Significant clinical benefit with the addition of isatuximab to carfilzomib-dexamethasone in relapsed/refractory multiple myeloma, irrespective of the number of prior treatment lines

Previously, results of the phase III IKEMA study established the combination of isatuximab-carfilzomib-dexamethasone (Isa-Kd) as a standard of care for patients with relapsed/refractory multiple myeloma (RRMM). A post-hoc subgroup analysis of this trial, presented at ASH 2022, shows that the benefit in progression-free survival (PFS) and depth of response induced by adding Isa to Kd was seen irrespective of the number of prior treatment lines. As such, these findings provide further support for Isa-Kd as a standard-of-care treatment for patients with RRMM, including patients in first relapse.

Background

Despite, significant advances in the number of therapies for MM, patients continue to experience consecutive relapses and/or become refractory to the available therapies. As such, there remains to be a need for novel treatment strategies in patients with RRMM. The current treatment guidelines for patients with RRMM give limited guidance on the optimal sequencing of the available therapies. Nevertheless, there is a broad consensus on the fact that the number of previous treatment lines and the types of agents that a patient previously received are important considerations when determining a treatment sequence. In this light, ASH 2022 featured the presentation of IKEMA data assessing the efficacy of Isa-Kd vs. Kd alone in function of the number of prior treatment lines.

Study design and previous results

In the randomized, phase III IKEMA study, a total of 302 adult patients with RRMM who received 1 to 3 prior lines of therapy were randomized (3:2) to receive either Isa-Kd (N=179) or Kd alone (N=123). The primary study endpoint was PFS assessed by independent response committee using the International Myeloma Working Group criteria, based on central lab M-protein quantification and central radiological evaluation. The final analysis of this trial demonstrated that the addition of Isa to Kd resulted in a significant improvement in PFS, with a hazard ratio of 0.58 (95.4%CI: 0.42–0.79). In addition to this, Isa-Kd proved to be associated with clinically meaningful increases in the rate of minimal residual disease (MRD) negativity (33.5% vs. 15.4%) and in the proportion of patients obtaining a complete response (CR) (44.1% vs. 28.5%).

Isa-Kd superior to Kd irrespective of the number of prior treatment lines

The median follow-up for the presented analysis was 44 months. Of the 302 patients that were randomized in the study, 134 (44.4%; 79 Isa-Kd, 55 Kd) received 1 prior line of therapy, while the remaining 168 (55.6%; 100 Isa-Kd, 68 Kd) had received more than 1 prior treatment line. Among patients who received 1 prior line of therapy, the Isa-Kd arm included a higher percentage of patients aged ≥65 years (57.0% vs. 40.0%), more patients with renal impairment (23.9% vs. 9.8%), and more patients with a 1q21 amplification (21.6% vs. 13.0%). In the subgroup of patients with >1 prior treatment line, baseline characteristics were a bit more balanced, although patients in the Isa-Kd arm did have a shorter time from initial diagnosis to randomization (3.98 vs. 5.27 years)

Importantly, the addition of Isa to Kd improved the PFS regardless of the number of prior treatment lines. Among patients with 1 prior treatment line, Isa-Kd was associated with a median PFS of 38.2 months as compared to 28.2 with Kd alone (HR[95.4%CI]: 0.723;[0.442–1.184]). In patients who received >1 prior treatment line, the median PFS with Isa-Kd was 12.2 months longer than what was seen with Kd alone (29.2 vs. 17.0 months; HR[95.4%CI]: 0.452[0.298–0.686]). Furthermore, also the depth of response was significantly improved with the addition of Isa to Kd across both subgroups. Regardless of the number of prior treatment lines, more patients achieved a CR with Isa-Kd than with Kd (1 prior line: 48.1% vs. 38.2%; ≥1 prior line: 41.0% vs. 20.6%). Similarly, the addition of Isa to Kd also yielded higher rates of both MRD–negativity (1 prior line: 39.2% vs. 21.8%; >1 prior line: 29.0% vs. 10.3%) and MRD–negativity in combination with a CR (1 prior line: 32.9% vs. 16.4%; >1 prior line: 21.0% vs. 8.8%) across both groups.

The median treatment duration was longer with Isa-Kd than with Kd alone in both subgroups (43 weeks longer among patients with 1 prior treatment line, 25 weeks longer in patients with ≥1 prior line). However, the median relative dose intensity for all three drugs was comparable across arms and subgroups. Overall, Isa-Kd came with a a manageable safety profile regardless of the number of prior lines of therapy and was consistent with earlier reports of this study.

Conclusions

The addition of Isa to Kd improves both the PFS and the depth of response in patients with RRMM, irrespective of the number of prior treatment lines. Also in terms of safety the presented analysis did not find any differences among patients with 1 or more prior lines of therapy. Results from this subgroup analysis are consistent with the benefit observed in the overall IKEMA study population and further support Isa-Kd as a standard-of-care treatment for patients with RRMM, including patients in first relapse.

Reference

M. Capra, et al. Isatuximab Plus Carfilzomib and Dexamethasone in Relapsed Multiple Myeloma: Ikema Subgroup Analysis By Number of Prior Lines of Treatment. Presented at ASH 2022; Abstract 3176.