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Blood. 2017 Nov 30;130(22):2401-2409. doi: 10.1182/blood-2017-06-788786. Epub 2017 Oct 10.

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

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Mayo Clinic, Rochester, MN.
Winship Cancer Institute of Emory University, Atlanta, GA.
Hematologic Malignancies & Cellular Therapy, Duke University, Durham, NC.
Mayo Clinic, Scottsdale, AZ.
Washington University School of Medicine, St. Louis, MO.
Centre Hospitalier Universitaire, Grenoble, France.
Centre Hospitalier Regional Universitaire, Tours, France.
Centre Hospitalier Regional Universitaire Lille, Hopital Huriez, Lille, France.
Centre Hospitalier Universitaire de Nantes, INSERM, Université de Nantes, France.
Genentech Inc., South San Francisco, CA; and.
AbbVie Inc., North Chicago, IL.


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 #NCT01794520.

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