KarMMa-3: Idecabtagene Vicleucel vs Standard Regimens in Patients With Relapsed or Refractory Multiple Myeloma (2024)

As reported in The New England Journal of Medicine by Rodriguez‑Otero et al, an interim analysis of the phase III KarMMa-3 trial showed superior progression-free survival with the B-cell maturation antigen–directed chimeric antigen receptor (CAR) T-cell therapy idecabtagene vicleucel (ide-cel) 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.

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

Study Details

In the open-label trial, 386 patients with disease refractory to their last regimen from sites in 12 countries were randomly assigned 2:1 between May 2019 and April 2022 to receive ide-cel 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 random assignment on the basis of 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)
• Elotuzumab, pomalidomide, and dexamethasone (n = 30).

A total of 29 patients in the ide-cel 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 random assignment 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 ide-cel 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 benefit of ide-cel 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.

Partial response or better was observed in 71% (95% CI = 66%–77%) of patients in the ide-cel 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). Complete response or 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 ide-cel 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%. Serious adverse events occurred in 52% vs 38% of patients. Overall, grade 5 events considered related to treatment occurred in six patients (3%) vs one patient (1%). Second primary cancers occurred in 6% vs 4% of patients.

Among the 225 patients who received ide-cel, cytokine-release syndrome occurred in 88% and was grade ≥ 3 in 5%, and neurotoxicity occurred in 15% and was grade ≥ 3 in 3%.

The investigators concluded, “Ide-cel 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 ide-cel was consistent with previous reports.”

Sergio Giralt, MD, of the Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, is the corresponding author for The New England Journal of Medicine article.

Disclosure: The study was funded by 2seventy bio and Celgene, a Bristol Myers Squibb company. For full disclosures of the study authors, visit nejm.org.