The objective of the IKEMA study was to compare isatuximab (Isa), an approved anti-CD38 immunoglobulin (Ig)G kappa monoclonal antibody, plus carfilzomib (K) and dexamethasone (d; Isa-Kd) with Kd via analysis of depth of response, long-term outcomes, and kinetics of tumor response.
The IKEMA study was a randomized, open-label, multicenter phase 3 clinical trial among patients with relapsed multiple myeloma 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, very good partial response or better (≥VGPR), and complete response (CR) rate. Primary and secondary end points were determined by an independent review committee. Minimal residual disease (MRD) was assessed in bone marrow aspirates from patients with ≥VGPR. To overcome the interference with Isa in standard immunofixation assay, measurement by mass spectrometry of serum M protein was performed. Cox proportional hazards model was used to estimate hazard ratios (HRs) and corresponding confidence intervals (CIs). 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 intention-to-treat (ITT).
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). MRD-negative status was achieved in 30% of patients in the Isa-Kd arm compared with 13% of patients in the Kd arm (ITT population; nominal P = .0004). The percentage of patients reaching both CR and MRD-negative status was 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. Potential to reach MRD-negativity with Isa-Kd is independent of adverse prognostic characteristics, including renal impairment, International Staging System stage 3 at diagnosis, and presence of gain(1q21).
Overall, response to treatment was observed relatively quickly. Among responders, median days to first response were 32.0 versus 33.0; best response, 120.0 versus 104.5; first CR, 184.0 versus 229.5; and first ≥VGPR, 88.0 versus 90.0 for the Isa-Kd and Kd arms, respectively. In addition, quality of life as measured by European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-C30 Global Health Status scores was maintained with Isa-Kd.
To examine the interference of Isa with M protein, 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. 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. Among these 11 patients, 7 were also MRD negative. These results suggest that the current CR rate (irrespective of MRD status) and MRD-negative CR rate in this study are both underestimated, with a potential adjusted CR rate of 45.8% and potential adjusted MRD-negative CR rate of 24%.
In conclusion, treatment with Isa-Kd resulted in a clinically meaningful improvement in depth of response compared with Kd. Based on subsequent analysis, it is likely that the CR rate of 39.7% in the Isa-Kd arm was underestimated as a result of interference of Isa with M protein, and that CR could be reached in 45.8% of these patients. Significantly more patients reached MRD-negativity and CR MRD-negativity with Isa-Kd versus Kd. In both arms, achieving MRD-negative status was associated with longer PFS.
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.