P-229: Exposure-Response Analysis of Venetoclax in Combination with Carfilzomib and Dexamethasone in t(11;14)-Positive Relapsed/Refractory Multiple Myeloma Patients

Introduction: Venetoclax is a first in class, selective BCL2 inhibitor that has gained approval for the treatment of CLL and AML and is currently being evaluated in other hematological indications including multiple myeloma (MM). This analysis aimed to characterize the exposure-response relationship of venetoclax (Ven) when administered in combination with carfilzomib and dexamethasone (Kd) in the biomarker selected, t(11;14)-positive relapsed/refractory MM patients.

Methods: 55 subjects enrolled in Study NCI: NCT02899052 (37 receiving VenKd and 18 in the control arm receiving Kd) were included in the analysis. A population pharmacokinetic model was developed, and individual post hoc empirical Bayes parameter estimates were used to derive individual subject venetoclax exposures (average area under the concentration time curve to the time of event [AUCavg] and steady state AUC [AUCss]). Quartile plots and logistic regression models were used to evaluate the exposure-efficacy and exposure-safety relationships of venetoclax. Efficacy endpoints assessed included clinical response of overall response rate (ORR), very good partial response or better (≥VGPR) rate and complete response or better (≥CR) rate. Safety endpoints evaluated included Grade ≥3 neutropenia, Grade ≥3 infections, Grade ≥3 treatment emergent adverse events and any grade serious treatment-emergent adverse events.

Results: Quartile plots demonstrated that compared to the control arm (Kd), adding venetoclax resulted in higher OR, ≥VGPR and ≥CR rates. Within the VenKd treatment arms, a flat exposure-response relationship for Ven was observed for all efficacy endpoints (ORR, ≥VGPR and ≥CR rates) suggesting that efficacy is maximized, and higher venetoclax exposures may not be associated with improved efficacy compared to lower exposures at the studied dose range of 400-800 mg. Both 400 mg and 800 mg venetoclax were generally tolerated, however exposure-safety analysis demonstrated that higher venetoclax exposures (associated with 800 mg venetoclax) trended with higher rates of Grade ≥3 neutropenia. Higher venetoclax exposures were not associated with higher rates of Grade ≥3 infections, Grade ≥3 treatment-emergent adverse events, or serious treatment-emergent adverse events (any grade). Study is ongoing and enrolling subjects; more mature data may be presented at the congress.

Conclusions: Exposure-response analyses confirm the benefit of adding venetoclax at 400-800 mg doses to carfilzomib and dexamethasone and support continued evaluation of the VenKd combination in the biomarker selected t(11;14)-positive relapsed/refractory MM population.