Phase III Non-Inferiority Trial of Lenalidomide, Bortezomib, Dexamethasone, and Isatuximab in Newly Diagnosed Multiple Myeloma Patients

The primary objective of this randomized phase III non-inferiority trial is to demonstrate the non-inferiority of **subcutaneous (SC) isatuximab** compared to intravenous (IV) isatuximab, both in combination with lenalidomide, bortezomib, and dexamethasone (RVd), with respect to achieving very good partial response (VGPR) or better after induction therapy in patients with newly diagnosed **multiple myeloma**. This is clinically relevant as it may offer a more convenient administration route without compromising efficacy, potentially improving patient compliance and quality of life.

Secondary objectives include:

• Comparison of patient-reported outcomes (PRO) regarding the route of administration of isatuximab (SC vs. IV) during induction therapy, assessed by a modified Cancer Therapy Satisfaction Questionnaire (CTSQ).
• Assessment of the non-inferiority of rates of minimal residual disease (MRD) negativity, evaluated by next-generation sequencing (NGS) from bone marrow aspirates, independent of standard International Myeloma Working Group (IMWG) response after induction therapy.

The clinical trial involves participants diagnosed with **Multiple Myeloma**, specifically targeting an age range of 18 to 70 years. The study includes both male and female subjects, with a **World Health Organization (WHO) performance status** of 0 to 2, indicating that participants are in relatively good health and capable of self-care. The trial does not include a vulnerable population. Participants were selected based on their confirmed diagnosis of untreated Multiple Myeloma requiring systemic therapy, and they must be eligible for high-dose melphalan and autologous stem cell transplantation. Lifestyle considerations include the requirement for all participants to use adequate contraception during the therapy and to abstain from donating blood while taking lenalidomide and for 28 days after its discontinuation. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy of subcutaneous versus intravenous administration of **isatuximab** in combination with lenalidomide, bortezomib, and dexamethasone for patients with newly diagnosed **multiple myeloma**. The primary objective is to demonstrate the non-inferiority of subcutaneous isatuximab compared to its intravenous counterpart, with respect to achieving very good partial response (VGPR) or better after induction therapy, as per the International Myeloma Working Group (IMWG) response criteria. The trial is expected to span approximately 18 months, with an estimated completion date by the end of 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, performance status, and measurable disease. Following successful screening, participants will be randomized to receive either subcutaneous or intravenous isatuximab. The study includes multiple follow-up visits to monitor treatment response and safety, with assessments conducted according to the IMWG criteria. The end-of-study visit will evaluate the primary and secondary endpoints, including VGPR rates and patient-reported outcomes.

The expected duration of participant involvement is up to 18 months, aligning with the maximum treatment period. Conditions that may lead to early termination from the study include adverse events, withdrawal of consent, or failure to adhere to the study protocol. Participants are required to comply with specific safety measures, such as using adequate contraception and abstaining from blood donation during and after lenalidomide therapy. The trial's design ensures rigorous monitoring and data collection to support the evaluation of the therapeutic regimen's efficacy and safety.

The clinical trial involves the administration of **Isatuximab**, a **solution for infusion** and **solution for injection**. Isatuximab is a protein-based therapeutic agent developed by Sanofi Aventis Recherche et Développement (SAR). It is administered intravenously at a maximum daily dose of 10 mg/kg, with a total maximum dose of 330 mg/kg over a treatment period of 18 months. Additionally, Isatuximab is also administered subcutaneously using the On Body Delivery System (OBDS), which is a sterile, single-use, disposable device designed for subcutaneous delivery. The subcutaneous administration involves a maximum daily dose of 1400 mg, with a total maximum dose of 15400 mg over the same treatment period.

**Lenalidomide** is used in the trial in various dosages, including 5 mg, 10 mg, 15 mg, and 25 mg hard capsules, marketed under the name Lenalidomid HEXAL by HEXAL AG. Lenalidomide is a chemical substance administered orally, with a maximum daily dose of 25 mg and a total maximum dose of 2100 mg over 18 months. It is a part of the standard-of-care therapy in the trial.

**Dexamethasone**, specifically in the form of **Betamethasone Sodium Phosphate**, is included as an auxiliary treatment. It is a chemical substance administered both orally and intravenously, with a maximum daily dose of 20 mg and a total maximum dose of 1080 mg over the treatment period. This treatment is used to support the primary therapeutic regimen.

**Bortezomib**, marketed as VELCADE, is a **powder for solution for injection**. It is a chemical substance administered subcutaneously, with a maximum daily dose of 1.3 mg/m² and a total maximum dose of 31.2 mg/m² over 18 months. Bortezomib is part of the comparator treatment in the trial, used in combination with other agents to assess the efficacy of the experimental treatment.

The efficacy of the clinical trial will be assessed primarily by evaluating the rates of **Very Good Partial Response (VGPR)** or better, as defined by the standard International Myeloma Working Group (IMWG) response criteria. This primary endpoint will measure the proportion of patients achieving at least VGPR after induction therapy. Secondary endpoints include patient-reported outcomes (PRO) scores, specifically the "satisfaction with therapy" subdomain assessed by the Cancer Therapy Satisfaction Questionnaire (CTSQ) for subcutaneous (SC) versus intravenous (IV) isatuximab application during induction therapy. Additionally, the rates of Next-Generation Sequencing Minimal Residual Disease (NGS-MRD) negativity, with a sensitivity of 10^-5 from bone marrow aspirates (BMA), will be evaluated after induction therapy.