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1888 Updated Analysis of Bellini, a Phase 3 Study of Venetoclax or Placebo in Combination with Bortezomib and Dexamethasone in Patients with Relapsed/Refractory Multiple MyelomaClinically Relevant Abstract

Program: Oral and Poster Abstracts
Session: 653. Myeloma: Therapy, excluding Transplantation: Poster I
Hematology Disease Topics & Pathways:
Diseases, apoptosis, Adult, Therapies, Combinations, Biological Processes, Technology and Procedures, cytogenetics, Study Population, Clinically relevant, Myeloid Malignancies
Saturday, December 7, 2019, 5:30 PM-7:30 PM
Hall B, Level 2 (Orange County Convention Center)

Philippe Moreau, MD1*, Simon Harrison, MBBS, MRCP, FRCPath, FRACP, PhD2, Michele Cavo3*, Javier De La Rubia4*, Rakesh Popat5*, Cristina Gasparetto, MD6, Vania T.M. Hungria, MD, PhD7, Hans Salwender8*, Kenshi Suzuki, MD, PhD9, Inho Kim, MD, PhD10*, Francesca Gay, MD11, Gábor Mikala, MD, PHD12*, Elizabeth A Punnoose, PhD13*, Wan-Jen Hong, MD14, Anjla Sood, MD15*, Muhammad Jalaluddin, PhD15*, Jeremy A. Ross, PhD15*, James E. Ward, MD15*, Paulo C. Maciag, MD, PhD16* and Shaji K. Kumar, MD17

1Clinical Hematology, University Hospital Hôtel-Dieu, Nantes, France
2Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia
3"Seràgnoli" Institute of Hematology, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
4Hematology Department, Internal Medicine, School of Medicine and Dentistry, Catholic University of Valencia and Hospital Doctor Peset, Valencia, Spain
5University College London Hospitals NHS Foundation Trust, London, United Kingdom
6Duke Univ. Medical Center, Durham, NC
7Hematology, Clinica São Germano, São Paulo, Brazil
8Asklepios Tumorzentrum Hamburg, AK Altona and AK St. Georg, Hamburg, Germany
9Department of Hematology, Japanese Red Cross Medical Center, Tokyo, Japan
10Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea, Republic of (South)
11Myeloma Unit, Division of Hematology, AOU Città della Salute e della Scienza di Torino, Torino, Italy
12Department of Hematology and Stem Cell Transplantation, South-Pest Central Hospital, National Institute for Hematology and Infectious Diseases, Budapest, Hungary
13Genentech, Inc., South San Francisco, CA
14Genentech, Inc., Mountain View, CA
15AbbVie, Inc., North Chicago, IL
16AbbVie Inc., North Chicago, IL
17Mayo Clinic, Rochester, MN

Background: Venetoclax (Ven) is a highly selective, potent, oral BCL-2 inhibitor that induces apoptosis in multiple myeloma (MM) cells and has shown synergistic activity with the proteasome inhibitor (PI) bortezomib (B) and dexamethasone (d). Ven ± d had encouraging clinical efficacy in both t(11;14) MM and in pts irrespective of genetic background when administered with B, with a tolerable safety profile in Phase 1 studies. Here, we provide updated efficacy and safety of Ven vs placebo (Pbo) + Bd in pts with relapsed/refractory (RR) MM, including subgroup analyses, in the BELLINI study.

Methods: BELLINI (NCT02755597) was a Phase 3, randomized, double-blind, multicenter study of Ven or Pbo + Bd in pts with RRMM who received 1 – 3 prior therapies and were either sensitive or naïve to PIs. Pts were randomized 2:1 to receive Ven 800 mg/day or Pbo + Bd. Cycles 1-8 were 21-day with B 1.3 mg/m2 on Days 1, 4, 8, 11 + d 20 mg on Days 1, 2, 4, 5, 8, 9, 11, 12. Cycles 9+ were 35-day with B 1.3 mg/m2 on Days 1, 8, 15, 22 + d 20 mg Day 1, 2, 8, 9, 15, 16, 22, 23. The primary endpoint was progression-free survival (PFS) by independent review committee (IRC).

Results: A total of 291 pts were randomized, 194 to the Ven arm and 97 to the Pbo arm. Median age was 66 (range, 36 – 87); 53% had ISS II/III disease; 54% received 2 or 3 prior lines of therapy; 59% had prior stem cell transplant; 70% had prior PI, 68% had prior immunomodulatory drug, 41% had both. Among pts with evaluable results, 18% had high-risk cytogenetics, 13% had MM positive for t(11;14), and 79% had high levels of BCL-2 protein by immunohistochemistry (IHC).

In the primary endpoint analysis per IRC, the median PFS was 22.4 months (m) in Ven vs 11.5 m in Pbo (HR=0.630, p=0.01), with a median follow-up of 18.7 m (as of 26 Nov 2018). As of updated analysis based on a data cut-off of 18 March 2019, the median PFS (per investigator [INV]) was 22.9 m in Ven vs 11.4 m in Pbo (HR=0.587, p=0.001; Table 1), with a median follow-up of 22.7 m. Per INV, higher overall response (ORR, 84% vs 70%, p=0.009) and very good partial or better response (≥VGPR, 61% vs 40%, p<0.001; Table 2) rates were observed in Ven vs Pbo. Minimal residual disease negativity rate (by next-generation sequencing) was also higher in the Ven arm vs Pbo (MRD- [10-5], 13% vs 1%). Median duration of response was 23.4 m for Ven and 12.8 m for Pbo. In the overall population, median overall survival (OS) was not reached in either arm but continued to favor Pbo (HR 1.474, 95% CI=0.870-2.498). A total of 70 deaths have been reported, 51 (26%) in the Ven arm and 19 (20%) in the Pbo arm.

In the safety population (N=289), the most common treatment-emergent adverse events (TEAEs; Ven/Pbo) were diarrhea (59%/48%), nausea (37%/22%), constipation (35%/31%), and fatigue (31%/32%). The most common Grade 3/4 TEAEs were neutropenia (18%/8%), pneumonia (17%/12%), anemia (16%/15%), thrombocytopenia (15%/30%), and diarrhea (15%/12%); 23%/12% discontinued Ven due to a TEAE. The rates of serious AEs (51%/51%) and serious infections (30%/28%) were comparable between arms. There were 69 deaths in the safety population: in the Ven arm, 14 were treatment-emergent (TE; treatment start to 30 days after discontinuation) and 36 were non-TE (>30 days after treatment discontinuation); in the Pbo arm, 1 was TE and 18 were non-TE.

In the t(11;14) subgroup, median PFS has not been reached for pts receiving Ven, but was 9.3 m for Pbo (HR=0.095; per INV). In the t(11;14)-negative (neg) subgroup, median PFS was 22.4 m and 10.7 m for Ven and Pbo, respectively (HR=0.627; per INV). Median OS has not been reached in either arm for the t(11;14) and t(11;14)-neg subgroups, although the HR favored Ven in t(11;14) pts, and Pbo in t(11;14)-neg pts. Analyses indicate that low BCL-2 expression by IHC and high-risk cytogenetics (defined as t(4;14, t(14;16), or del(17p)) were associated with decreased PFS and OS in the Ven arm (Table 1). In the high-risk cytogenetics pts, median PFS was 11.4 m in both arms (HR=0.99), and median OS has not been reached in either arm but favors Pbo (HR=10.6). In the subgroup with low BCL-2 expression by IHC, median PFS was 11.7 m and 17.0 m for Ven and Pbo, respectively (HR=1.42), and median OS was 21.3 m in the Ven arm and not reached in Pbo (HR=4.58).

Conclusions: Updated analysis of BELLINI continue to reflect a favorable benefit-risk profile in t(11;14) pts, with meaningful clinical responses and improvement in PFS, as well as a positive trend in OS in this subgroup when treated with Ven + Bd.

Disclosures: Moreau: Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Harrison: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: investigator on studies, Research Funding. Cavo: sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; bms: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; novartis: Honoraria. De La Rubia: Janssen: Consultancy; Takeda: Consultancy; Celgene Corporation: Consultancy; AMGEN: Consultancy; AbbVie: Consultancy. Popat: Takeda: Honoraria, Other: travel, accommodations, expenses; Janssen: Honoraria, Other: travel support to meetings; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses; GSK: Consultancy, Honoraria. Gasparetto: Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Hungria: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, 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, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Salwender: Amgen: Honoraria, Other: Travel or accommodations; Takeda: Honoraria, Other: Travel or accommodations; Bristol-Myers Squibb: Honoraria, Other: Travel or accommodations; Sanofi: Honoraria, Other: Travel or accommodations; Celgene: Honoraria, Other: Travel or accommodations; AbbVie: Honoraria; Janssen Cilag: Honoraria, Other: Travel or accommodations. Suzuki: Ono: Research Funding; BMS: Honoraria, Research Funding; Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Gay: AbbVie: 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; Roche: 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; 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. Mikala: Takeda: Honoraria; Roche: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Celgene: Honoraria, Research Funding; Amgen: Honoraria; AbbVie: Honoraria, Research Funding. Punnoose: Genentech, Inc.: Employment; Roche: Other: Stock/stock options. Hong: Genentech Inc.: Employment, Equity Ownership; Roche: Equity Ownership. Sood: AbbVie: Employment, Other: Stock/stock options. Jalaluddin: AbbVie: Employment, Other: Stock/stock options. Ross: AbbVie: Employment, Other: Stock/stock options. Ward: AbbVie: Employment, Other: Stock/stock options. Maciag: AbbVie: Employment, Other: Stock/stock options. Kumar: Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding.

OffLabel Disclosure: Venetoclax is a BCL-2 inhibitor that is FDA-approved in some indications. This presentation will focus on venetoclax for treatment of multiple myeloma, which is not an approved indication.

*signifies non-member of ASH