The U.S. Food and Drug Administration (FDA) has expanded approval for the CAR T-cell therapy idecabtagene vicleucel (ide-cel; Abecma) to include adults with relapsed or refractory multiple myeloma after two or more lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody, according to an April 4 news release from Bristol Myers Squibb and 2seventy bio, Inc.
The decision was based on results of the phase 3, open-label, global, randomized controlled KarMMa-3 clinical trial. Ide-cel demonstrated clinically meaningful and statistically significant improvements in progression-free survival, representing a 51% reduction in the risk of disease progression or death (95% confidence interval [CI], 13.3 months vs. 4.4 months for standard regimens [hazard ratio (HR), 0.49; P<0.0001]).
The study included 254 patients randomly assigned to receive ide-cel and 132 randomly assigned to receive standard regimens, with combinations that included daratumumab, pomalidomide, and dexamethasone (DPd); daratumumab, bortezomib, and dexamethasone (DVd); ixazomib, lenalidomide, and dexamethasone (IRd); carfilzomib and dexamethasone (Kd); or elotuzumab, pomalidomide, and dexamethasone (EPd), chosen based on their most recent treatment regimen and investigator discretion.
The trial also showed a significant improvement in overall response rates (P<0.0001), with most patients (71%) treated with ide-cel achieving a response and 39% achieving "a complete or stringent complete response." Ide-cel was well-tolerated with reports of mostly low-grade cytokine release syndrome (CRS) and neurotoxicity. No cases of Parkinsonism were reported.
"The results of the KarMMa-3 study are remarkable, especially given the historic outcomes with standard regimens for these patients with relapsed or refractory disease," said Al-Ola A. Abdallah, MD, with the University of Kansas in Lawrence, in a statement. "With this approval, these patients now have an opportunity to be treated at an earlier line of therapy with a potentially transformative therapy that offers significantly improved progression-free survival for this difficult-to-treat disease that has had no established treatment approach."
The expanded approval comes after two March 15 meetings held by the FDA's Oncologic Drugs Advisory Committee (ODAC) amid concerns about early deaths among patients enrolled in studies evaluating ide-cel and ciltacabtagene autoleucel (cilta-cel; Carvykti) in relapsed/refractory multiple myeloma. Committee members unanimously affirmed the risk–benefit assessment for cilta-cel; however, concerns over the interpretation of survival data for ide-cel resulted in an 8–3 vote.
In the KarMMa-3 trial, a higher proportion of patients experienced death within nine months in the ide-cel group (45 patients; 18%) compared with the standard regimens group (15 patients; 11%). Early deaths occurred in 8% (20 patients) and 0% before ide-cel infusion and standard regimen administration, respectively, and in 10% (25 patients) and 11% (15 patients) after ide-cel infusion and standard regimen administration, respectively. Out of the 25 deaths that occurred after ide-cel infusion, 10 were attributed to disease progression, 11 were due to adverse events, and 4 had unknown causes.
Ide-cel is administered as a one-time infusion and comes with boxed warnings regarding CRS, neurologic toxicities, hemophagocytic lymphohistiocytosis/macrophage activation syndrome, prolonged cytopenia, and secondary hematological malignancies. Among patients in the trials who received ide-cel, any-grade CRS occurred in 89% of patients, including grade 3 or higher CRS in 7% of patients; three cases (0.9%) of grade 5 CRS were reported. The median time to onset of any-grade CRS was 1 day, and the median duration was 5 days. Any-grade neurotoxicity was reported in 40% of patients who received ide-cel, including grade 3 neurotoxicity in 4%, and grade 4 neurotoxicity in 0.6%. One case of grade 5 neurotoxicity was noted at the safety update for the KarMMa-3 trial. The median time to start of neurotoxicity was 2 days, and the median duration was 8 days.
In 2021, the FDA approved ide-cel in patients with relapsed or refractory multiple myeloma who had received four or more prior lines of therapy. The treatment was recently approved in Japan, Switzerland, and the European Union for triple-class exposed patients.
