Fractionated initial infusion and booster dose of ARI0002h, a humanised, BCMA-directed CAR T-cell therapy, for patients with relapsed or refractory multiple myeloma (CARTBCMA-HCB-01): a single-arm, multicentre, academic pilot study

[Background]: Chimeric antigen receptor (CAR) T-cell therapy is a promising option for patients with heavily treated multiple myeloma. Point-of-care manufacturing can increase the availability of these treatments worldwide. We aimed to assess the safety and activity of ARI0002h, a BCMA-targeted CAR T-cell therapy developed by academia, in patients with relapsed or refractory multiple myeloma.[Methods]: CARTBCMA-HCB-01 is a single-arm, multicentre study done in five academic centres in Spain. Eligible patients had relapsed or refractory multiple myeloma and were aged 18–75 years; with an Eastern Cooperative Oncology Group performance status of 0–2; two or more previous lines of therapy including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody; refractoriness to the last line of therapy; and measurable disease according to the International Myeloma Working Group criteria. Patients received an initial fractionated infusion of 3 × 106 CAR T cells per kg bodyweight in three aliquots (0·3, 0·9, and 1·8 × 106 CAR-positive cells per kg intravenously on days 0, 3, and 7) and a non-fractionated booster dose of up to 3 × 106 CAR T cells per kg bodyweight, at least 100 days after the first infusion. The primary endpoints were overall response rate 100 days after first infusion and the proportion of patients developing cytokine-release syndrome or neurotoxic events in the first 30 days after receiving treatment. Here, we present an interim analysis of the ongoing trial; enrolment has ended. This study is registered with ClinicalTrials.gov, NCT04309981, and EudraCT, 2019-001472-11.[Findings]: Between June 2, 2020, and Feb 24, 2021, 44 patients were assessed for eligibility, of whom 35 (80%) were enrolled. 30 (86%) of 35 patients received ARI0002h (median age 61 years [IQR 53–65], 12 [40%] were female, and 18 [60%] were male). At the planned interim analysis (cutoff date Oct 20, 2021), with a median follow-up of 12·1 months (IQR 9·1–13·5), overall response during the first 100 days from infusion was 100%, including 24 (80%) of 30 patients with a very good partial response or better (15 [50%] with complete response, nine [30%] with very good partial response, and six [20%] with partial response). Cytokine-release syndrome was observed in 24 (80%) of 30 patients (all grade 1–2). No cases of neurotoxic events were observed. Persistent grade 3–4 cytopenias were observed in 20 (67%) patients. Infections were reported in 20 (67%) patients. Three patients died: one because of progression, one because of a head injury, and one due to COVID-19.[Interpretation]: ARI0002h administered in a fractioned manner with a booster dose after 3 months can provide deep and sustained responses in patients with relapsed or refractory multiple myeloma, with a low toxicity, especially in terms of neurological events, and with the possibility of a point-of-care approach.This work has been supported in part by grants from the Instituto de Salud Carlos III (cofunded by the EU), Spanish Ministry of Health (ICI19/00025, FIS PI18/00775, PI19/00669, and PI22/00647), complementary grant for CONCORD-023, RICORS-TERAV network (RD21/0017/0009 and RD21/0017/0019), Red de Terapia Celular TERCEL (RD16/0011/0005), Fondo Europeo de Desarrollo Regional (FEDER), 2017SGR00792 (AGAUR; Generalitat de Catalunya), Centro de Investigación Biomédica en Red de Cáncer CIBERONC (CB16/12/00369 and CB16/12/00489), La Caixa Foundation (CP042702/LCF/PR/GN18/50310007), Asociación Española Contra el Cancer (AECC) LABAE21971FERN, and Fundació Bosch I Aymerich support. AOC received funding from the resident grant Ajut Clínic-La Pedrera 2019, granted by Hospital Clínic de Barcelona.Peer reviewe