Bahlis, Nizar Jacques

Introduction: Daratumumab (DARA) is a human, CD38-targeted, IgG1κ monoclonal antibody approved as monotherapy in heavily pretreated relapsed/refractory multiple myeloma (RRMM) and in combination with standard-of-care regimens for transplant-ineligible NDMM and RRMM. The addition of DARA to standard-of-care regimens in phase 3 studies has consistently demonstrated a near doubling of complete response (CR) rates, tripling of minimal residual disease (MRD)-negativity rates, and reduction in the risk of disease progression or death by ≥44% in patients with transplant-ineligible NDMM or RRMM. In the primary analysis of the phase 3 MAIA study (median follow-up: 28.0 months), a significant progression-free survival (PFS) benefit (median not reached [NR] vs 31.9 months; hazard ratio [HR], 0.56; P<0.001) and a >3-fold increase in MRD-negativity rates (10-5 sensitivity threshold; 24.2% vs 7.3%; P<0.001) were observed for D-Rd vs Rd in patients with transplant-ineligible NDMM (Facon T, N Engl J Med 2019). Here, we report updated efficacy and safety findings from MAIA after 9 months of additional follow-up. Methods: Patients with NDMM ineligible for high-dose chemotherapy and autologous stem cell transplantation due to age ≥65 years or comorbidities were randomly assigned (1:1) to receive Rd ± DARA. Stratification factors included International Staging System stage (ISS [I vs II vs III]), region (North America vs other), and age (<75 vs ≥75 years). All patients received 28-day cycles of Rd (R: 25 mg orally once daily on Days 1-21; d: 40 mg orally on Days 1, 8, 15 and 22). In the D-Rd arm, DARA (16 mg/kg intravenously) was given weekly for Cycles 1-2, bi-weekly for Cycles 3-6, and every 4 weeks thereafter. Patients were treated until disease progression or unacceptable toxicity in both treatment arms. The primary endpoint was PFS. Key secondary endpoints included overall response rate (ORR), MRD-negativity rate (10-5 sensitivity, clonoSEQ® version 2.0), and safety. PFS on the next line of therapy (PFS2), defined as the time from randomization to progression on the next line of therapy or death, was also measured. Results: A total of 737 patients were randomized (D-Rd, N = 368; Rd, N = 369). Patient baseline characteristics were well balanced between the two treatment arms. Median (range) age was 73 (45-90) years, with 44% of patients ≥75 years of age. 27%, 43%, and 29% of all patients were ISS stage I, II, and III, respectively. Among 642 patients evaluable for FISH/karyotyping analysis, 86% had standard and 14% had high cytogenetic risk. After a median follow-up of 36.4 months, median PFS was NR with D-Rd vs 33.8 months with Rd (HR, 0.56; 95% confidence interval [CI], 0.44-0.71; P<0.0001; Figure). The estimated 36-month PFS rate was 68% with D-Rd vs 46% with Rd. The PFS benefit of D-Rd vs Rd was observed in all prespecified subgroups, except for patients with impaired hepatic function. Adding DARA to Rd continued to result in deeper responses with higher rates of ≥CR and ≥very good partial response (VGPR; Table). Median duration of response among responders was NR with D-Rd vs 40.7 months with Rd. Median PFS2 was NR vs 47.3 months with D-Rd vs Rd, respectively (HR, 0.69; 95% CI, 0.53-0.91; P=0.0079); follow up is ongoing. 143 (39%) vs 233 (64%) patients with D-Rd vs Rd, respectively, have discontinued treatment. 85 (23%) patients with D-Rd vs 103 (28%) patients with Rd have discontinued the study due to death. Grade 3/4 treatment-emergent adverse events (TEAEs; D-Rd/Rd) occurring in ≥10% of patients were neutropenia (51%/35%), lymphopenia (15%/11%), pneumonia (15%/9%), anemia (14%/21%), leukopenia (11%/6%), and hypokalemia (10%/10%); grade 3/4 infection rates were 36%/27%. The most common serious TEAE was pneumonia (14%/9%). 9% of patients in the D-Rd arm and 18% of patients in the Rd arm discontinued treatment due to TEAEs. The complete updated data set will be presented at the meeting with additional efficacy endpoints, including MRD-negativity rate. Conclusion: After longer follow up, the addition of DARA to Rd continues to demonstrate a significant PFS benefit and improved rates of deeper and more durable responses vs Rd alone in patients with transplant-ineligible NDMM. The longer follow-up also demonstrated a significant improvement in PFS2 favoring D-Rd, and no new safety concerns were observed. These results continue to support the use of D-Rd in the first line of treatment for transplant-ineligible patients with NDMM. Disclosures Bahlis: Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Facon:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Usmani:Amgen Array Biopharma, Bristol-Myers Squibb, Celgene, Janssen, Merck, Pharmacyclics, Sanofi, Takeda: Other: Research Grant; Amgen, Celgene, Janssen, Sanofi, Takeda: Speakers Bureau; Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, SkylineDX, Takeda: Other: Consultant/Advisor. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding. Plesner:Oncopeptides: Consultancy; Janssen: Consultancy, Research Funding; Takeda: Consultancy; AbbVie: Consultancy; Celgene: Consultancy; Genmab: Consultancy. Orlowski:Poseida Therapeutics, Inc.: Research Funding. Hulin:celgene: Consultancy, Honoraria; Janssen, AbbVie, Celgene, Amgen: Honoraria. Quach:Sanofi: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Goldschmidt:ArtTempi: Honoraria; John Hopkins University: Other: Grants and/or provision of Investigational Medicinal Product; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Dietmar-Hopp-Foundation: Other: Grants and/or provision of Investigational Medicinal Product; Mundipharma: Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; MSD: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Molecular Partners: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Honoraria, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding. O'Dwyer:GlycoMimetics Inc: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Onkimmune: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy. Venner:Janssen: Honoraria; J&J: Research Funding; Amgen: Honoraria, Research Funding; Sanofi: Honoraria; Takeda: Honoraria; Celgene: Honoraria. Weisel:GSK: Honoraria; Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Juno: Consultancy; Celgene Corporation: Consultancy, Honoraria, Research Funding; Adaptive Biotech: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Krevvata:Janssen: Employment. Pei:Janssen: Employment, Equity Ownership. Wang:Janssen: Employment. Van Rampelbergh:Janssen: Employment. Ukropec:Janssen: Employment, Equity Ownership. Uhlar:Janssen: Employment. Kobos:Janssen: Employment. Perrot:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Amgen: Honoraria; Sanofi: Honoraria.

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 Abstract 813FN2 Introduction: Carfilzomib is a next-generation proteasome inhibitor that selectively and irreversibly binds to its target, resulting in sustained inhibition absent of off-target effects relative to bortezomib. Carfilzomib has demonstrated durable anti-tumor activity and an acceptable tolerability profile in patients with multiple myeloma (MM). Final results will be presented for the bortezomib-naïve group of PX-171-004, a phase 2 study of single-agent carfilzomib in patients with relapsed and/or refractory MM. Herein we report the most recent data analysis available at time of abstract submission. Updated final results for the bortezomib-naïve group of PX-171-004, including OS data, will be presented at the meeting. Methods: Patients received either 20 mg/m2 for all treatment cycles (Cohort 1) or a stepped-up dose-escalating regimen of 20 mg/m2 for Cycle 1 and 27 mg/m2 for all treatment cycles thereafter (Cohort 2). Carfilzomib was administered over 2–10 minutes on Days 1, 2, 8, 9, 15, and 16 of every 28-day cycle, for a maximum of 12 cycles. The primary endpoint was the best overall response rate (ORR; [CR + VGPR + PR]) determined according to the IMWG Uniform Response Criteria. Secondary endpoints included the clinical benefit response rate (CBR; [ORR + MR per EBMT criteria]), progression-free survival (PFS), time to progression (TTP), duration of response (DOR), OS, and safety. The result of efficacy analysis from disease assessment by the Independent Review Committee is presented in this abstract. Results: 127 of 129 enrolled bortezomib-naïve patients were evaluable for response. Prior therapies included thalidomide (59%), lenalidomide (59%), alkylating agents (81%), and stem cell transplant (73%). Patients had received a median of 2 prior regimens (1 in 54 patients, 2 in 40 patients, 3 in 28 patients, and ≥4 in 7 patients). 84 patients (65%) were disease refractory to their most recent therapy, defined as ≤25% response or progression during or within 60 days after completion of therapy. The median duration of carfilzomib treatment is 7 cycles (range 1−12) in Cohort 1; 8 patients were receiving drug as of February 2011 in Cohort 2 with a median treatment of 6.5 cycles (range 1−13) at that time. Best ORR was 42% in Cohort 1 and 52% in Cohort 2. Median TTP was 8.3 months and median DOR was 13.1 months in Cohort 1. The median TTP and DOR for Cohort 2 have not been reached at the time of this interim analysis; the lower bound of the 95% CI for the median TTP was 10.2 months, and 84% were estimated to have DOR ≥1 year at the time of data cutoff. Higher response rates for Cohort 2 compared with Cohort 1 do not appear to be associated with higher toxicities. Patients with unfavorable cytogenetic characteristics (≥1 abnormality) per mSMART criteria had an ORR of 37% and CBR of 42% compared with 50% and 65%, respectively, for patients with no abnormality. The most common treatment-emergent adverse events (AEs), regardless of relationship to carfilzomib in Cohorts 1 and 2, respectively, were fatigue (71%, 54%), nausea (54%, 43%), anemia (46%, 37%), and dyspnea (49%, 33%). These were primarily ≤Grade 2 in severity. The most common Grade 3/4 AEs were anemia (15%), lymphopenia (15%), thrombocytopenia (13%), pneumonia (12%) and neutropenia (12%). Treatment-emergent peripheral neuropathy (PN) was mild and infrequent (16%). Only 1 case of Grade 3 PN (0.8%) was observed. Overall, 38 patients (30%) completed 12 cycles and 22 of these patients continued to receive carfilzomib therapy under a safety extension protocol (PX-171-010), an ongoing, multicenter, open-label phase 2 study to monitor long-term use of single-agent carfilzomib. Conclusions: To date we have seen robust and durable single-agent activity for carfilzomib in bortezomib-naïve patients with relapsed and often refractory MM with an ORR of 42−52% and a CBR of 59−63% from 2 separate dose cohorts in a population wherein 92% received an immunomodulatry drug and 73% had undergone an autologous stem cell transplant previously. These data are suggestive of a dose–response relationship and are being further evaluated in the exploratory phase 1b/2 study PX-171-007. Carfilzomib was associated with minimal PN and excellent long-term tolerability, with nearly one-third of patients completing 12 cycles and 22 of these continuing treatment beyond 1 year in the extension protocol PX-171-010. Disclosures: Vij: Onyx Pharmaceuticals: Consultancy, Research Funding; Celgene: Research Funding, Speakers Bureau; Millennium: Speakers Bureau. Kaufman:Millenium: Consultancy; Onyx Pharmaceuticals: Consultancy; Novartis: Consultancy; Keryx: Consultancy; Merck: Research Funding; Celgene: Research Funding. Jakubowiak:Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx Pharmaceuticals: Consultancy, 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; Exelixis: Consultancy, Honoraria. Wang:Onyx Pharmaceuticals: Research Funding. Jagannath:Millennium: Honoraria; Celgene: Honoraria; Onyx Pharmaceuticals: Honoraria; Merck: Honoraria; OrthoBiotec.Imedex: Membership on an entity's Board of Directors or advisory committees; Medicom World Wide: Membership on an entity's Board of Directors or advisory committees; Optum Health Education: Membership on an entity's Board of Directors or advisory committees; PER Group: Membership on an entity's Board of Directors or advisory committees. Kukreti:Celgene: Honoraria. Alsina:Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Allergan: Research Funding. Belch:Celgene: Research Funding; Onyx: Research Funding. Gabrail:Millennium: Research Funding. Matous:Celgene: Speakers Bureau; Millenium: Speakers Bureau; Cephalon: Speakers Bureau. Vesole:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Speakers Bureau. Orlowski:Onyx Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kunkel:VLST biothech: Consultancy; Threshold: Consultancy; Onyx Pharmaceuticals: Consultancy. Wong:Onyx Pharmaceuticals: Employment, Equity Ownership. Stewart:Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding.

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 430 Background: Peripheral neuropathy (PN) is a feature of multiple myeloma (MM) itself as well as a debilitating side effect and major dose-limiting toxicity of thalidomide (THAL) and bortezomib (BTZ) (Chaudry et al, J Peripher Nerv Syst. 2008). Although the mechanism of BTZ-induced PN (BIPN) is unknown, PN may not be a proteasome inhibitor class effect. Carfilzomib (CFZ) is a highly selective proteasome inhibitor with activity in relapsed or refractory MM. CFZ overcomes BTZ-resistance in vitro (Kuhn et al, Blood 2007), lacks the off-target activities of BTZ (Kapur et al, Blood 2008), and does not cause neurotoxicity in long-term chronic (e.g. up to 9 months) animal toxicology studies (Kirk et al, Blood 2008). In Phase I and 1b/2 trials (total n=138), CFZ was not associated with dose-limiting PN. Here we report on the experience of CFZ treatment from two ongoing Phase 2 trials in relapsed or refractory MM. Methods: Patients with relapsed or refractory MM received CFZ, 20 mg/m2 IV, Days 1, 2, 8, 9, 15, and 16 in a 28-day cycle for up to 12 cycles on studies PX-171-003 and PX-171-004. Neuropathy history, neurological physical exam and PN-related quality of life data (FACT-GOG/NTx v 4.0 scores) were collected at screening. Prospective neurological exams and subjective reporting of PN using the FACT-GOG/Ntx subscale v.4 questionnaire occurred every 2 cycles until study discontinuation to proactively assess for PN. Adverse Event (AE) data were also collected. AEs reported as ‘neuropathy peripheral', ‘neuropathic pain', ‘neuropathy', and ‘peripheral sensory neuropathy' were included as PN. AE reports of ‘paraesthesias' and ‘dysesthesias' were counted separately. Results: To date, baseline data are availabel for 136 patients. At screening, 73 (54%) patients had active PN, including 64 (47%) with Grade (G) 1 and 9 (7%) with G2. 111 (82%) patients had a history of PN which was attributed to prior chemotherapy, 86 cases of which were attributed to either THAL or BTZ. THAL was implicated in 57 cases, BTZ in 45 cases, and both THAL and BTZ in 17 cases. For 27 of these patients, PN was the primary reason for THAL or BTZ discontinuation. The mean number of CFZ doses was 27 (4.5 four-week cycles) and 27 (20%) patients completed at least 8 cycles. Peripheral neuropathy AEs (all grades) were reported in 21 (15%) patients; 12 (9%) cases were considered possibly related to CFZ. Grade ≥ 3 PN was reported in only 3 (2%) patients. In one patient, the Grade 3 neuropathy lasted from treatment days 2 to 3 (i.e., < 36 hours) and resolved; the patient continued on CFZ at full dose for 30 days before discontinuing study due to progressive MM. In a second patient, Grade 3 neuropathy occurred on study day 91. The dose was reduced from 20 mg/m2 to 15 mg/m2, at the same twice-weekly frequency; the PN resolved to G1 and the patient continued on therapy until day 133. The third patient had G3 PN that occurred from days 260-281 and resolved to G1 while still on full dose CFZ. This patient completed the full 12-cycle protocol (∼1 year CFZ treatment). Paraesthesias and dysesthesia were reported in 10 (7%) patients; all were G1 or 2. There were no missed doses or CFZ treatment discontinuations due to PN, paraesthesias or dysesthesias. Comparative FACT-GOG/Ntx subscale scores were availabel for 95 patients. There was no statistically significant change in FACT-GOG/NTx scores from baseline to the end of the study. Neurological exams did not identify any additional peripheral neuropathy beyond those reported as AEs. Conclusions: In MM patients receiving CFZ therapy, reports of PN, paraesthesias and dysesthesia are generally mild and do not result in missed doses or CFZ discontinuation, allowing long-term treatment and prolonged disease control. These data, along with the experience from other clinical trials, indicate that PN is not a class effect of proteasome inhibitors. Disclosures: Vij: Proteolix: Consultancy, Research Funding. Wang:Proteolix, Inc.: Research Funding. Stewart:Genzyme, Celgene, Millenium, Proteolix: Honoraria; Takeda, Millenium: Research Funding; Takeda-Millenium, Celgene, Novartis, Amgen: Consultancy. Lonial:Celgene: Consultancy; Millennium: Consultancy, Research Funding; BMS: Consultancy; Novartis: Consultancy; Gloucester: Research Funding. Trudel:Celgene: Honoraria, Speakers Bureau; Ortho Biotech: Honoraria. Jakubowiak:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Centocor Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers-Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Belch:Ortho Biotech: Honoraria, Research Funding. Bahlis:Celgene: Honoraria, Speakers Bureau; Ortho Biotech: Honoraria, Speakers Bureau. Le:Proteolix, Inc.: Employment. Cruickshank:Proteolix, Inc.: Employment. Bennett:Proteolix: Employment. Molineaux:Proteolix, Inc.: Employment, Equity Ownership. Siegel:Celgene: 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.

Abstract Abstract 3861 Poster Board III-797 Previous studies have reported that multiple myeloma (MM) patients (pts) with t(4;14) identified by FISH who are treated with a single ASCT as part of first-line therapy have worse outcomes than those lacking this adverse cytogenetic marker; two trials have described a median progression-free survival (PFS) of only 8-9 months and median overall survival (OS) of 18 mos in this setting (Chang H, et al. Bone Marrow Transplant 2005; 36: 793; Gertz M, et al. Blood 2005; 106: 2837). Since the novel agent bortezomib appears to have efficacy in patients with t(4;14), we designed a phase II protocol in which pts receive induction with pegylated liposomal doxorubicin, bortezomib and dexamethasone (DBD) x 4 cycles, followed by post-induction therapy with oral cyclophosphamide 300 mg/m2 days 1,8 15, 22 with bortezomib 1.5 mg/m2 days 1,8,15 and prednisone 100 mg q 2 days of a 28-day cycle (CyBor-P) x 8 additional cycles. Maintenance therapy with dexamethasone (dex) 40 mg/month was then administered until progression. Although elective stem cell collection was recommended after induction, routine ASCT was not performed in the absence of disease progression. Between February 2008-August 2009, 153 newly diagnosed MM pts were screened for t(4;14) in 7 Canadian centers, and 14 (9%) were found to be positive by FISH. Four did not meet the critieria for symptomatic MM, 2 had received ≥ 2 mos of prior therapy while 8 were entered onto study. One of these was later determined to have a variant abnormality of chromosome 4 but not t(4;14) and underwent ASCT after induction; this pt is included in the safety analysis only. The median age was 56 (49-69) and 43% were male. The median percent nuclei positive for t(4;14) was 30% (10-41%), serum β2-microglobulin 394 nmol/L (190-1695) and albumin 34 g/L (28-39); one pt had ISS stage 1,3 had stage 2 and 3 had stage 3 MM. Immunoglobulin subtype included IgGκ in 2 and IgAκ in 2 and IgAλ in 3. All pts have completed DBD induction, with the best response in the 7 evaluable pts consisting of PR in 2 and VGPR in 5; one in PR progressed quickly after induction and has achieved nCR after D-PACE followed by ASCT and lenalidomide maintenance. Four are receiving post-induction therapy with CyBor-P currently, with VGPR in 3 and PR in 1. No SAEs or grade3/4 neutropenia or thrombocytopenia has occurred; other toxicities were mild, with grade 2 skin toxicity noted in 37.5% and grade 2 neurotoxicity observed in 7.4%. All pts are alive at a median follow-up (F/U) of 8 mos (2-11), and 6 (86%) are free of progression. We conclude: 1) the incidence of t(4;14) in newly diagnosed MM pts appears to be lower than the 15% anticipated; 2) 28% of newly diagnosed pts with this entity have asymptomatic MM; 3) preliminarily, DBD induction has resulted in ≥ PR in all pts although 1 progressed quickly; 4) this bortezomib-based regimen is very well-tolerated; 5) longer F/U is required to determine the PFS and OS with this approach. Disclosures: Reece: Ortho Biotech: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau. Off Label Use: Use of bortezomib as part of initial therapy with pegylated liposomal doxorubicin and dexamethasone. Piza Rodriguez:Ortho Biotech: Honoraria. Belch:Ortho Biotech: Honoraria, Research Funding. Shustik:Ortho Biotech: Honoraria. Bahlis:Ortho Biotech: Honoraria; Celgene: Honoraria. White:Ortho Biotech: Honoraria, Research Funding. Chen:Ortho Biotech: Honoraria. Kukreti:Celgene: Honoraria. Stewart:Genzyme, Celgene, Millenium, Proteolix: Honoraria; Takeda, Millenium: Research Funding; Takeda-Millenium, Celgene, Novartis, Amgen: Consultancy. Trudel:Ortho Biotech: Honoraria, Research Funding.

Abstract Abstract 1875 Introduction: Carfilzomib (CFZ) is a next-generation proteasome inhibitor that has demonstrated durable single-agent antitumor activity in patients (pts) with relapsed and/or refractory multiple myeloma (R/R MM). Previously we have shown that unfavorable cytogenetic features, defined as presence of any of del 13 or hypodiploidy by metaphase cytogenetic analysis and/or del 17p13, t(4;14), t (14;16) by fluorescence in situ hybridization (FISH), did not appreciably affect overall (≥PR) and clinical benefit (≥MR) response rates (ORR and CBR) in PX-171-003-A1, a large phase 2 study of single-agent CFZ in pts with R/R MM (Jakubowiak et al. Ann Oncol. 2011;22(S4): Abstract 117). The objectives of the present analysis were to evaluate the impact of specific cytogenetic abnormalities on efficacy and treatment outcomes. Methods: Pts with unfavorable cytogenetic abnormalities (defined above) were eligible for inclusion in this analysis. All pts received CFZ at 20 mg/m2 IV on days 1, 2, 8, 9, 15, and 16 of 28-day cycles (C) and were dose-escalated to 27 mg/m2 at C2. Pts were treated for up to 12 C. Responses were assessed by International Myeloma Working Group criteria, with minimal response (MR) by European Group for Blood and Marrow Transplantation criteria. Assessments were confirmed by an Independent Review Committee (IRC). Results: A total of 234 pts were included in this analysis. Metaphase cytogenetic data were available for 203 pts (87%), and FISH data were available for 210 pts (90%); 178 pts had both (76%). Seventy-five of 234 pts (32%) had ≥1 abnormality and represented the unfavorable group in this analysis. Of these, 49 (65%) had abnormalities detected via metaphase cytogenetics, 47 (63%) by FISH, and 21 (28%) by both methods. Characteristics of pts in the unfavorable and normal/favorable groups were comparable overall, with the exception of a higher proportion of pts with International Staging System stage II/III in the unfavorable group (83% vs 64%). Response rates per the IRC, presented previously, included an ORR of 30% for pts with ≥1 abnormality compared with 23% for pts with none. The corresponding CBRs were 34% and 40%, respectively. Duration of response (DOR) and time to progression (TTP) values were 7 months (mo) (95% CI 4–9) and 4 mo (95% CI 3–6), respectively, for pts with ≥1 abnormality and 8 mo (95% CI 6–12) and 5 mo (95% CI 3–6), respectively, for pts with none. The ORRs, CBRs, and disease control rates (DCRs) according to specific cytogenetic abnormalities are presented below. Response rates were largely unaffected by the presence of specific unfavorable cytogenetic abnormalities, with the possible exceptions of trends toward a higher response rate for t(4;14) and a lower rate for t(14;16), although the latter abnormality was only noted in 3 pts. The trend for better response rates in pts with t(4;14) corresponded to a DOR of 5.6 mo (95% CI 2.8–10.2). In contrast, the DOR appeared shorter for the subgroup of pts with del 17p13 (4.6 mo, 95% CI: 3.7–Not reached). Time-to-event endpoints including TTP are being analyzed for these and the other subpopulations, and data on these will be presented, along with overall survival stratified by cytogenetic abnormality. Conclusions: CFZ demonstrated comparable response rates in pts with relapsed/refractory MM in both the absence and presence of unfavorable cytogenetic abnormalities in the 003-A1 study. Similarly, in the phase 2 PX-171-004 study, no significant difference in response rates between unfavorable and normal/favorable groups has been observed in a population of less heavily-pretreated pts with relapsed or R/R MM. Taken together, the results of these and other analyses to date suggest that responses to single-agent CFZ can be achieved in heavily pretreated pts and that overall, these responses appear not to be significantly influenced by poor prognostic cytogenetic features. Further analyses from studies with CFZ in newly diagnosed MM and in less heavily-pretreated pts are needed to determine whether a trend toward lower response rates and DOR for pts with del 17p13 is consistently observed in other populations. Disclosures: Jakubowiak: Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx Pharmaceuticals: Consultancy, 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; Exelixis: Consultancy, Honoraria. Off Label Use: Use of the investigational agent carfilzomib, proteasome inhibitor, in the treatment of relapsed and/or refractory multiple myeloma. Siegel:Millennium: 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. Singhal:Celgene: Speakers Bureau; Millennium: Speakers Bureau; Onyx Pharmaceuticals: Research Funding. Martin:Celgene: Honoraria; Onyx Pharmaceuticals: Consultancy. Lonial:Onyx: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Millennium Pharmaceuticals, Inc.: Consultancy; Merck: Consultancy. Kukreti:Celgene: Honoraria. Bahlis:Celgene: Honoraria, Speakers Bureau. Alsina:Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Allergan: Research Funding. Kunkel:Onyx Pharmaceuticals: Consultancy; Threshold: Consultancy; VLST biothech: Consultancy. Wong:Onyx Pharmaceuticals: Employment, Equity Ownership. Orlowski:Onyx Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Stewart:Celgene Corporation: Consultancy, Research Funding; Millenium: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Jagannath:Millennium: Honoraria; Celgene: Honoraria; Onyx Pharmaceuticals: Honoraria; Merck: Honoraria; OrthoBiotec. Imedex: Membership on an entity's Board of Directors or advisory committees; Medicom World Wide: Membership on an entity's Board of Directors or advisory committees; Optum Health Education: Membership on an entity's Board of Directors or advisory committees; PER Group: Membership on an entity's Board of Directors or advisory committees. Wang:Onyx Pharmaceuticals: Research Funding.

Abstract Abstract 985 Introduction: CFZ is a novel and highly selective epoxyketone proteasome inhibitor currently in clinical development for the treatment of multiple myeloma (MM). Ph 1 and 2 studies with CFZ have demonstrated durable single-agent antitumor activity in pts with relapsed or refractory (R/R) MM. The present study, PX-171-003-A1, was an open-label, single-arm Ph 2b trial and enrolled patients with multiply relapsed MM whose disease was refractory (defined as <25% response on, or progression during or <60 days after completion of, therapy) to their last treatment regimen. Patients must have received ≥2 prior therapies including: 1) bortezomib (BTZ) and either thalidomide (THAL) or lenalidomide (LEN), and 2) an alkylating agent. Materials and Methods: Pts received CFZ at 20 mg/m2 on a QDx2 schedule (Days 1, 2, 8, 9, 15, and 16 every 28 days) in cycle (C) 1 and were dose escalated to 27 mg/m2 on the same schedule thereafter for up to 12 C. Pts completing 12 C were eligible to enter an extension study (PX-171-010). The primary endpoint was overall response rate (ORR) (≥ partial response [PR]). Secondary endpoints included: clinical benefit response (CBR) (ORR + Minimal response [MR]), duration of response for ≥PR (DOR), overall survival (OS), time to progression (TTP), progression free survival (PFS), and safety. Responses and progression were determined according to the International Myeloma Working Group (IMWG) criteria and were assessed and confirmed by an Independent Response Committee (IRC). Results: 266 pts were enrolled with a median duration of MM of 5.4 years including 83% whose disease had progressed on or within 60 d of last therapy and 17% whose disease had achieved <25 % response to the regimen immediately preceding study entry. Of the 266 pts enrolled pts, 257 were evaluable for response; 9 patients were considered not evaluable based on missing baseline or lacking at least one post-baseline M-protein. An ORR (≥PR) of 24% with a median DOR of 7.4 mo (range 6.2–10.3) was determined. Responses are detailed in the table. The CBR (ORR + MR) was 36%. Median DOR of pts with MRs was 6.3 months, indicating that long-term MRs were observed. An additional 32% (83 pts) achieved SD for at least 6 wks. To date, 79 pts (30%) completed ≥6 C and >11% of pts have completed all 12 C of protocol specified therapy and most have entered the extension protocol; 15 pts remain on study (all >10 C). OS and TTP data for the overall population will also be reported. The enrolled pts in this study were heavily pretreated having received a median of 5 prior lines of therapy (range 1–20, median of 13 anti-myeloma agents). 85% of pts had received at least 2 and 37% had received at least 3 drugs in the regimen just prior to entering the study. Prior anti-myeloma agents included 99.6% (265/266 pts) BTZ (median 2 prior regimens containing BTZ), 99.6% either THAL (74%) or LEN (94%), 98% corticosteroids, 91% alkylating agents, and 74% stem cell transplant; 65% of pts were refractory to BTZ at any point in time prior to study entry. The most common treatment-emergent adverse events ≥ Grade (G) 3 regardless of relationship to study drug were predominantly hematologic and included thrombocytopenia (22%), anemia (20%), lymphopenia (10%), pneumonia (8%), neutropenia (8%), fatigue (7%), hyponatremia (5%), and hypercalcemia (5%). Although 206 pts (77%) had G1/2 peripheral neuropathy (PN) at baseline, new onset PN was infrequent and G ≥3 PN occurred in <1%. Interestingly, in this subset of patients, efficacy response was nearly identical to that seen in the full study population with an ORR (≥PR) of 24%. Conclusions: Single-agent CFZ achieved durable responses in pts with R/R MM whose disease had relapsed after all available therapies including BTZ and immunomodulatory agents. The CBR and median DOR achieved with this steroid-sparing regimen establish that CFZ has the potential to offer substantial clinical benefit to patients with relapsed or refractory disease. CFZ was well-tolerated and side effects were clinically manageable with no new or unexpected toxicities observed. Importantly, exacerbation of pre-existing PN was uncommon. Cumulative side effects were not observed, allowing prolonged single-agent dosing for chronic disease control. Disclosures: Siegel: Millenium: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Martin:Celgene: Honoraria; Onyx: Consultancy. Wang:Celgene: Research Funding; Onyx: Research Funding; Millenium: Research Funding; Novartis: Research Funding. Vij:Onyx: Honoraria. Jakubowiak:Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria; Centocor Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Exelixis: 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. Jagannath:Millenium, OrthoBiotec, Celgene, Merck, Onyx: Honoraria; Imedex, Medicom World Wide, Optum Health Education, PER Group: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Lonial:Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Kukreti:Celgene: Honoraria; Roche: Honoraria; Ortho Biotech: Honoraria. Alsina:Millenium: Consultancy, Research Funding; Celgene: Research Funding; Novartis: Consultancy. Zonder:Millenium: Consultancy, Honoraria, Research Funding; Cephalon: Research Funding; Celgene: Honoraria. Wong:Onyx Pharmaceuticals: Employment. Vallone:Onyx Pharmaceuticals: Employment. Chang:Onyx Pharmaceuticals: Employment. Kauffman:Onyx Pharmaceuticals: Employment. Stewart:Millennium: Consultancy; Celgene: Honoraria. Singhal:Celgene: Speakers Bureau; Takeda/Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx : Research Funding.

Abstract Introduction: Cytogenetic abnormalities in patients (pts) with multiple myeloma (MM) are of prognostic importance and can be associated with poor outcomes (Bergsagel, Blood, 2011). The FIRST trial is a pivotal phase 3 study with the largest data set in transplant-ineligible pts with newly diagnosed MM (NDMM). This subanalysis evaluates the impact of cytogenetics on outcomes in transplant-ineligible pts with NDMM continuously treated with lenalidomide plus low-dose dexamethasone until disease progression (Rd continuous). Methods: Transplant-ineligible pts with NDMM were randomized to 1 of 3 treatment arms: Rd continuous, Rd18 (Rd for 18 cycles [72 weeks]), or melphalan-prednisone-thalidomide (MPT; for 12 cycles [72 weeks]). Cytogenetics were assessed using fluorescence in situ hybridization. Pts were categorized into cytogenetic risk groups according to International Myeloma Working Group criteria. High-risk cytogenetics included del(17p), t(4;14), and t(14;16); all other pts were categorized as non-high risk. The primary endpoint was progression-free survival (PFS; primary comparators were Rd continuous vs MPT), and key secondary endpoints were overall survival (OS), overall response rate (ORR), and safety. Results: A total of 762 of 1623 pts from the intent-to-treat population had validated cytogenetic profiles, with 142 pts in the high-risk group and 620 pts in the non-high-risk group. Baseline characteristics were well balanced across cytogenetic risk groups (Table 1). The median follow-up for OS was 40.2 months for the 762 pts in this analysis (data cutoff, March 03, 2014). In the non-high-risk group, median duration of treatment was 19.4 months with Rd continuous and 16.6 months with both Rd18 and MPT. In the high-risk group, median duration of treatment was 10.0 months with Rd continuous, 8.2 months with Rd18, and 12.0 months with MPT. Rd continuous treatment resulted in a 24% reduced risk of death or progression compared with MPT and an even greater 32% reduced risk in pts without high-risk cytogenetics (Table 2). In non-high-risk pts, median PFS was 31.1 months with Rd continuous compared with 21.2 and 24.9 months with Rd18 and MPT, respectively (Figure). However, in high-risk pts, the observed numerical median PFS favoring Rd18 is mainly due to small pt numbers influenced by long runners (n = 5), and the greatly overlapping 95% CIs from all 3 arms show the difference is likely to be minimal. Rd continuous treatment resulted in a 28% reduced risk of death vs MPT overall and a 34% reduced risk in pts without high-risk cytogenetics. OS was similar across treatment arms for high-risk pts. ORRs in all cytogenetic risk groups favored Rd continuous vs MPT. In pts with high-risk cytogenetics, higher-quality responses were also observed with Rd continuous vs MPT treatment. Similar results were seen with Rd continuous compared with Rd18, although OS and ORR benefits overall and in pts without high-risk cytogenetics were not as pronounced. In all 3 treatment arms, adverse events were consistent across cytogenetic risk groups. Conclusions: Rd continuous treatment resulted in PFS and OS benefits vs MPT in pts with validated cytogenetic profiles. This was largely due to PFS and OS improvements in pts without high-risk cytogenetics. In the high-risk group, the longest PFS was observed with Rd18 treatment and OS was similar across treatment arms. Despite being on the continuous vs fixed duration treatment arm, high-risk pts on Rd continuous received a shorter duration of treatment than those on MPT, which may explain why PFS favored MPT vs Rd continuous. Higher response rates were observed with Rd continuous vs MPT, regardless of cytogenetic risk, and greater quality responses were observed in pts with high-risk cytogenetics. The safety profile of Rd continuous was manageable and consistent between cytogenetic risk groups. Results support Rd continuous as a standard treatment option for pts with NDMM who are ineligible for transplant, especially those without high-risk cytogenetics. Additional PFS and OS benefits may be achieved in pts with high-risk cytogenetics when Rd continuous is used as a backbone for combination therapy with a novel agent. Promising activity in pts with high-risk cytogenetic abnormalities has been demonstrated using this approach (Lonial et al, N Engl J Med, 2015; Stewart et al, N Engl J Med, 2015). Disclosures Hulin: Celgene Corporation: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Bristol Myers Squibb: Honoraria. Dimopoulos:Celgene: Honoraria; Onyx: Honoraria; Novartis: Honoraria; Janssen-Cilag: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Genesis: Honoraria. Reece:Lundbeck: Honoraria; Amgen: Honoraria; Merck: Research Funding; Bristol-Myers Squibb: Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Onyx: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Millennium Takeda: Research Funding; Otsuka: Research Funding. Catalano:Roche: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Celgene Corporation: Consultancy, Honoraria. Pinto:Takeda: Honoraria, Research Funding; Celgene Corporation: Honoraria; Spectrum: Honoraria. Ludwig:Takeda: Research Funding; Celgene Corporation: Honoraria, Speakers Bureau; Onyx: Honoraria, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau; Janssen Cilag: Honoraria, Speakers Bureau. Bahlis:Celgene Corporation: Honoraria, Research Funding. Cavo:Janssen-Cilag, Celgene, Amgen, BMS: Honoraria. Moreau:Takeda: Other: Adboard; Janssen: Other: Adboard; Novartis: Other: Adboard; Amgen: Other: Adboard; Celgene: Honoraria, Other: Adboard. Qiu:Johnson & Johnson: Speakers Bureau; Celgene Corporation: Speakers Bureau; Roche: Speakers Bureau. Schots:Celgene Corporation: Research Funding. Marek:Celgene Corporation: Employment, Equity Ownership. Chen:Celgene Corporation: Employment, Equity Ownership. Yiu:Celgene Corporation: Employment, Equity Ownership. Ervin-Haynes:Celgene Corporation: Employment. Facon:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Pierre Fabre: Membership on an entity's Board of Directors or advisory committees.

Background Ixazomib is the first orally administered PI studied in the clinic. The feasibility of combining ixazomib weekly and lenalidomide-dexamethasone (Rd) in the first all-oral PI- and immunomodulatory drug-containing triplet regimen was evaluated in a phase 1/2 trial of 65 pts with newly diagnosed MM. Results indicated a 90% ORR (62% ≥VGPR) using ixazomib 4 mg (recommended phase 2/3 dose), with a manageable safety profile, including 14% gr ≥3 skin/subcutaneous tissue disorders and limited (4% gr 3) peripheral neuropathy (PN) (Kumar et al, Lancet Oncol 2014). These data provided the rationale for phase 3 investigation of IRd vs placebo-Rd in pts with RRMM in this randomized, double-blind, placebo-controlled, international, multicenter study. Methods Adults with RRMM after 1-3 prior lines of therapy who were not refractory to prior lenalidomide or PI-based therapy were randomized 1:1 to receive ixazomib 4 mg or matching placebo weekly on d 1, 8, and 15, plus lenalidomide 25 mg PO on d 1-21 (dose reduced for renal impairment per local label/practice) and dexamethasone 40 mg PO on d 1, 8, 15, and 22, in 28-d cycles. Randomization was stratified by number of prior therapies (1 vs 2/3), PI exposure (naïve vs exposed), and ISS disease stage (I/II vs III). Cycles were repeated until disease progression or unacceptable toxicity. Primary endpoint was PFS as assessed by an independent review committee blinded to treatment, per IMWG criteria. Key secondary endpoints were OS and OS in high-risk pts with del(17). Sample size was determined to provide 80% power for the OS endpoint and adequate power to test PFS. Three interim analyses (IAs) and a final analysis were planned to test PFS and OS; here, we report data from the first IA, the final analysis for PFS. Results 722 pts were randomized (360 IRd; 362 Rd). Baseline characteristics were balanced between groups; overall median age was 66 yrs (30-91), 70% were PI-exposed, 88% were ISS stage I/II, 59% had received 1 prior therapy, and 77%/11%/11% were relapsed/refractory/relapsed and refractory, with 6% primary refractory. Based primarily (97%) on central laboratory evaluation, 19% had high-risk cytogenetics by FISH (del(17), t(4;14), or t(14;16)), including 10% del(17). Prior therapies included 69% bortezomib, 45% thalidomide, and 12% lenalidomide. The study met the primary endpoint at the first IA (median follow-up 14.8 vs 14.6 mos with IRd vs Rd), demonstrating a 35% improvement in PFS with IRd vs Rd (HR 0.742; p=0.012; Table). In pts with high-risk cytogenetics, the PFS HR was 0.543 with IRd vs Rd (HR 0.596 in pts with del(17)), with a median PFS similar to the overall IRd group, indicating ixazomib may overcome the negative impact of cytogenetic alterations. OS data were not yet mature. Key response data are shown in the Table. Pts received a median of 13 (1-26) vs 12 (1-25) cycles of IRd vs Rd; 55% and 52% of pts remained on treatment. With IRd vs Rd, 68% vs 61% of pts had gr ≥3 AEs (driven by thrombocytopenia), 40% vs 44% had serious AEs, 13% vs 11% discontinued all study drugs due to AEs, and 3% vs 5% died on treatment. AEs observed with IRd were consistent with reported safety profiles for the individual agents. Common gr ≥3 AEs were neutropenia (19% vs 16%), anemia (9% vs 13%), thrombocytopenia (13% vs 5%), and pneumonia (6% vs 8%). Gastrointestinal events included 42% vs 36% diarrhea (6% vs 2% gr 3), 26% vs 21% nausea (2% vs 0% gr 3), and 22% vs 11% vomiting (1% vs <1% gr 3). PN rates were 28% vs 21% (2% vs 2% gr 3), 35% vs 21% had rash events (4% vs 1% gr 3), 4% vs 6% had renal failure (2% vs 3% gr ≥3), and 4% vs 3% had heart failure (2% vs 2% gr ≥3). Conclusion At this first prespecified IA, addition of ixazomib to Rd in pts with RRMM increased median PFS to 20.6 from 14.7 mos without a substantial increase in overall toxicity, including cardiac and PN toxicity. Benefit with IRd was also noted in pts with high-risk cytogenetics, including those with del(17), in whom median PFS was similar to all IRd-treated pts indicating that ixazomib may have a favorable impact on the adverse prognosis associated with genetic mutations. If approved, this all-oral combination of IRd may become a new standard of care in this setting. Table. Key efficacy data IRd Rd HR / OR Median PFS, mos 20.6 14.7 HR 0.742; 95% CI: 0.587-0.939; p=0.012 Confirmed ORR, % 78.3 71.5 OR 1.44; p=0.035 CR 11.7 6.6 OR 1.87; p=0.019 ≥VGPR 48.1 39.0 OR 1.45; p=0.014 Median time to first response (ITT analysis), mos 1.1 1.9 Median duration of response (≥PR), mos 20.5 15.0 Disclosures Moreau: Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Investigational proteasome inhibitor ixazomib in combination with lenalidomide and dexamethasone for patients with relapsed/refractory multiple myeloma. Masszi:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Bahlis:Johnson & Johnson: Speakers Bureau; Johnson & Johnson: Consultancy; Amgen: Consultancy; Johnson & Johnson: Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Sandhu:Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Ganly:Novartis: Honoraria; Roche: Honoraria; Medipics: Equity Ownership. Baker:Janssen-Cilag New Zealand: Membership on an entity's Board of Directors or advisory committees. Stoppa:Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Simpson:Celgene: Honoraria; Janssen-Cilag: Honoraria; Onyx Pharmaceuticals: Research Funding; Roche: Honoraria. Gimsing:Amgen: Honoraria. Palumbo:Celgene, Millennium Pharmaceuticals, Amgen, Bristol-Myers Squibb, Genmab, Janssen-Cilag, Onyx Pharmaceuticals: Consultancy, Honoraria; Novartis, Sanofi Aventis: Honoraria. Garderet:Bristol-Myers Squibb: Consultancy. Cavo:Janssen-Cilag, Celgene, Amgen, BMS: Honoraria. Kumar:AbbVie: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Onyx: Research Funding; Celgene, Millenium, Sanofi, Skyline, BMS, Onyx, Noxxon,: Other: Consultant, no compensation,; Skyline, Noxxon: Honoraria; Millenium/Takeda: Research Funding. Touzeau:AbbVie: Research Funding. Laubach:Novartis: Research Funding; Onyx: Research Funding; Celgene: Research Funding; Millennium: Research Funding. Lin:Millennium Pharmaceuticals, Inc.: Employment. Berg:Millennium Pharmaceuticals, Inc.: Employment. DiBacco:Millennium Pharmaceuticals, Inc.: Employment. Hui:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Richardson:Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Millennium Takeda: 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.