October 2023

Katie Robinson

A fractionated dose of ARI0002hm, an investigational autologous chimeric antigen receptor (CAR) T-cell therapy targeting B-cell maturation antigen (BCMA), combined with a booster dose after three months provided deep and sustained responses in patients with relapsed or refractory multiple myeloma (R/R MM). This is according to an interim analysis of a study, published in The Lancet Oncology, that reported no cases of neurotoxicity.

“ARI0002h might be a reasonable alternative to other BCMA-directed CAR T-cell constructs for patients with R/R MM,” said corresponding author Carlos Fernández de Larrea, MD, PhD, of the Hospital Clínico of Barcelona in Spain. “ARI0002h can be manufactured at up to a quarter of the cost of that of commercial CAR T cells.”

The ongoing single-arm, multicenter study aimed to assess the safety and activity of ARI0002h, which is being developed at the Hospital Clínico of Barcelona. Eligible patients had R/R MM with two or more previous lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody. Between June 2, 2020, and February 24, 2021, 30 patients (median age = 61; 60% male) received ARI0002h, with an initial fractionated infusion of 3 x 106 CAR T cells/kg in three aliquots (0.3, 0.9, and 1.8 x 106 CAR-positive cells/kg intravenously on days 0, 3, and 7) and a non-fractionated booster dose of up to 3 x 106 CAR T cells/kg at least 100 days after the first infusion.

The primary endpoints included the overall response rate (ORR) during the first 100 days from initial infusion and the proportion of patients developing cytokine-release syndrome (CRS) or neurotoxic events during the first 30 days post-treatment.

At the planned interim analysis (October 20, 2021, cutoff) with a median follow-up of 12.1 months, the ORR during the first 100 days from infusion was 100%. This included 80% of the 30 patients with a very good partial response or better (50% with complete response, 30% with very good partial response, and 20% with partial response). On day 100, 26 patients were evaluable for measurable residual disease (MRD), and 92% were MRD negative (95% CI 76-98).

The rate of grade 1-2 CRS was 80% (n=24). No neurotoxic events were observed. The rates of persistent grade 3-4 cytopenias and infections were both 67% (n=20). Three patients died because of disease progression, head injury, and COVID-19, respectively.

“In this study, all treated patients had at least a partial response, with good results in terms of MRD negativity,” said Dr. Fernández de Larrea. “The development of CRS was similar to that of other BCMA CAR T-cell therapies, showing a lower grade of severity, with none at grade 3 or above, and no cases of ICANS [immune effector cell-associated neurotoxicity syndrome] or late neurotoxicity, thanks in part to the administration schedule in three fractions of the first dose.

“In addition to the 30 patients participating in this study, another 30 patients were also added, and the treatment was administered on a compassionate-use basis in 12 more patients,” said Dr. Fernández de Larrea. “The Spanish Agency of Medicines and Medical Devices (AEMPS) is evaluating the documentation based on the results of this study for approval as a non-industrially manufactured advanced therapy medicinal product.”

Because there is no comparator group in this trial, the role of the booster dose is difficult to establish. A randomized study exploring efficiency of the booster dose is needed. Researchers are also especially interested in finding strategies to overcome relapse because patients’ disease continued to relapse after treatment with ARI0002hm.