Isatuximab Plus Carfilzomib and Dexamethasone Versus Carfilzomib and Dexamethasone in Relapsed Multiple Myeloma Patients with Renal Impairment: Ikema Subgroup Analysis

Introduction: Renal impairment (RI) is a common feature in multiple myeloma (MM) and an adverse predictor of survival. Anti-myeloma treatments that can also improve renal function in patients (pts) with MM are required. Isatuximab (Isa), a monoclonal CD38 antibody, is approved in combination with pomalidomide and dexamethasone (d), in the United States, the European Union, Canada, Australia, Switzerland, and Japan for the treatment of adult pts with relapsed/refractory MM who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor. IKEMA (NCT03275285) was a randomized, open-label, multicenter, Phase 3 study that demonstrated the benefit of adding Isa to carfilzomib (K) plus d vs Kd in pts with relapsed MM. This subgroup analysis of IKEMA examined efficacy, renal response, and safety in pts with RI.

Methods: Pts with 1-3 prior lines of therapy were randomized 3:2 and stratified by number of prior lines and revised international staging system (R-ISS) stage to receive Isa-Kd or Kd. The Isa-Kd arm received Isa 10 mg/kg intravenously weekly for 4 weeks, then every 2 weeks thereafter. Both arms received recommended doses of Kd. Treatment continued until disease progression or unacceptable adverse events. Interim efficacy analysis was planned when 65% of the total expected progression-free survival (PFS) events determined by an Independent Response Committee were observed. RI was defined as estimated glomerular filtration rate ([eGFR]; using the Modification of Diet in Renal Disease equation) <60 mL/min/1.73m² at baseline. Complete renal response (CrR) was defined as improvement in eGFR from <50 mL/min/1.73m² at baseline to ≥60 mL/min/1.73m² (no RI) in at least one post-baseline assessment (International Myeloma Working Group recommendations), and was classified as durable if lasting ≥60 days.

Results: A total of 302 pts (179 Isa-Kd; 123 Kd) were randomized. Pts with baseline eGFR as low as 15 mL/min/1.73m² (severe RI) were allowed to enroll. more pts with RI in the Isa-Kd arm (26.1%) vs Kd (16.2%). As expected, elderly pts had more RI. The median age in years (range) was 67 (39-86) for Isa-Kd vs 69 (49-90) for Kd among RI pts, and 64 (37-81) for Isa-Kd vs 62 (33-78) for Kd among pts with no RI. In RI pts, 60.5% vs 72.2% pts had ≥2 prior lines of therapy, 11.6% vs 16.7% had R-ISS stage III, and 20.9% vs 27.8% had high risk cytogenetics, in Isa-Kd vs Kd, respectively. More RI pts were still on treatment at the cut-off date in Isa-Kd (55.8%) vs Kd (16.7%). Median PFS for RI pts was not reached for Isa-Kd vs 13.4 months for Kd (HR 0.27; 95% CI 0.11-0.66), and not reached for both study arms among pts with no RI (HR 0.63; 95% CI 0.39-1.00). The overall response rate, ≥very good partial response rate, and minimal residual disease negativity for RI pts was higher with Isa-Kd than Kd: 93.0% vs 61.1%, 79.1% vs 44.4%, and 30.2% vs 11.1%, respectively. CrR accessed in pts with eGFR <50 mL/min/1.73m² (15.2% Isa-Kd vs 11.7% Kd) occurred more frequently in Isa-Kd (52%) vs Kd (30.8%), and these were durable in 32.0% vs 7.7% pts. The treatment exposure was higher in RI pts treated with Isa-Kd, with median number of cycles started and median duration of exposure being 20 vs 9 cycles and 81.0 vs 35.7 weeks in Isa-Kd vs Kd. In pts with RI, Grade ≥3 and serious treatment emergent adverse events (TEAEs) were reported in 79.1% (Isa-Kd) vs 77.8% (Kd) and 62.8% (Isa-Kd) vs 77.8% (Kd) pts, respectively. Grade 5 TEAEs (Isa-Kd, 0%; Kd, 11.1%) and TEAEs leading to treatment discontinuation were lower with Isa-Kd (Isa-Kd, 7.0%; Kd, 27.8%). End-stage renal disease on treatment occurred in 1.8% Isa-Kd vs 2.7% Kd pts. The most common TEAEs in RI pts in Isa-Kd vs Kd were diarrhea (41.9% vs 22.2%), upper respiratory tract infection (39.5% vs 27.8%), infusion reaction (37.2% vs 5.6%), hypertension (34.9% vs 27.8%), fatigue (34.9% vs 22.2%), and dyspnea (32.6% vs 11.1%). The most common Grade ≥3 TEAEs in RI pts in Isa-Kd vs Kd were hypertension (20.9% vs 22.2%) and pneumonia (11.6% vs 22.2%).

Conclusions: The addition of Isa to Kd improved PFS and disease response in pts with RI, with a manageable safety profile, consistent with the benefit observed in the overall IKEMA study population. Also, more pts treated with Isa-Kd showed reversal of RI and durable renal responses compared with Kd. Finally, RI pts treated with Isa-Kd received twice the number of cycles and had a lower treatment discontinuation rate compared with Kd pts.