AZD0120 Versus Standard Regimens in Relapsed or Refractory Multiple Myeloma: A Phase III Randomised Study

The primary objectives of this study are to demonstrate the superiority of AZD0120 compared to standard regimens in participants with relapsed or refractory multiple myeloma. Clinical assessment will be performed through the evaluation of progression-free survival and the minimal residual disease negative complete response rate at 9 months. Efficacy will be further evaluated by assessing complete response rate, overall response rate, and overall survival, alongside additional efficacy parameters. The study will also evaluate the safety profile of AZD0120 in comparison to standard therapy. Additional outcomes of interest include immunogenicity, patient-reported outcomes, biomarkers of response and resistance, and health care utilization.

The study population consists of 355 participants diagnosed with relapsed or refractory multiple myeloma. The cohort includes both male and female individuals within specific age ranges. Eligible participants must be 18 years of age or older and possess a documented diagnosis according to IMWG diagnostic criteria. Inclusion requires evidence of measurable disease, defined by specific serum or urine M-protein levels or free light chain concentrations. Participants must have experienced progressive disease and have received between one and three prior lines of therapy, including an immunomodulatory drug and either a proteasome inhibitor or an anti-CD38 antibody. Additionally, subjects must demonstrate an ECOG performance status of 0 to 1 and possess adequate organ and bone marrow function. The primary objectives of the trial are:

• To demonstrate the superiority of AZD0120 relative to standard therapy by assessment of progression-free survival.
• To demonstrate the superiority of AZD0120 relative to standard therapy by assessment of minimal residual disease negative complete response rate at 9 months.

This is a Phase III, open-label, randomised, multicentre study designed to compare the efficacy and safety of AZD0120, a dual-targeting autologous chimeric antigen receptor T-cell therapy, against standard regimens in participants with relapsed or refractory multiple myeloma. The trial aims to demonstrate the superiority of AZD0120 regarding progression-free survival and the minimal residual disease negative complete response rate at 9 months. The research methodology involves assigning participants to either Arm A or Arm B to receive the investigational product or comparator therapies such as bortezomib, daratumumab, carfilzomib, dexamethasone, or pomalidomide. The study sequence begins with a screening visit to confirm eligibility based on diagnostic criteria, prior therapy history, and organ function. Following randomisation, participants will undergo various follow-up assessments to monitor clinical responses and safety through the evaluation of adverse events. The overall study is estimated to occur between June 2026 and August 2030. Participant involvement is subject to clinical monitoring, and early termination may occur based on investigator determination or protocol-defined conditions.

The experimental treatment consists of AZD0120, an autologous chimeric antigen receptor T-cell therapy. This medication is administered as a solution for infusion via intravenous use.

Comparator treatments include the following substances:

• Daratumumab, administered as a solution for injection via intravenous use.
• Carfilzomib, administered as a solution for infusion via intravenous use.
• Bortezomib, administered as a solution for injection via intravenous use.
• Pomalidomide, administered as a hard capsule via oral use.
• Dexamethasone, administered as a tablet via oral use.

The efficacy of AZD0120 in participants with relapsed or refractory multiple myeloma will be evaluated through several primary and secondary endpoints. The primary efficacy endpoints include progression-free survival (PFS), defined as the time from randomization to documented disease progression according to IMWG 2016 criteria as assessed by blinded independent central review (BICR) or death from any cause, and the MRD negative complete response rate at 9 months. This rate is defined as the proportion of participants achieving minimal residual disease (MRD) negative status and a response of complete response (CR) or stringent complete response (sCR) at 9 months (± 3 months) from randomization, prior to the initiation of subsequent anti-myeloma therapy.

Secondary efficacy parameters include:

• Overall survival (OS), defined as the time from randomization to death from any cause.
• Complete response rate (CRR), representing the proportion of participants achieving a best response of CR or better as assessed by BICR.
• Overall response rate (ORR), defined as the proportion of participants achieving partial response (PR) or better as assessed by BICR.
• Duration of response (DoR), measured from the first documented confirmed response to documented progressive disease (PD) or death.
• Time to response (TTR), defined as the time from randomization to the date of the first documented objective response.
• The proportion of participants achieving MRD negative status with a CR or sCR at any time after randomization and before subsequent therapy.
• The rate of sustained MRD negative CR, defined as achieving MRD negative status and a CR or sCR, confirmed at least 1 year apart without intervening MRD positive status.
• PFS-2, defined as the time from randomization to progression on the next line of therapy.
• Time to next therapy (TFI), defined as the time from the last dose of study intervention to the first dose of subsequent anti-myeloma therapy.

Safety will be assessed through the monitoring of adverse events (AEs), vital signs, and clinical laboratory results.