Isatuximab (Isa), a novel CD38 monoclonal antibody, demonstrated significant improvement in progression-free survival (PFS) in the primary interim analysis of IKEMA, an ongoing phase 3 study evaluating the efficacy and safety of Isa in combination with carfilzomib (K) and dexamethasone (d) versus Kd alone in patients with relapsed and refractory multiple myeloma (RRMM). Based on these results, Isa in combination with Kd is approved in many countries for the treatment of patients with RRMM after ≥1 prior lines of therapy. At the 2022 ESMO virtual plenary meeting, Phillipe Moreau presented updated PFS and depth of response from the IKEMA trial.
A total of 302 patients with RRMM underwent randomization; 179 patients were treated with Isa-Kd while 123 patients were treated with Kd alone. The primary end point in the study was PFS, and key secondary end points included overall response rate (ORR), very good partial response or better (≥VGPR), minimal residual disease (MRD) negativity rate, complete response (CR) rate, and overall survival (OS). The prespecified analysis at 159 PFS events was maintained to evaluate longer-term outcomes for PFS, MRD negativity rate, CR rate, MRD negativity and CR rate in all patients, and safety. Patient demographics and baseline characteristics were similar between the 2 groups; median prior lines of therapy in both groups was 2, 23.5% had high-risk cytogenetics in the Isa-Kd group, and 25.2% had high-risk cytogenetics in the Kd-alone group. After a median follow-up of 44 months, 27.4% of patients continued with Isa-Kd treatment while 8.9% were still receiving Kd treatment alone.
In the updated PFS analysis, the median PFS was 35.7 months with Isa-Kd versus 19.2 months with Kd alone. The longest PFS seen when using a proteasome inhibitor (PI) backbone in the RRMM setting is 35.7 months. The PFS benefit was consistent across subgroups, regardless of age, prior lines of therapy, or prior PI or immunomodulatory drug treatment. Additionally, with the addition of Isa to Kd, the probability of relapse and death was reduced by 42%. Deeper responses were seen with Isa-Kd versus Kd alone: ORR was 86.6% versus 83.7%, ≥VGPR was 72.6% versus 56.1%, and CR rate was 44.1% versus 28.5%. MRD negativity rate in the intention-to-treat (ITT) population was 33.5% with Isa-Kd versus 15.4% with Kd alone. In patients reaching CR, MRD negativity rate was 26.3% with Isa-Kd versus 12.2% with Kd alone. In the ITT population, Isa-Kd delayed time to next treatment: 44.9 months with Isa-Kd versus 25 months with Kd alone. The OS data are not mature at this time; however, a final OS analysis is planned 3 years after the interim PFS analysis. Safety findings were consistent with the interim analysis, and the addition of Isa did not increase fatal treatment-related adverse events. The most common adverse events were infusion reactions, but mostly grade 1 or 2.
After a median follow-up of 44 months, these results are consistent with findings from the interim analysis and support the use of Isa-Kd as standard of care for patients with RRMM.
- Moreau P, Mikhael J. Updated progression-free survival (PFS) and depth of response in IKEMA, a randomized phase III trial of isatuximab, carfilzomib and dexamethasone (Isa-Kd) vs Kd in relapsed multiple myeloma (MM). Presented at: European Society of Medical Oncology Virtual Plenary; May 19-20, 2022; Virtual. Abstract VP5-2022.