Joint modeling of serum M-protein and PFS to predict response to isatuximab in combination with bortezomib/lenalidomide/dexamethasone in newly diagnosed multiple myeloma patients

Objectives: Bortezomib, lenalidomide and dexamethasone (VRd) is a preferred first-line treatment option for newly diagnosed multiple myeloma (NDMM) patients. Adding anti-CD38 monoclonal antibody isatuximab (Isa) to VRd was associated with a significant, clinically meaningful benefit in progression-free survival (PFS) in NDMM patients not eligible for transplant (IMROZ, NCT03319667) [ 1]. We aimed to characterize the effects of treatment and baseline covariates on serum M-protein dynamics and its link to PFS in NDMM patients in both arms of the IMROZ trial using a joint model and to evaluate alternative Isa dosing regimens by simulations. Methods: Data from the IMROZ trial comparing Isa 10 mg/kg weekly for 4 weeks then every 2 weeks, then every month at cycle 18 onwards in combination with VRd vs VRd in 357 evaluable NDMM patients were used. Longitudinal data of serum M-protein and PFS data were analyzed separately and then in a joint model to describe their association [ 2]. Covariate analysis was performed to examine the influence of baseline covariates on serum M-protein and hazard rate of PFS. Parameters were estimated using the SAEM algorithm in Monolix 2024R1. Trial simulations were performed using individual PK/PD parameters to evaluate if efficacy is maintained upon switching to an Isa monthly regimen after 6 or 12 months in IMROZ patients. 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 VRd dosing data and a TGI model for serum M-protein data with treatment effect driven by exposure (i.e average daily AUC) of the 4 drugs. For PFS, a Weibull model best characterized the underlying baseline hazard distribution. The predicted dynamic difference in M-protein relative to its current lowest value was the best on-treatment predictor of PFS. The significant baseline covariates in the joint model were Ig MM type, beta-2 micro-globulin (B2MG) and albumin (ALB). Patients with high B2MG tended to have higher serum M-protein at baseline and increased risk of progression. Non-IgG patients were likely to have faster M-protein decrease during first 6 months, but similar PFS compared to IgG patients. Low ALB was associated with higher serum M-protein at baseline but had limited impact on PFS. Simulation results showed that switching to monthly regimen after 6 months for patients with stable “at least” very good partial response (VGPR) status (defined as a 90 % reduction of serum M-protein from baseline in the last 3 months) or after 12 months for all patients instead of 18 months would minimally impact the clinical benefit: 60-month PFS rate (75.4, 76.2 vs 77.7%), HR (0.55, 0.543 vs 0.518). Conclusions: The joint model adequately predicted patients’ response in the IMROZ trial. Simulations suggested that the monthly Isa dosing regimens after 12 months for all NMDD patients or 6 months for patients achieving stable at least VGPR status could not compromise the efficacy vs switching to monthly regimen after 18 months.