Phase 3 Randomized Study of BMS-986393 CAR-T Therapy Versus Standard Regimens in Relapsed/Refractory Lenalidomide-Refractory Multiple Myeloma

The primary objective of this Phase 3, randomized, open-label, multicenter study is to evaluate the efficacy of **BMS-986393**, a GPRC5D-directed CAR-T cell therapy, compared to standard regimens in adult participants with relapsed or refractory and lenalidomide-refractory **multiple myeloma**. This is achieved by comparing two main effectiveness measures, which is clinically relevant as it may offer a new therapeutic option for patients who have limited treatment alternatives due to resistance to existing therapies.

Secondary objectives include:

• Comparing additional effectiveness measures between BMS-986393 and standard treatments, specifically Daratumumab with Pomalidomide and Dexamethasone (DPd) or Carfilzomib with Dexamethasone (Kd).
• Assessing the safety profile of BMS-986393, focusing on the type, frequency, and severity of side effects, alongside other effectiveness measures.

The clinical trial involves a total of **251 participants** diagnosed with **Relapsed or Refractory and Lenalidomide-refractory Multiple Myeloma**. The study population includes both male and female subjects, aged 18 years and older, who have received 1-3 prior lines of therapy for multiple myeloma and have demonstrated disease progression during or after their last treatment. Participants are required to have measurable signs of multiple myeloma and adequate organ function and performance status as per the study criteria. The trial does not include vulnerable populations. Selection criteria focus on individuals with a specific medical history and current health status, ensuring a targeted approach to evaluating the effectiveness of the investigational treatment compared to standard therapies. Lifestyle factors such as diet and physical activity are not specified as part of the selection process.

The clinical trial is designed as a **randomized**, open-label, multicenter study aimed at evaluating the efficacy and safety of a GPRC5D-directed CAR-T cell therapy compared to standard regimens in adult participants with relapsed or refractory and lenalidomide-refractory **multiple myeloma**. The trial will involve a comparison between the investigational product, BMS-986393, and standard treatments, which include Daratumumab with Pomalidomide and Dexamethasone (DPd) or Carfilzomib with Dexamethasone (Kd). The primary endpoints of the study are progression-free survival (PFS) and minimal residual disease (MRD)-negative complete response at 9 months ± 3 months. Secondary endpoints include overall survival (OS) and overall response rate (ORR).

The trial is expected to commence recruitment on April 1, 2025, and is estimated to conclude by June 21, 2032. Participants will be involved in the study for a maximum treatment period of 9999 days, depending on the treatment arm and response to therapy. The study will include several key visits: an initial screening visit to confirm eligibility based on criteria such as having received 1-3 prior lines of therapy and having measurable signs of multiple myeloma, followed by regular follow-up visits to monitor treatment response and safety. The end-of-study visit will assess the final outcomes and any long-term effects of the treatment.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The investigational product, BMS-986393, is administered via intravenous infusion, while comparator treatments involve various administration routes, including subcutaneous, oral, and intravenous methods. The trial is not categorized as low intervention and is classified as a Phase 3 study, focusing on the comparative effectiveness of the investigational therapy against established treatment regimens.

The clinical trial involves the administration of several experimental and non-experimental treatments to evaluate their efficacy and safety in participants with relapsed or refractory and lenalidomide-refractory **multiple myeloma**. The primary experimental treatment is **GPRC5D-TARGETED CAR T** (BMS-986393, CC-95266), which is a solution for injection containing the active substance **arlocabtagene autoleucel**. This treatment consists of autologous T cells transduced with a lentiviral vector encoding a chimeric antigen receptor specific for G protein-coupled receptor class C, group 5, member D (GPRC5D). It is administered via intravenous infusion, with a maximum treatment period of one day.

**Daratumumab** is used as a comparator treatment in the study. It is a solution for injection, administered subcutaneously. Daratumumab is a human monoclonal IgG1κ antibody targeting the CD38 antigen. The maximum daily and total dose amounts are set at 999 mg/l, with a treatment period of up to 999 days.

**Fludarabine phosphate** is included as an auxiliary treatment. It is available in two pharmaceutical forms: concentrate for solution for injection/infusion and powder for solution for injection or infusion. Both forms are administered intravenously, with a maximum daily and total dose of 999 mg/m² and a treatment period of up to 9999 days.

**Pomalidomide** is another comparator treatment, provided in hard capsule form for oral administration. The maximum daily and total dose amounts are 999 mg, with a treatment period of up to 999 days.

**Dexamethasone** is used as an auxiliary treatment in various forms, including tablets for oral administration and solutions for injection for intravenous administration. The maximum daily and total dose amounts are 999 mg, with a treatment period of up to 9999 days.

**Dexamethasone sodium phosphate** is also used as an auxiliary treatment, available as a solution for injection administered intravenously. The maximum daily and total dose amounts are 999 mg/ml, with a treatment period of up to 999 days.

**Tocilizumab** is included as a comparator treatment, provided as a concentrate for solution for infusion. It is administered via intravenous infusion, with a maximum daily and total dose of 999 mg/ml and a treatment period of up to 999 days.

**Cyclophosphamide** is used as an auxiliary treatment, available as a powder for solution for injection administered intravenously. The maximum daily and total dose amounts are 999 mg, with a treatment period of up to 9999 days.

**Carfilzomib** is another auxiliary treatment, provided as a powder for solution for infusion. It is administered intravenously, with a maximum daily and total dose of 999 mg/ml and a treatment period of up to 9999 days.

Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the treatment protocols. All medications are over-labelled and repackaged for clinical trial use, ensuring consistency and traceability in the study. The trial aims to compare the efficacy of the experimental GPRC5D-TARGETED CAR T therapy against standard regimens, including Daratumumab with Pomalidomide and Dexamethasone (DPd) or Carfilzomib with Dexamethasone (Kd).

The efficacy of the clinical trial will be assessed using two primary endpoints: **Progression Free Survival (PFS)** and **Minimal Residual Disease (MRD)-negative, Complete Response (CR)** at 9 months ± 3 months after the initiation of the study. PFS measures the average time participants remain alive without their multiple myeloma worsening post-treatment initiation. MRD-negative, CR is defined as the absence of detectable signs of multiple myeloma in the participant's body within the specified timeframe.

Secondary endpoints include **Overall Survival (OS)** and **Overall Response Rate (ORR)**. OS evaluates the average duration participants survive following the commencement of the study. ORR quantifies the proportion of participants exhibiting a positive response to the treatment regimen. These endpoints will be measured and analyzed at predetermined intervals throughout the study duration to ensure comprehensive efficacy evaluation.