SAN DIEGO – A new head-to-head study presented at the American Society of Hematology's annual meeting on Monday is shedding light on the relative benefits of two competing multiple myeloma therapies: Bristol Myers Squibb and 2seventy Bio's Abecma (idecabtagene vicleucel) and Janssen and Legend Biotech's Carvykti (ciltacabtagene autoleucel).
Both autologous CAR T-cell therapies are designed to target the B-cell maturation antigen (BCMA) on the surface of multiple myeloma cells. The therapies, which involve harvesting patients' immune cells, modifying them to express chimeric antigen receptors targeting BCMA, then reinfusing them as a one-time treatment, are both US Food and Drug Administration-approved for patients with relapsed or refractory multiple myeloma. Though Abecma and Carvykti have recently netted regulatory approvals as earlier-line therapies, both were initially approved for patients who'd received at least four prior treatments. This heavily pretreated patient population is the group that researchers focused on in their head-to-head study.
The clinical trials that first led to Carvykti's and Abecma's approvals were single-arm trials. As such, they didn't prove their respective CAR T-cell therapies were any more effective than existing multiple myeloma therapies — including other treatments in the same class.
Indeed, neither BMS nor Janssen has sponsored a direct-comparison trial, in which patients are randomized to Abecma or Carvykti. Oncologists instead have been left to choose a therapy without evidence on which is the best option in terms of safety and efficacy.
"In lieu of a randomized prospective clinical trial, we set out to compare the safety and efficacy outcomes of ide-cel and cilta-cel in the standard-of-care setting for relapsed or refractory multiple myeloma," said Doris Hansen, a hematologist and oncologist from the Moffitt Cancer Center, who presented the results of the retrospective study on Sunday. The researchers looked specifically at patients receiving these CAR T-cell therapies after four or more prior treatments.
Comparative efficacy
Though the retrospective study was not a randomized, prospective head-to-head trial, oncologists at the meeting appeared to find the research involving a total of 641 patients across 19 institutions informative, nonetheless.
Although 641 patients underwent leukapheresis and had their cells harvested with the intention to manufacture one of the CAR T-cell therapies, only 586 patients ended up receiving these infusions. Of these patients, 350 received Abecma and 236 received Carvykti. The investigators did their best using statistical modeling to ensure patients' characteristics were balanced in the arms, Hansen noted.
After a median follow-up of 13 months with Abecma and 12.6 months with Carvykti, the researchers found that more patients responded to Carvykti than Abecma. The best overall response rate for Carvykti was 89 percent, versus 79 percent with Abecma. Of the patients who received Carvykti, 70 percent experienced a complete response, whereas the same was true for 47 percent of patients who received Abecma.
The progression-free survival and overall survival outcomes were significantly superior with Carvykti, too. Carvykti reduced patients' risk of disease progression or death by 52 percent versus Abecma and reduced the risk of death by 33 percent compared to Abecma.
When the researchers homed in only on the population of patients who were treated after March 2022, after both CAR T-cell therapies netted FDA approval, they found that the relative benefit remained consistent. This was also true when they considered the full intent-to-treat population, including patients who didn't ultimately receive their CAR T-cell infusions due to progressive disease, death, or other reasons.
Across most patient subgroups broken down by age, disease characteristics, and baseline risk factors, these observations still held.
Improved efficacy brings greater side effects
Despite its improved relative efficacy, the side effects appeared more severe with Carvykti. Patients on Carvykti were more likely to experience grade 3 or higher cytokine release syndrome as well as infections, for instance. Twelve patients, or 5 percent, experienced grade 3 or higher cytokine release syndrome after Carvykti, whereas the same was true for 2 percent, or six patients, after Abecma. With Carvykti, 47 percent of patients experienced infections versus 35 percent with Abecma.
Patients who received Carvykti had a slightly higher, though non-statistically significant, rate of non-relapse mortality than Abecma-treated patients, meaning that they were more likely to die from causes other than their myelomas progressing. Hansen noted that the higher infection rates may have played into this discrepancy.
Carvykti-treated patients were more likely to experience delayed neurotoxicity than Abecma-treated patients, too. In the Carvykti cohort, 24 patients, or 10 percent, experienced delayed neurotoxicity, compared to two patients, or 1 percent, of patients in the Abecma-treated cohort.
Across the Abecma and Carvykti cohorts, Hansen noted that there were no differences in severe immune effector cell-associated neurotoxicity or severe cytopenias, among other notable side effects.
Although the difference wasn't statistically significant, Hansen did point out a slightly higher likelihood of developing second primary malignancies among patients receiving Carvykti. Importantly, this wasn't true of hematologic second primary malignancies specifically. Oncologists are particularly interested in the likelihood of patients developing a second primary blood cancer following CAR T-cell therapy since the FDA required sponsors add a boxed warning to the labels for these therapies detailing such risks.
There's been subsequent debate about whether these malignancies were truly caused by the CAR T cells, or if the risk is greater in patients eligible for CAR T-cell therapy than in the general population in the first place. Oncologists are still trying to understand the potential link.
"We hope that this study aids in clinical decision-making, patient counseling, and guiding selection of CAR T-cell products," Hansen said, pointing out that the study was not a randomized trial, and there is potential for inherent bias in the data.
Going forward, she said the field would benefit from comparative data from even larger analyses, including larger patient subgroups. "Treatment is personalized, and patient factors and comorbidities must be taken into account," she said.