clinical Trial Support Other, Membership on an entity’s Board of Directors or advisory committees; Novartis: Clinical Trial Support, Clinical Trial Support Other; Onyx: Clinical Trial Support Other, Membership on an entity’s Board of Directors or advisory committees. Lebovic:Celgene: Speakers Bureau; Onyx: Speakers Bureau. Lonial:Millennium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Sanofi: Consultancy; Onyx: Consultancy. Reece:Onyx: Honoraria; Novartis: Honoraria; Millennium: Research Funding; Merck: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Research Funding. Siegel:Celgene: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Millennium: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Onyx: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Vij:Celgene: Honoraria, Research Funding, Speakers Bureau; Millennium: Honoraria, Speakers Bureau; Onyx: Honoraria, Research Funding, Speakers Bureau. Zimmerman:Celgene: Honoraria; Millennium: Honoraria; Onyx: Honoraria. Fonseca:Medtronic: Consultancy; Otsuka: Consultancy; Celgene: Consultancy; Genzyme: Consultancy; BMS: Consultancy; Lilly: Consultancy; Onyx: Consultancy, Research Funding; Binding Site: Consultancy; Millennium: Consultancy; AMGEN: Consultancy; Cylene: Research Funding; Prognostication of MM based on genetic categorization of the disease: Prognostication of MM based on genetic categorization of the disease, Prognostication of MM based on genetic categorization of the disease Patents & Royalties.

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 Background Ex-vivo analysis of platelet inhibition by aspirin (ASA) suggests that an optimal decrease in platelet function occurs when 90-95% of platelets are inhibited with ASA. In patients with known vascular disease a daily aspirin decreases the probability of a future vascular event by about 25%. However, platelets from patients with diabetes mellitus (DM) are highly reactive with an increased turnover rate, and prophylaxis with a daily aspirin is not nearly as effective. Because platelet response among individuals is highly variable, we developed a light aggregation based assay that measures platelet function with 100% blockade of an individual’s platelet thromboxane A2 receptor (100% “aspirinated” platelets). This assay is utilized to determine the percentage of platelets inhibited by aspirin, “aspirinated” platelets (ASA-PLTS). Methods Platelet prostaglandin agonist (PPA), (Analytical Control Systems, Fishers IN) an agonist known to be sensitive to the amount of platelet inhibition with aspirin, was used to develop a light aggregometry based technique that measures ASA-PLTS. A specific inhibitor of the thromboxane A2 receptor SQ 29,548(S.Q.)(Cayman Chemicals, Ann Arbor, Mi.) was used to verify that maximal (100%) inhibition of platelets by aspirin was present 2 hrs after ingestion of 325mg ASA. In separate experiments platelets obtained 2 hrs after 325mg ASA (100% ASA-PLTS) were mixed with platelets from the same subject obtained just before aspirin ingestion (0% ASA-PLTS) so that the PPA light aggregation slopes could be measured with 95%, 90%, 85% and 80% ASA-PLTS. The slope of the PPA-AGG curve measured 24 hours after 325mg ASA was compared to the slopes obtained with known concentrations of ASA-PLTS using the formula T24-T2/ T0-T2. (T24= slope 24 hrs post ASA; T2=slope 2 hrs post ASA; T0=slope off ASA). Results Two hours after ingestion of 325mg ASA the slopes of the PPA-AGG curves with and without S.Q. were identical in 7 normal subjects reflecting the aspirin response with 100% ASA-PLTS. Because of the large range of response among individuals, eac subject served as their own control to develop an aspirin response curve for the different percentages of ASA-PLTS. 24 hours after 325mg ASA the percentage of ASA-PLTS in 6 of 7 normal subjects was greater than 90%. Conclusion 1. The slope of the PPA stimulated light aggregation curve with and without S.Q. obtained 2 hrs after 325mg of aspirin in normal subjects can be used as a measure of 100% ASA-PLTS response. 2. Platelet response in most normal subjects 24 hours after aspirin shows that at least 90% of their platelets are “aspirinated”. Comment This technique can identify patients, like those with DM whose percentage of ASA-PLTS may fall below 90% at the end of the dosing interval. A shorter aspirin dosing interval in these patients may result in a higher percentage of ASA-PLTS at the end of the dosing period and possibly decrease the patient’s probability of a subsequent vascular event, but these questions can only be answered with clinical studies. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 1409 MYC is among the most prolific oncogenes in cancer, yet pharmacologic strategies to modulate the function of the c-Myc oncoprotein do not exist. Toward this objective, we have undertaken to target c-Myc transcription by interfering with chromatin-dependent signal transduction to RNA polymerase, specifically by inhibiting the acetyl-lysine recognition domains (bromodomains) of putative co-activator proteins implicated in transcriptional initiation and elongation. Using a selective small-molecule bromodomain inhibitor, JQ1, we identify BET bromodomain-containing proteins as transcriptional regulatory factors for c-Myc. BET inhibition with JQ1 rapidly downregulates c-Myc transcription, followed by depletion of chromatin-bound c-Myc and genome-wide downregulation of Myc-dependent target genes. In translational model systems of multiple myeloma and Burkitt's lymphoma, both canonical MYC -dependent hematologic malignancies, JQ1 treatment produces a potent antiproliferative effect associated with cell cycle arrest. In multiple myeloma, adhesion to bone marrow stroma is associated with upregulation of BRD4, a BET bromomdomain coactivator protein. Inhibition of Myc function with JQ1 leads to impaired adhesion to stroma and cellular senescence, a classical Myc-specific phenotype. Mechanistically, JQ1 treatment depletes BRD4 from IgH enhancers, leading to prompt and robust downregulation of MYC transcription. In vivo efficacy of JQ1 in two disseminated models of multiple myeloma and in a Burkitt's lymphoma human xenograft establishes the therapeutic rationale for BET bromodomain inhibition in these diseases. Together, these studies identify a mechanistic rationale for targeting c-Myc in human cancer, and potentially other undruggable oncogenes driven by immunoglobulin rearrangement. Note: G.C.I. and J.E.D. have made equal contributions to this research; C.S.M. and J.E.B. are jointly senior authors Disclosures: Richardson: Millennium: Advisory Board; Celgene: Advisory Board; Johnson & Johnson: Advisory Board; Novartis: Advisory Board; Bristol Myers Squibb: Advisory Board. Ghobrial:Bristol-Myers Squibb: Research Funding; Millennium: Research Funding; Noxxon:; Millennium:; Celgene:; Novartis:. Anderson:Celgene: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Kung:Novartis Pharmaceuticals: Consultancy, Research Funding. Mitsiades:Millennium Pharmaceuticals: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Novartis Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Kosan: Consultancy, Honoraria; Pharmion: Consultancy, Honoraria; Centocor: Consultancy, Honoraria; Amnis Therapeutics: Consultancy, Honoraria; PharmaMar:; OSI Pharmaceuticals: Research Funding; Amgen: Research Funding; AVEO Pharma: Research Funding; EMD Serono: Research Funding; Sunesis: Research Funding; Gloucester Pharmaceuticals: Research Funding; Genzyme: Research Funding; Johnson & Johnson: Research Funding. Bradner:Acetylon Pharmaceuticals: Scientific Founder; SHAPE Pharmaceuticals: Scientific Founder; Tensha Therapeutics: Scientific Founder.