Originally published by our sister publication Clinical Oncology News

By Clinical Oncology News Staff

The FDA approved idecabtagene vicleucel (ide-cel) (Abecma, Bristol Myers Squibb/2seventy bio) for the treatment of adult patients with relapsed or refractory multiple myeloma after two or more prior lines of therapy including an immunomodulatory agent (IMiD), a proteasome inhibitor (PI) and an anti-CD38 monoclonal antibody, based on results from the KarMMa-3 trial. This approval expands ide-cel’s indication, making it available in earlier lines to patients who have relapsed or become refractory after exposure to these three main classes of treatment (triple-class exposed), after two prior lines of therapy. Ide-cel is administered as a one-time infusion, with a new recommended dose range of 300 to 510x10⁶ chimeric antigen receptor (CAR)-positive T cells. 

The KarMMa-3 trial is a phase 3, open-label, global, randomized controlled trial evaluating ide-cel compared with standard regimens in patients with relapsed and refractory multiple myeloma who have received two to four prior lines of treatment, including an IMiD, a PI and an anti-CD38 antibody, and were refractory to the last treatment regimen, with 94% of patients with disease refractory to prior treatment with daratumumab (Darzalex, Janssen). KarMMa-3 is the only phase 3 trial to evaluate a CAR T-cell therapy in a patient population consisting entirely of triple-class–exposed patients with relapsed and refractory multiple myeloma. The trial’s patient-centric design allowed for crossover from standard regimens to ide-cel upon confirmed disease progression. At the time of the final progression-free survival (PFS) analysis, 56% of patients in the standard regimens arm crossed over to receive ide-cel as a subsequent therapy.

In the study, 254 patients were randomized to receive ide-cel and 132 to standard regimens that consisted of 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) based on their most recent treatment regimen and investigator discretion. In the ide-cel arm, pretreatment consisted of leukapheresis and optional bridging therapy. The choice to use bridging therapy was at the discretion of the investigator.

At an estimated median duration of follow-up of 15.9 months at the primary PFS analysis, ide-cel more than tripled the primary end point of PFS compared with standard regimens, with a median PFS of 13.3 months (95% CI, 11.8-16.1 months) versus 4.4 months (95% CI, 3.4-5.9 months), respectively (hazard ratio, 0.49; 95% CI, 0.38-0.64; P<0.0001), representing a 51% reduction in the risk for disease progression or death with ide-cel. Ide-cel also showed a significant improvement in overall response rates (P<0.0001) with the majority (71%) of patients treated with ide-cel achieving a response, and 39% achieving a complete or stringent complete response. In comparison, less than half of patients (42%) who received standard regimens achieved a response, with 5% experiencing a complete response or stringent complete response. Responses were durable with ide-cel with a median duration of response of 14.8 months (95% CI, 12.0-18.6 months). In those patients who derived a complete response or better, median duration of response was 20 months (95% CI, 15.8-24.3 months).

Ide-cel has exhibited a well-established and consistent safety profile with mostly low-grade cytokine release syndrome (CRS) and neurotoxicity. Among patients who received ide-cel in the KarMMa and KarMMa-3 studies (n=349), any-grade CRS occurred in 89% of patients, including grade >3 CRS in 7% of patients, and three cases (0.9%) of grade 5 CRS reported. The median time to onset of CRS was one day (range, one to 27 days), and the median duration of CRS was five days (range, one to 63 days). Any-grade neurotoxicity occurred in 40% of patients treated with ide-cel in the KarMMa and KarMMa-3 studies, including grade 3 neurotoxicity in 4% of patients, and two cases (0.6%) of grade 4 neurotoxicity reported. At the safety update for KarMMa-3, one case of grade 5 neurotoxicity was reported. The median time to onset of neurotoxicity was two days (range, one to 148 days), and the median duration of neurotoxicity was eight days (range, one to 720 days).

The drug carries a boxed warning regarding CRS, neurologic toxicities, hemophagocytic lymphohistiocytosis/macrophage activation syndrome, prolonged cytopenia and secondary hematologic malignancies.

Based on a press release from Bristol Myers Squibb.