Significant benefit from the addition of isatuximab to carfilzomib-dexamethasone irrespective of the time to relapse on prior therapy in patients with relapse/refractory multiple myeloma

The phase III IKEMA trial established the combination of isatuximab, carfilzomib and dexamethasone (Isa-Kd) as a standard of care for patients with relapsed or refractory multiple myeloma (RRMM). As patients with an early relapse to therapy tend to have a more dismal outcome than patients with a more prolonged treatment response, the IKEMA investigators assessed whether the time to relapse on the last prior line of therapy had an impact on the efficacy and safety of Isa-Kd. Results of this analysis show that the addition of Isa to Kd significantly delays disease progression and deepens responses irrespective of whether patients had an early or late relapse to the prior line of therapy.

Introduction

Despite major therapeutic advances over the last decades, MM remains to be a chronic disease that is characterized by a series of consecutive remissions and relapses. In this respect, data have shown that patients with an early relapse face a more dismal outcome than patients who relapse later. In the phase III IKEMA study, the addition of Isa to Kd resulted in a significantly longer progression-free survival (median PFS: 35.7 vs. 19.2 months; HR[95.4%CI]: 0.58[0.42–0.79]) and a clinically meaningful increase in the percentage of patients with minimal residual disease (MRD) negativity (33.5% vs. 15.4%) or a complete response (CR) (44.1% vs. 28.5%) following therapy. During the 2022 annual ASH meeting, results were presented of an IKEMA subgroup analysis looking at the efficacy of Isa-Kd vs. Kd in patients who experienced an early or a late relapse following their last line of prior therapy.

Study design

The randomized, phase III IKEMA study enrolled a total of 302 RRMM patients who received 1–3 prior lines of therapy (LOT) and randomized (3:2) them to receive Isa-Kd (N=179) or Kd (N=123) alone. Patients with prior carfilzomib exposure were excluded from the study as were patients with refractoriness to anti-CD38 therapy. Treatment was given until progression or unacceptable toxicity. The primary endpoint of the study was PFS, with objective response rate (ORR), the percentage of patients with at least a very good partial response (≥VGPR), MRD negativity, CR rate and overall survival (OS) as secondary objectives. The presented analysis was based on results from the prespecified final PFS analysis of IKEMA. For this analysis, an early relapse was defined as a relapse within 12 months from initiation of the most recent LOT for patients with ≥2 prior LOT, within 18 months for patients who received only 1 prior LOT, or within 12 months following an autologous stem-cell transplantation (ASCT). In contrast, late relapsers were patients with a relapse ≥12 months from initiation of the most recent LOT for those with ≥2 prior LOT and ≥18 months for patients with 1 prior LOT.

Results

In total, the IKEMA study included 107 patients with an early relapse of whom 61 and 46 were treated with Isa-Kd and Kd alone, respectively. The additional 176 patients included in this analysis were late relapsers of whom 104 patients received Isa-Kd vs. 72 Kd alone. Some imbalances were noted between treatment arms and between early and late relapsers. Not surprisingly, patients with an early relapse tended to have a more advanced ISS stage at study entry and more frequently presented with high-risk cytogenetics. Furthermore, patients with an early relapse also received a higher median number of prior LOTs, received less ASCTs and had a higher level of treatment refractoriness. While the median duration of treatment with Isa-Kd or Kd was longer for patients with a late relapse, the relative dose intensity in these patients was slightly lower compared to early relapsers.

At data cut-off, the median PFS was longer for patients treated with Isa-Kd vs. Kd in both the early (24.7 vs. 17.2 months; HR[95.4%]: 0.662[0.404–1.087]) and late relapse (42.7 vs. 21.9 months; HR[95.4%]: 0.542 [95.4% CI, 0.353–0.833]) cohorts. Similar PFS curves were also reported for early and late relapsers who were refractory to their last prior LOT, favoring Isa-Kd over Kd in both groups (HR 0.54 and 0.55, respectively). In addition, more patients achieved a ≥VGPR (early relapse: 67.2% vs. 52.2%; late relapse: 76.0% vs. 58.3%), MRD-negativity (early relapse: 24.6% vs. 15.2%; late relapse: 37.5% vs. 16.7%), or an MRD-negative ≥CR (early relapse: 18.0% vs. 10.9%; late relapse: 30.8% vs. 13.9%) with Isa-Kd than with Kd in both early and late relapse patients.

With respect to safety, the incidence of grade ≥3 and serious treatment-emergent adverse events (TEAEs) was similar in both treatment arms in early relapse patients but tended to be higher for Isa-Kd in patients with a late relapse. The latter is likely related to the longer treatment exposure in these patients However, the rates of TEAEs leading to definitive discontinuation or death were similar in both treatment arms across both early and late relapse patients.

Conclusions

Adding Isa to Kd results in a significantly improved PFS and depth of response, with a manageable safety profile in both MM patients with an early or late relapse following their last prior line of therapy. As such, these findings support Isa-Kd as a standard of care for patients with RRMM, regardless of their time to relapse on prior therapy.

Reference

Martin T, et al. Isatuximab Plus Carfilzomib and Dexamethasone in Patients with Early Versus Late Relapsed Multiple Myeloma: Ikema Subgroup Analysis. Presented at ASH 2022; Abstract 753