Ross, Jeremy A.

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.

Background:Venetoclax (Ven) is a highly selective, potent, oral BCL‐2 inhibitor that induces apoptosis in malignant cells dependent on BCL‐2 for survival. Proteasome inhibitors (PIs) and dexamethasone (d) were shown to increase BCL‐2 dependence in multiple myeloma (MM) cells, and preclinical studies showed enhanced inhibition of MM tumor growth with Ven+PI compared to either alone. Moreover, d has been shown to indirectly promote BCL‐2 dependency in MM cells. Clinical trials have since demonstrated efficacy of Ven in combination with the PI bortezomib in patients (pts) with relapsed/refractory MM (RRMM).Aims:We report interim data for Ven combined with second‐generation PI carfilzomib (K) and d in pts with RRMM.Methods:In this ongoing Phase 2 study (NCT02899052), pts with RRMM (1–3 prior lines of therapy) and no prior K exposure received VenKd on 28‐day cycles in 4 dose‐finding and 1 expansion cohort: Ven 400 mg/day + K 27 mg/m2 Day 1, 2, 8, 9, 15, 16 + d 40 mg Day 1, 8, 15, 22 (Cohort 1); same regimen but with Ven 800 mg/day (Cohort 2); Ven 800 mg/day + K 70 mg/m2 Day 1, 8, 15 + d 40 mg Day 1, 8, 15, 22 (Cohort 3/expansion cohort); or Ven 800 mg + K 56 mg/m2 Day 1, 2, 8, 9, 15, 16 + d 40 mg Day 1, 2, 8, 9, 15, 16, 22, 23 (Cohort 4). Treatment continued until progressive disease or unacceptable toxicity.Results:As of the clinical data cut‐off of 1 Feb 2019, 43 pts were enrolled. Median age was 67 (range, 37–79), 26 (62%) pts had ISS II/III disease, and 8 (19%) were t (11;14)+. Median number of prior lines of therapy was 2 (range, 1–3). Forty (93%) pts received prior PI (49% refractory), 33 (77%) received prior immunomodulatory drug (IMiD, 61% refractory), and 33 (77%) received prior PI+IMiD (33% double refractory).All pts had at least 1 adverse event (AE). The most common AEs of any grade were diarrhea (65%), nausea (49%), fatigue (47%), cough (35%), insomnia, dyspnea, vomiting, upper respiratory infection (33% each), lymphopenia (28%), thrombocytopenia, and dyspepsia (26% each). Thirty‐six (84%) pts had a Grade 3/4 AE, the most common being lymphopenia (23%), pneumonia, hypertension (16% each), and hypophosphatemia (12%).The overall response rate (ORR) was 79%, complete response or better (≥CR) rate was 40%, and very good partial response or better (≥VGPR) rate was 64% for all pts (Table). Median follow‐up for 42 pts was 10.4 months (95% CI = 8.0–13.8); 15 pts had progression‐free survival (PFS) events, with median PFS yet to be achieved. Baseline bone marrow core biopsy samples from 25 pts were evaluated for BCL‐2 expression by immunohistochemistry, with high expression (≥50% of tumor cells with moderate or higher cytoplasmic staining) seen in 23 (92%) samples. Pts with high BCL‐2 expression had response rates similar to the overall study population. Other correlative biomarker analyses are ongoing.Summary/Conclusion:The combination of VenKd was found to be tolerable with no new safety signals. VenKd demonstrates promising efficacy in pts with RRMM. The study remains ongoing with an additional 60 pts with RRMM enrolling to assess efficacy and safety in a larger group of pts with similar eligibility (Cohort 6) and t (11;14)+ pts (Cohort 7).image

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).

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.