A phase III, randomised, KarMMa-3 study directly compared a B-cell maturation antigen (BCMA)–directed CAR T-cell therapy, idecabtagene vicleucel with standard regimens in triple-class–exposed relapsed and refractory multiple myeloma. In this patient population, idecabtagene vicleucel resulted in significantly longer progression-free survival (PFS) than standard regimens, with a 51% lower risk of disease progression or death. In addition, treatment with idecabtagene vicleucel resulted in a significantly higher percentage of patients with a response and with deeper responses than were observed in the standard regimens group. The efficacy of idecabtagene vicleucel was striking considering that 65% of patients had triple-class–refractory disease in a short time from diagnosis with disease relapse at a median of approximately 7 months during the last previous regimen. The study findings are reported at EBMT-EHA 5th European CAR T-cell Meeting (9-11 February 2023, Rotterdam, The Netherlands) and simultaneously published on 10 February by Dr. Sergio Giralt of the Department of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center in New York, NY, US and colleagues in The New England Journal of Medicine.
The authors explained in the background that the treatment landscape for relapsed and refractory multiple myeloma has evolved with the use of immunomodulatory agents, proteasome inhibitors, and anti-CD38 monoclonal antibodies in doublet, triplet, or quadruplet combinations in the context of first-line and treatment for relapsed disease. These combinations have helped control disease, but relapse is common. Therefore, patients have triple-class exposure earlier in their treatment course and limited treatment options. Responses in the triple-class–exposed population are suboptimal with poor survival and a standard care approach in this patient population has not been established.
In the phase II KarMMa study, the use of the BCMA-directed CAR T-cell therapy idecabtagene vicleucel led to deep, durable responses in triple-class–exposed, heavily pretreated patients with relapsed and refractory multiple myeloma. Data from this study supported the approval of idecabtagene vicleucel use after the receipt of at least four previous lines of treatment in the US and after the receipt of at least three previous treatments in the EU.
The KarMMa-3 evaluated idecabtagene vicleucel compared to standard regimens in patients with triple-class–exposed relapsed and refractory multiple myeloma who had received two to four lines of treatment previously and who had disease refractory to the last regimen. The patients were randomly assigned in a 2:1 ratio to receive either idecabtagene vicleucel (dose range, 150×106 to 450×106 CAR-positive T-cells) or one of five standard regimens. The primary endpoint was PFS. Key secondary endpoints were overall response (partial response or better) and overall survival (OS). Safety was assessed.
A total of 386 patients were randomised, 254 to idecabtagene vicleucel and 132 to a standard regimens group; 66% of the patients had triple-class–refractory disease and 95% had daratumumab-refractory disease. At a median follow-up of 18.6 months, the median PFS was 13.3 months in the idecabtagene vicleucel group, as compared with 4.4 months in the standard regimens group (hazard ratio for disease progression or death 0.49; 95% confidence interval 0.38 to 0.65; p < 0.001). A response occurred in 71% of the patients in the idecabtagene vicleucel group and in 42% of those in the standard regimens group (p < 0.001); a complete response occurred in 39% and 5%. Data on OS were immature.
Adverse events of grade 3 or 4 occurred in 93% of the patients in the idecabtagene vicleucel group and in 75% of those in the standard regimens group. Among the 225 patients who received idecabtagene vicleucel, cytokine release syndrome occurred in 88%, with 5% having an event of grade 3 or higher, and investigator-identified neurotoxic effects occurred in 15%, with 3% having an event of grade 3 or higher.
The authors commented that in this study, idecabtagene vicleucel resulted in significantly longer PFS than was seen with standard regimens, and responses were deeper. The benefits of idecabtagene vicleucel were derived from a single infusion, whereas standard regimens required continuous treatment. The safety profile of idecabtagene vicleucel was consistent with that observed in previous studies. Given the prolonged PFS and improved response across multiple patient subgroups, the study findings provide potential support for the use of idecabtagene vicleucel in patients with triple-class–exposed relapsed and refractory multiple myeloma, a population with poor survival outcomes.
In contrast to CD19-directed CAR T-cell therapy for acute lymphocytic leukaemia, in which antigen loss is relatively common, BCMA antigen loss was reported in only 3% of the patients in the KarMMa study. Preliminary findings from the KarMMa-3 study showed the presence of BCMA expression in tumour cells and soluble BCMA that were obtained from patients treated with idecabtagene vicleucel at myeloma progression, a finding suggesting that antigen loss is not the primary mechanism of idecabtagene vicleucel resistance in this context. Investigations are under way to assess potential mechanisms of resistance.
The study was supported by 2seventy bio (formerly bluebird bio) and Celgene, a Bristol-Myers Squibb company.
Rodriguez-Otero P, Ailawadhi S, Arnulf B, et al. Ide-cel or Standard Regimens in Relapsed and Refractory Multiple Myeloma. NEJM; Published online 10 February 2023. DOI: 10.1056/NEJMoa2213614