Anitocabtagene autoleucel associated with sustained clinical response in heavily pretreated multiple myeloma

1. In this phase 1 trial involving patients with triple-class refractory multiple myeloma, treatment with anitocabtagene autoleucel led to a complete response in more than three-quarters of participants.

2. At the dose selected for further study, nearly all patients had cytokine release syndrome, but events were mild to moderate in severity.

Evidence Rating Level: 2 (Good)

Study Rundown: Multiple myeloma commonly relapses after successive treatments, leaving patients whose disease is resistant to several drug classes with limited options. Chimeric antigen receptor (CAR) T-cell therapies directed against B-cell maturation antigen (BCMA) can produce deep responses, but cytokine release syndrome, neurologic toxicity, and cytopenias remain concerns. Anitocabtagene autoleucel (anito-cel) uses a small synthetic BCMA-binding domain with a fast off-rate to limit antigen-independent aggregation observed with conventional CAR binders. In this first-in-human study, anito-cel was administered to adults with heavily pretreated relapsed or refractory myeloma. All treated patients had a response, most achieved a complete response, and disease control often lasted for years. Cytopenias were the most frequent adverse events of grade 3 or higher, and infections developed in more than half of the cohort, although most infections were mild to moderate. Severe cytokine release syndrome was not observed, but severe neurotoxicity occurred in one individual. Laboratory experiments suggested that anito-cel had similar cytotoxicity to target cell lines while releasing fewer inflammatory cytokines than a comparator binder. This biophysical comparison could not establish that binder design was responsible for the observed clinical safety profile, and patients were not directly compared with recipients of another CAR T product. Nonetheless, anito-cel showed promising, durable activity in this cohort, and larger studies are needed to confirm its safety and define its role in treatment.

Click to read the study in NEJM

Relevant Reading: CAR-T cell therapy in Multiple Myeloma: current status and future challenges

In-Depth [prospective cohort]: This phase 1 study involved 38 patients with multiple myeloma who had triple-class refractory disease or had previously received three or more lines of therapy. Over two-thirds of the cohort had penta-drug refractory disease. A total of 32 participants received anitocabtagene autoleucel at the recommended phase 2 dose of 100 million CAR-positive T cells, and 6 participants received 300 million cells. At a median follow-up of 38.1 months, the overall response rate was 100% (95% confidence interval [CI], 91 to 100), and the complete response rate was 79% (95% CI, 63 to 90). Median progression-free survival was 30.2 months (95% CI, 16.6 to 36.2), with an estimated 24-month progression-free survival of 57%. Among 28 patients evaluable for minimal residual disease, 25 (89%) were negative at a sensitivity threshold of 10⁻⁵. During the treatment period, 37 patients (97%) had an adverse event of grade 3 or higher, most commonly a cytopenia. At the recommended dose, 30 (94%) had grade 1 or 2 cytokine release syndrome, with no grade 3 or higher events. A total of 6 subjects (19%) had immune effector cell–associated neurotoxicity syndrome, including one grade 3 event. Across both doses, 6 participants (16%) had a grade 3 or higher infection. No delayed neurologic toxicity was observed. In summary, anito-cel had an acceptable safety profile and led to significant clinical response among patients with heavily pretreated multiple myeloma.

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