Isatuximab plus carfilzomib and dexamethasone in patients with early versus late relapsed multiple myeloma: IKEMA subgroup analysis

Abstract

Patients with multiple myeloma (MM) who experience early relapse within 12 months of therapy initiation are considered functional high-risk and represent an unmet need, needing better therapies to improve outcomes. The final IKEMA (clinicaltrials gov. identifier: NCT03275285) progression-free survival (PFS) analysis confirmed the significant PFS improvement reported at interim analysis with isatuximab (Isa) plus carfilzomib and dexamethasone (Kd; Isa-Kd) versus Kd in patients with relapsed MM (updated median PFS: 35.7 vs. 19.2 months; hazard ratio [HR] =0.58, 95% confidence interval [CI]: 0.42- 0.79). This IKEMA subgroup analysis examined efficacy and safety of Isa-Kd versus Kd in patients who experienced early (n=61 [Isa-Kd], n=46 [Kd]) vs. late relapse (n=104 [Isa-Kd], n=72 [Kd]). As expected, more aggressive features in baseline characteristics were observed in early relapse patients. Consistent with IKEMA overall population results, median PFS (early relapse: 24.7 vs. 17.2 months, HR=0.662, 95% CI: 0.407-1.077; late relapse: 42.7 vs. 21.9 months, HR=0.542, 95% CI: 0.355- 0.826), minimal residual disease negativity (MRD-) (early relapse: 24.6% vs. 15.2%; late relapse: 37.5% vs. 16.7%), and MRD- complete response (≥CR) rates (early relapse: 18.0% vs. 10.9%; late relapse: 30.8% vs. 13.9%) were higher with Isa-Kd versus Kd, respectively, in both early and late relapse patients. Grade ≥3, serious treatment-emergent adverse events, and death rates were higher in the late relapse Isa-Kd arm. However, the numbers of deaths were low and treatment exposure was significantly longer in Isa-Kd versus Kd late relapse patients. These results support the addition of Isa to Kd as standardof- care therapy for relapsed and/or refractory MM regardless of relapse timing.

Figure 1.

Median progression-free survival of early and late relapse patients in the IKEMA intent-to-treat population. (A) Median progression-free survival (mPFS) of early relapse patients. (B) mPFS of late relapse patients. Cut-off date: January 14, 2022. Median follow-up time: 44 months. ^*As per Independent Review Committee. ^†mPFS and 95% confidence interval (CI) were calculated by the Kaplan-Meier method. ^†† Non-stratified Cox proportional hazards models using treatment as a covariate were used to estimate hazard ratios (HR). For adjusted HR estimates, the confounding factors - age, renal impairment, International Staging System (ISS) stage at study entry, 1q21+, and number of prior lines - were used as adjustment covariates. When adjusted for confounding factors, the PFS HR was similar between early (0.577) and late relapse (0.527) patients and in favor of the isatuximab plus carfilzomib and dexamethasone (Isa-Kd) arm.

Figure 2.

Median progression-free survival of early and late relapse patients refractory to the last regimen. (A) Median progression-free survival (mPFS) of early relapse patients refractory to the last regimen. (B) mPFS of late relapse patients refractory to the last regimen. Cut-off date: January 14, 2022. Median follow-up time: 44 months. ^*As per Independent Review Committee. ^†mPFS and 95% confidence interval (CI) were calculated by the Kaplan-Meier method. ^††Non-stratified Cox proportional hazards models using treatment as a covariate were used to estimate hazard ratios (HR). Isa: isatuximab; Kd: carfilzomib and dexameth-asone.

Figure 3.

Depth of response of early and late relapse patients in the IKEMA intent-to-treat population. Cut-off date: January 14, 2022. Median follow-up time: 44 months. Minimal residual disease negativity (MRD^-) was assessed by next-generation sequencing Adaptive ClonoSEQ Assay (Adaptive Biotechnologies) at 10^-5 sensitivity. For analysis purpose, subjects in the intent-to-treat population but without MRD assessment were considered as having positive MRD. ≥Complete response (≥CR) rate is the proportion of patients who achieved stringent complete response (sCR) or CR as the best overall response according to the International Myeloma Working Group response criteria. Isa: isatuximab; Kd: carfilzomib and dexamethasone; ORR: overall response rate; VGPR: very good partial response.

Figure 4.

Depth of response of early and late relapse patients refractory to the last regimen. Cut-off date: January 14, 2022. Median follow-up time: 44 months. Minimal residual disease negativity (MRD^-) was assessed by next-generation sequencing Adaptive ClonoSEQ Assay (Adaptive Biotechnologies) at 10^-5 sensitivity. For analysis purpose, subjects in the intent-to-treat population but without MRD assessment were considered as having positive MRD. ≥Complete response (≥CR) is the proportion of patients who achieved stringent complete response (sCR) or CR as the best overall response according to the International Myeloma Working Group response criteria. Isa: isatuximab; Kd: carfilzomib and dexamethasone; ORR: overall response rate; VGPR: very good partial response.

Figure 5.

Depth of response of early and late relapse patients according to the number of prior lines of treatment or prior transplant. Depth of response after (A) 1 prior line of treament (LOT), or (B) ≥2 prior LOT, or (C) prior autologous stem cell transplant. Cut-off date: January 14, 2022. Median follow-up time: 44 months. Minimal residual disease negativity (MRD^-) was assessed by next-generation sequencing Adaptive ClonoSEQ Assay (Adaptive Biotechnologies) at 10^-5 sensitivity. For analysis purpose, subjects in the intent-to-treat population but without MRD assessment were considered as having positive MRD. ≥Complete response (≥CR) is the proportion of patients who achieved stringent complete response (sCR) or CR as the best overall response according to the International Myeloma Working Group response criteria. Isa: isatuximab; Kd: carfilzomib and dexamethasone; ORR: overall response rate; VGPR: very good partial response.