Oriol, Albert

8503 Background: Outcomes are poor in triple-class exposed RRMM patients (pts) who progress on immunomodulatory agents (IMiDs), proteasome inhibitors (PIs), and CD38 antibodies (mAbs). Ide-cel, a BCMA targeted CAR T cell therapy, showed promising tolerability and efficacy in RRMM pts in the phase I CRB-401 study ( NEJM2019;380:1726). We present primary efficacy and safety data from the pivotal phase II KarMMa trial of ide-cel in RRMM (NCT03361748). Methods: Enrolled pts had ≥3 prior regimens (including IMiD, PI, and CD38 mAb) and were refractory to their last regimen per IMWG criteria. After lymphodepletion (cyclophosphamide 300 mg/m2+ fludarabine 30 mg/m2 x 3), pts received 150─450 × 106 CAR+ T cells (target dose range). Endpoints included overall response rate (ORR; primary), complete response (CR) rate, duration of response (DoR), and PFS. Results: Of 140 pts enrolled, 128 received ide-cel. Median age was 61 y; median no. of prior regimens was 6; 84% were triple- and 26% were penta-refractory. Most pts (88%) had bridging therapy. At data cutoff (16 Oct 2019), median follow up was 11.3 mo. ORR was 73% and median PFS was 8.6 mo; both increased with higher dose (Table). All subgroups had an ORR ≥50%, including older and high-risk pts. Most common any-grade (Gr) toxicities were cytopenias (97%) and cytokine release syndrome (CRS; 84%). CRS was mainly Gr 1/2; 5 pts (5%) had Gr 3, 1 had Gr 4, and 1 had Gr 5 (at 300 × 106). Neurotoxicity developed in 23 pts (18%); 4 (3%) Gr 3 and 0 Gr ≥4. Median peak CAR+ T cell expansion occurred at 11 d. Expansion was higher in responders and parameters (AUC0−28d, Cmax) increased with higher dose, with exposure overlap across doses. Persistence was durable, with CAR+ T cells detected in 29/49 (59%) and 4/11 pts (36%) at 6 and 12 mo. Conclusions: Ide-cel demonstrated deep, durable responses in heavily pretreated RRMM pts. Efficacy and safety reflected prior reports and support a favorable ide-cel clinical benefit-risk profile across the target dose range. Clinical trial information: NCT03361748 . [Table: see text]

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 Introduction: Single-agent carfilzomib has shown encouraging activity in patients with relapsed and refractory multiple myeloma who harbor high-risk cytogenetic abnormalities (Jakubowiak et al, Leukemia 2013;27:2351-56). The phase 3 study ASPIRE (NCT01080391; N=792 patients) demonstrated that progression-free survival (PFS) was significantly improved with carfilzomib, lenalidomide, and dexamethasone (KRd), compared with lenalidomide and dexamethasone (Rd) in patients with relapsed multiple myeloma (RMM) (Stewart et al, N Engl J Med 2015;372:142-52). We present a pre-planned subgroup analysis of the efficacy and safety of KRd vs Rd in the ASPIRE study according to baseline cytogenetic risk status. Methods: Adults with RMM (1-3 prior lines of therapy) were eligible. Patients were randomized (1:1) to KRd or Rd. Treatment was administered in 28-day cycles. Patients in the KRd arm received carfilzomib as a 10-minute intravenous infusion on days 1, 2, 8, 9, 15, and 16 (starting dose, 20 mg/m2 on days 1 and 2 of cycle 1; target dose, 27 mg/m2 thereafter) during cycles 1-12; carfilzomib was omitted on days 8 and 9 during cycles 13-18 and was discontinued after 18 cycles. All patients received lenalidomide 25 mg on days 1-21 and dexamethasone 40 mg on days 1, 8, 15, and 22. The primary end point was PFS. Secondary end points included overall survival, overall response rate (ORR), duration of response (DOR), health-related quality of life, and safety. Cytogenetic risk status was assessed using fluorescence in situ hybridization. The high-risk group consisted of patients with the genetic subtype t(4;14) or t(14;16) or with deletion 17p in ≥60% of plasma cells, according to central review of bone marrow samples obtained at study entry. The standard-risk group consisted of all other patients with known baseline cytogenetics. The cutoff value of 60% for the proportion of plasma cells with deletion 17p was used on the basis of recommendations from the International Myeloma Workshop Consensus Panel 2 (Munshi et al. Blood 2011;117:4696-700). Results: A total of 792 patients were randomized to KRd (n=396) or Rd (n=396). In patients with known baseline cytogenetics, baseline cytogenetic risk status was similar between the treatment arms (high-risk: KRd, 24.6%; Rd, 23.4%; standard-risk: KRd, 75.4%; Rd, 76.6%). Efficacy outcomes by cytogenetic risk status are presented in the Table. Median PFS in the high-risk group (n=100) was 23.1 months (95% confidence interval [CI]: 12.5-24.2) for KRd vs 13.9 months (95% CI: 9.5-16.7) for Rd (hazard ratio [HR]: 0.639; 95% CI: 0.369-1.106). Median PFS in the standard-risk group (n=317) was 29.6 months (95% CI: 24.1-not estimable) for KRd vs 19.5 months (95% CI: 14.8-26.0) for Rd (HR: 0.657; 95% CI: 0.480-0.901). ORRs were 79.2% (KRd) vs 59.6% (Rd) in the high-risk group, and 91.2% (KRd) vs 73.5% (Rd) in the standard-risk group. In the high-risk group, 29.2% (KRd) and 5.8% (Rd) of patients achieved a complete response (CR) or better, including 16.7% (KRd) and 3.8% (Rd) with a stringent complete response (sCR). In the standard-risk group, 38.1% (KRd) and 6.5% (Rd) of patients achieved ≥CR, including 15.0% (KRd) and 3.5% (Rd) with an sCR. Median DOR in the high-risk group was 22.2 months for KRd vs 14.9 months for Rd. Median DOR in the standard-risk group was 30.4 months for KRd vs 20.4 months for Rd. The rate of grade ≥3 adverse events was 89.1% (KRd) vs 78.4% (Rd) in the high-risk group, and 85.6% (KRd) vs 84.5% (Rd) in the standard-risk group. Rates of grade ≥3 adverse events of interest (dyspnea, hypertension, acute renal failure, cardiac failure, ischemic heart disease, and peripheral neuropathy) by cytogenetic risk status are presented in the Table. Conclusion: In patients with high-risk cytogenetics, treatment with KRd resulted in a median PFS of nearly 2 years, which was a 9-month improvement relative to that in patients treated with Rd. Treatment with KRd also led to a 10-month improvement in median PFS vs Rd in patients with standard-risk cytogenetics; similar reductions in the risk of progression or death with Kd vs Vd were observed in both cytogenetics risk groups. Treatment with KRd also led to higher response rates, greater response depth, and a longer DOR compared with Rd in patients with high- or standard-risk cytogenetics. KRd had a favorable benefit-risk profile in patients with RMM, irrespective of baseline cytogenetic risk status, and improved outcomes in patients with high-risk disease. Disclosures Fonseca: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Applied Biosciences: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Onyx/Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Binding Site: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Siegel:Celgene Corporation: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Novartis: Speakers Bureau; Merck: Speakers Bureau. Dimopoulos:Celgene: Honoraria; Onyx: Honoraria; Genesis: Honoraria; Janssen-Cilag: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Amgen: Honoraria. Spicka:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Masszi:Novartis: Consultancy; Janssen-Cilag: Consultancy; BMS: Consultancy; Takeda: Consultancy. Hájek:Janssen-Cilag: Honoraria; Celgene, Merck Sharp & Dohme: Consultancy, Honoraria. Rosiñol:Celgene: Honoraria; Janssen: Honoraria. Mateos:Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy; Onyx: Consultancy. Wang:Celgene: Research Funding. Niesvizky:Celgene: Consultancy, Speakers Bureau. Oriol:Celgene: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Jakubowiak:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SkylineDx: Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: 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, Other: institutional funding for support of clinical trial conduct, Speakers Bureau; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SkylineDx: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Palumbo:Celgene, Millennium Pharmaceuticals, Amgen, Bristol-Myers Squibb, Genmab, Janssen-Cilag, Onyx Pharmaceuticals: Consultancy, Honoraria; Novartis, Sanofi Aventis: Honoraria. Bensinger:Onyx: Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Acetylon: Research Funding; BMS: 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, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Research Funding. Kukreti:Lundbeck: Honoraria; Ortho: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Tonda:Onyx: Employment. Obreja:Amgen Inc: Employment. Moreau:Bristol-Myers Squibb: 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; Millennium: 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; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract Background: Treatment of multiple myeloma has evolved considerably in the past few years with availability of several news drugs as well as increasing use of multidrug combinations. These changes have no doubt led to the improved survival seen among patients with MM. We have previously shown that outcomes of patients intolerant or refractory to one of the IMiDs and bortezomib had a poor outcome. Since that time, other drugs of the same class as well as new classes of drugs have been introduced for the treatment of MM. We designed this retrospective study to estimate the outcomes in patients with relapsed myeloma, who have become refractory to the current generation IMiDs and proteasome inhibitors. Patients and Methods: Patients with relapsed multiple myeloma who have received at least 3 prior lines of therapy, is refractory to both an IMiD (lenalidomide or pomalidomide) AND a proteasome inhibitor (bortezomib or carfilzomib), and has been exposed to an alkylating agent were identified from multiple centers. The time patients met the above criteria was defined as T0, and details of all treatment regimens before and after T0 were collected using electronic CRFs. The study was approved by the IRB at the respective centers. Results: 543 patients were enrolled in this study; median age was 62 years (31-87) and 61% were males. Patients were enrolled from centers in North America (n=181), Europe (n=318), and Asia Pacific (n=44). Patients were diagnosed between 2006 and 2014, the median duration between diagnosis of myeloma and study entry (T0) was 3.1 years (0.3 to 9). The median (95% CI) estimated follow up from diagnosis and from T0 were 61 (57, 66) months and 13 (11, 15) months respectively. The median number of lines of therapy prior to T0 was 4 (3-13), 48% had a prior transplant. The median OS from T0 for the entire cohort was 13 (11, 15) months. For these 462 patients, the median number of recorded regimens was 2 (1-9). The overall response and the depth of response to each line of treatment following T0 are as shown in the table. The median (95% CI) PFS and OS from T0 was 5 (4, 6), and 15.2 (13, 17), respectively. The overall survival for the 81 patients with no treatment post T0 was only 2.1 months. In a multivariate analysis, duration from diagnosis to T0, ISS stage III and number of lines of therapy were all associated with inferior PFS, as well as OS, and in addition, serum creatinine>2 mg/dL at T0 also predicted inferior OS. Conclusions: The study provides the expected outcome following development of myeloma that is refractory to a PI and an IMiD. The outcomes of these patients appear to be better than we had seen historically in patients refractory/ intolerant to bortezomib and IMiDs, highlighting the increased treatment options available for these patients. However, there is decreasing response rate to sequential regimens highlighting the development of drug resistance. The data provides a bench mark for comparison of new therapies that are being evaluated in this disease. Table Table. Disclosures Dimopoulos: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: 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; Genesis: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Kastritis:Takeda: Consultancy, Honoraria; Genesis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Terpos:BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Celgene: Honoraria; Takeda: Consultancy, Honoraria; Genesis: Consultancy, Honoraria, Other: Travel expenses; Amgen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Novartis: Honoraria. Hillengass:Sanofi: Research Funding; Novartis: Research Funding; Amgen: Consultancy, Honoraria; BMS: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria. Leleu:TEVA: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; LeoPharma: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Pierre Fabre: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Takeda: Honoraria. Oriol:Janssen: Honoraria, Other: Expert board committee; Amgen: Honoraria, Other: Expert board committee. Cavo:Celgene: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Mateos: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, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Vij:Shire: Consultancy; Takeda: Consultancy, Research Funding; Jazz: Consultancy; Karyopharma: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Bristol-Myers Squibb: Consultancy; Amgen: Consultancy, Research Funding. Lokhorst:Genmab: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. van de Donk:Amgen: Research Funding; Janssen: Research Funding; BMS: Research Funding; Celgene: Research Funding. Mark:Onyx: Research Funding, Speakers Bureau; Millenium: 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, Research Funding, Speakers Bureau. Ludwig:Amgen: Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau; BMS: Speakers Bureau; Janssen: Speakers Bureau. Jagannath:Novartis: Consultancy; Janssen: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy; Merck: Consultancy. Usmani:Array: Research Funding; Britsol-Myers Squibb: Consultancy, Research Funding; Skyline: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BioPharma: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau. Dytfeld:Janssen Poland: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Amgen: Consultancy, 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. Moreau:Novartis: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Janssen: Honoraria, Speakers Bureau. Lee:Amgen: Membership on an entity's Board of Directors or advisory committees. Shustik:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. de la Rubia:Celgene: Consultancy; Bristol Myers: Consultancy; Amgen,: Consultancy; Janssen: Consultancy. Durie:Takeda: Consultancy; Amgen: Consultancy; Janssen: Consultancy.

Abstract Background: Lenalidomide with dexamethasone (Rd) is a standard of care used for pts with relapsed multiple myeloma (RMM). The randomized, open-label, multicenter, phase 3 study ASPIRE (NCT01080391) is comparing carfilzomib, lenalidomide, and dexamethasone (KRd) to Rd in pts with RMM. The primary end point is progression-free survival (PFS; assessed by an independent review committee). Secondary end points include overall survival (OS), overall response rate (ORR), duration of response (DOR), health-related quality of life (EORTC QLQ-C30 Global Health Status/QoL), and safety. Methods: Adults with RMM who received 1–3 prior regimens were eligible. Pts were randomized (1:1) to receive KRd or Rd and were stratified by β2-microglobulin levels (<2.5 vs ≥2.5 mg/L), prior bortezomib (no vs yes), and prior R (no vs yes). All pts received lenalidomide (25 mg) on days 1–21 and dexamethasone (40 mg) on days 1, 8, 15, and 22 of a 28-day cycle. In addition, KRd pts received K as a 10-min infusion on days 1, 2, 8, 9, 15, and 16 during cycles 1–12 (20 mg/m2 [days 1 and 2 of cycle 1]; 27 mg/m2 thereafter); K was omitted on days 8 and 9 during cycles 13–18 and was not administered beyond 18 cycles. Cycles were repeated until disease progression, unacceptable toxicity, or withdrawal of consent. The study had 90% power to detect a 25% reduction in risk for PFS events for KRd vs Rd (hazard ratio [HR]=0.75) at a 1-sided significance level of 0.025. A stratified log-rank test was used for the PFS comparison. Results: Data are presented for KRd followed by Rd throughout the abstract. Between July 2010 and March 2012, 792 pts from 20 countries were randomized. Baseline characteristics were balanced between the 2 groups. Median age was 64.0 years (range: 31.0‒91.0). Pts received a median of 2 prior regimens in each group. In both the KRd and Rd groups, 66% of pts received prior bortezomib; 20% of pts in each arm received prior R. Median treatment exposure was 22 cycles (KRd) and 14 cycles (Rd). At the time of the prespecified interim analysis, the study met the primary end point for PFS (HR=0.69; 95% confidence interval [CI]: 0.57–0.83; P<.0001), with a longer duration of median PFS in the KRd group (26.3 months [mo]; 95% CI: 23.3–30.5) compared with the Rd group (17.6 mo; 95% CI: 15.0–20.6). Median OS was not reached in either group; however, there was a trend toward longer OS with KRd compared with Rd (HR=0.79; 95% CI: 0.63–0.99; P=.018), which did not meet the prespecified statistical boundary at the interim analysis of survival (P=.005). The Kaplan-Meier OS event-free rates at 24 mo were 73.3% (95% CI: 68.6‒77.5) and 65.0% (95% CI: 59.9‒69.5). The ORR was 87.4% (95% CI: 83.7–90.5) with KRd and 66.9% (95% CI: 62.0–71.5) with Rd. Median DOR was 28.6 mo (95% CI: 24.9–31.3) and 21.2 mo (95% CI: 16.7–25.8). In the KRd and Rd groups, 31.8% vs 9.4% achieved a stringent complete response (sCR) or complete response (CR) (sCR: 14.1% vs 4.3%; CR: 17.7% vs 5.1%), and 70.4% and 40.7% achieved ≥very good partial response. KRd consistently improved Global Health Status/QoL compared with Rd over 18 cycles of treatment (P=.0001). Treatment discontinuation due to an adverse event (AE) occurred in 15.2% (KRd) and 17.4% (Rd) of pts. In each group, 7.7% and 8.5% of pts died while still on study treatment or within 30 days of receiving the last dose of study treatment. The most common hematologic treatment-emergent AEs (TEAEs) (≥grade 3) included neutropenia (29.6% vs 26.5%), anemia (17.9% vs 17.2%), and thrombocytopenia (16.6% vs 12.3%). The most common nonhematologic TEAEs (all grade) included diarrhea (42.3% vs 33.7%), fatigue (32.9% vs 30.6%), and cough (28.8% vs 17.2%). The most common nonhematologic TEAEs (≥grade 3) included pneumonia (12.5% vs 10.5%), hypokalemia (9.4% vs 4.9%), and hypophosphatemia (8.4% vs 4.6%). Other TEAEs of interest (grouped terms; all grade) included dyspnea (22.4% vs 18.0%), hypertension (preferred term; all grade: 14.3% vs 6.9%; grade 3: 4.3% vs 1.8%), acute renal failure (8.4% vs 7.2%), cardiac failure (6.4% vs 4.1%), and ischemic heart disease (5.9% vs 4.6%). Rates of peripheral neuropathy (PN) (grouped terms; all grade) were 17.1% and 17.0%; ≥grade 3 PN was infrequent (2.6% and 3.1%). Conclusion: The addition of carfilzomib to lenalidomide and dexamethasone in pts with RMM resulted in a statistically significant and clinically meaningful improvement in PFS. KRd had an acceptable safety and tolerability profile and represents a potential new standard of care. Disclosures Stewart: Novartis: Consultancy; Array BioPharma: Consultancy; BMS: Consultancy; Millenium: Research Funding; Celgene: Consultancy. Off Label Use: Carfilzomib is approved in the United States for the treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy. ASPIRE is a randomized, multi-center, phase 3 study investigating the use of carfilzomib in combination with lenalidomide and dexamethasone for the treatment of patients with relapsed multiple myeloma who have received 1–3 prior regimens.. Dimopoulos:Celgene: Consultancy, Honoraria; Onyx: Consultancy, Honoraria. Masszi:Janssen Cilag: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Spicka:Janssen-Cilag: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Oriol:Celgene: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau. Hájek:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rosiñol:Celgene: Honoraria; Janssen: Honoraria. Siegel:Onyx: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Millennium: Honoraria, Speakers Bureau. Niesvizky:Onyx Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Millennium: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau. Jakubowiak:Onyx Pharmaceticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. San Miguel:Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Millinnium: Membership on an entity's Board of Directors or advisory committees. Ludwig:Celgene: Research Funding, Speakers Bureau; Takeda Celgene: Research Funding, Speakers Bureau; Bristol-Myers: Research Funding, Speakers Bureau. Zojwalla:Onyx Pharmaceticals, an Amgen subsidiary: Employment, Equity Ownership. Tonda:Onyx Pharmaceticals, an Amgen subsidiary: Employment, Equity Ownership. Xing:Onyx Pharmaceticals, an Amgen subsidiary: Employment, Equity Ownership. Moreau:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; 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; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees. Palumbo:Onyx Pharmaceuticals: Consultancy, Honoraria; Millennium Pharmaceuticals: Consultancy, Honoraria; Janseen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Genmab A/S: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen, Inc,: Consultancy, Honoraria; Array BioPharma: Honoraria.

Abstract Next-generation sequencing (NGS) has revealed new insight into the complexity of clonal and subclonal architecture of multiple myeloma (MM). The introduction of targeted studies allows the detection of mutations with very low allele frequencies at affordable price. However, there is few information about the prognostic impact of this mutational profile in series of homogeneously treated MM patients. In this study, we analyzed the most frequently mutated genes in MM from patients included in a randomized clinical trial applying the highest read depth to date. We performed a correlation study between our results and cytogenetics aberrations and clinical outcomes. We used Ampliseq Library Kit 2.0 to target 77 genes (M3Pv2.0 panel) related to critical pathophysiological pathways, associated to drug resistance or targetable with molecular drugs in MM. We sequenced DNA (15ng) from CD138+ purified plasma cells from 80 MM patients at diagnosis included in GEM2010MAS65 clinical trial. We sequenced at an average read depth of 1500X and using Ion Proton sequencer (Thermo Fisher, USA, PaloAlto, CA). We used Ion Reporter software applying in-house modifications in call variants process. We also sequenced DNA from CD138 negative population in 30% of patients in order to filter out potential artifacts and stablish conditions for excluding germline variants. We first fitted a cox-proportional hazard model to predict survival and a second approach using a penalized regression LASSO. We identified 137 gene mutations in the 80 patients analyzed, 54 mutations were predicted pathogenic by Shif and Poliphen and 65 have been described in COSMIC database. 85% of patients harbored at least 1 mutation. The most frequently mutated genes were KRAS (16%), DIS3 (15%), NRAS (13%), BRAF (6%), and TP53 (5%), accounting for the 54% of the total number of mutations. The most frequently mutated pathways were RAS and NFKB in 34% and 28% of patients respectively. Mutational allele frequency for KRAS, BRAF and TP53 was, in all cases, lower than 50% while DIS3 showed mutations in a broad range (from 2 to 85%). Only one patient presented one mutation in NRAS at 73 % of allele frequency. For patients with more than one mutation, two different scenarios have been found. Some patients showed several genes mutated in a similar allele frequency values. On the contrary, a complex subclonal structure was confirmed in 3 patients, with mutations at very different clonal frequency. CD138 negative fraction was sequenced to confirm that these mutations were exclusive of plasma cells. The first of them had two mutations in DIS3 at 8 and 53% of allele frequency, second in KRAS and DIS3 at 13 and 63% respectively and the third in NRAS and IFNGR2 at 5 and 37% respectively. We found no differences in the survival based on pathway, mutational allele frequency or number of mutations. We also investigated pairwise associations between events and we not found significant correlations (Figure 1). Cox-proportional hazard model only showed a negative impact in survival of patients with TP53 mutations. This ultra-deep targeted sequencing strategy is able to detect mutations in most of patients, at very low allele frequency and using a minimal amount of DNA. Despite of its huge capacity to detect mutations, we have not identified new prognostic factors in MM patients treated with highly efficient therapies. However, this study again confirms the complexity of the genomic landscape of MM and the great heterogeneity between patients. The role of theses mutations at relapse as well as in the subsequent treatment effectiveness remains unknown and should be preferably investigated in larger cohorts of homogeneously treated MM patients. Figure 1 Figure 1. Disclosures Martínez-López: Novartis: Honoraria, Speakers Bureau. Oriol:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Stewart:celgene: Consultancy.

Abstract Background: In the pivotal FIRST trial, at the pre-specified planned analysis for progression-free survival (PFS), treatment (Tx) with lenalidomide plus low-dose dexamethasone until disease progression (Rd continuous) improved outcomes for transplant-ineligible patients (pts) with newly diagnosed multiple myeloma (NDMM) compared with melphalan, prednisone, and thalidomide (MPT), as well as Rd for 18 cycles (Rd18; Benboubker, NEJM 2014). Rd18 was added as a third arm to investigate whether Rd continuous Tx would control progression of NDMM longer than Rd18. Here, we present the final analysis of the overall survival (OS) data from the trial. Methods: Transplant-ineligible pts with NDMM were randomized 1:1:1 to Rd continuous (with lenalidomide given on days 1-21 of 28-day cycles until disease progression), Rd18 (with lenalidomide given on days 1-21 of eighteen 28-day cycles), or MPT (twelve 42-day cycles); both Rd18 and MPT were 72 weeks in duration. The primary endpoint was PFS and the key secondary endpoint was OS; the primary comparison was Rd continuous vs MPT. Other secondary endpoints included time to second therapy (TTST) and safety. Time from randomization to second progression or death (PFS2) was an exploratory analysis. Response assessment used for PFS and PFS2 analysis was determined by investigators based on International Myeloma Working Group criteria. Results: At the time of cutoff for the final OS analysis (January 21, 2016), 52 of the 535 pts in the Rd continuous arm and none of the pts in the Rd18 (n = 541) and MPT (n = 547) arms continued to receive Tx. The median follow-up for surviving pts was 67.0 months (range, 0-86.8 months). In the pre-specified final OS analysis for the primary comparison, a statistically significant advantage in OS was shown with Rd continuous over MPT (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.67-0.92; P = .00234; Table). OS for Rd continuous vs Rd18 was evaluated (HR, 1.02; 95% CI, 0.86-1.20). In this updated analysis, a PFS advantage continued to be seen for Rd continuous vs MPT (HR, 0.69; 95% CI, 0.59-0.79; P < .00001) and vs Rd18 (HR, 0.70; 95% CI, 0.60-0.81). Median TTST was longer for Rd continuous vs MPT (HR, 0.63; 95% CI, 0.54-0.73; Table). More pts in the Rd18 and MPT arms started second-line therapy (n = 377 and 381, respectively) compared with the Rd continuous arm (n = 299). Pts received a variety of Tx at progression, with bortezomib-based regimens the most common in the Rd continuous (n = 179; 59.9%), Rd18 (n = 208; 55.2%), and MPT (n = 170; 44.6%) arms. Pts who received bortezomib after Rd continuous or Rd18 had better outcomes than those who received it after MPT. PFS2 for Rd continuous was improved vs MPT (HR, 0.74; 95% CI, 0.64-0.85). Grade 3/4 adverse events (AEs) occurred in 86.3%, 80.2%, and 88.7% of the 532, 540, and 541 pts in the safety populations of the Rd continuous, Rd18, and MPT arms, respectively; the most common grade 3/4 AEs were neutropenia (29.5%, 26.5%, and 44.9%) and infections (31.6%, 21.9%, and 17.2%), and no new safety signals were seen compared with earlier analyses. Study discontinuation was most commonly due to disease progression and was less common in the Rd continuous vs Rd18 and MPT arms (50.7% vs 66.9% and 61.6%, respectively). Discontinuation due to AEs was similar across the Rd continuous, Rd18, and MPT arms (12.0%, 13.1%, and 13.9%). Solid tumor second primary malignancies (SPMs) occurred in 6.0, 6.9%, and 5.9% of pts, and hematologic malignancies occurred in 0.8%, 0.4%, and 2.6% of pts in the Rd continuous, Rd18, and MPT arms, respectively. Conclusions: Rd continuous significantly prolonged PFS and OS, and improved other secondary endpoints compared with MPT in transplant-ineligible pts with NDMM. Rd continuous also showed a PFS benefit compared with Rd18, delaying the time to next Tx. PFS2 outcomes suggest that Rd does not induce resistant relapses. Few hematologic malignancies occurred in the Rd arms, and the incidence of SPMs was similar between Rd continuous and Rd18. Rd continuous remains a standard of care for transplant-ineligible pts with NDMM. Disclosures Facon: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: travel and expense, Speakers Bureau. Dimopoulos:Genesis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Dispenzieri:Celgene: Research Funding. Belch:Takeda: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Celgene: Honoraria. Cavo:Bristol-Myers Squibb: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Millennium: Consultancy, Honoraria. Weisel:BMS: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Onyx: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Ludwig:Janssen: Speakers Bureau; BMS: Speakers Bureau; Takeda: Research Funding, Speakers Bureau; Amgen: Research Funding, Speakers Bureau. Bahlis:BMS: Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; Onyx: Consultancy, Honoraria. Delforge:Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Cavenagh:Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Geraldes:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Oriol:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. De La Rubia:Amgen, Bristol, Celgene, Janssen: Consultancy, Speakers Bureau. White:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Moreau:Celgene: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Janssen: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Honoraria. Attal:janssen: Consultancy, Research Funding; amgen: Consultancy, Research Funding; celgene: Consultancy, Research Funding; sanofi: Consultancy. Ervin-Haynes:Celgene: Employment, Equity Ownership. Chen:Celgene: Employment, Equity Ownership. Houck:Celgene: Employment. Hulin:celgene: Honoraria; Bristol: Honoraria; Janssen: Honoraria; Amgen: Honoraria; takeda: Honoraria. Benboubker:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; 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.

Abstract Abstract LBA-6 Background: Multiple myeloma (MM) patients who have become refractory to bortezomib (BORT) and refractory or otherwise ineligible for thalidomide or lenalidomide (LEN) have a poor prognosis, with a median overall survival (OS) of 9 months (Kumar. Leukemia. 2012). There is no standard treatment available for these patients. Pomalidomide (POM) is a novel immunomodulatory drug that has shown activity in LEN- and BORT-refractory patients (Vij. ASCO 2012). MM-003 is an open-label, multicenter, phase 3 trial designed to compare the efficacy and safety of POM + low-dose dexamethasone (LoDEX) vs high-dose dexamethasone (HiDEX) in a population of patients who are refractory to both LEN and BORT. Here we present the final progression-free survival (PFS) and interim OS analysis of MM-003. Methods: Eligible patients with primary refractory or relapsed and refractory disease were enrolled. All patients with documented disease progression during treatment or within 60 days of completing their last myeloma therapy (including ≥ 2 consecutive cycles of LEN and BORT either alone or in combination), were randomized 2:1 to receive either POM + LoDEX (arm A) or HiDEX alone (arm B). Patients progressing on HiDEX had the opportunity to receive POM in the companion trial, MM-003C. Patients in arm A received POM 4 mg on days 1–21 and DEX 40 mg (20 mg for patients > 75 years of age) on days 1, 8, 15, and 22 in a 28-day cycle. Patients in arm B received DEX 40 mg (20 mg for patients > 75 years of age) on days 1–4, 9–12, and 17–20 in a 28-day cycle. Treatment was continued until progressive disease or unacceptable toxicity. Patients were stratified by age (≤ 75 vs > 75 years), disease population (refractory vs refractory and relapsed vs refractory and intolerant [intolerant to BORT only]), and number of prior therapies (2 vs > 2). The primary endpoint was PFS; secondary endpoints included safety, OS, overall response rate (ORR; ≥ partial response) by IMWG and EBMT criteria, duration of response, time to progression, and quality of life. OS was to be tested only if PFS would be statistically significant; therefore, alpha was controlled at 0.05 2-sided for both PFS and OS. Results: The Data and Safety Monitoring Board (DSMB) reviewed the protocol-specified final analysis results. 455 patients were randomized from March 2011 to Sept 2012. 302 patients received POM + LoDEX, and 153 patients received HiDEX. At the time of analysis, 45% of patients in arm A and 25% of patients in arm B remained on study. The median number of prior therapies was 5 (range, 1–17). 72% of patients were refractory to both LEN and BORT. At the PFS final analysis, with a median follow-up of 18 weeks, PFS was significantly longer with POM + LoDEX vs HiDEX alone (median 15.7 vs 8.0 weeks; 267 total events; hazard ratio [HR], 0.45; P <.001). OS interim analysis was performed as planned; OS also was significantly longer with POM + LoDEX vs HiDEX alone (median not reached vs 34 weeks; 134 events; HR, 0.53; P<.001), crossing the prespecified O’brien-Fleming superiority boundary. This includes 45 pts who received POM after progressing on HiDEX. Median duration of treatment was 12.4 weeks in arm A and 8 weeks in arm B. Following DSMB review of the data, immediate crossover of arm B patients to arm A was recommended. Overall, 25% of patients in arm A and 38% in arm B died, with progressive disease and infections as the primary reasons. Frequent grade 3/4 hematologic toxicities included neutropenia (42% in arm A vs 15% in arm B), thrombocytopenia (21% vs 24%), and febrile neutropenia (7% vs 0%). Other toxicities (grade 3/4) were predominantly infections (24% vs 23%), hemorrhage (3% vs 5%), glucose intolerance (3% vs 7%), neuropathy (1% vs 1%), and venous thromboembolism (1% vs 0%). The primary reason for discontinuation was progressive disease: 35% arm A and 49% arm B. Complete results will be presented at the meeting. Conclusions: POM + LoDEX significantly increased PFS and OS compared with HiDEX in patients who are refractory to LEN and BORT, a population with limited treatment options. The OS superiority boundary was crossed. Based on these data, POM + LoDEX should become the new standard of care in patients who have exhausted the novel agents, LEN and BORT. Disclosures: Dimopoulos: Celgene: Honoraria. Off Label Use: Pomalidomide is an investigational drug and is not approved for the treatment of patients with any condition. Lacy:Celgene: Research Funding. Moreau:Celgene: Honoraria, Speakers Bureau. Weisel:Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Song:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Delforge:Celgene: Consultancy, Honoraria, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria; OrthoBiotech: Consultancy, Honoraria, Speakers Bureau. Karlin:Celgene: Consultancy. Goldschmidt:Novartis: Honoraria, Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau. Yu:Celgene: Employment. Sternas:Celgene: Employment, Equity Ownership. Jacques:Celgene: Employment, Equity Ownership. Zaki:Celgene: Employment, Equity Ownership. San Miguel:Onyx: Membership on an entity’s Board of Directors or advisory committees; Janssen: Membership on an entity’s Board of Directors or advisory committees; Millennium: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees; Novartis: Membership on an entity’s Board of Directors or advisory committees.