TY - JOUR
T1 - Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma
AU - Kumar, Shaji
AU - Kaufman, Jonathan L.
AU - Gasparetto, Cristina
AU - Mikhael, Joseph
AU - Vij, Ravi
AU - Pegourie, Brigitte
AU - Benboubker, Lofti
AU - Facon, Thierry
AU - Amiot, Martine
AU - Moreau, Philippe
AU - Punnoose, Elizabeth A.
AU - Alzate, Stefanie
AU - Dunbar, Martin
AU - Xu, Tu
AU - Agarwal, Suresh K.
AU - Enschede, Sari Heitner
AU - Leverson, Joel D.
AU - Ross, Jeremy A.
AU - Maciag, Paulo C.
AU - Verdugo, Maria
AU - Touzeau, Cyrille
N1 - Funding Information:
Venetoclax is being developed in collaboration between AbbVie and Genentech. AbbVie and Genentech provided financial support for the study and participated in the design, study conduct, analysis and interpretation of data, as well as the writing, review, and approval of the manuscript. This study was supported by research funding from AbbVie and Genentech to S.K., J.L.K., C.G., J.M., R.V., B.P., L.B., T.F., M.A., P.M., and C.T.
Publisher Copyright:
© 2017 by The American Society of Hematology.
PY - 2017/11/30
Y1 - 2017/11/30
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85036544223&partnerID=8YFLogxK
U2 - 10.1182/blood-2017-06-788786
DO - 10.1182/blood-2017-06-788786
M3 - Article
C2 - 29018077
AN - SCOPUS:85036544223
SN - 0006-4971
VL - 130
SP - 2401
EP - 2409
JO - Blood
JF - Blood
IS - 22
ER -