Marc Cerou 1, Antoine Pitoy 1, Jean-Baptiste Fau 1, Corina Oprea 2, Dorothée Semiond 1, Hoai-Thu Thai 1
1 Sanofi, Translational Medicine Unit, Quantitative Pharmacology (, ), 2 Sanofi, Oncology Development (, )
Objectives: Carfilzomib and dexamethasone (Kd) is an effective treatment option for patients with relapsed/refractory multiple myeloma (RRMM). The addition of the anti-CD38 monoclonal antibody Isatuximab (Isa) to the Kd regimen was associated with a significant and clinically meaningful benefit in progression-free survival (PFS) in RRMM patients previously treated with 1 to 3 prior lines (IKEMA, NCT03275285) [1]. The aims of this work were (1) to characterize the effects of treatment and baseline covariates on serum M-protein kinetics and the link to PFS in RRMM patients in both arms of the IKEMA trial using a joint modeling framework and (2) to evaluate alternative dosing regimens by simulations.
Methods: Data from the IKEMA trial comparing Isa 10 mg/kg weekly for 4 weeks then every 2 weeks (QW/Q2W) in combination with Kd versus Kd in 269 evaluable RRMM patients were used. Longitudinal data of serum M-protein and PFS data were first analyzed separately and then in a joint model to characterize the link between serum M-protein and PFS [2]. The relationships between baseline covariates and model parameters were evaluated using univariate analysis followed by the automatic covariate selection procedure based on the correlation tests (COSSAC). Trial simulations were performed to evaluate whether efficacy is maintained after switching to monthly regimen after 6 or 12 months. Simulations (N=1000 trials) were based on individual PK/PD parameters of IKEMA patients in IKd arm and Kd arm. Model parameters were estimated using the SAEM algorithm implemented in Monolix2024R1; simulations were performed using SimulX2024R1 and R version 4.4.0.
Results: The best longitudinal model for serum M-protein involved a two-compartment PK model for Isa with parallel linear and nonlinear elimination and time-dependence of the linear clearance (3), a K-PD model for Kd dosing data and a Claret TGI model for serum M-protein data with treatment effect driven by exposure (i.e., average daily AUC) of the 3 drugs. For PFS, a log-logistic model best characterized the baseline hazard distribution. The best link between serum M-protein and PFS was the dynamic difference in M-protein relative to its current lowest value. The significant baseline covariates in the joint model were serum albumin, beta-2-microglobulin (B2MG), bone marrow plasma cells (BMPC), revised international staging system (R-ISS), cytogenetic risks, Fc gamma, IgG MM type, bilirubin (BILN). Baseline M-protein tends to increase with lower serum albumin levels, higher β2-microglobulin levels or higher % of plasma cells in bone marrow. A higher proliferation rate was observed in non-IgG patients, those with high cytogenetic risk, and with lower serum albumin levels. An increased kill rate under Kd exposure was detected in non-IgG patients, while lower bilirubin levels were associated with increased resistance. Regarding PFS, the FCGR3A F/F genotype was associated with a protective effect, though the underlying mechanism remains unclear and may involve confounding factors. A higher RISS status (RISS = 3) or high cytogenetic risk were associated with higher risk of progression. Simulation results suggested that switching to monthly regimen after 12 months would have a minimal impact on clinical benefit compared to QW/Q2W regimen at the population level: slightly higher HR (0.705 vs 0.643). An earlier switch at 6 months demonstrated nearly comparable population-level outcomes (HR = 0.727 vs. 0.705); however, the difference became more slightly pronounced when compared to the QW/Q2W regimen. Among patients at risk at the time of switch (96.8% at 6M and 86% at 12M), switching to monthly dosing after 12 months shortened time to progression (TTP) by a median of 6.3 months in 8.1% of patients who progressed ≥4 weeks earlier than with QW/Q2W regimen. The 6-month switch showed greater individual level impact, with TTP shortened by a median of 8.3 months in 14.4 % of patients who progressed ≥4 weeks earlier than with QW/Q2W regimen.
Conclusions: This analysis supports the use of monthly ISA dosing regimens after 12 months for all patients in RRMM patients without compromising the efficacy compared to the approved QW/Q2W regimen.
References:
1. Moreau P, Dimopoulos MA, Mikhael J, et al. Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised phase 3 trial. Lancet. 2021;397(10292):2361-2371.
2. Thai H-T, Gaudel N, Cerou M, Ayral G, Fau J-B, Sebastien B, et al. Joint modelling and simulation of M-protein dynamics and progression-free survival for alternative isatuximab dosing with pomalidomide/dexamethasone. British Journal of Clinical Pharmacology. 2022;88(5):2052-64.
3. Fau, J.-B., El-Cheikh, R., Brillac, C., Koiwai, K., Mace, N., Campana, F., Semiond, D. and Nguyen, L. Drug-Disease Interaction and Time-Dependent Population Pharmacokinetics of Isatuximab in Relapsed/Refractory Multiple Myeloma Patients. CPT Pharmacometrics Syst Pharmacol.2020, 9: 649-658.
Reference: PAGE 34 (2026) Abstr 11983 [www.page-meeting.org/?abstract=11983]
Poster: Drug/Disease Modelling - Oncology