Isatuximab Plus Carfilzomib and Dexamethasone Versus Carfilzomib and Dexamethasone in Patients with Relapsed Multiple Myeloma: IKEMA Subgroup Analysis by Prior Transplantation.

In the era of highly active novel agents for multiple myeloma (MM), the role, ideal timing, and impact of transplantation on further therapy after relapse remains a matter of debate. The impact of prior transplantation on treatment benefit from monoclonal antibodies in patients with relapsed/refractory MM (RRMM) is largely unknown. Few Phase 3 studies of monoclonal antibody combinations with proteasome inhibitors or immunomodulatory agents have reported outcomes according to transplantation status. This subgroup analysis examined efficacy and safety in patients from the Phase 3 IKEMA study with and without previous transplantation. IKEMA (NCT03275285) was a randomized, open-label, multinational, parallel-group Phase 3 study that investigated isatuximab (Isa), an anti-CD38 monoclonal antibody, combined with carfilzomib and dexamethasone (Isa-Kd; experimental group) versus Kd (control group) in 302 patients with RRMM and 1 to 3 prior lines of therapy. Patients were randomized in a 3:2 ratio to either Isa-Kd or Kd, with stratification by number of prior lines (1 versus more than 1) and Revised International Staging System (R-ISS) stage (I or II versus III versus not classified). Treatment was given until progressive disease, unacceptable adverse events, or patient choice. Of the 302 randomized patients in IKEMA, 185 (61.3%) had received a prior transplant, comprising 116 of 179 (64.8%) patients in the Isa-Kd arm and 69 of 123 (56.1%) patients in the Kd arm. After a median follow-up of 20.6 months, median progression-free survival (PFS) in patients with prior transplant was not reached with Isa-Kd versus 19.15 months with Kd (hazard ratio [HR] = 0.60; 99% confidence interval [CI], 0.31-1.16). After a median follow-up of 20.8 months, median PFS in patients without prior transplant was not reached with Isa-Kd versus 18.99 months with Kd (HR = 0.44; 99% CI, 0.18-1.05). The overall response rate in patients with prior transplant was 87.9% (Isa-Kd) versus 85.5% (Kd). More patients in the Isa-Kd arm achieved a complete response or better compared with the Kd arm (43.1% versus 29.0%). The overall response rate in patients without prior transplant was 84.1% (Isa-Kd) versus 79.6% (Kd). More patients in the Isa-Kd arm achieved a complete response or better compared with the Kd arm (33.3% versus 25.9%). The minimal residual disease negativity rate was higher with Isa-Kd versus Kd in patients with (31.9% versus 13.0%) and without prior transplantation (25.4% versus 13.0%). In patients with prior transplant, Grade 3 or higher treatment-emergent adverse events (TEAEs) were more common with Isa-Kd; however, no increases in serious TEAEs or definitive treatment discontinuations were seen versus Kd. Among patients without prior transplant, serious treatment-related TEAEs were similar, and there were fewer TEAEs leading to definitive discontinuation with Isa-Kd. The most common Grade 3 or higher TEAEs in patients with and without prior transplant were hypertension and pneumonia. For patients who underwent prior transplantation, Isa-Kd is an effective treatment option. Overall, these data demonstrate that Isa-Kd represents a standard of care for patients with RRMM, regardless of prior transplant status.