Go-CART4: Cilta-cel Seeks Pole Position in Early-relapsing Multiple Myeloma

Therapeutic advancements over the past two decades have dramatically improved survival rates among patients with both newly diagnosed and relapsed multiple myeloma (MM), primarily through the introduction of effective combination regimens.^1,2  More recent studies have highlighted the efficacy of chimeric antigen receptor T-cell (CAR-T) therapies targeting the B-cell maturation antigen (BCMA) in patients with advanced relapsed and/or refractory MM. Idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) received accelerated regulatory approval in patients who have already received four or more lines of therapy (including an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 monoclonal antibody) in 2021 and 2022, respectively.^3,4  As a follow-up to these single-arm studies, randomized phase III trials have begun to investigate the clinical value of both products. Earlier this year, the phase III KarMMa-3 trial reported improved progression-free survival (PFS) for ide-cel versus standard therapy in patients with relapsed and/or refractory MM who have received two to four prior lines of therapy (including an immunomodulatory drug and an anti-CD38 antibody).⁵ 

The multicenter, international, randomized phase III CARTITUDE-4 study compared cilta-cel with standard-of-care regimens in a cohort of 419 patients with MM exhibiting lenalidomide-resistant disease, 136 of whom had received only one prior line of treatment. All patients had previously received at least one lenalidomide-containing regimen, and the study included patients who had experienced treatment failure with up to three prior lines of therapy.⁶  Patients were randomized 1:1 to receive either a single cilta-cel infusion (target dose: 0.75 × 10⁶ viable, CAR-positive T cells/kg) or one of the following standard-of-care regimens, selected at the discretion of the physician: combination therapy with pomalidomide, bortezomib, and dexamethasone (PVd) or combination therapy with daratumumab, pomalidomide, and dexamethasone (DPd). Patients treated with cilta-cel also received bridging therapy with PVd or DPd. Crossover was not allowed.

PFS was the primary outcome in the intention-to-treat population, all of whom underwent randomization. Baseline characteristics were well balanced between the cilta-cel and standard-care groups, with most patients carrying high-risk cytogenetics (59.4% vs. 62.9%) and ISS stage I disease (65.4% vs. 62.9%). Soft-tissue plasmacytomas were slightly more common in the cita-cel group than in the standard-care group (21.2% vs. 16.6%). Most patients had received two lines of therapy (39.9% vs. 41.2%), although significant proportions had received one (32.7% vs. 32.3%) and three lines (27.4% vs. 26.4%). Triple-class (14.4% vs. 15.6%) and penta-drug refractory (6.7% vs. 4.7%) disease were noted in a small proportion of patients in each group.

Although median PFS was 11.8 months in the standard-care group, it was not reached in the cilta-cel group. At 12 months, the PFS (75.9% vs. 48.6%), overall response (ORR; 84.6% vs. 67.3%), and stringent complete response (sCR; 58.2% vs 15.2%) rates were higher in the cita-cel group than in the standard-care group. Among patients with evaluable samples and at all time points, minimal residual disease (MRD) negativity was also more frequent in the cilta-cel group (87.5% vs. 32.7%). An analysis of adverse events revealed that the cilta-cel group had relatively higher rates of thrombocytopenia (54.3% vs. 31.2%) and anemia (54.3% vs. 26.0%), while rates of neutropenia were high but similar between groups (89.9% vs. 85.1%). Infections were common, with a slightly lower rate observed in the cilta-cel group (62.0% vs. 71.2%). Rates of CAR-T-associated adverse events including cytokine release syndrome (all grades: 76.1%, grade ≥3: 1.1%) and neurotoxicity (all grades: 20.5%, grade ≥3: 2.8%) were similar to those observed in studies of BCMA-directed CAR T-cell therapy.^4,5,7