Population pharmacokinetic and exposure-response analyses of elotuzumab plus pomalidomide and dexamethasone for relapsed and refractory multiple myeloma.

Purpose: Elotuzumab plus pomalidomide/dexamethasone (E-Pd) demonstrated efficacy and safety in relapsed and refractory multiple myeloma (RRMM). The clinical pharmacology of elotuzumab [± lenalidomide/dexamethasone (Ld)] was characterized previously. These analyses describe elotuzumab population pharmacokinetics (PPK), the effect of Pd, and assess elotuzumab exposure-response relationships for efficacy and safety in patients with RRMM.

Methods: A previously established PPK model was updated with E-Pd data from the phase 2 ELOQUENT-3 study (NCT02654132). The dataset included 8180 serum concentrations from 440 patients with RRMM from 5 clinical trials. Elotuzumab PK parameter estimates were used to generate individual daily time-varying average concentrations (daily C) for multi-variable time-to-event exposure-response analyses of progression-free survival (PFS) and time to the first occurrence of grade 3 + adverse events (AEs) in RRMM.

Results: Elotuzumab PK were well-described by a two-compartment model with parallel linear and Michaelis-Menten elimination from the central compartment (V) and non-renewable target-mediated elimination from the peripheral compartment (K). Co-administration with Pd resulted in a 19% and 51% decrease in elotuzumab linear clearance and K, respectively, versus Ld; steady-state exposures were similar. V increased with increasing serum M-protein. Hazard ratios (95% confidence intervals) for daily C were 0.9983 (0.9969-0.9997) and 0.9981 (0.9964-0.9998) for PFS and grade 3 + AEs, respectively.

Conclusions: The PPK model adequately described the data and was appropriate for determining exposures for exposure-response analyses. There were no clinically relevant differences in elotuzumab exposures between Pd and Ld backbones. In ELOQUENT-3, increasing elotuzumab daily C prolonged PFS without increasing grade 3 + AEs.