Real World CAR T-Cell Therapy Outcomes ‘Favorable’ in Relapsed/Refractory Myeloma

Real-world outcomes of patients with relapsed/refractory multiple myeloma treated with the chimeric antigen receptor (CAR) T-cell therapy ciltacabtagene autoleucel (cilta-cel, Carvykti) showed “favorable” efficacy results, even though many of them would not have been eligible for the trial that led to the drug’s approval, according to a retrospective study.

Among patients who received cilta-cel infusions at 16 U.S. medical centers in 2022, the overall response rate (ORR) was 89%, while 70% had a complete response (CR), reported Surbhi Sidana, MD, of the Stanford University School of Medicine in California, and colleagues in Blood.

By comparison, a 98% overall response rate and an 83% stringent complete response rate was seen in the phase Ib/II CARTITUDE-I trial, which led to FDA approval of cilta-cel in 2022 for the treatment of patients with relapsed or refractory multiple myeloma after ≥4 prior lines of therapy.

However, Sidana and colleagues pointed out that more than half of the patients in their study would have been ineligible to participate in CARTITUDE-1, which required patients to have adequate organ function, limited comorbidities, and no prior exposure to B-cell maturation antigen (BCMA)-targeted therapy.

In the current study, patients receiving standard of care cilta-cel had a numerically greater aggressive disease burden compared to the CARTITUDE-1 population, including high-risk cytogenetics (39% vs 24%) and plasma cell leukemia (6% vs 0%). Extramedullary disease was also more common (26% vs 13%), and 14% had prior BCMA-targeted therapy. Among infused patients, 54% would not have met CARTITUDE-1 eligibility criteria.

“Despite this, [standard of care] cilta-cel resulted in high response rates,” Sidana and colleagues wrote.

“Even though in the real world a majority of patients are not as fit in terms of performance status, organ function, or baseline blood counts as they were in the clinical trial that led to FDA approval [of this therapy], these patients can do very well,” Sidana said in a release. “We saw very high response rates that appeared to be durable, despite over half of the patients not meeting [the trial’s] eligibility criteria.”

Researchers retrospectively analyzed outcomes among 255 patients who underwent leukapheresis for cilta-cel manufacturing from March through December of 2022; 236 patients ended up receiving cilta-cel. Among those, median age was 64 years, with 26% ≥70 years. Most were white (76%), while 11% were Black and 8% were Hispanic.

Cilta-cel’s approval was expanded to earlier lines of treatment in April 2024, but the current study focused on patients who had received treatment under the initial approval indication for heavily pre-treated patients. Participants had received a median of six prior lines of therapy (and up to 18 lines of therapy).

In infused patients, the estimated 12-month progression-free survival (PFS) was 68% and overall survival (OS) was 82%, while in the initial publication from CARTITUDE-1, the 12-month PFS and OS estimates were 77% and 89%, respectively.

In the final analysis from CARTITUDE-1, median PFS was 34.9 months, while median OS was still not reached.

“While it is difficult to make direct comparisons, response rates and estimated PFS in our cohort appear to be somewhat lower than the CARTITUDE-1 population, likely due to differences in patient selection, as half of the patients in our cohort were trial ineligible and such patients had inferior PFS,” the authors observed.

A subgroup analysis of 108 patients who would have been eligible for CARTITUDE-1 found that the overall response and complete response rates in this group were 93% and 74%, respectively, and 12-month estimates for PFS and OS were 76% and 85%, respectively.

Rates of serious side effects were similar to those reported in previous clinical trials, study authors noted. Of those who received cilta-cel infusions, 75% experienced cytokine release syndrome, with 5% experiencing events of grade 3 or higher. Overall, 14% of study participants experienced immune effector cell-associated neurotoxicity syndrome, with delayed neurotoxicity (DNT) in 10%, including 2% who experienced parkinsonism.

At last follow-up, 10% of patients had died due to non-relapse mortality (NRM), mostly from infections. The overall rate of second primary malignancies (SPMs) was 8.5%.

“These numbers are likely to increase with longer follow-up,” the authors suggested.

“Close surveillance for late complications like [secondary primary malignancies] remains crucial,” they added. “Future efforts should focus on measures to decrease NRM, mitigate and manage DNT and a priori identification of patients at risk of developing SPMs.”

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