Hoai-Thu Thai 1, Marc Cerou 1, Jean-Baptiste Fau 2, Maya Stefanova-Urena 3, Florence Suzan 4, Dorothée Semiond 5
1 Sanofi, Translational Medicine Unit, Quantitative Pharmacology (Gentilly, France), 2 Sanofi, Translational Medicine Unit, Quantitative Pharmacology (Vitry-sur-Seine, France), 3 Sanofi, Oncology Development (Morristown, USA), 4 Sanofi, Oncology Development (Vitry-sur-Sein, USA), 5 Sanofi, Translational Medicine Unit, Quantitative Pharmacology (Cambridge, USA)
Introduction: The subcutaneous (SC) formulation of isatuximab (Isa) combined with pomalidomide and dexamethasone (Pd) demonstrated non-inferiority to Isa intravenous (IV) in relapsed/refractory multiple myeloma (RRMM) patients in the IRAKLIA phase 3 study (NCT05405166), meeting co-primary endpoints of overall response rate and steady-state trough levels [1]. The objectives of the present analysis were (i) to characterize treatment effects on serum M-protein dynamics in RRMM patients receiving isatuximab combined with Pd, (ii) to identify baseline covariates impacting M-protein response, and (iii) to compare the efficacy of isatuximab SC 1400 mg administered via on-body delivery system (OBDS) versus the approved IV dose of 10 mg/kg weekly for 4 weeks then every 2 weeks (QW/Q2W) in combination with Pd.
Methods: Data from 367 M-protein evaluable RRMM patients from the IRAKLIA study were included in this analysis. A tumor growth inhibition (TGI) model accounting for M-protein dynamics, antitumor drug effect, and resistance was developed. Treatment exposure was incorporated using individual predicted pharmacokinetic (PK) parameters for isatuximab from the population PK model and a kinetic-pharmacodynamic (K-PD) model for Pd. Covariate relationships were evaluated using univariate analysis followed by automatic covariate selection based on correlation tests (COSSAC) [2], retaining only the significant covariates by Wald test (p<0.05). Simulations using the SC arm population (N=177) and individual PK/PD parameters compared Isa-SC 1400 mg OBDS versus IV 10 mg/kg. Time to progression (TTP) based on IMWG M-protein criteria (≥25% increase from nadir with ≥5 g/L) was derived from simulated M-protein profiles. Model selection was based on the corrected version of Bayesian Information Criteria (BICc). Model parameters were estimated using the SAEM algorithm in Monolix2024R1; simulations were performed using SimulX2024R1 and R version 4.4.0. Results: Longitudinal serum M-protein data were best described by the Claret TGI model, consistent with the model previously published with ICARIA-MM data [3], where isatuximab and Pd stimulate M-protein elimination. A common resistance rate for all agents was assumed given the absence of Pd-alone data. Individual parameter distributions were highly similar between SC and IV arms, indicating comparable M-protein response. Treatment arm effects tested on five TGI parameters were not statistically significant (Wald test) and the models including treatment effects increased BICc, confirming formulation equivalence. Seven baseline covariates were identified: age, serum albumin, beta-2 microglobulin (B2MG), hemoglobin, and normalized lactate dehydrogenase (LDHN) affected baseline M-protein levels; B2MG and immunoglobulin type (Ig MM) influenced M-protein proliferation rate; Ig MM type affected isatuximab-induced shrinkage; and B2MG and race (Asian vs Non-Asian) impacted Pd-induced shrinkage. Patients with low albumin or low hemoglobin or low lactate dehydrogenase, or elevated B2MG presented higher baseline M-protein. Non-IgG patients demonstrated faster M-protein reduction and slower regrowth versus IgG patients. Asian patients exhibited faster response and slower regrowth compared to non-Asian patients. Elderly patients (76.8 years) showed accelerated tumor regrowth despite lower baseline M-protein versus typical patients (67 years). Simulations suggested that Isa-SC 1400 mg would induce similar decreases in serum M-protein from baseline and slightly slower M-protein regrowth after 18 months versus Isa-IV 10 mg/kg, with comparable TTP profiles. In patients with extreme body weights (≤50 kg or ≥100 kg), Kaplan-Meier estimates of TTP remained similar regardless of formulation, supporting no dose adjustment requirement. Conclusions: Isatuximab SC 1400 mg provides at least comparable efficacy to IV 10 mg/kg in M-protein reduction and time to progression when combined with Pd. This analysis confirms the SC 1400 mg dose via OBDS for RRMM treatment and justifies no dose adjustment across body weight subgroups. References: 1. Ailawadhi S et all. Isatuximab Subcutaneous by On-Body Injector Versus Isatuximab Intravenous Plus Pomalidomide and Dexamethasone in Relapsed/Refractory Multiple Myeloma: Phase III IRAKLIA Study. J Clin Oncol. 2025 Aug;43(22):2527-2537. 2. Ayral G, et al. A novel method based on unbiased correlations tests for covariate selection in nonlinear mixed effects models: The COSSAC approach. CPT Pharmacometrics Syst Pharmacol. 10, 318–329 (2021). 3. Thai H, et al. Joint modelling and simulation of M-protein dynamics and progression-free survival for alternative isatuximab dosing with pomalidomide/dexamethasone. Br J Clin Pharmacol. 88, 2052–2064 (2022).
Reference: PAGE 34 (2026) Abstr 12269 [www.page-meeting.org/?abstract=12269]
Poster: Drug/Disease Modelling - Oncology