Population Pharmacokinetics of Orvacabtagene Autoleucel, an Autologous BCMA-Directed Chimeric Antigen Receptor T-Cell Product, in Patients with Relapsed/Refractory Multiple Myeloma.

PURPOSE Orvacabtagene autoleucel (orva-cel; JCARH125), a CAR T-cell therapy targeting B-cell maturation antigen (BCMA), was evaluated in relapsed/refractory multiple myeloma (RRMM) patients in the EVOLVE phase 1/2 study (NCT03430011). We applied a modified piecewise model to characterize orva-cel transgene kinetics and assessed the impact of various covariates on its pharmacokinetics (PK). EXPERIMENTAL DESIGN The population PK analysis included 159 patients from the EVOLVE study. Traditional piecewise models, employing a first-order expansion rate with or without lag time followed by a bi-exponential contraction phase, were compared with a modified model incorporating a cell number-dependent expansion phase aligned with cellular physiology. Covariates assessed encompassed baseline demographics, dose levels (50 to 600 × 106 CD3+ CAR+ T cells), prior/concomitant medications, baseline disease burden, and anti-therapeutic antibody (ATA) status. RESULTS Traditional piecewise models failed to accurately describe maximum orva-cel transgene level (Cmax) and underestimated the time to Cmax (Tmax). Our modified model incorporating a cell number-dependent expansion rate outperformed traditional models by 1) more accurately capturing the cellular expansion phase, and 2) yielding a Tmax that closely matches observed values. Additionally, dose level, percentage of plasma cells in bone marrow, and treatment-induced ATA were identified as statistically significant covariates and associated with orva-cel expansion and/or persistence. CONCLUSIONS Orva-cel PK were adequately described by the modified piecewise model incorporating a cell number-dependent expansion phase, which aligns closely with T cell biology.