According to the IKEMA study interim analysis, isatuximab (Isa) plus carfilzomib and dexamethasone (Isa-Kd) resulted in a clinically meaningful improvement in depth of response; more patients reached minimal residual disease (MRD)-negative status when compared with those patients who received carfilzomib and dexamethasone alone.
The objective of the IKEMA study was to compare Isa, an approved anti-CD38 IgG kappa monoclonal antibody, plus Isa-Kd to Kd via analysis of depth of response, long-term outcomes, and kinetics of tumor response. The IKEMA study, a randomized, open-label, multicenter, phase 3 clinical trial, evaluated patients with relapsed multiple myeloma (RMM) who had received 1 to 3 lines of therapy. The primary end point was progression-free survival (PFS). Secondary end points included overall response rate (ORR), very good partial response or better (≥VGPR), and complete response (CR) rate. An independent response committee determined the primary and secondary end points. Bone marrow aspirates from patients with ≥VGPR were used to assess MRD. Measurement by mass spectrometry of serum M-protein was performed to overcome the interference with Isa in standard immunofixation assay. Cox proportional hazards model was used to estimate hazard ratios (HRs) and corresponding confidence intervals (CIs). In addition, the Cochran-Mantel-Haenszel test was used to compare treatment arms for secondary end points. All randomized patients not achieving MRD-negative status and those without MRD assessment were analyzed as MRD-positive per intent to treat.
A total of 302 patients were randomized (Isa-Kd: N = 179; Kd: N = 123). Deeper responses were observed in patients treated with Isa-Kd versus Kd at a median follow-up of 20.7 months (≥VGPR 72.6% vs 56.1% [nominal P = .011]; ≥CR 39.7% vs 27.6%, respectively). In 30% of patients, MRD-negative status was achieved in the Isa-Kd arm compared with 13% of patients in the Kd arm (nominal P = .0004). The percentages of patients reaching both CR and MRD-negative status were 20.1% in the Isa-Kd arm and 10.6% in the Kd arm. For PFS, HRs favor Isa-Kd versus Kd in both MRD-negative patients (HR, 0.578; 95% CI, 0.052-6.405) and MRD-positive patients (HR, 0.670; 95% CI, 0.452-0.993). Overall, PFS was longer for MRD-negative patients than for MRD-positive patients.
Overall, treatment response was observed relatively quickly. Among responders, median days to first response was 32.0 versus 33.0, best response was 120.0 versus 104.5, first CR was 184.0 versus 229.5, and first ≥VGPR was 88.0 versus 90.0 for the Isa-Kd and Kd arms, respectively. In addition, as measured by QLQ-C30 Global Health Status scores, quality of life was maintained with Isa-Kd.
Samples from 27 patients in the Isa-Kd arm with near CR (only serum immunofixation [IF]-positive IgG kappa) or potential CR (serum remaining M-protein ≤0.5 g/dL with IF-positive IgG kappa) were tested by mass spectrometry to examine the interference of Isa with M-protein. In this sample, 11 patients with near CR or potential CR had documented bone marrow plasma cell abundance of <5% and were mass spectrometry negative; 7 patients were also MRD-negative among these 11 patients. These results suggest that the current CR rate (irrespective of MRD status) and MRD-negative CR rate in this study are both underestimated. Potential adjusted CR and MRD-negative rates are 45.8% and 24%, respectively.
In conclusion, when compared with treatment with Kd, treatment with Isa-Kd resulted in a clinically meaningful improvement in depth of response. Based on subsequent analysis, it is likely that the CR rate of 39.7% in Isa-Kd was underestimated as a result of interference of Isa with M-protein and that in 45.8% of these patients, CR could be reached. Significantly more patients reached MRD-negative and CR MRD-negative status with Isa-Kd versus Kd. In both arms, longer PFS was associated with the achievement of MRD-negative status.
Abstract 414. ASH 2020. December 6, 2020. Depth of response and response kinetics of isatuximab plus carfilzomib and dexamethasone in relapsed multiple myeloma: IKEMA interim analysis.