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Promising efficacy and acceptable safety of venetoclax plus bortezomib and dexamethasone in relapsed/ refractory MM

Philippe Moreau, Asher Chanan-Khan, Andrew W. Roberts, Amit B. Agarwal, Thierry Facon, Shaji Kumar, Cyrille Touzeau, Elizabeth A. Punnoose, Jaclyn Cordero, Wijith Munasinghe, Jia Jia, Ahmed Hamed Salem, Kevin J. Freise, Joel D. Leverson, Sari Heitner Enschede, Jeremy A. Ross, Paulo C. Maciag, Maria Verdugo and Simon J. Harrison

Key points

  • In R/R MM, venetoclax plus bortezomib and dexamethasone appears to be safe and efficacious

  • This is a novel therapeutic approach for MM

Abstract

Anti-apoptotic proteins BCL-2 and myeloid cell leukemia sequence 1 (MCL-1) promote multiple myeloma (MM) cell survival. Venetoclax is a selective, orally bioavailable small-molecule BCL-2 inhibitor; bortezomib can indirectly inhibit MCL-1. In preclinical studies, venetoclax enhanced bortezomib activity, suggesting that co-targeting of BCL-2 and MCL-1 could be an effective treatment strategy in myeloma. This phase Ib trial studied patients with relapsed/refractory MM receiving daily venetoclax (50-1200 mg per designated dose cohort; 800 mg in safety expansion) in combination with bortezomib and dexamethasone. Sixty-six patients were enrolled (54, dose-escalation cohorts; 12, safety expansion). Patients had received median 3 prior therapies (range: 1-13); 26 (39%) were refractory to prior bortezomib, 35 (53%) to lenalidomide; 39 (59%) had prior stem cell transplant. The combination was generally well tolerated, and common adverse events included mild gastrointestinal toxicities (diarrhea [46%], constipation [41%], nausea [38%]) and grade 3/4 cytopenias (thrombocytopenia [29%] and anemia [15%]). The overall response rate (ORR) was 67% (44/66); 42% achieved very good partial response or better (≥VGPR). Median time to progression and duration of response were 9.5 and 9.7 months, respectively. ORR of 97% and ≥VGPR 73% were seen in patients not refractory to bortezomib who had 1-3 prior therapies. Patients with high BCL2 expression had high ORR (94% [17/18]) vs patients with low BCL2 expression (59% [16/27]). This novel combination of venetoclax with bortezomib and dexamethasone has an acceptable safety profile and promising efficacy in patients with relapsed/refractory MM. This trial was registered at www.clinicaltrials.gov as #NCT01794507.

  • Submitted June 6, 2017.
  • Accepted August 21, 2017.