Updated Data from KarMMA-3 Show Improved PFS in Relapsed/Refractory Myeloma

Updates from the phase 3 KarMMa-3 trial (NCT03651128) investigating idecabtagene vicleucel (ide-cel; Abecma) vs standard of care (SOC) combination regimens for relapsed/refractory multiple myeloma after 2 to 4 lines of therapy showed significant improvement in the trial’s primary end point of progression-free survival favoring the experimental arm.^1,2

"These results will allow use of [idecabtagene vicleucel] in patients wtih suboptimal treatment options," according to the lead author of the phase 3 KarMMa-3 trial.

The updated results were presented at the 5th European CAR T-cell Meeting, and simultaneously published in The New England Journal of Medicine. At a median follow-up of 18.6 months, the progression-free survival (PFS) was 13.3 months (95% CI, 11.8-16.1) compared with 4.4 months (95% CI, 3.4-5.9) in the SOC arm (HR, 0.49; 95% CI, 0.38-0.65; P <.001). At 6 months, the PFS rate was 73% in the ide-cel arm vs 40% in the SOC arm, and the 12-month PFS rates were 55% vs 30%, respectively.

A supplemental biologics license application is expected to be submitted to the FDA in 2023.

“These data will impact clinical practice. It is the first phase 3 trial demonstrating PFS benefit for a [B-cell maturation agent] BCMA CAR vs standard regimens in an early disease setting in patients who have already been exposed the 3 main classes of anti-myeloma drugs—namely, immunomodulatory drugs, proteosome inhibitors, and anti-CD38 monoclonal antibodies,” lead author, Paula Rodríguez Otero, MD, PhD, medical coordinator of the Central Unit for Clinical Trials at Clinica Universidad de Navarra, Pamplona, Spain, said in a comment to CancerNetwork^®.

“These results will allow early use of ide-cel in patients with suboptimal treatment options.”

A total of 254 patients were randomly assigned to the ide-cel arm vs 132 in the SOC arm. Baseline characteristics were well balanced, except for Black race, which comprised 7% of patients in the ide-cel arm vs 14% of those in the SOC arm. Additionally, 42% vs 46% had high-risk cytogenetic abnormalities.

The median time since diagnosis was 4 years, and the median time to progression on a previous antimyeloma therapy was 7 months. Additionally, patients received an average of 3 prior therapies. Moreover, 90% of patients were refractory to immunomodulatory agents and 74% were refractory to proteasome inhibitors. Sixty-five percent of patients in the ide-cel arm vs 67% in the SOC arm were triple-class refractory.

A partial response or better was observed in 71% of patients in the ide-cel arm (95% CI, 66%-77%) vs 42% (95% CI, 33%-50%) in the SOC arm (Odds ratio [OR], 3.47; 95% CI, 2.24-5.39; P <.001). A complete response (CR) or stringent CR or higher was observed in 39% of patients in the ide-cel arm vs 5% in the SOC arm.

Patients had a median time to response of 2.9 months in the ide-cel arm and 2.1 months in the SOC arm, and the median duration of response was 14.8 months (95% CI, 12.0-18.6) vs 9.7 months (95% CI, 5.4-16.3) in each respective arm. The minimal residual disease negativity status within 3 months prior to the occurrence was observed in 20% of patients in the ide-cel arm and 1% in the SOC arm.

The overall survival data were immature and still blinded at data cutoff.

In terms of safety, grade 3/4 adverse effects (AEs) were observed in 93% of patients in the ide-cel group and 75% in the SOC group, while 14% vs 6% had grade 5 AEs, respectively. Common any-grade hematologic AEs in each respective arm included neutropenia (78% vs 44%), anemia (66% vs 36%), and thrombocytopenia (54% vs 29%) in the ide-cel and SOC arms, respectively.

Among those in the ide-cel group whose grade 3/4 thrombocytopenia lasted 1 month or longer, the median time to recovery was 1.9 months (95% CI, 1.5-2.1) and 1.7 months (95% CI, 1.5-1.9) for neutropenia.

Infection occurred in 58% of patients in the ide-cel arm and 54% in the SOC arm. Grade 3/4 events of infection were observed in 24% vs 18% and grade 5 AEs in 4% vs 2% in the ide-cel and SOC arms, respectively. The most common infections were upper respiratory tract infection in 12% vs 7%, and pneumonia in 10% vs 7% in the ide-cel and SOC arms, respectively.

Serious AEs of grade 5 or higher occurred in 3% vs 1%, the most common of which was sepsis in 2% vs 1% of those in the ide-cel and SOC arms, respectively.

Grade 3/4 cytokine release syndrome (CRS) occurred in 4% of patients, and 1% was grade 5. The cause of death included a decline of organ function and concomitant grade 5 candida-related sepsis. The median time to CRS was 1 day and it lasted a median of 3.5 days.

Of note, 30% of patients in the ide-cel group and 26% in the SOC group died. The most common cause of death was disease progression in 17% of patients in both groups, respectively.

“There is a full portfolio of studies evaluating BCMA CAR T-cell therapies and particularly ide-cel in other settings of clinical need, such as patients with a suboptimal response after frontline therapy, patients with high-risk disease in addition to autologous stem cell transplant, frontline multiple myeloma. Surely the next steps will be to evaluate these potent therapies as part of the frontline treatment of myeloma patients aiming for a cure for this disease,” Otero concluded.

References

1. Abecma (idecabtagene vicleucel) reduced the risk of disease progression or death by 51% versus standard regimens in earlier lines of therapy for relapsed and refractory multiple myeloma based on results from phase 3 KarMMa-3 study. News release. Bristol Myers Squibb. February 10, 2023. Accessed February 10, 2023. https://bit.ly/3XkmJYo
2. 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. doi:10.1056/NEJMoa2213614