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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.

Author information

1
Mayo Clinic, Rochester, MN.
2
Winship Cancer Institute of Emory University, Atlanta, GA.
3
Hematologic Malignancies & Cellular Therapy, Duke University, Durham, NC.
4
Mayo Clinic, Scottsdale, AZ.
5
Washington University School of Medicine, St. Louis, MO.
6
Centre Hospitalier Universitaire, Grenoble, France.
7
Centre Hospitalier Regional Universitaire, Tours, France.
8
Centre Hospitalier Regional Universitaire Lille, Hopital Huriez, Lille, France.
9
Centre Hospitalier Universitaire de Nantes, INSERM, Université de Nantes, France.
10
Genentech Inc., South San Francisco, CA; and.
11
AbbVie Inc., North Chicago, IL.

Abstract

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.

PMID:
29018077
DOI:
10.1182/blood-2017-06-788786
[Indexed for MEDLINE]
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