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

• Published in: Blood Vol. 130; no. 22; pp. 2392 - 2400
• Main 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.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30.11.2017
• Subjects: Adult; Aged; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Bortezomib - administration & dosage; Bortezomib - adverse effects; Bortezomib - therapeutic use; Bridged Bicyclo Compounds, Heterocyclic - administration & dosage; Bridged Bicyclo Compounds, Heterocyclic - adverse effects; Bridged Bicyclo Compounds, Heterocyclic - therapeutic use; Dexamethasone - administration & dosage; Dexamethasone - adverse effects; Dexamethasone - therapeutic use; Female; Humans; Male; Middle Aged; Multiple Myeloma - drug therapy; Neoplasm Recurrence, Local - drug therapy; Sulfonamides - administration & dosage; Sulfonamides - adverse effects; Sulfonamides - therapeutic use; Treatment Outcome
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2017-06-788323

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. •In relapsed/refractory MM, venetoclax plus bortezomib and dexamethasone appears to be safe and efficacious.•This is a novel therapeutic approach for MM. [Display omitted]