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CAR-T Makes Its Case for Earlier Use in Multiple Myeloma

— Ide-cel tripled median PFS versus standard regimens in phase III study

MedpageToday
A computer rendering of CAR T-cells attacking a cancer cell.

Chimeric antigen receptor (CAR) T-cell therapy with idecabtagene vicleucel (ide-cel; Abecma) significantly improved outcomes in patients with triple-class-exposed, relapsed and refractory multiple myeloma, according to the phase III

Median progression-free survival (PFS) improved from 4.4 months with standard regimens to 13.3 months with the B-cell maturation antigen (BCMA)-directed CAR T-cell therapy (HR 0.49, 95% CI 0.38-0.65, P<0.001), reported Sergio Giralt, MD, of Memorial Sloan Kettering Cancer Center in New York City, and colleagues in the .

Overall, 71% of patients in the ide-cel group achieved an overall response versus 42% in the standard-regimen group (P<0.001), with complete responses occurring in 39% and 5%, respectively.

"Efficacy of ide-cel therapy was striking," the investigators observed, given that two-thirds of patients had triple-class-refractory disease -- defined as failure with an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody.

"We are seeing efficacy among a population with historically difficult-to-treat disease, with a significant improvement in progression-free survival and deep and lasting responses," Giralt said in a press release, noting that no standard approach currently exists that provides durable responses in this setting.

The results "introduce the potential for this anti-BCMA CAR T-cell therapy to become a standard of care earlier in the treatment course for relapsed and refractory multiple myeloma," said Giralt.

Furthermore, the investigators noted, the benefits were achieved with a single infusion of ide-cel, compared with standard regimens that required continuous treatment

Results from KarMMa-3 were presented simultaneously at the European Society for Blood and Marrow Transplantation and European Hematology Association in Rotterdam, The Netherlands.

Patients in the study were enrolled from May 2019 through April 2022 at 49 sites in 12 countries, with 254 patients randomly assigned to ide-cel and 132 to one of five standard regimens chosen before randomization on the basis of the patient's most recent treatment regimen, as well as the investigator's discretion.

Participants were age 65 years and older; had received two to four prior therapies, including immunomodulatory agents, proteasome inhibitors, and daratumumab (Darzalex), for at least two consecutive cycles; and had documented disease progression within 60 days after the completion of the last therapy.

In both groups, the median time since diagnosis was approximately 4 years, and the median time to progression during the last previous anti-myeloma therapy was approximately 7 months.

Six-month PFS rates were 73% in the ide-cel group versus 40% in the standard-regimen group, while rates at 12 months were 55% and 30%, respectively.

Among the responders, the median duration of response was 14.8 months with ide-cel and 9.7 months with the standard regimens. Median time to response was similar, 2.9 months and 2.1 months, respectively.

Data for overall survival were immature at data cutoff, the team noted.

Regarding safety, adverse events (AEs) were reported in nearly all patients in the two groups, with grade 3/4 AEs occurring in 93% of patients in the ide-cel group and 75% in the standard-regimen group. Grade 5 events occurred in 14% and 8%, respectively.

The most common hematologic AEs were neutropenia (78% of the patients in the ide-cel group and 44% in the standard-regimen group), anemia (66% and 36%), and thrombocytopenia (54% and 29%).

Cytokine release syndrome occurred in 88% of patients receiving ide-cel, though only 5% were grade 3 or higher, while neurotoxic effects occurred in 15% of ide-cel patients, with 3% having an event that was grade 3 or higher.

"Overall, the incidence, type, and severity distribution of the adverse events that were observed with ide-cel therapy in the KarMMa-3 trial were consistent with those of previous studies, with no new safety signals identified," the researchers wrote.

  • author['full_name']

    Mike Bassett is a staff writer focusing on oncology and hematology. He is based in Massachusetts.

Disclosures

The study was funded by 2seventy bio and Celgene (Bristol Myers Squibb).

Giralt disclosed relationships with Actinium Pharmaceuticals, Amgen, Celgene/Bristol Myers Squibb, Incyte, Janssen/Johnson & Johnson, Jazz Pharmaceuticals, Kite Pharma, Miltenyi Biotec, Novartis, Omeros, Sanofi, Spectrum Pharmaceuticals, and Takeda Oncology; co-authors also reported multiple relationships with industry.

Primary Source

New England Journal of Medicine

Rodriguez-Otero P, et al "Ide-cel or standard regimens in relapsed and refractory multiple myeloma" N Engl J Med 2023; DOI: 10.1056/NEJMoa2213614.