Purpose: 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).
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 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.
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 (i) more accurately capturing the cellular expansion phase and (ii) yielding a Tmax 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.
Conclusions: 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.
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