ISKIA

The ISKIA trial is a phase 3 study that investigated the sustained MRD negativity in patients with newly diagnosed multiple myeloma who were treated with a combination of carfilzomib, lenalidomide, and dexamethasone (KRd) with or without isatuximab (Isa). The primary focus of this analysis was on the sustained MRD negativity as a measure of treatment effectiveness, using highly sensitive next-generation sequencing methods with sensitivity levels of 10^-5 and 10^-6. The trial enrolled 302 patients, who were stratified by FISH  and ISS stage to evaluate how different risk categories respond to treatment.

In this analysis, patients in the Isa-KRd arm showed significantly higher MRD negativity rates at both 10^-5 and 10^-6 sensitivity compared to the KRd alone arm. After full-dose consolidation, the Isa-KRd group demonstrated 77% MRD negativity at 10^-5 and 68% at 10^-6, whereas the KRd group showed 67% at 10^-5 and 48% at 10^-6. Furthermore, after the light consolidation phase, Isa-KRd showed a 10^-5 MRD negativity rate increase from 77% to 79%. This difference is higher in the KRd arm, from 67% after full-dose consolidation to 74% after light consolidation. In 10^-6  MRD negativity rates, the differences between measured after full-dose consolidation and after light consolidation are bigger (from 68% to 74% in the Isa-KRd arm vs from 48% to 64% in the KRd arm.

The one-year sustained MRD negativity rate was also significantly higher in the Isa-KRd arm at 66%, compared to 59% in the KRd arm, with patients in the high-risk groups demonstrating even more pronounced benefits. For example, patients with IMWG high-risk cytogenetic features had a 1-year sustained 10^-6  MRD negativity of 44% in the Isa-KRd arm, versus 31% in the KRd arm. Similarly, patients with two or more high-risk cytogenetic abnormalities had a 1-year sustained 10^-6  MRD negativity of 62% in the Isa-KRd group, compared to 20% in the KRd group.

Safety data revealed that Isa-KRd was well tolerated, with neutropenia being the most common adverse event in both arms, but no significant increase in toxicity was noted with the addition of isatuximab. The rate of discontinuation due to adverse events was similar between both treatment arms.

In conclusion, Isa-KRd significantly increased the MRD negativity rates, particularly at the more sensitive 10^-6 level, and showed substantial benefit, especially in high-risk patients. The data also highlighted a lower rate of early relapse in both arms, further supporting the efficacy of the second-generation proteasome inhibitor carfilzomib in this context. The regimen was effective and well tolerated, with no major increase in toxicity compared to KRd alone. The results suggest that Isa-KRd may offer a superior treatment option for newly diagnosed multiple myeloma patients, especially those with high-risk cytogenetic abnormalities.  These data underscore the importance of MRD negativity as a meaningful endpoint in evaluating long-term treatment, also proving that 10^-6 MRD negativity rates are more informative than 10^-5 MRD negativity rates.