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

Abstract 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.