Moreau, Philippe

Abstract Background: The initial therapies for multiple myeloma have changed significantly in the recent years with routine incorporation of combinations containing IMiDs and proteasome inhibitors. However, patients with MM invariably relapse after their initial treatment and undergo successive therapies for continued control of their disease. The increasing access to new therapies for treatment of relapsed disease has led to improved survival of patients with MM. Many recent phase 3 trials have studied the impact of new agents on outcome of patients with MM who are relapsing after the initial lines of therapy for relapsed disease. However, the natural history of relapsed myeloma earlier in the course of relapsed disease has not been studied in detail. Patients and methods: We designed a global, multicenter, retrospective study to examine the current treatment approaches for initial relapses in MM and patient outcomes following application of successive treatment regimens. Patients with multiple myeloma who experience a first relapse between January 1, 2007 and December 31, 2011 were identified at participating sites. Clinical and laboratory data pertaining to the time of diagnosis and from the time of individual relapses up to and including the third relapse will be obtained from the clinical records. The first date of treatment with an anti-myeloma regimen for first disease relapse was termed time zero (T0). Results: Three hundred and fifteen patients were enrolled; median age at diagnosis was 59 years (range: 35 - 86), 59% were male. Patients were enrolled from North America (33%), Europe (35%) or Asia (32%). The patients were diagnosed between 1997 and 2011 and the median time to T0 from diagnosis was 23.9 months (range: 0.8 - 131.9 months). An IMiD (thalidomide or lenalidomide), bortezomib or alkylator (melphalan or cyclophosphamide) was part of the initial therapy in 63%, 36% and 51% of patients, respectively; 93 (33%) patients had stem cell transplantation as part of initial treatment. The median follow up from the study entry was 56 months; 117 were alive at the time of data extraction. A second line, third line and fourth line of treatment were recorded in 307, 163 and 84 patients respectively. An IMiD (thalidomide, lenalidomide, or pomalidomide), proteasome inhibitor (bortezomib or carfilzomib) or alkylator (melphalan or cyclophosphamide) was part of the therapy for first relapse in 50%, 59% and 33% of patients, respectively. The responses to the regimens after T0, the TTNT, PFS and OS to each line of therapy are provided in the Table. Conclusion: The current study provides an assessment of the current treatment approaches used for initial treatment of MM and the salvage treatment options utilized. The study again demonstrates the progressively shorter duration of disease control with each successive treatment regimen, reflecting ongoing development of drug resistance. The overall survival of over 3 years from the time of therapy for first relapse highlights the impact of the newer therapies that have been introduced for this disease. Table. Treatment outcomes after initial relapse Endpoint 2nd line therapyN=307 3rd line therapyN=163 4th line therapyN=84 Partial response or better Median in Months (95% Confidence Interval) Overall Survival 36.1 (30.2, 42.4) 18.4 (14.5, 26.8) 12.6 (10.4, 19.0) Progression-Free Survival 13.4 (11.8, 15.8) 8.3 (6.5, 11.2) 6.4 (5.0, 8.1) Time to Next Treatment 15 (12,17) 9.8 (7.4, 12.0) 6.6 (5.8, 8.7) Figure 1. Figure 1. Disclosures Kumar: Onyx: Consultancy, Research Funding; Skyline: Consultancy, Honoraria; BMS: Consultancy; Sanofi: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Novartis: Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Dimopoulos:Novartis: Honoraria; Amgen: Honoraria; Janssen-Cilag: Honoraria; Genesis: Honoraria; Janssen: Honoraria; Onyx: Honoraria; Celgene: Honoraria. Leleu:Janssen: Honoraria; Celgene: Honoraria; Takeda: Honoraria; Amgen: Honoraria; TEVA: Honoraria; Novartis: Honoraria; BMS: Honoraria; Pierre Fabre: Honoraria; LeoPharma: Honoraria; Chugai: Honoraria. Moreau:Celgene, Janssen, Takeda, Novartis, Amgen: Membership on an entity's Board of Directors or advisory committees. Lahuerta:Janssen Cilag, Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Vij:Takeda, Onyx: Research Funding; Celgene, Onyx, Takeda, Novartis, BMS, Sanofi, Janssen, Merck: Consultancy.

Abstract Abstract 3989 Background: Treatment patterns of multiple myeloma (MM) vary across the globe, mostly dictated by the availability and patient access to different drug therapies. The outcomes of patients with MM, especially relapsed myeloma can be significantly affected by the availability of newer treatments, as well as potential biological differences related to ethnicity. We have previously shown that the outcome of patients relapsing after therapy with bortezomib (Bz) and one or more of the IMiDs remain poor with the currently available treatments and represent a difficult group of patients to treat. We undertook the current analysis on a set of patients from United States, several European countries and South Korea. Methods: We designed a multicenter, retrospective study that enrolled 294 patients with relapsed MM, from 14 sites (122 from Europe, 107 from US, and 65 from Korea). Patients were refractory to Bz, defined as no response to prior Bz-containing regimen or disease progression within 60 days of a Bz-containing regimen. Patients were also relapsed, refractory, intolerant, and/or ineligible, to treatment with an IMiD (thalidomide or lenalidomide). The date patients satisfied the above entry criteria was defined as time zero (T0). Clinical and laboratory data from diagnosis and individual relapses were collected along with details of all MM drug therapies before and after T0. Responses were assessed by IMWG or EBMT criteria. The goal of the study was to compare the characteristics of patients who satisfy the above inclusion criteria, the therapies employed prior to and after T0 and clinical outcome among these patients from different parts of the world. Results: The mean (median, range) time to reaching T0 from diagnosis was 4.5 (4.0, 12.8), 4.2 (3.2, 18.6), and 3.2 (2.8, 9.6) years from diagnosis for patients from US, Europe and Korea, respectively, P=0.021. The mean (median, range) number of therapies for the three groups were 8 (8, 13), 4 (4, 10), 5 (4, 7), respectively; P<0.001. The response rates (>=PR) to the initial therapy at diagnosis were 56%, 77% and 49% respectively for the US, European and Korean cohorts. Overall 220 patients had at least one therapy after T0, and 114 (52%) had a novel agent (Bz, len or thal) containing regimen as their first treatment after T0. Patients in US were more likely to receive additional therapies after the first post-T0 therapy; 62%, 32%, and 12% of patients from US, Europe and Korea, respectively, began a second post-T0 regimen within 2 years following time zero. The median number of therapies post T0 was 2, 1, and 1 for patients in US, Europe and Korea respectively. The response rates to the first regimen after T0 were 15%, 33% and 19% for the US, European and Korean cohorts, and were similar between those receiving a regimen with one of the novel drugs compared to rest. Patients younger than 60 years and those with prior transplants were more likely to respond to post T0 regimens. The median time to progression or death from T0was similar for the three patient cohorts, 5 months (Figure 1A). The median overall survival (95% CI) from T0 was 13 months (10, 16), 7 (5,9) and 8 (4,9) respectively for the US, European and Korean cohorts (Figure 1B). Conventional prognostic factors, especially the ISS stage was predictive of OS post T0. Additionally, presence of extramedullary disease was associated with a shorter overall survival. Conclusion: The results of the current study demonstrate significant differences between different parts of the world in terms of the treatment patterns both in the setting of initial therapy as well as treatment of relapsed disease. Patients in the US were more likely to receive multiple regimens both before and after T0. This is likely a reflection of increasing numbers of new drugs that have gone into clinical trials and thus enhancing options. The study further highlights the poor outcome of patients who have relapsed after the new drugs, irrespective of the geographical location. Disclosures: Kumar: Merck: Consultancy, Honoraria; Genzyme: Consultancy; Celgene: Consultancy. Richardson:Millennium: ; Celgene: ; Johnson & Johnson: ; Novartis: ; Bristol Myers Squibb:. Moreau:Millennium Pharmaceuticals, Inc.: Advisory board, Honoraria; Janssen: Advisory board, Honoraria. Sonneveld:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding. Siegel:Merck: Honoraria; Millenium: Honoraria, Research Funding, Speakers Bureau. San Miguel:Janssen-Cilag: Honoraria; Celgene: Honoraria. Palumbo:celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Durie:Celgene: Membership on an entity's Board of Directors or advisory committees.

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: The anti-apoptotic proteins BCL-2 and MCL-1 promote multiple myeloma (MM) cell survival. Bortezomib (BTZ) can inhibit MCL-1 activity by stabilizing the MCL-1 antagonist, NOXA. Venetoclax is an orally bioavailable, highly selective BCL-2 inhibitor, which enhances BTZ efficacy in MM xenograft models. This Phase 1 study evaluates venetoclax with BTZ and dexamethasone (Dex) in patients (pts) with relapsed/refractory MM. Methods: Objectives include safety, pharmacokinetics, preliminary efficacy and maximum therapeutic dose of venetoclax with BTZ and Dex. A fixed dose of venetoclax ranging from 50 to 800 mg PO daily, according to dose cohort assignment, was given in combination in cycles (C) 1-11 and alone in C12 and beyond. Dose escalation decisions were made using the continual reassessment method. Pts received BTZ (1.3 mg/m2 SC, days [D] 1, 4, 8, 11) and Dex (20 mg PO, D1, 2, 4, 5, 8, 9, 11, 12) in cycles (C)1-8 (21D), then BTZ + Dex (D1, 8, 15, 22) in C9-11 (35D). Results: Forty-one pts were enrolled as of June 15, 2015 (pts in each cohort: 50 mg, n=3; 100 mg, n=5; 200 mg, n=6; 300 mg, n=7; 400 mg, n=6; 500 mg, n=7; 600 mg, n=5; 800 mg, n=2). Median age was 65 (38-79); 15/26 F/M. 14 were ISS stage I, 11 stage II, 11 stage III, 5 missing. Median (range) number of prior lines of therapy was 5 (1-15). Thirty-five pts had received prior BTZ (10 refractory), 34 prior lenalidomide (22 refractory); 29 had undergone stem cell transplantation. Based on FISH analysis, 5 pts had MM with t(11;14); 3 with t(4;14), 20 with del 17p, and 10 with del 13q. Treatment-emergent AEs occurring in ≥20% of pts were constipation (37%), diarrhea (37%), thrombocytopenia (32%), asthenia (29%), insomnia (29%), anemia (27%), peripheral neuropathy (27%), dyspnea (24%), peripheral edema (22%), and nausea (20%). Grade 3/4 AEs in ≥10% of pts were thrombocytopenia (20%), and anemia (17%). SAEs occurred in 18 pts; SAEs in ≥2 pts were cardiac failure, embolism, pyrexia, respiratory failure, sepsis, thrombocytopenia (n=2 each, no SAEs were venetoclax-related). Twenty-nine pts have discontinued treatment: 23 due to PD, 2 due to AEs [adenocarcinoma; cardiac and respiratory decompensation attributed to Dex (DLT at 300 mg)], and 4 withdrew consent. Three deaths occurred (all due to PD). No TLS occurred. In preliminary PK analyses (n=41), dose-normalized venetoclax exposure when given with BTZ+Dex was similar when compared to venetoclax monotherapy in MM as well as CLL and NHL pts. Forty of 41 pts were evaluable for efficacy. All responses occurred in BTZ sensitive or naïve pts. Median (range) duration or response was 5.9 (0-14.1) months in all pts, 8.5 (2.3-11.4) months in BTZ naïve pts, and 4.7 (0-14.1) months in BTZ-sensitive pts. Conclusions: Venetoclax with BTZ and Dex has an acceptable safety profile in heavily pretreated MM pts; no new safety signals were identified compared to other venetoclax studies. These early data suggest the combination of proteasome and BCL-2 inhibition resulted in anti-tumor activity. Responses were observed only in pts naïve or sensitive to prior BTZ (ORR = 100% and 58%, respectively) and occurred in all dose cohorts. The study is currently enrolling pts in the 1000 mg dose escalation cohort. Figure 1. Figure 1. Disclosures Moreau: Celgene, Janssen, Takeda, Novartis, Amgen: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Venetoclax is an investigational drug that is not yet approved in this indication. Roberts:AbbVie and Genentech: Research Funding; Walter and Eliza Hall Institute of Medical Research: Employment. Agarwal:Amgen, Millennium: Consultancy; Celgene, Onyx: Speakers Bureau; AbbVie: Research Funding. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; 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; 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. Kumar:Skyline, Noxxon: Honoraria; Celgene, Millennium, Onyx, Janssen, Noxxon, Sanofi, BMS, Skyline: Consultancy; Celgene, Millennium, Onyx, Novartis, Janssen, Sanofi: Research Funding. Touzeau:AbbVie: Research Funding. Darden:AbbVie: Employment, Equity Ownership. Morris:AbbVie: Employment, Equity Ownership. Ross:AbbVie: Employment, Equity Ownership. Salem:AbbVie: Employment, Equity Ownership. Munasinghe:AbbVie: Employment, Equity Ownership. Zhu:AbbVie: Employment, Equity Ownership. Leverson:AbbVie: Employment, Equity Ownership. Maciag:AbbVie: Employment, Equity Ownership. Enschede:AbbVie: Employment, Equity Ownership. Verdugo:AbbVie: Employment, Equity Ownership. Humerickhouse:AbbVie: Employment, Equity Ownership. Harrison:Celgene: Honoraria, Research Funding; Janssen: Research Funding, Speakers Bureau; AbbVie: Research Funding.

Abstract Background: The anti-apoptotic protein BCL-2 has been implicated in mediating the survival of multiple myeloma (MM) cells. Venetoclax is a potent, selective, orally bioavailable small-molecule BCL-2 inhibitor. Venetoclax induces cell death in MM cell lines in vitro and primary MM samples ex vivo. Certain genetic subtypes of MM cells are particularly sensitive to venetoclax, including t(11;14) cells, which express a high ratio of BCL2 to MCL1 (venetoclax resistance factor). The current Phase 1 study evaluates safety, efficacy, and pharmacokinetics (PK) in patients (pts) with relapsed/refractory MM. Methods: Primary objectives are to evaluate safety, PK, and recommended phase two dose; other objectives include assessing preliminary efficacy and the impact of chromosomal abnormalities. In dose-escalation (DE) cohorts, venetoclax was given orally daily at 300, 600, 900, or 1200 mg after a 2-week dose ramp-up (3+3 design). Patients in the safety expansion (SE) cohort received 1200 mg daily after ramp-up. All patients were monitored for tumor lysis syndrome (TLS). Results: As of June 17, 2015, 37 patients were enrolled in the study: 30 from DE cohorts and 7 from the SE. Median (range) age was 66 years; 19 (51%) were female. Fourteen were ISS stage I, 13 stage II, 8 stage III, 2 unknown. The median (range) number of prior lines of therapy was 6 (1-19). Thirty-two had prior bortezomib (20 refractory), 35 lenalidomide (18 refractory), and 26 had prior stem cell transplant. Fourteen patients had t(11;14), 4 had t(4;14), 5 had del 17p, and 17 had del 13q. Adverse events (AEs) in ≥20% of patients were nausea (49%), diarrhea (38%), vomiting (30%), anemia (27%), fatigue (24%). Grade 3/4 AEs (≥10%): thrombocytopenia (22%), anemia (19%), neutropenia (11 %). Serious AEs (≥2 patients): pyrexia (n=3), cough, malignant neoplasm progression, and sepsis (2 each); 2 (upper abdominal pain and anemia) were possibly related to venetoclax. Thirty (81%) patients have discontinued venetoclax: 24 due to PD, 3 for AEs (worsening shortness of breath, hypokalemia, and nausea), 2 withdrew consent, 1 due to death (brain hemorrhage following injury). Four deaths occurred (2 due to PD, 1 due to brain hemorrhage, 1 due to pneumopathy). Two of the 6 patients in the 600 mg cohort experienced DLTs of upper abdominal pain and nausea with abdominal pain. No patients met the criteria for laboratory or clinical TLS. Based on preliminary PK (n=21), the mean Cmax and AUC24 were ~dose-proportional at all studied doses (300, 600, 1200 mg) except 900 mg, and dose-normalized venetoclax exposure in MM was similar to that in CLL and NHL pts. Thirty-two of the 37 patients were evaluable for preliminary efficacy (Table). Two patients, both t(11;14), achieved a complete response (1 at 600 mg and 1 at 900 mg). Responses were first achieved at 1.8 and 1.1 months and were maintained for 9.7 and 9.0 months, respectively (900 mg pt remains in CR). Among the 16 patients receiving 1200 mg in the DE or SE cohort, 6 of whom had t(11;14), 5 achieved SD, 6 experienced PD, and 5 are not yet evaluable. Conclusions: Venetoclax monotherapy had a tolerable safety profile in heavily-pretreated relapsed/refractory MM, and no new safety signals were observed compared to other venetoclax studies. The study continues to enroll in the SE cohort at 1200 mg. Responses (including CR) and longer time on venetoclax were observed in t(11;14) patients. These early results suggest that venetoclax has single agent activity, most prominently in t(11;14) patients. Figure 1. Figure 1. Disclosures Kumar: Celgene: Research Funding; Millenium/Takeda: Research Funding; Onyx: Research Funding; AbbVie: Research Funding; Janssen: Research Funding; Sanofi: Research Funding; Celgene, Millenium, Sanofi, Skyline, BMS, Onyx, Noxxon,: Other: Consultant, no compensation,; Skyline, Noxxon: Honoraria. Off Label Use: Venetoclax is an investigational drug that is not yet approved in this indication.. Vij:Takeda, Onyx: Research Funding; Celgene, Onyx, Takeda, Novartis, BMS, Sanofi, Janssen, Merck: Consultancy. Kaufman:Janssen: Consultancy; Spectrum: Consultancy; Merck: Research Funding; Celgene: Consultancy; Onyx: Consultancy; Novartis: Consultancy; Novartis: Research Funding; Onyx: Research Funding. Mikhael:Sanofi: Research Funding; AbbVie: Research Funding; Celgene: Research Funding; Onyx: Research Funding. Moreau:Takeda: Other: Adboard; Janssen: Other: Adboard; Celgene: Other: Adboard; Novartis: Other: Adboard; Amgen: Other: Adboard. Alzate:AbbVie: Employment, Equity Ownership. Morris:AbbVie: Employment, Equity Ownership. Ross:AbbVie: Employment, Equity Ownership. Dunbar:AbbVie: Employment, Equity Ownership. Zhu:AbbVie: Employment, Equity Ownership. Maciag:AbbVie: Employment, Equity Ownership. Agarwal:AbbVie: Employment, Equity Ownership. Leverson:AbbVie: Employment, Equity Ownership. Enschede:AbbVie: Employment, Equity Ownership. Humerickhouse:AbbVie: Employment, Equity Ownership. Touzeau:AbbVie: Research Funding.

Abstract Abstract 2878 Poster Board II-854 Background: Significant advances have been made in the treatment of myeloma with the introduction of thalidomide, its analogue, lenalidomide, and the proteasome inhibitor bortezomib. While these new drugs have improved the outcome of patients with myeloma, the disease still remains incurable. Effectiveness of upcoming new therapies will need to be assessed in the context of anticipated outcome with the currently available therapies. However, given the rapid pace of development over the past decade, outcome of patients who have relapsed on the new therapies remain unclear. Methods: In order to further study this group of patients, we undertook a study of patients who have relapsed on or are refractory to one of the IMiDs (thalidomide or lenalidomide) as well as bortezomib. A total of 300 cases from 8 sites in the US, 5 sites in Europe and one site in Asia were identified for this study. Enrolled patients had relapsed and refractory multiple myeloma, per the EBMT or IMWG response criteria, after at least 2 prior treatments. Patients were refractory to bortezomib, defined as having no response on a prior bortezomib-containing regimen or experiencing disease progression within 60 days of a bortezomib-containing regimen. Patients also should have relapsed, refractory, intolerant, and/or ineligible in the opinion of the investigator, to other therapies, including an IMiD (thalidomide or lenalidomide). Clinical and laboratory data pertaining to the time of diagnosis and from the time of individual relapses were obtained from the clinical records. The date patients satisfied the above entry criteria was defined as time zero. Results: The current analysis includes the first 119 patients with complete data available. The median age at initial diagnosis was 59 years (range, 31-86 yr); 71% were males. The ISS stage distribution at diagnosis was 33%, 39% and 28% for stages 1, 2, and 3 respectively. 19 patients (37%) had high risk disease by FISH [t(4;14), t(14;16), del17p] or by cytogenetics [del 13, hypodiploidy]. The median time from diagnosis to time zero was 3.8 yrs (range 0.2-18.7 yr) and the median reported lines of therapy before time zero was 2. 74% patients had at least 1 autologous stem cell transplant prior to becoming eligible for the study. Following time zero, 77 (65%) pts had a treatment recorded, including an autologous SCT in 21 (18%), with the treatment regimen starting at a median of 1 month after time zero. A variety of treatment regimens were utilized beyond time zero (median=1; range 0-7). Thirty-two (27%) patients had a response any time following time zero, and only 8 had a subsequent response. Response to the first treatment, or supportive care for patients not treated, recorded following time zero included minor response or stable disease (n=14; 12%), PR (n=17, 14%), and VGPR or better (n=6, 5%). Patients treated with SCT had a higher rate of PR or better compared to patients receiving other treatments (85%; 17/20 vs. 26%; 15/57). In a multivariate analysis, the only significant predictor of a PR or better after time zero was younger age (<60 yrs). The median overall survival (OS) and event free survival (EFS) were 6 mos (95% CI, 4-7 mos) and 1 month (95% CI,1-2 mos) respectively. In a multivariate analysis normal creatinine predicted for a better overall survival and having an IgG M protein type predicted for better EFS. A complete analysis from all 300 patients will be presented at the meeting. Conclusions: This study confirms the poor outcome of patients once they become relapsed and refractory to agents that have become the mainstay of myeloma therapy. The findings highlight the incurable nature of the disease and urgent need to develop newer effective therapeutic agents for this group of patients, who currently do not have effective treatment options. Disclosures: Kumar: CELGENE: Research Funding; MILLENNIUM: Research Funding; BAYER: Research Funding; GENZYME: Research Funding; NOVARTIS: Research Funding. Jagannath:Merck: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees. Laubach:Novartis: . Palumbo:Ortho Biotech, Janssen-Cilag: Honoraria; Celgene: Honoraria, Speakers Bureau. Richardson:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Johnson and Johnson: 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, Speakers Bureau; Keryx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. San Miguel:Millennium: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Siegel:Celgene: Speakers Bureau; Millennium: Speakers Bureau. Sonneveld:Janssen-Cilag: Honoraria. Durie:Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: 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 Background: Venetoclax (VEN) is a potent, selective, orally available small-molecule BCL-2 inhibitor that induces cell death in multiple myeloma (MM) cell lines and primary samples, particularly those with t(11;14), which mostly have a favorable high BCL-2, low BCL-XL, and low MCL-1 profile. Methods: In this Phase 1, open-label study, patients (pts) with relapsed/refractory (R/R) MM received VEN monotherapy. Objectives of the study were to assess safety, pharmacokinetics, maximum tolerated dose, recommended phase 2 dose, and efficacy (objective response rate [ORR], time to progression [TTP], and duration of response [DoR]) of VEN. After a 2-week lead in period with weekly dose escalation, VEN was given daily at final doses of 300, 600, 900, or 1200mg in dose escalation cohorts and 1200mg in the safety expansion. Pts who progressed during VEN monotherapy could receive VEN plus dexamethasone and continue in the study. Results: As of 01July2016, 66 pts were enrolled in the study (30 in dose escalation cohorts and 36 in safety expansion). Median age was 63 years and 39 (62%) pts were ISS stage II/III. The median number of prior therapies was 5 (range: 1-15), and 62 (94%) pts had received bortezomib (46 [70%] refractory), 62 (94%) received lenalidomide (51 [77%] refractory), and 50 (76%) had prior autologous stem cell transplant. Thirty (46%) pts had t(11;14) MM. Median time on VEN monotherapy for all pts was 2.5 months (.2-23); 17 (26%) elected to receive VEN and dexamethasone combination after disease progression for a median of 1.4 months (.1-11). Fifty-one (77%) pts discontinued the study for the following primary reasons: 39 related to disease progression, 5 due to AEs/toxicity, 2 withdrew consent, 1 was lost to follow up, and 4 for other reasons not specified. Common adverse events (AEs) in ≥20% of pts were nausea (48%), diarrhea (36%), neutropenia (32%), thrombocytopenia (32%), fatigue (27%), anemia (23%), back pain (21%), and vomiting (21%). Grade 3/4 AEs in ≥10% of pts were thrombocytopenia (26%), neutropenia (20%), lymphopenia (15%), anemia (14%), and decreased white blood cells (12%). Serious AEs in ≥2 pts were pneumonia (n=5), sepsis (3), pain, pyrexia, cough, and hypotension (2 each). Two pts experienced dose-limiting toxicities at 600mg of abdominal pain and nausea. Eight deaths were reported: 6 due to disease progression, 1 due to lung disorder, and 1 due to brain hemorrhage following injury; neither were considered by the investigator as related to VEN. Steady state VEN exposures were approximately dose proportional at all doses but 900mg. As of 20July2016, ORR for all pts on VEN monotherapy was 21% (14/66) and 10 (15%) achieved very good partial response (VGPR) or better (2 stringent complete response [sCR], 2 CR, 6 VGPR) (Figure); median DoR and TTP was 9.7 and 2.6 months, respectively. Most objective responses (12/14 [86%]) were reported in the subset of pts with t(11;14) MM. In this group, ORR was 40% (12/30) and 27% (8/30) achieved a response of ≥VGPR; median DoR for pts with t(11;14) was 9.7 months (95% CI: 6.3, -). Pts who achieved at least minimal response in the t(11;14) group (14/30) had a median of 4 prior therapies and were mostly refractory to bortezomib, lenalidomide, or double refractory (71% [10/14] each). For two pts with response in the non-t(11;14)/undetermined group, 1 had a translocation of chromosome 14 with an unidentified partner, and the other had no cytogenetics data available. DoR was 9.5 and 7.2 months in these pts and both are still ongoing. Median TTP for pts with or without/undetermined t(11;14) was 6.6 and 1.9 months, respectively. The median best percent change in primary M protein for pts with t(11;14) (n=23) was -53% vs +11% in the non-t(11;14)/undetermined group (n=23). Additional biomarker subgroup analyses (n=32) showed that efficacy was primarily observed in pts with myeloma cells expressing a favorable BCL-2 family expression profile (high BCL-2, low BCL-XL, low MCL-1) by immunohistochemistry, which was significantly enriched in the t(11;14) population. Indeed, although high BCL-2 expression was observed in a majority of bone marrow core biopsy samples (88%), the t(11;14) subgroup was enriched (81% vs 25%) for tumors expressing high BCL-2, low BCL-XL, and low MCL-1. Conclusions: VEN monotherapy has an acceptable safety profile and clear anti-myeloma activity in pts with R/R MM, primarily with t(11;14) having a high BCL-2, low BCL-XL and low MCL-1 expression levels. Figure Figure. Disclosures Kumar: Janssen: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Research Funding; Glycomimetics: Consultancy; AbbVie: Research Funding; Array BioPharma: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Kesios: Consultancy; BMS: Consultancy. Kaufman:Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Pharmacyclics: Consultancy; Incyte: Consultancy. Mikhael:Abbvie: Research Funding; Celgene: Research Funding; Onyx: Research Funding; Sanofi: Research Funding. Facon:Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy; Bristol: Consultancy; Millenium/Takeda: Consultancy; Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Karyopharm: Consultancy. Benboubker:Takeda: 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; Amgen: 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. Moreau:Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Amgen: Honoraria. Alzate:AbbVie: Employment. Ross:AbbVie: Employment, Equity Ownership. Dunbar:AbbVie Inc.: Employment, Other: may own stock. Xu:AbbVie: Employment. Agarwal:AbbVie: Employment. Leverson:AbbVie: Employment, Other: Shareholder in AbbVie. Maciag:AbbVie: Employment. Verdugo:AbbVie: Employment, Other: may own stock. Touzeau:AbbVie: Research Funding.

Abstract Introduction: IgM-secreting myeloma is rare, encompassing about 1% of all the myeloma cases. Given its rarity, the characteristics and survival of these patients have not been extensively studied. Therefore, we carried out a multicenter retrospective study in patients with IgM myeloma. Methods: The study protocol was reviewed and approved by the Institutional Review Board of each participating institution. Clinical data were gathered and included age, sex, hemoglobin, calcium, LDH, estimated glomerular filtration rate (GFR), presence of lytic bone lesions, International Staging System score, cytogenetic abnormalities, final outcome and overall survival (OS) time. OS was defined as the time in months from diagnosis to last follow-up or death. The Chi-square and the rank-sum tests were used to compare categorical and continuous variables, respectively. The Kaplan-Meier method was used to estimate OS and the log-rank waas used to compare groups. The Cox proportional-hazard regression method was used to fit univariate and multivariate survival models, reported as hazard ratio (HR) with 95% confidence intervals (CI). All reported p-values are two-sided, and were considered significant if less than 0.05. Results: A total of 159 patients with IgM myeloma from 20 centers from Europe, USA and Latin America were included in this analysis. Patients were diagnosed between 1996 and 2015. The median age at diagnosis was 65 years (range 37-86 years) with a male predominance (68%). The median serum IgM level was 2510 mg/dl (range 27-12,100 mg/dl) with 25% of patients having a serum IgM within normal limits but an IgM monoclonal spike detectable in serum electrophoresis. Hemoglobin levels <10 g/dl were seen in 49 patients (32%), serum calcium was elevated in 24 (16%), estimated GFR of 60 ml/min or less in 56 (37%), lytic lesions were detected in 86 (58%), and serum LDH was elevated in 28 (24%). ISS scores of 1, 2 and 3 were seen in 53 (36%), 63 (43%) and 31 (21%) of patients, respectively. Although immunohistochemistry and/or flow cytometry data were limited, CD20 expression was seen in 15/26 (58%) and cyclin D1 in 10/15 (67%) patients. The most common cytogenetic abnormalities were t(11;14) in 26/67 (39%), del13q in 25/76 (33%) and del17p in 6/76 (8%) patients. 149 patients (94%) received at least one line of systemic therapy for myeloma of which 13 (9%) received rituximab as part of initial therapy. After a median follow-up of 47 months, 74 patients (47%) have died. The median OS was 62 months (95% CI 51-79 months). Cause of death was known in 38 patients, and the most common was myeloma progression (74%). IN the univariate analysis, prognostic factors associated with a worse OS were age (HR 1.03, 95% CI 1.01-1.06; p=0.01) and ISS score (ISS 2: HR 1.43, 95% CI 0.83-2.48; p=0.2, and ISS 3: HR 3.03, 95% CI 1.54-5.98; p=0.001, using ISS 1 as reference group), while male sex was associated with a better OS (HR 0.56, 95% CI 0.34-0.90; p=0.02). Hemoglobin, calcium, estimated GFR and lytic lesions were not associated with OS. In the multivariate analysis, male sex was associated with a better OS (HR 0.57, 95% CI 0.35-0.95; p=0.03) and ISS with worse OS (ISS 2: HR 1.57, 95% CI 0.89-2.74; p=0.12, and ISS 3: HR 2.76, 95% CI 1.38-5.55; p=0.004, using ISS 1 as reference group). Conclusion: Patients with IgM myeloma apparently present with similar clinical characteristics as patients with non-IgM myeloma. Pathologically, CD20 and cyclin D1 expression is common. The most common cytogenetic abnormalities identified were t(11;14) and del13q. Survival does not appear shorter than non-IgM myeloma patients, and the ISS appears to have similar prognostic value. Disclosures Castillo: Millennium: Research Funding; Janssen: Honoraria; Otsuka: Consultancy; Biogen: Consultancy; Abbvie: Research Funding; Pharmacyclics: Honoraria. Ghobrial:Celgene: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria; Takeda: Honoraria; Noxxon: Honoraria; Amgen: Honoraria. Hájek:Celgene: Consultancy, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; BMS: Honoraria; Takeda: Consultancy. Hungria:International Myeloma Foundation Latin America: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Amgen: Consultancy; Roche: Consultancy; Bristol: Consultancy; Janssen: Consultancy, Speakers Bureau. Niesvizky:Celgene: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau; Onyx: Consultancy, Research Funding, Speakers Bureau. Reagan:Alexion: Honoraria; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees. Spicka:Janssen Cilag: 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, Research Funding; Amgen: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Millenium: Honoraria. Gertz:Celgene: Honoraria; Med Learning Group: Honoraria, Speakers Bureau; Research to Practice: Honoraria, Speakers Bureau; Alnylam Pharmaceuticals: Research Funding; Novartis: Research Funding; Prothena Therapeutics: Research Funding; Ionis: Research Funding; NCI Frederick: Honoraria; Sandoz Inc: Honoraria; GSK: Honoraria; Annexon Biosciences: Research Funding.