Isatuximab is a CD38 monoclonal antibody currently approved in combination with carfilzomib and dexamethasone (Isa-Kd) for adults with relapsed/refractory multiple myeloma (RRMM) with 1 to 3 prior lines of therapy, based on the results from the IKEMA phase 3 trial. In the pivotal IKEMA study, Isa-Kd showed improved progression-free survival (PFS) compared with Kd; in addition, meaningful increases in minimal residual disease (MRD) negativity and complete response (CR), and a reasonable safety profile were also seen.
The results from a prespecified subanalysis of IKEMA, which evaluated the safety and efficacy of Isa-Kd versus Kd based on number of prior lines of therapy, were recently released. The subanalysis also included results from an exploratory analysis based on refractoriness to 2 frequently used frontline agents, lenalidomide and bortezomib.
A total of 302 patients were randomly assigned: 179 to Isa-Kd and 123 to Kd alone. Subgroup analysis was conducted based on 1 line of therapy versus >1 line of therapy. Overall, patients received a median of 2 prior lines of therapy, and 44.4% of patients received 1 prior line of therapy. In addition, 32.8% of patients were refractory to lenalidomide, and 30.1% were refractory to bortezomib. More patients were aged ≥75 years in the Isa-Kd group with 1 prior line of therapy compared with the Kd group, and more patients were aged <65 years in the lenalidomide-refractory subgroup compared with Kd.
The median number of treatment cycles in patients with 1 prior line of therapy with Isa-Kd was 20.0 versus 16.5 with Kd; the median in patients with >1 prior line of therapy was 18.0 with Isa-Kd versus 12.5 with Kd; in lenalidomide-refractory patients, the median was 14.0 with Isa-Kd versus 11.5 with Kd; and in bortezomib-refractory patients, the median was 13.5 with Isa-Kd versus 13.0 with Kd. More patients received ≥18 cycles in all subgroups with Isa-Kd compared with Kd, which is consistent with the IKEMA overall population, in which a longer treatment duration was seen with Isa-Kd treatment. In addition, improvement in PFS across all subgroups was seen with Isa-Kd regardless of prior line of therapy or refractory status. No significant difference was seen in overall response rate (ORR) in the overall IKEMA population.
In this subgroup analysis, similar results were observed regardless of prior line of therapy, although a trend toward higher ORR was observed with Isa-Kd in refractory subgroups. Also consistent with the overall IKEMA population, very good partial response or better (≥VGPR) and MRD negativity rates were better in the Isa-Kd group compared with Kd across all subgroups: 1 prior line (≥VGPR, 75.0% Isa-Kd vs 61.8% Kd; MRD, 33.8% Isa-Kd vs 18.2% Kd); >1 prior line (≥VGPR, 70.7% Isa-Kd vs 51.5% Kd; MRD, 26.3% Isa-Kd vs 8.8% Kd); lenalidomide-refractory (≥VGPR, 66.7% Isa-Kd vs 35.7% Kd; MRD, 24.6% Isa-Kd vs 9.5% Kd); lenalidomide-refractory at last regimen (≥VGPR, 72.2% Isa-Kd vs 38.7% Kd; MRD, 27.8% Isa-Kd vs 9.7% Kd); bortezomib-refractory (≥VGPR, 55.8% Isa-Kd vs 51.3% Kd; MRD, 17.3% Isa-Kd vs 10.3% Kd); and bortezomib-refractory at last regimen (≥VGPR, 62.5% Isa-Kd vs 47.8% Kd; MRD, 25.0% Isa-Kd vs 8.7% Kd). In addition, a meaningful difference in CR rates was observed with Isa-Kd versus Kd for all subgroups.
The incidence of all-grade treatment-emergent adverse events (TEAEs) was similar across all subgroups to the overall IKEMA population. Infusion-related reactions were the most frequent, along with pneumonia and bronchitis in 1 prior line and upper respiratory infection, fatigue, and vomiting in >1 prior line. Across all subgroups, the incidence of grade 3/4 TEAEs was higher in the Isa-Kd group; the most common were hypertension and pneumonia. The rate of patients discontinuing treatment due to TEAEs was similar or lower with Isa-Kd versus Kd in all subgroups.
This analysis strongly supports the use of Isa-Kd regardless of prior lines of therapy or refractory status to lenalidomide and bortezomib.
Source
Dimopoulos MA, Moreau P, Augustson B, et al. Isatuximab plus carfilzomib and dexamethasone in patients with relapsed multiple myeloma based on prior lines of treatment and refractory status: IKEMA subgroup analysis. Am J Hematol. May 23, 2022. Epub ahead of print.