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

Orvacabtagene autoleucel (orva-cel; JCARH125), a chimeric antigen receptor T-cell therapy targeting B-cell maturation antigen, was evaluated in patients with relapsed/refractory multiple myeloma in the EVOLVE phase I/II 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).

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 biexponential 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 (50–600 × 10⁶ CD3⁺ chimeric antigen receptor⁺ T cells), prior/concomitant medications, baseline disease burden, and antitherapeutic antibody status.

Traditional piecewise models failed to accurately describe maximum orva-cel transgene level (C_max) and underestimated the time to C_max (T_max). Our modified model incorporating a cell number–dependent expansion rate outperformed traditional models by (i) more accurately capturing the cellular expansion phase and (ii) yielding a T_max that closely matches observed values. Additionally, dose level, percentage of plasma cells in bone marrow, and treatment-induced antitherapeutic antibody were identified as statistically significant covariates and associated with orva-cel expansion and/or persistence.

Orva-cel PK was adequately described by the modified piecewise model incorporating a cell number–dependent expansion phase, which aligns closely with T-cell biology.