Treatment of Newly Diagnosed Myeloma (excluding t-cell redirection therapy)

Category: Treatment of Newly Diagnosed Myeloma (excluding t-cell redirection therapy)

Model-based assessment of monthly isatuximab dosing performance in newly diagnosed multiple myeloma patients using IMROZ phase 3 data

(PA-439) Model-based Assessment of Monthly Isatuximab Dosing Performance in Newly Diagnosed Multiple Myeloma Patients Using IMROZ Phase 3 Data

Thursday, September 18, 2025

Dorothee Semiond, PhD

Research and Development
Sanofi

Introduction: Isatuximab (Isa) with bortezomib, lenalidomide and dexamethasone (VRd) is associated with a significant benefit in progression-free survival (PFS) in patients (pts) with newly diagnosed multiple myeloma (NDMM) ineligible for transplant (IMROZ, NCT03319667). As approximately 70% of Isa-VRd pts achieved very good partial response (VGPR) within the first 3 mo and maintained it, an earlier switch to monthly Isa dosing than the current 18-mo may reduce treatment burden without compromising efficacy. The current study evaluates alternative dosing strategies via simulation, using joint modeling of serum M-protein dynamics and PFS within the IMROZ trial framework.

Methods:   Data from IMROZ comparing Isa 10mg/kg QW for 4 wk then Q2W, then Q4W at cycle 18 onwards in combination with VRd vs VRd in 357 evaluable NDMM pts were used. Longitudinal data of serum M-protein and PFS data were analyzed separately then in a joint model to describe their association using Monolix 2024R1. A tumor growth inhibition model was developed to describe serum M-protein dynamics, accounting for tumor growth, isatuximab-induced anti-tumor effect, combined with VRd, along with drug resistance effect. A covariate analysis assessed baseline pts characteristics’ influence on serum M-protein kinetics and PFS. Trial simulations evaluated if efficacy is maintained upon switching to a Q4W dosing after 6 or 12 mo versus approved 18 mo, including a targeted approach for pts achieving 3 mo-stable ≥VGPR status (≥90% reduction of M-protein from baseline with ≥5 g/L and disease stability over the last 3 mo).

Results:   Isa and VRd individual drug exposures (average daily AUC) were used to predict treatment effect on serum M-protein. The dynamic difference in M-protein relative to its current lowest value was the best on-treatment predictor of PFS. Pts with high β-microglobulin tended to have higher serum M-protein at baseline and higher risk of progression; non-IgG pts were likely to have faster M-protein shrinkage rate induced by VRd, causing faster M-protein decrease during first 6 mo but similar PFS vs IgG pts. Simulation results showed switching to monthly regimen after 12 mo instead of 18 minimally impacted efficacy: 60-mo PFS rate (76.2 vs 77.7%), HR (0.543 vs 0.518), 12.4% of pts expected to have shorter time to progression (TTP) by an average 4 mo. Earlier switch after 6 mo instead of 18 mo slightly reduced efficacy (60-mo PFS rate: 74.9% vs 77.7%; HR: 0.563 vs 0.518). However when restricted to pts with 3 mo-stable ≥VGPR status at 6 mo (78.6% of pts), outcomes were comparable vs 12-mo switch at population level (60-mo PFS rate: 75.4 vs 76.2%; HR: 0.55 vs 0.543), though 5% of individual pts could experience ≥8 mo shorter TTP, possibly due to poorer prognostic factors with higher proportion of R-ISS stage 3 pts.

Conclusions:   Simulations suggest that Q4W Isa dosing after 12 mo in all NDMM pts or after 6 mo in pts achieving stable ≥VGPR status did not compromise treatment efficacy vs switching after 18 mo.