As reported in The New England Journal of Medicine by Paula Rodriguez-Otero, MD, PhD, of Clínica Universidad de Navarra, Pamplona, Spain, and colleagues, an interim analysis of the phase III KarMMa-3 trial has shown superior progression-free survival with the B-cell maturation antigen–directed chimeric antigen receptor (CAR) T-cell therapy idecabtagene vicleucel vs standard regimens in patients with relapsed or refractory multiple myeloma who had received two to four prior regimens, including triple-class exposure to immunomodulatory agents, proteasome inhibitors, and daratumumab.¹

Idecabtagene vicleucel was approved for relapsed or refractory multiple myeloma after at least four prior lines of therapy, including an immunomodulatory agent, proteasome inhibitor, and anti-CD38 monoclonal antibody, in March 2021 based on response rate and duration in the phase II KarMMa trial.²

Paula Rodriguez-Otero, MD, PhD

Study Details

In the open-label trial, 386 patients with disease refractory to their last regimen from sites in 12 countries were randomly assigned on a 2:1 basis between May 2019 and April 2022 to receive idecabtagene vicleucel at a dose range of 150 × 10⁶ to 450 × 10⁶ CAR-positive T cells (n = 254) or one of five standard regimens (n = 132). Standard regimens were selected prior to randomization based on the patient’s most recent regimen and investigator discretion. Regimens consisted of daratumumab, pomalidomide, and dexamethasone (n = 43); daratumumab, bortezomib, and dexamethasone (n = 7); ixazomib, lenalidomide, and dexamethasone (n = 22); carfilzomib and dexamethasone (n =30); and elotuzumab, pomalidomide, and dexamethasone (n = 30). Randomization was stratified according to age (< 65 vs ≥ 65 years), number of previous regimens (two vs three or four), and presence or absence of high-risk cytogenetic abnormalities. A total of 29 patients in the idecabtagene vicleucel group and 6 in the standard regimen group did not receive assigned treatment. The primary endpoint was progression-free survival on independent response committee assessment in the intent-to-treat population.

Progression-Free Survival

At interim analysis, median follow-up from randomization to data cutoff (in April 2022) was 18.6 months (range = 0.4–35.4 months). Median progression-free survival was 13.3 months (95% confidence interval [CI] = 11.8–16.1 months) in the idecabtagene vicleucel group vs 4.4 months (95% CI = 3.4–5.9 months) in the standard regimen group (hazard ratio [HR] = 0.49, 95% CI = 0.38–0.65, P < .001). Rates at 6 and 12 months were 73% vs 40% and 55% vs 30%, respectively.

The progression-free survival benefit of idecabtagene vicleucel was consistent across subgroups, including according to age, race, number of previous regimens, high-risk cytogenetic abnormalities, extramedullary disease, high tumor burden, and triple class–refractory status. For the stratification subgroups, hazard ratios were 0.57 (95% CI = 0.40–0.80) among patients aged younger than 65 years and 0.43 (95% CI = 0.28–0.64) among those aged 65 and older;  0.51 (95% CI = 0.31–0.84) among patients with two prior regimens and 0.51 (95% CI = 0.37–0.69) among those with three or four prior regimens; and 0.61 (95% CI = 0.41–0.90) among patients with high-risk cytogenetic abnormalities and 0.44 (95% CI = 0.31–0.63) among those without such abnormalities or of unknown status. Hazard ratios were 0.46 (95% CI = 0.34–0.62) among patients with and 0.65 (95% CI = 0.39–1.09) among those without triple class–refractory disease.

A partial response or better was observed in 71% (95% CI = 66%–77%) of patients in the idecabtagene vicleucel group vs 42% (95% CI = 33%–50%) of patients in the standard regimen group (odds ratio = 3.47, 95% CI = 2.24–5.39, P < .001). A complete response or a stringent complete response was observed in 39% vs 5% of patients. Median duration of response was 14.8 months (95% CI = 12.0–18.6 months) vs 9.7 months (95% CI = 5.4–16.3 months).

Overall survival data were immature and remained blinded at data cutoff.

Adverse Events

Among patients who received study treatment, grade 3 or 4 adverse events occurred in 93% of the idecabtagene vicleucel group vs 75% of the standard regimen group. Grade 5 events occurred in 14% vs 6%. The most common grade 3 or 4 adverse events in both groups were hematologic, including neutropenia (76% vs 40%), anemia (51% vs 18%), and thrombocytopenia (42% vs 17%). Grade 3 or 4 infection occurred in 24% vs 18% of patients and grade 5 infection in 4% vs 2%. Among the 225 patients who received idecabtagene vicleucel, cytokine-release syndrome of any grade occurred in 88% and was grade 3 or 4 in 9 patients (4%) and grade 5 in 2 patients (1%); any-grade neurotoxicity occurred in 15% and was grade 3 or 4 in 7 patients (3%). Serious adverse events occurred in 52% vs 38% of patients, most commonly infections (24% vs 20%). Second primary cancers occurred in 6% vs 4% of patients. Grade 5 events considered related to treatment occurred in six patients (3%) vs one patient (1%).

The investigators concluded: “[Idecabtagene vicleucel] therapy significantly prolonged progression-free survival and improved response as compared with standard regimens in patients with triple class–exposed relapsed and refractory multiple myeloma who had received two to four regimens previously. The toxicity of [idecabtagene vicleucel] was consistent with previous reports.” 

DISCLOSURE: The study was funded by 2seventy bio and Celgene, a Bristol Myers Squibb company. Dr. Rodriguez-Otero has served as a consultant for AbbVie, Bristol Myers Squibb, GlaxoSmithKline, Janssen, Pfizer, and Sanofi Pasteur; has received honoraria from Amgen; and has been a member of a speakers bureau for Regeneron.

REFERENCES

1. Rodriguez‑Otero P, Ailawadhi S, Arnulf B, et al: Ide-cel or standard regimens in relapsed and refractory multiple myeloma. N Engl J Med. February 10, 2023 (early release online).

2. Munshi NC, Anderson LD Jr, Shah N, et al: Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N Engl J Med 384:705-716, 2021.