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.