Phase III Trial of ARI0002h CAR T-Cell Therapy versus Standard of Care in Patients with Relapsed or Refractory Multiple Myeloma

The primary objective of this phase III trial is to compare progression-free survival between patients receiving ARI0002h, an academically produced BCMA-directed CAR T-cell therapy, and those receiving the current standard of care in the context of relapsed/refractory multiple myeloma. This comparison is clinically significant for determining the efficacy of novel chimeric antigen receptor T-cell therapy in patients previously treated with 2-4 lines of therapy. Secondary objectives include:

• Evaluation of response rates, including overall response rate, stringent complete response, complete remission, very good partial response, partial response, and minimal residual disease negativity.
• Correlation of minimal residual disease negativity with various efficacy endpoints.
• Assessment of duration of response and overall survival.
• Evaluation of tolerability, specifically regarding cytokine release syndrome, immune effector cell-associated encephalopathy, and delayed neurotoxicity.
• Monitoring for the development of secondary malignancies.
• Assessment of quality of life.
• Analysis of cost-effectiveness compared to standard regimens.
• Investigation of CAR T-cell expansion, persistence, and T-cell characteristics, alongside production characteristics and the proportion of successful batches.
• Evaluation of the association between functional product characteristics and clinical outcomes, including adverse events and progression-free survival.

The sponsor did not provide information regarding the total number of participants. The study population consists of male and female patients with relapsed/refractory multiple myeloma. Eligible participants are aged 18 years or older and have received between 2 and 4 prior lines of antimyeloma therapy, including an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. Inclusion requires refractory disease according to International Myeloma Working Group criteria, measurable disease at screening, and suitability for one of five standard of care regimens. Participants must possess an ECOG performance status of 0-2 and demonstrate adequate hematological, renal, hepatic, pulmonary, and cardiac function.

This phase III randomized clinical trial is designed to compare the efficacy and safety of cesnicabtagene autoleucel, an autologous genetically modified T lymphocyte product, against various standard of care regimens in patients with relapsed/refractory multiple myeloma. The primary objective is to evaluate progression free survival. The study involves a screening process to confirm eligibility based on prior exposure to immunomodulatory drugs, proteasome inhibitors, and anti-CD38 monoclonal antibodies, as well as measurable disease and adequate organ function. Participants are randomized to receive either the investigational CAR T-cell therapy or a comparator regimen, which may include agents such as carfilzomib, daratumumab, cyclophosphamide, dexamethasone, bortezomib, elotuzumab, or pomalidomide. The trial is expected to conclude recruitment by August 2030.

The experimental treatment consists of Cesnicabtagene autoleucel, which is an autologous genetically modified T lymphocytes transduced with lentivirus expressing CAR protein directed against BCMA. This agent is administered as a dispersion for infusion via intravenous injection at a dose of 3,000,000 units.

Comparator treatments include carfilzomib, provided as a solution for infusion for intravenous administration at a dosage of 70 mg/m2. Daratumumab is administered as a solution for injection via subcutaneous injection at a dose of 1800 mg. Cyclophosphamide monohydrate is administered as a film-coated tablet through an oral route at a dose of 50 mg. Dexamethasone is provided as a tablet for oral administration at a dose of 40 mg. Bortezomib is administered as a solution for injection via subcutaneous injection at a dose of 1.3 mg/m2. Elotuzumab is administered as a solution for infusion via intravenous administration at a dose of 20 mg/kg. Pomalidomide is administered as a hard capsule through an oral route at a dose of 4 mg.

The primary efficacy endpoint is progression-free survival in patients with relapsed/refractory multiple myeloma. Secondary endpoints include overall response rate, best overall response, duration of response, and overall survival from the date of randomization. The assessment of efficacy also involves evaluating overall and sustained MRD-negativity, specifically MRD-negative CR/sCR and MRD-negative VGPR+, alongside the correlation of minimal residual disease negativity with efficacy endpoints. Additionally, the trial will evaluate patient-reported outcome and quality of life.

The study further aims to assess CAR T-cell expansion, persistence, and T-cell characteristics in patients receiving the test product. This includes analyzing the association between the functional characteristics of the CAR T-cell products and clinical outcomes such as adverse events, response rates, and progression-free survival. Other secondary measures include the proportion of successful batches and the evaluation of production and additional health care costs.