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, Simon J. Harrison

Research output: Contribution to journalArticle

109 Scopus citations

Abstract

The antiapoptotic 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 cotargeting of BCL-2 and MCL-1 could be an effective treatment strategy in myeloma. This phase 1b 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. A total of 66 patients were enrolled (54 in the dose-escalation cohorts and 12 in the safety expansion). Patients had received a median of 3 prior therapies (range, 1-13); 26 (39%) were refractory to prior bortezomib and 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%], and 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 to 3 prior therapies. Patients with high BCL2 expression had a higher ORR (94% [17/18]) than 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.

Original languageEnglish (US)
Pages (from-to)2392-2400
Number of pages9
JournalBlood
Volume130
Issue number22
DOIs
StatePublished - Nov 30 2017

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Moreau, P., Chanan-Khan, A., Roberts, A. W., Agarwal, A. B., Facon, T., Kumar, S., Touzeau, C., Punnoose, E. A., Cordero, J., Munasinghe, W., Jia, J., Salem, A. H., Freise, K. J., Leverson, J. D., Enschede, S. H., Ross, J. A., Maciag, P. C., Verdugo, M., & Harrison, S. J. (2017). Promising efficacy and acceptable safety of venetoclax plus bortezomib and dexamethasone in relapsed/refractory MM. Blood, 130(22), 2392-2400. https://doi.org/10.1182/blood-2017-06-788323