Phase 3 Study of Subcutaneous vs. Intravenous Isatuximab with Pomalidomide and Dexamethasone in Relapsed/Refractory Multiple Myeloma Patients

The primary objective of this study is to demonstrate the **efficacy** non-inferiority between isatuximab subcutaneous (SC) and isatuximab intravenous (IV) in combination with pomalidomide and dexamethasone (Pd) in patients with relapsed and/or refractory multiple myeloma. This is clinically relevant as it may offer a more convenient administration route without compromising treatment effectiveness. Additionally, the study aims to demonstrate the pharmacokinetic (PK) non-inferiority between isatuximab SC and IV in combination with Pd, which is crucial for ensuring consistent drug exposure and therapeutic outcomes.

The secondary objectives include:

• Assessing the efficacy of isatuximab SC compared to isatuximab IV in combination with Pd.
• Demonstrating the PK non-inferiority between isatuximab SC and IV in combination with Pd.
• Assessing the safety of isatuximab SC and IV in combination with Pd.
• Evaluating participant satisfaction with isatuximab SC and IV.
• Assessing the local tolerability of isatuximab SC in combination with Pd.
• Characterizing the PK of isatuximab SC and IV in combination with Pd.
• Assessing the delivery performance of the investigational device injector.
• Evaluating the potential immunogenicity of isatuximab SC and IV in combination with Pd.
• Assessing the clinical outcome of isatuximab SC and IV in combination with Pd.
• Exploring chromosomal abnormalities, such as t(4;14), t(14;16), del(17p), and 1q21+, and their potential association with clinical outcomes.

The clinical trial involves a total of **389 participants** diagnosed with **plasma cell myeloma recurrent**, commonly known as multiple myeloma. The study population includes both male and female subjects, with an age range of 18 years and older. Participants were selected based on their previous treatment history, having received at least one prior line of anti-myeloma therapy, which must include lenalidomide and a proteasome inhibitor, either alone or in combination. The trial includes individuals with measurable serum M-protein or urine M-protein levels, or an abnormal serum free light chain ratio. The study population is characterized by a diverse health status, as it includes a vulnerable population. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data. The selection criteria ensure that the participants have a measurable disease, which is crucial for assessing the efficacy and pharmacokinetics of the treatments being compared.

The clinical trial is designed as a **randomized**, open-label, Phase 3 study to evaluate the efficacy and pharmacokinetics of subcutaneous versus intravenous administration of **isatuximab** in combination with **pomalidomide** and **dexamethasone** in adult patients with relapsed and/or refractory multiple myeloma. The trial aims to demonstrate the non-inferiority of subcutaneous administration compared to intravenous administration in terms of efficacy and pharmacokinetic parameters. The study is expected to run from November 2022 to July 2027, with an estimated duration of 80 weeks for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as prior treatment history and measurable disease markers. Following randomization, participants will attend regular follow-up visits to monitor treatment response, safety, and pharmacokinetic parameters. The primary endpoints include overall response rate and observed concentration before dosing at steady state, while secondary endpoints encompass a range of efficacy, safety, and patient satisfaction measures. The end-of-study visit will conclude the participant's involvement, assessing overall outcomes and any long-term effects.

Participant involvement is expected to last for the full duration of the treatment period, approximately 80 weeks, unless early termination is warranted. Conditions that may lead to early termination include the occurrence of treatment-emergent adverse events, serious adverse events, or disease progression that necessitates discontinuation of the study medication. The trial will adhere to rigorous methodological standards to ensure the reliability and validity of the findings, contributing valuable insights into the treatment of relapsed and/or refractory multiple myeloma.

The clinical trial involves the administration of several treatments, including **pomalidomide**, **isatuximab**, and **dexamethasone**, in patients with relapsed and/or refractory multiple myeloma. The experimental medication **pomalidomide** is provided in the form of hard capsules under the brand name Imnovid, available in dosages of 1 mg, 2 mg, 3 mg, and 4 mg. The capsules are administered orally with a maximum daily dose of 4 mg and a total maximum dose of 6720 mg over a treatment period of 80 days. The pharmaceutical form is a hard capsule, and the active substance is of chemical origin. The product is manufactured by Bristol-Myers Squibb Pharma EEIG and is subject to repackaging and relabeling for clinical supplies.

**Isatuximab** is administered in two forms: as a solution for infusion and as a solution for injection. The solution for infusion is provided under the sponsor product code SAR650984 and is administered intravenously with a maximum daily dose of 10 mg/kg and a total maximum dose of 226800 mg over 80 days. The solution for injection is administered subcutaneously using the On Body Delivery System (OBDS), a sterile, single-use, disposable device designed for subcutaneous delivery. The active substance is a protein of other origin, and the product is developed by Sanofi Aventis Recherche et Développement (SAR).

**Dexamethasone** is provided in tablet form under the brand name Dexamethason JENAPHARM®, available in dosages of 4 mg and 8 mg. The tablets are administered orally with a maximum daily dose of 40 mg and a total maximum dose of 12800 mg over a treatment period of 80 days. The active substance is of chemical origin, and the product is manufactured by MIBE GmbH Arzneimittel. The tablets are also subject to repackaging and relabeling for clinical supplies.

In addition to the experimental treatments, the trial includes the use of **montelukast sodium** as an auxiliary treatment. However, the specific pharmaceutical form and route of administration for montelukast sodium are not specified due to the diversity of the ATC level selected. The active substance is of chemical origin, and the product is identified by the scientific product code SCP1139557.

The efficacy of the clinical trial will be assessed using a range of primary and secondary endpoints. The primary endpoints include the **Overall Response Rate (ORR)** and the observed concentration before dosing (Cthrough) at steady state. Secondary endpoints encompass a variety of measures such as the Very Good Partial Response or better rate (VGPR), incidence rate of infusion reactions, and progression-free survival (PFS). Additionally, patient-reported outcomes will be evaluated through questionnaires like the Patient Experience and Satisfaction Questionnaire and the European Organization for Research and Treatment of Cancer core quality of life questionnaire (EORTC QLQ-C30).

Data collection will occur at specified intervals throughout the trial, with key timepoints including baseline, during treatment, and at the end of treatment. The trial will utilize validated scales and laboratory tests to measure these endpoints. The analysis will focus on comparing the efficacy of subcutaneous versus intravenous administration of isatuximab in combination with pomalidomide and dexamethasone in patients with relapsed and/or refractory multiple myeloma. The trial aims to demonstrate non-inferiority in both efficacy and pharmacokinetics between the two administration routes.