Eckert, Doerthe

Abstract Venetoclax, a potent BCL‐2 inhibitor, is currently under development for treatment of t(11;14) Multiple myeloma (MM). The objective of this research was to investigate the exposure–response relationships of venetoclax for a phase 1/2 study evaluating venetoclax monotherapy or in combination with dexamethasone in relapsed or refractory MM. A total of 117 patients receiving venetoclax at 300, 600, 800, 900, or 1200 mg were included in the analysis. The impact of venetoclax exposures on efficacy (objective response rate [ORR], progression‐free survival [PFS] and overall survival [OS]) as well as safety (treatment‐emergent adverse effects (grade ≥3) of neutropenia, infection, and any grade of serious treatment‐emergent adverse effects) was evaluated. In the t(11;14)‐positive subpopulation, venetoclax exposure relationships to PFS and OS indicated a trend of longer PFS and OS with higher exposures. Moreover, logistic regression analyses for clinical response (ORR and ≥VGPR rate) demonstrated a statistically significant ( p < 0.05) relationship with exposure. Evaluation of the exposure‐safety relationships demonstrated a lack of a relationship between venetoclax exposures (AUC avg ) and grade ≥3 infections, grade ≥3 neutropenia, grade ≥3 treatment‐emergent adverse events or any grade serious treatment‐emergent adverse events. These findings support further study of venetoclax at 800 mg QD dose in combination with dexamethasone in the t(11;14)‐positive patient population where increased efficacy was observed without an increase in safety events.Clinical Trial: NCT01794520 registered 20 February 2013.