Updated Progression-Free Survival and Depth of Response in IKEMA, a randomized phase 3 trial of Isatuximab, Carfilzomib and Dexamethasone (Isa-Kd) vs Kd in Relapsed Multiple Myeloma

Background

• Isatuximab, (Isa), an IgG1 monoclonal antibody targeting a specific epitope of the CD38 transmembrane glycoprotein in MM, has multiple mechanisms of action:
  • ADCC, CDC, and ADCP
  • Direct apoptosis
  • Immunomodulation
  • Inhibition of ectoenzyme activity
• Isa given in combination with carfilzomib and dexamethasone (Kd) is approved in various countries for patients (pts) with relapsed and/or refractory MM after at least 1 prior therapy, based on results of the IKEMA study.

Methods

• This prespecified analysis (179 pts randomized to Isa-Kd, 123 to Kd) evaluated PFS (primary endpoint) at 159 PFS events, PFS2, minimal residual disease negativity (MRD-) rate, complete response (CR) rate, MRD- and CR rate in all pts, and safety.
• Isa 10 mg/kg was given IV weekly for 4 wks and then every 2 wks; Kd (20/56 mg/m2) was administered in both arms.

Results

• At cutoff, 49 (27.4%) pts in Isa-Kd and 11 (8.9%) in Kd were still on treatment. On Jan 14, 2022, median follow-up was 44 mo.
• The PFS update is consistent with the IA results that demonstrated significant benefit in favor of Isa-Kd: HR 0.58 (95.4% CI 0.42–0.79) with median (m) PFS 35.7 vs 19.2 mo in Isa-Kd vs Kd. PFS2 HR was 0.68 (95% CI 0.50–0.94) with mPFS2 47.2 vs 35.6 mo in Isa-Kd vs Kd.
• With additional follow up and using the Hydrashift Isa immunofixation assay to rule out potential Isa interference in CR determination, final CR rate was 44.1% in Isa-Kd vs 28.5% in Kd. 33.5% pts reached MRD- in Isa-Kd vs 15.4% in Kd.
• The rate of MRD- CR pts was 26.3% in Isa-Kd vs 12.2% in Kd. Safety profiles in both arms remain consistent with prior IKEMA findings.
• Serious TEAEs were reported in 70.1% of Isa-Kd pts vs 59.8% in Kd.
• The most common, any-grade, non-hematologic TEAEs in Isa-Kd were infusion reaction (45.8%), diarrhea (39.5%), hypertension (37.9%), and upper respiratory tract infection (37.3%).

Conclusions

• Results of this prespecified PFS updated analysis are consistent with the interim analysis and demonstrate improvement in PFS with addition of isatuximab (Isa) to Kd (HR: 0.58 [95.4% CI: 0.42–0.79] vs Kd), with unprecedented median PFS of 3 years, the longest PFS on a PI backbone in the relapsed MM setting
• Consistent PFS benefit was observed across patients subgroups, including patients with poor prognosis
• The impressive CR rate and MRD-negative CR rate in ITT of 44.1% and 26.3% in Isa-Kd vs 28.5% and 12.2% in Kd, are the highest rates reported in a PI-based regimen in relapsed MM
• PFS2 in favor of Isa-Kd vs Kd (HR: 0.68 [95% CI: 0.496–0.941]) supports sustained treatment effect through subsequent therapies
• With 2 additional years of follow-up and despite the Covid-19 pandemic, the safety profile remains similar to the interim analysis results.

Moreau P, Dimopoulos MAC, Mikhael J et al. Updated Progression-Free Survival and Depth of Response in IKEMA, a randomized phase 3 trial of Isatuximab, Carfilzomib and Dexamethasone (Isa-Kd) vs Kd in Relapsed Multiple Myeloma. Abstract presented at: 2022 European Society of Medical Oncology Virtual Plenary, May 19-20, 2022; Virtual. Abstract # VP5-2022.