Phase 3 Randomized Study of Mezigdomide, Bortezomib, and Dexamethasone vs. Pomalidomide, Bortezomib, and Dexamethasone in Relapsed/Refractory Multiple Myeloma

The primary objective of this study is to compare the **progression-free survival (PFS)** of a combination therapy consisting of mezigdomide, bortezomib, and dexamethasone (MeziVd) to that of pomalidomide, bortezomib, and dexamethasone (PVd) in subjects with **relapsed or refractory multiple myeloma (RRMM)**. This comparison is clinically relevant as it aims to determine the efficacy of the new combination therapy in prolonging the time patients live without disease progression, which is a critical measure of treatment effectiveness in RRMM.

Secondary objectives include:

• In Stage 1, determining the dose of mezigdomide in combination with bortezomib and dexamethasone to continue in Stage 2 of the study.
• In Stage 1, determining the plasma concentrations of mezigdomide in combination with bortezomib and dexamethasone.
• Comparing overall survival (OS) between MeziVd and PVd in subjects with RRMM.
• Evaluating additional efficacy parameters in subjects with RRMM treated with MeziVd compared to PVd.
• Evaluating minimal residual disease (MRD) negativity rate in subjects treated with MeziVd compared to those treated with PVd.
• Evaluating safety of MeziVd compared to PVd in subjects with RRMM.
• In subjects randomized to Stage 2, evaluating cancer-related symptoms and health-related quality of life (HRQoL) using the European Organization for Research and Treatment of Cancer - Quality of Life C30 questionnaire (EORTC QLQ-C30) and the European Quality of Life Multiple Myeloma Module (EORTC QLQ-MY20) in subjects treated with MeziVd compared to PVd.

The clinical trial involves a total of **576 participants** diagnosed with **Relapsed or Refractory Multiple Myeloma (RRMM)**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically represent adults and older adults. Participants were selected based on specific criteria, including a documented diagnosis of multiple myeloma with measurable disease, having received 1 to 3 prior lines of anti-myeloma therapy, and prior treatment with a lenalidomide-containing regimen. Additionally, subjects must have achieved at least a minimal response to previous therapy and have documented disease progression. The trial includes individuals with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2, indicating they are ambulatory and capable of self-care. The trial population is inclusive of vulnerable groups, ensuring a comprehensive evaluation of the treatment's efficacy across diverse demographics. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **randomized**, open-label, multicenter study to evaluate the efficacy and safety of **mezigdomide** in combination with **bortezomib** and **dexamethasone** compared to **pomalidomide**, bortezomib, and dexamethasone in subjects with **relapsed or refractory multiple myeloma** (RRMM). The primary objective is to compare the progression-free survival (PFS) between the two treatment regimens. Secondary endpoints include overall survival, overall response rate, and safety, among others. The trial is expected to run until July 28, 2034, with recruitment having started on September 20, 2022.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a documented diagnosis of multiple myeloma and measurable disease. Following randomization, participants will attend regular follow-up visits to monitor treatment response and safety. These visits will include assessments such as laboratory tests, imaging studies, and physical examinations. The end-of-study visit will occur after the completion of the treatment period or upon early termination.

The expected duration of participant involvement in the trial is contingent upon individual response to treatment and disease progression. Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The trial is structured to ensure rigorous monitoring and data collection to support the evaluation of the investigational treatment's efficacy and safety profile.

The clinical trial involves the administration of several treatments to evaluate their efficacy in subjects with **relapsed or refractory multiple myeloma**. The experimental medication, **Mezigdomide** (CC-92480), is provided in capsule form for oral administration. It is a chemical compound developed by Celgene Corporation. The dosage and frequency of administration are determined based on the study protocol, with a maximum daily dose and total dose amount set at 9999 mg. Participant compliance is monitored throughout the trial to ensure adherence to the dosing schedule.

**Bortezomib**, marketed as VELCADE, is used as a comparator treatment in the study. It is supplied as a powder for solution for injection and is administered subcutaneously. The dosage is measured in milligrams, with a maximum daily and total dose amount of 9999 mg. The administration schedule is designed to align with the study's objectives, and participant compliance is closely monitored.

**Dexamethasone** is utilized in multiple formulations within the trial. It is available as a solution for injection under the name Dexamethason CF 20 mg/ml, provided by Centrafarm B.V., and administered intravenously. Additionally, dexamethasone is available in tablet form, marketed as Dexamethason 4 mg JENAPHARM® and Dexamethason-ratiopharm® 4 mg Tabletten, for oral administration. The maximum daily and total dose amounts are set at 9999 mg for each formulation, with compliance monitoring in place.

**Pomalidomide**, marketed as Imnovid, is another comparator treatment in the study. It is provided in hard capsule form for oral administration, with available dosages of 1 mg, 2 mg, 3 mg, and 4 mg. The maximum daily and total dose amounts are 9999 mg. The administration schedule is tailored to the study's requirements, and participant adherence is monitored to ensure compliance.

The efficacy of the clinical trial will be assessed primarily through the evaluation of **Progression-Free Survival (PFS)**. This primary endpoint will compare the duration during which patients with relapsed or refractory multiple myeloma (RRMM) remain free from disease progression when treated with the combination of mezigdomide, bortezomib, and dexamethasone (MeziVd) versus pomalidomide, bortezomib, and dexamethasone (PVd). Secondary endpoints include a range of measures such as the recommended mezigdomide dose, pharmacokinetics, **Overall Survival (OS)**, **Overall Response Rate (OR)**, **Complete Response Rate (CR)** or better, **Very Good Partial Response Rate (VGPR)** or better, **Time to Response (TTR)**, **Duration of Response (DOR)**, **Time to Progression (TTP)**, **Time to Next Treatment (TTNT)**, **Progression-Free Survival 2 (PFS-2)**, minimal residual disease (MRD) negativity, safety, and Health Related Quality of Life (HRQoL) evaluation.

The trial will employ a randomized, multicenter, open-label design to ensure robust data collection and analysis. The schedule for measuring and collecting these efficacy parameters will be aligned with the trial's protocol, ensuring that data is gathered at appropriate intervals to accurately assess the treatment's impact. The analysis will be conducted using validated scales and laboratory tests, where applicable, to ensure the reliability and validity of the findings. The trial is expected to conclude by July 28, 2034, with recruitment having started on September 20, 2022.