Idecabtagene vicleucel boosts PFS and responses vs standard regimens in triple class–exposed R/R MM

Idecabtagene vicleucel (ide-cel), a B-cell maturation antigen–directed chimeric antigen receptor (CAR) T-cell therapy, improves progression-free survival (PFS) and responses vs standard regimens in patients with triple class–exposed relapsed and refractory multiple myeloma (R/R MM), the phase III KarMMa-3 trial has shown.

In the international open-label trial, adult patients (median age, 63 years) with R/R MM who had received 2–4 previous regimens (median, 3), including immunomodulatory agents, proteasome inhibitors (PIs) and daratumumab, were randomized 2:1 to undergo treatment with ide-cel (single infusion; dose range, 150 x 10⁶–450 x 10⁶ CAR-positive T cells) (n=254) or one of five standard regimens (daratumumab, pomalidomide and dexamethasone; daratumumab, bortezomib and dexamethasone; ixazomib, lenalidomide and dexamethasone; carfilzomib and dexamethasone; or elotuzumab, pomalidomide and dexamethasone) (n=132). The choice of standard regimen was based on the patient’s most recent treatment and investigator discretion. [N Engl J Med 2023;388:1002-1014]

“In the overall trial population, 66 percent of patients had triple class–refractory disease. A total of 95 percent of patients had daratumumab-refractory disease, 90 percent were refractory to immunomodulatory agents, and 74 percent had PI-refractory disease,” reported the investigators. “Baseline characteristics were generally balanced in the two groups except for Black race [7 percent vs 14 percent of patients in the ide-cel vs standard-regimen group].”

Interim analysis at a median follow-up of 18.6 months showed significantly improved PFS (primary endpoint) in the ide-cel vs standard-regimen group (median, 13.3 months vs 4.4 months; hazard ratio [HR], 0.49; 95 percent confidence interval [CI], 0.38–0.65; p<0.001). PFS rates at 6 and 12 months were 73 percent vs 40 percent and 55 percent vs 30 percent, respectively.

“The PFS benefit with ide-cel therapy was consistently observed across prespecified subgroups, including those defined according to age, race, number of previous regimens, or presence or absence of high-risk cytogenetic abnormalities, extramedullary disease, high tumour burden, or triple class–refractory status,” the investigators noted.

“In addition, treatment with ide-cel resulted in a significantly higher percentage of patients with a response and with deeper responses vs standard regimens,” they continued.

Partial response or better was observed in 71 percent of patients in the ide-cel group vs 42 percent of those in the standard-regimen group (odds ratio, 3.47; 95 percent CI, 2.24–5.39; p<0.001), while complete response (CR) or stringent CR was observed in 39 percent vs 5 percent of patients. The median duration of response was 14.8 months vs 9.7 months.

Minimal residual disease negativity within 3 months before a ≥CR was confirmed in 20 percent vs 1 percent of patients in the ide-cel vs standard-regimen group.

Overall survival data were immature at the time of data cut-off.

“The efficacy of ide-cel therapy was striking, considering that 65 percent of patients [in the ide-cel group] had triple class–refractory disease in a short time from diagnosis [4 years], with disease relapse at a median of approximately 7 months during the last previous regimen,” the investigators highlighted.

“The toxicity of ide-cel was consistent with previous reports,” they noted.

Grade 3/4 adverse events (AEs) occurred in 93 percent vs 75 percent of patients in the ide-cel vs standard-regimen group. “Cytokine release syndrome [CRS] occurred in 88 percent of the 225 patients who received ide-cel and was mostly of grade 1/2 [83 percent]. The median duration of CRS was 3.5 days,” the investigators reported. “Investigator-identified neurotoxic events occurred in 15 percent of ide-cel recipients and were mostly of grade 1/2 [12 percent].”