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

Authors :
Moreau, Philippe
Chanan-Khan, Asher
Roberts, Andrew W.
Agarwal, Amit B.
Facon, Thierry
Kumar, Shaji
Touzeau, Cyrille
Punnoose, Elizabeth A.
Cordero, Jaclyn
Munasinghe, Wijith
Jia Jia
Salem, Ahmed Hamed
Freise, Kevin J.
Leverson, Joel D.
Enschede, Sari Heitner
Ross, Jeremy A.
Maciag, Paulo C.
Verdugo, Maria
Harrison, Simon J.
Source :
Blood. 11/30/2017, Vol. 130 Issue 22, p2392-2400. 9p.
Publication Year :
2017

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/refractoryMM receiving daily venetoclax (50-1200 mg per designated dose cohort; 800mgin 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). Mediantime 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/refractoryMM.This trialwas registered atwww.clinicaltrials.gov as#NCT01794507 [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00064971
Volume :
130
Issue :
22
Database :
Academic Search Index
Journal :
Blood
Publication Type :
Academic Journal
Accession number :
126499058
Full Text :
https://doi.org/10.1182/blood-2017-06-788323