Agarwal, Amit B.

8525 Background: RRMM patients (pts) triple-class exposed (to immunomodulatory drugs [IMiDs], proteasome inhibitors [PIs] and anti-CD38 monoclonal antibodies [mAbs]) have limited treatment (tx) options. The ongoing phase II KarMMa study (NCT03361748) is examining idecabtagene vicleucel (ide-cel; bb2121), a BCMA targeted CAR T cell therapy, in RRMM pts with ≥3 prior regimens (IMiD, PI and CD38 mAb inclusive) who are refractory to their last tx per IMWG criteria. This study aimed to 1) assess tx patterns and outcomes in real world (RW) RRMM pts similar to the KarMMa population and; 2) compare outcomes with SoC in a synthetic cohort vs ide-cel in KarMMa. Methods: In this global, noninterventional, retrospective study (KarMMa-RW), pt-level data from clinical sites, registries and databases were collated into a single data model. RW pts meeting KarMMa eligibility criteria (eligible cohort; EC) were compared with KarMMa (N = 128) using trimmed stabilized inverse probability of tx weighted propensity scores (IPTW PS) for pts in both studies with Poisson regression for ORR and ≥VGPR, and Cox models with study as a term for PFS. All models were adjusted for unbalanced covariates. Results: Of 1949 RW pts, 1171 were refractory to last regimen (median age, 68 y; median no. of prior regimens, 5; triple-class refractory, 41%). Further selection for subsequent tx, organ function and no comorbidities yielded 190 EC pts who had > 90 distinct tx regimens. With a median follow-up of 11.3 mo (KarMMa) and 10.2 mo (EC) at data cutoff (Oct 30, 2019), ORR, ≥VGPR and PFS were significantly improved in KarMMa vs EC (Table). Conclusions: Results from the KarMMa-RW study confirm that there is no clear SoC for heavily pretreated RW RRMM pts and responses are suboptimal with currently available therapies. Ide-cel showed deep, durable responses and significantly improved PFS in RRMM pts, representing a potential new tx option in RRMM. Clinical trial information: tbd . [Table: see text]

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: BCL-2 and MCL-1 promote multiple myeloma (MM) cell survival. Venetoclax (VEN) is a potent, selective, orally bioavailable small-molecular inhibitor of BCL-2. When combined with bortezomib, which can inhibit MCL-1, VEN can enhance the activity of bortezomib in MM cell lines and xenograft models. Methods: In this Phase 1b, open label, dose escalation study, patients with relapsed/refractory (R/R) MM received daily VEN (50 - 1200 mg per designated dose cohort) with bortezomib and dexamethasone. The objectives of the study were to assess the safety, pharmacokinetics, maximum tolerated dose, recommended phase 2 dose (R2PD), and efficacy (objective response rate [ORR], time to progression [TTP], and duration of response [DoR]) of combination therapy in this patient population. Results: As of 01July2016, 66 patients were enrolled, with 54 in the dose escalation cohort and 12 in the safety expansion at R2PD of 800 mg. The median age was 64 years and 39 (59%) were ISS stage II/III. The median number of prior therapies was 3 (range: 1 - 13), and 21 (32%) were refractory to prior bortezomib, 37 (56%) were refractory to prior lenalidomide, and 41 (62%) had prior stem cell transplant. Forty-three (65%) patients discontinued the study for the following primary reasons: 33 related to disease progression, 5 due to AEs (1 each: respiratory failure and cardiac failure, lung adenocarcinoma, sepsis, renal impairment, and Guillain-Barre syndrome; none were considered by the investigator as related to VEN), 2 withdrew consent, and 3 for other reasons not specified. Adverse events (AEs) were reported in 65 (99%) patients, with common AEs in ≥20% of patients being diarrhea (41%), thrombocytopenia (39%), constipation (38%), nausea (36%), insomnia (32%), peripheral neuropathy (30%), peripheral edema (29%), anemia (27%), peripheral sensory neuropathy (27%), dyspnea (24%), fatigue (24%), and asthenia (24%). Grade 3/4 AEs in ≥10% of patients included thrombocytopenia (29%), anemia (15%) and neutropenia (14%). Serious AEs in ≥2 patients were febrile neutropenia, thrombocytopenia, cardiac failure, pyrexia, influenza, lower respiratory tract infection, pneumonia, sepsis, acute kidney injury, respiratory failure, embolism, and hypotension. One dose-limiting toxicity of lower abdominal pain was reported for a patient who received 1200 mg VEN. Five deaths were reported during the study, 4 due to disease progression and 1 due to respiratory syncytial virus infection (not considered by the investigator as related to VEN). After co-administration with bortezomib and dexamethasone, dose-normalized VEN exposure at steady-state appeared to be within the exposure range observed with VEN monotherapy in patients with MM. The ORR for all evaluable patients was 68% (44/65) and 26 (40%) achieved very good partial response (VGPR) or better (3 stringent complete response [sCR], 8 CR, 15 VGPR) (Figure). For all patients, median DoR was 8.8 months (95% CI: 7.2, 15.8) and TTP was 8.6 months (95% CI: 5.7, 10.2), with a median follow up of 4.9 months (range: .03 - 26.7). High ORR of 89% was seen in patients who were non-refractory to prior bortezomib (39/45) or who had 1 - 3 prior therapies (31/35). In 31 patients who were non-refractory to bortezomib and had 1 - 3 prior therapies had ORR of 94% (29/31), 68% (21/31) with VGPR or better; median DoR was 10.6 months and TTP was 11.3 months for this subgroup. Moreover, patients who were bortezomib naïve and had 1 - 3 prior lines of therapy had ORR of 100% (12/12), and median DoR was 15.8 months and TTP was 17.1 months. In patients who were non-refractory to prior bortezomib but who were refractory to lenalidomide, the ORR was 86% (19/22) as compared with 91% (20/22) in those non-refractory to lenalidomide. Clinical responses were comparable in patients with t(11;14) MM (ORR, 78% [7/9]) and without t(11;14) MM (ORR, 66% [37/56]). In the t(11;14) group, 3 patients were bortezomib-refractory, and 2 of them achieved a PR as best response. Also, 4 patients had more than 3 prior lines, with 3 of them achieving PR. Conclusions: VEN in combination with bortezomib and dexamethasone has an acceptable safety profile in patients with R/R MM. Efficacy results, including 68% ORR in all patients and 94% ORR in patients not refractory to bortezomib and who received 1 - 3 prior lines of therapy, indicates promising efficacy of this novel combination and supports the ongoing Phase 3 trial with this regimen in patients with R/R MM. Figure. Figure. Disclosures Moreau: Janssen: Honoraria, Speakers Bureau; Novartis: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria. Roberts:Genentech: Patents & Royalties: Employee of Walter and Eliza Hall Institute of Medical Research which receives milestone payments related to venetoclax; AbbVie: Research Funding; Servier: Research Funding; Janssen: Research Funding; Genentech: Research Funding. Agarwal:AbbVie: Honoraria, Research Funding; Millennium: Consultancy; Amgen: Consultancy; Janssen: Speakers Bureau; Onyx: Speakers Bureau; Celgene: Speakers Bureau. Facon:Amgen: Consultancy, Speakers Bureau; Millenium/Takeda: Consultancy; Bristol: Consultancy; Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy; Celgene: Consultancy, Speakers Bureau; Karyopharm: Consultancy. Kumar:Glycomimetics: Consultancy; AbbVie: Research Funding; Janssen: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; BMS: Consultancy; Celgene: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Kesios: Consultancy; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Noxxon Pharma: Consultancy, Research Funding. Touzeau:AbbVie: Research Funding. Cordero:AbbVie: Employment. Ross:AbbVie: Employment, Equity Ownership. Munasinghe:AbbVie: Employment. Jia:AbbVie: Employment. Salem:AbbVie: Employment. Leverson:AbbVie: Employment, Other: Shareholder in AbbVie. Maciag:AbbVie: Employment. Verdugo:AbbVie: Employment, Other: may own stock. Harrison:Janssen Cilag: Research Funding, Speakers Bureau; AbbVie: Research Funding.

Key Points In relapsed/refractory MM, venetoclax plus bortezomib and dexamethasone appears to be safe and efficacious. This is a novel therapeutic approach for MM.