Depth of Response of Isatuximab (Isa) plus Carfilzomib (K) and Dexamethasone (d) in Relapsed Multiple Myeloma: IKEMA Updated Analysis

Introduction:
Achievement of minimal residual disease negativity (MRD–) status in multiple myeloma (MM) is associated with improved progression-free survival (PFS) and overall survival. Isa-Kd is approved for relapsed MM patients (pts) after ≥1 prior therapy, based on primary interim analysis of Phase 3 IKEMA study (NCT03275285). Here, we report updated, longer-term depth of response results from IKEMA, including MRD– status.
Methods:
IKEMA is a randomized, open-label, multicenter Phase 3 study investigating Isa-Kd (n=179) vs Kd (n=123) in relapsed MM pts who received 1-3 prior lines of therapy. Intravenous (IV) Isa 10 mg/kg was given weekly for 4 weeks and then every other week. Both arms received the approved schedule of K (IV) and d (oral or IV). This prespecified analysis evaluated PFS (primary endpoint) at 159 events and secondary endpoints of ≥complete response ([CR] + stringent CR), MRD–, and ≥CR + MRD– rates, as determined by Independent Response Committee (IRC) based on central laboratory data and IRC review of local radiology. MRD status was assessed by next-generation sequencing at a sensitivity threshold of at least 10 in bone marrow aspirates from pts achieving ≥very good partial response. HYDRASHIFT Isa immunofixation (IFE) test, removing interference of Isa in IFE, was used to update ≥CR rate. For secondary endpoints, one-sided p-value assessed by Cochran-Mantel-Haenszel test is provided for descriptive purpose only. All randomized pts not reaching MRD– or without MRD assessment were considered as MRD+.
Results:
As of 14Jan2022 (cutoff), at a median follow-up of 44 months, deeper responses were observed in Isa-Kd vs Kd, with ≥CR rates 44.1% vs 28.5% (odds ratio [OR]: 2.09; 95% CI: 1.26–3.48; descriptive p=0.0021). MRD– (10 ) occurred in 33.5% vs 15.4% of Isa-Kd vs Kd pts (OR: 2.78; 95% CI: 1.55–4.99; descriptive p=0.0002), with 26.3% vs 12.2% of Isa-Kd vs Kd pts reaching ≥CR + MRD– (10 ; OR: 2.57; 95% CI: 1.35–4.88; p=0.0015). In subgroup analyses, MRD– rates with Isa-Kd (vs Kd) were higher among pts with poor prognostic characteristics such as older age, renal impairment, higher ISS stage at diagnosis, 1q21+, >1 prior lines of therapy, and refractoriness to lenalidomide. MRD– at 10 sensitivity level occurred in 10.6% vs 3.3% of Isa-Kd vs Kd pts. MRD– pts (10 ) had longer median PFS than MRD+ pts in both arms: not calculable ([NC]; 95% CI: NC–NC) for Isa-Kd MRD– pts and 21.7 (95% CI: 16.4–30.1) months for Isa-Kd MRD+ pts vs NC (95% CI: 34.5–NC) for Kd MRD– pts and 17.0 (95% CI: 13.4–21.9) months for Kd MRD+ pts.
Discussion:
These results demonstrate clinically meaningful improvement in depth of response with Isa-Kd vs Kd. Impressive ≥CR rates and ≥CR + MRD– (10 ) rates of 44.1% and 26.3% in Isa-Kd vs 28.5% and 12.2% in Kd are the highest reported for proteasome inhibitor-based regimen in relapsed MM. Achieving MRD– led to better outcomes in both treatment arms, with Isa-Kd pts having more than 2-fold higher likelihood of achieving MRD–. Additionally, isatuximab improved outcomes of MRD+ pts.