Population cellular kinetics of idecabtagene vicleucel in patients with triple-class-exposed relapsed/refractory multiple myeloma
Authors: Wu Fan , Zheng Xirong , Zhou Jian , Masilamani Madhan , Cheng Yiming , Caia Andrea , Cook Mark , Piasecki Julia , Lamba Manisha 
Published: February 2025

Ide-cel (Idecabtagene Vicleucel, ABECMA) is an autologous, B-cell maturation antigen (BCMA)-directed, chimeric antigen receptor (CAR) T-cell therapy, which has demonstrated significantly improved progression-free survival and overall response rate in patients with Triple-Class-Exposed Relapsed/Refractory Multiple Myeloma (TCE RRMM) [1]. The current modeling analyses aim to characterize cellular kinetics of ide-cel and to assess covariate effects impacting ide-cel cellular kinetics A modified piecewise model was developed to characterize the cellular kinetics (CK) through the nonlinear mixed effect method provided in Monolix (Version 2020R1) . The model parameterization was conducted using the ide-cel whole-blood transgene data in CK evaluable subjects (N&#3f221) from the ide-cel arm of Study KarMMa-3 (NCT03651128). The structural model consists of an initial lag phase and then saturable cell expansion, followed by conversion from effector cells to memory cells and their elimination. Covariates for the analyses include actual ide-cel doses, baseline demographic factors, disease characteristics, baseline anti-therapeutic antibodies (ATA) status, and formulation. The treatment-associated ATA status was included as a time-varying covariate in the model. Model simulations were further performed to evaluate correlation between cellular kinetic parameters and objective responses or progression-free survival.The piecewise CK model with saturable expansion sufficiently captured the clinically observed ide-cel transgene data. The estimated population CK parameters were 228 copies/ug for initial transgene level (E0), 2.09 days for lag in expansion (Tlag), 8.61 days for time of maximal expansion (Tmax), 6.97×10^4 cells/day for maximal expansion rate (Vmax), 5.51×10^4 cells for a transgene level at which expansion rate is saturated to half of Vmax (Km), 3.20×10^-4 1/day for conversion rate from effector cells to memory cells (r), 0.113 1/day for elimination rate of effector cells (dE), and 5.30×10^-4 1/day for elimination rate of memory cells (dM). The analyses suggested that post-infusion ATA appeared to increase elimination of memory CAR T cells and reduce persistence of ide-cel. In addition, the population cellular kinetics analyses did not identify any clinically relevant covariate effects on ide-cel kinetics, which were smaller than the between-subject variability in the population.This is the first quantitative characterization of cellular kinetics of ide-cel, a BCMA targeting cellular therapy for MM, using patient-level data. The cellular kinetics of ide-cel can be adequately described by the modified piecewise model. No clinically relevant covariate effects on cellular kinetics were identified from this modeling study. The population CK model suggests that higher cell expansion rate, lower effector-to-memory-cells conversion rate, and lower elimination rates of effector and memory cells were observed in responders or patients with longer PFS.Citations: [1] Rodriguez‑Otero P et al., Ide-cel or Standard Regimens in Relapsed and Refractory Multiple Myeloma, N Engl J Med 2023;388:1002-1014