Simultaneous Population PKPD Analysis of Belantamab Mafodotin, Soluble BCMA, and Serum M-Protein in Relapsed/Refractory Multiple Myeloma

Abstract

A simultaneous pharmacokinetic (PK)/pharmacodynamic (PD) analysis was conducted to characterize relationships between anti-B-cell maturation antigen (BCMA)-targeting antibody-drug conjugate, belantamab mafodotin, and longitudinal multiple myeloma (MM) disease markers (soluble BCMA [sBCMA], M-protein). Data from patients with relapsed/refractory MM receiving belantamab mafodotin monotherapy in the DREAMM-1 (NCT02064387), DREAMM-2 (NCT03525678), DREAMM-3 (NCT04162210), or DREAMM-5 (NCT04126200) trials were included. The dataset contained 510 patients with 15,860 PK and PD observations. Previous population PK and M-protein PD models were combined to create a new starting model. Overparameterization was reduced using sensitivity analyses to create a 2-compartment base model for belantamab mafodotin with a linear clearance component and target-mediated drug disposition assuming quasi-equilibrium between belantamab mafodotin and sBCMA binding. Free belantamab mafodotin affected M-protein elimination rate via a direct effect, and M-protein in turn scaled sBCMA synthesis rate. sBCMA was assumed to transfer into the central free sBCMA compartment through a reservoir compartment, allowing capture of observed differences in timescales. Stepwise covariate modeling led to the final model, which contained eight covariate effects (baseline sBCMA, albumin, body weight, and sex on belantamab mafodotin clearance; baseline body weight and sex on belantamab mafodotin central volume of distribution; extramedullary disease at screening and baseline sBCMA on M-protein death rate constant). Simulations of belantamab mafodotin doses/schedules showed concentrations of free sBCMA and M-protein decreased as free and total belantamab mafodotin increased with higher doses. The PKPD model captured the clearance of belantamab mafodotin and the highly dynamic interactions between belantamab mafodotin PK, M-protein, and sBCMA.