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

Abstract

Key Points• In relapsed/refractory MM, venetoclax plus bortezomib and dexamethasone appears to be safe and efficacious.• This is a novel therapeutic approach for MM.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 smallmolecule 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. (Blood. 2017;130(22):2392-2400

Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma

“…28 Accordingly, an ongoing phase 1b study of venetoclax in combination with bortezomib and dexamethasone (NCT01794507) has shown high response rates in patients with relapsed/refractory MM irrespective of t (11;14) status. 29 In the present study, the addition of dexamethasone at the time of progression did not appear to add any clinical benefit for patients on venetoclax monotherapy.…”

Found in Translation: How Preclinical Research Is Guiding the Clinical Development of the BCL2-Selective Inhibitor Venetoclax

“…Based on this strong mechanistic rationale and a strong preclinical data package, a phase 1 study investigating the combination of venetoclax with bortezomib and dexamethasone was initiated. Preliminary results have shown an acceptable safety profile and promising responses, particularly in patients naïve or sensitive to prior bortezomib therapy (78). Synergistic effects with BCL-2 antagonists have also been explored with histone deacetylase and insulin-like growth factor-1 inhibitors as potential therapeutic options for patients with MM (79–81).…”

BCL-2 Inhibition in the Treatment of Multiple Myeloma

“…Moreover, for those patients not refractory to proteasome inhibitors and immunomodulatory agents, the response rate for the triple combination reached an impressive 92%. Overall response rates were similar across different cytogenetic profiles; most notably it was 47% in those patients [15] who had deletion 17p, a particularly high-risk subgroup with severely compromised apoptosis process. The importance of high BCL-2 expression predicting better and more prolonged clinical response was also underlined in this study.…”

“…It was also shown that dexamethason sensitizes myeloma cell lines and primary myeloma cells to venetoclax activity, therefore clinical study M12-901 was initiated to test this triple combination (bortezomib-venetoclaxdexamethason) in relapsed/refractory myeloma patients [15]. Here, the objective response level reached 67% and was not restricted at all to t(11;14) patients, proving the validity of the approach.…”