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

Shaji Kumar*, Jonathan L. Kaufman, Cristina Gasparetto, Joseph Mikhael, Ravi Vij, Brigitte Pegourie, Lofti Benboubker, Thierry Facon, Martine Amiot, Philippe Moreau, Elizabeth A. Punnoose, Stefanie Alzate, Martin Dunbar, Tu Xu, Suresh K. Agarwal, Sari Heitner Enschede, Joel D. Leverson, Jeremy A. Ross, Paulo C. Maciag, Maria VerdugoCyrille Touzeau

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

383 Scopus citations


Venetoclax is a selective, orally bioavailable BCL-2 inhibitor that induces cell death in multiple myeloma (MM) cells, particularly in those harboring t(11;14), which express high levels of BCL-2 relative to BCL-XL and MCL-1. In this phase 1 study, patients with relapsed/refractory MM received venetoclax monotherapy. After a 2-week lead-in with weekly dose escalation, daily venetoclax was given at 300, 600, 900, or 1200 mg in dose-escalation cohorts and 1200 mg in the safety expansion. Dexamethasone could be added on progression during treatment. Sixty-six patients were enrolled (30, dose-escalation cohorts; 36, safety expansion). Patients received a median of 5 prior therapies (range, 1-15); 61% were bortezomib and lenalidomide double refractory, and 46% had t(11;14). Venetoclax was generally well tolerated. Most common adverse events included mild gastrointestinal symptoms (nausea [47%], diarrhea [36%], vomiting [21%]). Cytopenias were the most common grade 3/4 events, with thrombocytopenia (32%), neutropenia (27%), anemia (23%), and leukopenia (23%) reported. The overall response rate (ORR) was 21% (14/66), and 15% achieved very good partial response or better (‡VGPR). Most responses (12/14 [86%]) were reported in patients with t(11;14). In this group, ORR was 40%, with 27% of patients achieving ‡VGPR. Biomarker analysis confirmed that response to venetoclax correlated with higher BCL2:BCL2L1 and BCL2:MCL1 mRNA expression ratios. Venetoclax monotherapy at a daily dose up to 1200 mg has an acceptable safety profile and evidence of single-agent antimyeloma activity in patients with relapsed/refractory MM, predominantly in patients with t(11;14) abnormality and those with a favorable BCL2 family profile. Registered at www.clinicaltrials.gov: #NCT01794520.

Original languageEnglish
Pages (from-to)2401-2409
Number of pages9
Issue number22
StatePublished - 30 Nov 2017
Externally publishedYes


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