Elranatamab Population Pharmacokinetics and Exposure–Response for Cytokine Release Syndrome in Patients with Relapsed or Refractory Multiple Myeloma

A population pharmacokinetics (PopPK) model was developed for elranatamab, a bispecific antibody targeting both B-cell maturation antigen (BCMA) and cluster of differentiation 3 (CD3), to characterize the PopPK of elranatamab and guide clinical development. Elranatamab is approved in several countries for the treatment of relapsed or refractory multiple myeloma. The PopPK model incorporated data from four clinical studies and described both free and total elranatamab as well as soluble BCMA (sBCMA) using a semi-mechanistic two-compartment target-binding model. In total there were 13,233 observations from 321 participants who received intravenous (IV) or subcutaneous (SC) elranatamab monotherapy with doses ranging from 0.1 to 1000 µg/kg. Elranatamab exhibited approximately linear PK over the dose range evaluated (i.e., 6–76 mg SC), with limited cellular target-mediated drug disposition and generally proportional exposure, with modest deviations at very high baseline sBCMA. None of the potential covariates evaluated, including age, sex, body weight, baseline sBCMA, and immunogenicity, were found to be clinically significant predictors of elranatamab exposure. Exposure–response analyses identified early peak exposure and tumor burden as key predictors of cytokine release syndrome (CRS), primarily after the first step-up dose. Simulations supported restarting treatment without re-priming after dose interruptions of up to 12 weeks. These findings support the approved fixed-dose regimen and provide a framework for clinical management of elranatamab in relapsed or refractory multiple myeloma. NCT03269136, NCT04798586, NCT04649359, NCT05014412.