Citations

Abstract Background: Combination regimens incorporating bortezomib (VELCADE®, Vc), lenalidomide (REVLIMID®, Rev), dexamethasone (Dex) and cyclophosphamide (Cy) (Vc–Dex, Rev–Dex, Vc–Dex–Rev [VDR], and Vc–Dex–Cy [VDC]), have all shown substantial activity in previously untreated multiple myeloma (MM). A combination of all four agents (VDCR) may result in even greater activity. This randomized multi-center 3-arm phase I/II EVOLUTION study is investigating the efficacy and safety of VDR, VDC, and VDCR as initial therapy in previously untreated MM patients (pts). We now report safety and efficacy results from the phase l dose-escalation portion of the study, which sought to determine the maximum tolerated dose (MTD) of the VDCR regimen. These results represent the first clinical data with this novel 4-drug combination that includes bortezomib, lenalidomide, an alkylator, and a corticosteroid. Methods: Pts received Vc 1.3 mg/m2 IV (d 1, 4, 8, 11), Dex 40 mg PO (d 1, 8, 15), Rev 15 mg PO (d 1–14), plus Cy 100, 200, 300, 400, or 500 mg/m2 PO (d 1, 8) for up to eight 21-d cycles, followed by Vc 1.3 mg/m2 (d 1, 8, 15, 22) for four 42-d maintenance cycles. Pts received prophylactic antibiotics, acyclovir, transfusion support and concomitant anticoagulants as required. Eligible pts wishing to receive autologous stem cell transplant (ASCT) could undergo stem cell mobilization any time after cycle 2, and discontinue therapy for ASCT any time after cycle 4. The MTD was defined as the highest dose of Cy in combination with VDR resulting in ≤1 dose-limiting toxicity (DLT) in 6 pts. A DLT was defined as: platelet count <25,000/mm3 lasting >7 days or any platelet count <10,000/mm3; grade 4 neutropenia lasting >7 days; any ≥grade 3 non-hematologic toxicity considered to be related to Cy except for inadequately treated nausea, vomiting, and diarrhea, or any toxicity resulting in a >2 week treatment delay. Results: Twenty-six pts were enrolled; 1 pt was not dosed due to a heart problem and was excluded (dose level 4) and 4 pts were not evaluable for DLT. In the 25 treated pts, median age was 61 years (range 49–79); 52% were male; 48% had ISS Stage lI and 4% Stage III disease, and 44% had KPS ≤80%. At data cut-off, 11 pts remain on treatment and 9 have undergone successful ASCT. To date, median treatment duration is 4 cycles (range 2–11). Two pts experienced DLT: 1 grade 4 febrile neutropenia at dose level 4 (Cy 400 mg/m2), and 1 grade 3 herpes zoster virus reactivation despite antiviral prophylaxis at dose level 5 (Cy 500 mg/m2). The recommended phase II dose of Cy in the VDCR regimen was the highest planned dose of 500 mg/m2. The most common treatment-emergent AEs were constipation (64%), fatigue (60%), and nausea (52%). Hematologic toxicities were acceptable, with grade 3 neutropenia in 16% of patients, grade 4 in 4%, and grade 4 thrombocytopenia in 4%. Peripheral neuropathy (56%), included 8% grade 3 but no grade 4; no deep-vein thrombosis/pulmonary embolism events were reported. Overall rate of serious AEs was 40%; the only SAE reported in >1 pt was febrile neutropenia (2 pts). Best responses to date by International Uniform Response Criteria are shown in the table. Preliminary response rates are: 100% ≥PR, 68% ≥VGPR, 32% CR/nCR, 28% CR/stringent CR and 20% sCR. Ten pts have undergone stem cell mobilization with median CD34+ yield of 4.95×106/kg. Conclusions: VDCR was well tolerated and hematologic toxicities were manageable. The current study shows that the VDCR regimen is feasible and highly active in newly diagnosed myeloma and merits further testing in clinical trials. Enrollment to the 3 arms (VDR, VDC and VDCR) of the phase ll portion of the study and testing for minimal residual disease by flow cytometry are ongoing. Best unconfirmed response to date with VDCR Dose level 1 2 3 4 5 Cyclophosphamide dose, mg/m2 100 200 300 400 500 Enrolled 3 4 4 8 7 Treated 3 4 4 7 7 Still on treatment – 1 1 2 7 Best unconfirmed response to date CR (sCR) 2 (2) 1 (1) 1 (1) 2 1 (1) VGPR (nCR) 1 – 3 (1) 4 2 PR – 3 – 1 4

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.

Key Points Venetoclax monotherapy at a daily dose up to 1200 mg has an acceptable safety profile in patients with relapsed/refractory MM. Venetoclax monotherapy has demonstrated antimyeloma activity in patients with relapsed/refractory MM positive for t(11;14).