Targeting BCL ‐2 with venetoclax and dexamethasone in patients with relapsed/refractory t(11;14) multiple myeloma

作者：Jonathan L. Kaufman, Cristina Gasparetto, Fredrik Schjesvold, Philippe Moreau, Cyrille Touzeau, Thierry Façon, Lawrence Boise, Yanwen Jiang, Xiaoqing Yang, Fengjiao Dunbar, Deeksha Vishwamitra, Stefanie Unger, Tammy Macartney, John C. Pesko, Yao Yu, Ahmed Hamed Salem, Jeremy A. Ross, Wan‐Jen Hong, Paulo Maciag, James M. Pauff, Shaji Kumar · 发表于：American Journal of Hematology · 年份：2020 · DOI：10.1002/ajh.26083 · 被引用次数：112 · 研究领域：Multiple Myeloma Research and Treatments、Protein Degradation and Inhibitors、Peptidase Inhibition and Analysis

Abstract Venetoclax (Ven) is a selective small‐molecule inhibitor of BCL‐2 that exhibits antitumoral activity against MM cells with t(11;14) translocation. We evaluated the safety and efficacy of Ven and dexamethasone (VenDex) combination in patients with t(11;14) positive relapsed/refractory (R/R) multiple myeloma (MM). This open‐label, multicenter study had two distinct phases (phase one [P1], phase two [P2]). Patients in both phases received VenDex (oral Ven 800 mg/day + oral Dex 40 mg [20 mg for patients ≥75 years] on days 1, 8, and 15, per 21–day cycle). The primary objective of the P1 VenDex cohort was to assess safety and pharmacokinetics. Phase two further evaluated efficacy with objective response rate (ORR) and very good partial response or better. Correlative studies explored baseline BCL2 (BCL‐2) and BCL2L1 (BCL‐XL) gene expression, cytogenetics, and recurrent somatic mutations in MM. Twenty and 31 patients in P1 and P2 with t(11;14) positive translocation received VenDex. P1/P2 patients had received a median of 3/5 lines of prior therapy, and 20%/87% were refractory to daratumumab. Predominant grade 3/4 hematological adverse events (AEs) with ≥10% occurrence included lymphopenia (20%/19%), neutropenia (15%/7%), thrombocytopenia (10%/10%), and anemia (5%/16%). At a median follow‐up of 12.3/9.2 months, ORR was 60%/48%. The duration of response estimate at 12 months was 50%/61%, and the median time to progression was 12.4/10.8 months. In biomarker evaluable patients...