A Randomized, Open-Label, Phase 3 Trial to Compare the Efficacy and Safety of Idecabtagene Vicleucel with Lenalidomide Maintenance Versus Lenalidomide Maintenance Therapy Alone in Adult Participants with Newly Diagnosed Multiple Myeloma Who Have Suboptimal Response After Autologous Stem Cell Transplantation

The primary objective of this study is to compare the **efficacy** of idecabtagene vicleucel (ide-cel) with lenalidomide (LEN) maintenance therapy versus LEN maintenance therapy alone in adult participants with newly diagnosed **Multiple Myeloma** who have achieved a suboptimal response after autologous stem cell transplantation (ASCT). This is measured by progression-free survival (PFS), which is a critical endpoint in evaluating the effectiveness of cancer treatments, as it reflects the time during which a patient's disease does not worsen.

Secondary objectives include:

• Comparing the efficacy of ide-cel with LEN maintenance to LEN maintenance alone in terms of overall survival (OS) and minimal residual disease negative (MRDneg) complete response (CR) rate.
• Evaluating additional efficacy parameters between the two treatment regimens.
• Assessing the safety profile of ide-cel with LEN maintenance relative to LEN maintenance alone.
• Characterizing the expansion and persistence of CAR T cells in the peripheral blood of participants treated with ide-cel with LEN maintenance.
• Assessing key symptoms, functioning, and overall quality of life in participants treated with ide-cel with LEN maintenance or LEN maintenance alone.

The clinical trial involves a total of **349 participants** diagnosed with **Newly Diagnosed Multiple Myeloma** who have shown a suboptimal response following **Autologous Stem Cell Transplantation**. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on their receipt of induction therapy followed by high-dose chemotherapy and a single autologous stem cell transplantation, without subsequent consolidation or maintenance, except for a brief lenalidomide maintenance therapy under specific conditions. The trial does not include a vulnerable population. Participants must have achieved a documented response of partial response (PR) or very good partial response (VGPR) at the time of consent and must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, with exceptions for those with ECOG 2 due to myeloma-associated bone pain. Additionally, participants must have recovered to Grade 1 or lower for any nonhematologic toxicities from prior treatments, excluding alopecia and Grade 2 neuropathy. Lifestyle factors such as diet and physical activity are not specified in the trial data provided.

The clinical trial is designed as a **randomized**, open-label, Phase 3 study to evaluate the efficacy and safety of **idecabtagene vicleucel** in combination with **lenalidomide** maintenance therapy compared to lenalidomide maintenance therapy alone in adult participants with newly diagnosed **multiple myeloma** who have shown a suboptimal response following autologous stem cell transplantation. The primary objective is to assess progression-free survival, with secondary endpoints including overall survival, minimal residual disease negative complete response, and event-free survival, among others. The trial is expected to conclude by March 2032, with recruitment having commenced in July 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, prior treatment history, and performance status. Following randomization, participants will attend regular follow-up visits to monitor treatment efficacy and safety, with assessments including laboratory tests, imaging, and clinical evaluations. The end-of-study visit will occur upon completion of the treatment period or earlier if specific conditions necessitate withdrawal, such as disease progression or unacceptable adverse events.

The expected duration of participant involvement is contingent upon the treatment arm and individual response, with a maximum treatment period of 89 days for lenalidomide maintenance. Participants may be withdrawn from the study prematurely due to reasons such as non-compliance, withdrawal of consent, or adverse events that compromise safety. The trial's design ensures rigorous monitoring and data collection to support the evaluation of the investigational therapy's impact on disease progression and overall patient outcomes.

The clinical trial involves the administration of **idecabtagene vicleucel**, a cell suspension for injection, as the primary experimental treatment. Idecabtagene vicleucel is a structurally diverse substance used in cell therapy, specifically designed for intravenous administration. The maximum dose is 460 units, administered once during the trial period. This treatment is designated as an orphan drug, indicating its use for a rare condition.

**Lenalidomide** is used as a comparator treatment in the form of hard capsules. It is a chemical substance administered orally. The trial includes three different dosages of lenalidomide: 2.5 mg, 5 mg, 10 mg, and 15 mg capsules. The maximum daily dose is 15 mg, with a total maximum dose of 36,960 mg over a treatment period of 89 days. Lenalidomide capsules are repackaged from their commercial blisters into bottles labeled for clinical trial use to ensure compliance and accurate dosing.

**Fludarabine phosphate** is utilized as an auxiliary treatment in various formulations, including Neoflubin, Fludarabine Accord, Bendarabin, Fludarabin HEXAL, and Fludarabinphosphat-GRY. These are solutions for injection or infusion, administered via intravenous infusion. The maximum daily dose is 30 mg/m², with a total maximum dose of 180 mg/m² over a 6-day treatment period. Fludarabine phosphate is a chemical substance used to support the primary treatment regimen.

**Cyclophosphamide monohydrate**, marketed as Endoxan, is another auxiliary treatment in the form of a solution for injection. It is administered via intravenous infusion with a maximum daily dose of 300 mg/m² and a total maximum dose of 1800 mg/m² over a 6-day treatment period. Cyclophosphamide is a chemical substance used to enhance the efficacy of the primary treatment.

**Tocilizumab**, marketed as RoActemra, is a solution for infusion administered intravenously. It is a protein-based substance used to manage potential inflammatory responses during the trial. The maximum dose is 32 mg/kg, administered once over a 14-day period.

**Diphenhydramine hydrochloride** and **paracetamol** are used as supportive treatments to manage side effects. Both are chemical substances administered orally. Diphenhydramine hydrochloride has a maximum daily dose of 1000 mg, while paracetamol also has a maximum daily dose of 1000 mg, each administered over a single day.

The efficacy of the clinical trial will be assessed primarily through **Progression Free Survival (PFS)**, which serves as the primary endpoint. This parameter will measure the length of time during and after the treatment that a participant lives with the disease without it getting worse. Secondary endpoints include **Overall Survival (OS)**, the percentage of participants achieving **Minimal Residual Disease Negative (MRDneg) Complete Response (CR)** for 12 months, **Event-Free Survival (EFS)**, **Duration of Response (DOR)**, and the percentage of participants with **Complete Response (CR)**. Additional secondary endpoints involve **Time to Progression (TTP)**, **Progression post-next line of treatment (PFS2)**, **Time to Next Treatment (TTNT)**, and the number of participants experiencing adverse events (AEs) and adverse events of special interest (AESI).

Pharmacokinetic parameters such as **Maximum Observed Plasma Concentration (Cmax)**, **Time of Maximum Observed Plasma Concentration (Tmax)**, **Area Under the Curve (AUC) from time zero to 28 days post infusion (AUC [0-28D])**, and **Time of Last Measurable Observed Plasma Concentration (Tlast)** will also be evaluated. Patient-reported outcomes will be assessed through mean changes from baseline in EORTC QLQ-C30 and QLQ-MY20 selected subscales. The efficacy assessments will be conducted at specified intervals throughout the trial duration, with the final analysis occurring at the end of the treatment period. The trial is designed to compare the efficacy of idecabtagene vicleucel with lenalidomide maintenance versus lenalidomide maintenance therapy alone in adult participants with newly diagnosed multiple myeloma who have a suboptimal response after autologous stem cell transplantation.