A Phase 3, Two-stage, Randomized, Multi-center, Controlled, Open-label Study Comparing Iberdomide Maintenance to Lenalidomide Maintenance Therapy after Autologous Stem Cell Transplantation (ASCT) in Participants with Newly Diagnosed Multiple Myeloma (NDMM) (EXCALIBER-Maintenance)

The primary objective of this study is to compare the efficacy of **iberdomide** to that of **lenalidomide** in participants with newly diagnosed multiple myeloma (NDMM) after autologous stem cell transplantation (ASCT), as measured by progression-free survival (PFS). This is clinically relevant as PFS is a critical endpoint in evaluating the effectiveness of maintenance therapies in prolonging the time patients remain free from disease progression, thereby potentially improving overall survival and quality of life.

Secondary objectives include:

• Comparing the minimal residual disease (MRD) negativity rate in participants with a response of complete response (CR) or better after 12 months of maintenance treatment with iberdomide versus lenalidomide.
• Evaluating overall survival (OS) in participants with NDMM after ASCT treated with iberdomide compared to lenalidomide.
• Informing the dose of iberdomide to continue in Stage 2 of the study.
• Assessing the pharmacokinetics (PK) of iberdomide in Stage 1.
• Evaluating the safety of iberdomide maintenance compared to lenalidomide maintenance in participants with NDMM after ASCT.
• Evaluating progression-free survival on the next line of treatment (PFS2) in participants with NDMM after ASCT when treated with iberdomide compared to lenalidomide.
• Comparing the overall rate of MRD negativity of iberdomide versus lenalidomide maintenance treatment in participants with a response of CR or better.
• Evaluating the frequency of conversion from MRD-positive to MRD-negative in participants with a response of CR or better, in participants with NDMM after ASCT when treated with iberdomide compared to lenalidomide.
• Evaluating the sustainability of MRD negativity in participants with NDMM after ASCT when treated with iberdomide compared to lenalidomide.
• Evaluating time to progression (TTP) in participants with NDMM after ASCT treated with iberdomide compared to lenalidomide.
• Evaluating time to next treatment (TTNT) in participants with NDMM after ASCT treated with iberdomide compared to lenalidomide.
• Evaluating the percentage of participants in the study with a response of partial response (PR) improving to very good partial response (VGPR) or better and those with VGPR achieving CR or stringent CR (sCR) as well as maintaining best overall response for participants who enroll in the study at CR.
• Evaluating cancer-related symptoms, multiple myeloma-specific symptoms, and health-related quality of life (HRQoL) in participants with NDMM after ASCT treated with iberdomide compared to lenalidomide.

The clinical trial involves a total of **752 participants** diagnosed with **Newly Diagnosed Multiple Myeloma (NDMM)**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on specific inclusion criteria, including a confirmed diagnosis of symptomatic multiple myeloma and an Eastern Cooperative Oncology Group performance status score of 0, 1, or 2. All participants have undergone 3 to 6 cycles of induction therapy, which includes a proteasome inhibitor and immunomodulatory compound, with or without a CD38 monoclonal antibody, followed by autologous stem cell transplantation (ASCT). The trial population is characterized by individuals who have achieved at least a partial response post-ASCT, with or without consolidation therapy, according to the International Myeloma Working Group (IMWG) 2016 criteria. The study does not specify particular lifestyle considerations such as diet or physical activity. Both vulnerable and non-vulnerable populations are included in the trial, ensuring a comprehensive evaluation of the treatment efficacy across diverse demographic groups.

The clinical trial is designed as a **randomized**, multi-center, controlled, open-label study to evaluate the efficacy of **iberdomide** compared to **lenalidomide** in participants with newly diagnosed **multiple myeloma** (NDMM) following autologous stem cell transplantation (ASCT). The primary objective is to assess progression-free survival (PFS) from randomization to the first documentation of progressive disease or death. Secondary endpoints include achieving minimal residual disease (MRD) negativity, overall survival (OS), and safety assessments. The trial is expected to commence recruitment on December 1, 2023, and conclude by January 1, 2036.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a confirmed diagnosis of symptomatic multiple myeloma and specific treatment history. Following randomization, participants will attend regular follow-up visits to monitor treatment response, adverse events, and other clinical parameters. The end-of-study visit will occur upon completion of the treatment period or upon early termination. The expected duration of participant involvement is contingent on the treatment response and progression, with a maximum treatment period of 9999 days for iberdomide and 260 days for lenalidomide.

Participants may be withdrawn from the study early due to disease progression, unacceptable toxicity, or withdrawal of consent. The trial will adhere to rigorous ethical standards and regulatory requirements to ensure participant safety and data integrity throughout the study duration.

The clinical trial involves the use of several treatments, including both experimental and non-experimental medications. The primary experimental medication is **Iberdomide**, a small molecule administered in capsule form. It is produced by Celgene Corporation and is identified by the sponsor product code CC-220. Iberdomide is administered orally, with a maximum daily dose of 9999 mg and a maximum treatment period of 9999 days. The active substance, iberdomide, is of chemical origin. Participant compliance with the dosing schedule will be monitored throughout the trial.

**Lenalidomide**, marketed as Revlimid, is used as a comparator treatment in the study. It is available in hard capsule form and is administered orally. The maximum daily dose is 15 mg, with a total maximum dose of 27300 mg over a treatment period of 260 days. The active substance, lenalidomide, is also of chemical origin and is provided by Bristol-Myers Squibb Pharma EEIG. The clinical supplies may differ in packaging from the commercial product, which is marked with the dosage strength.

Additional non-experimental treatments include **Aspirin 75mg gastro-resistant tablets**, **Clexane 10,000 IU (100mg)/1ml Solution for Injection**, **Eliquis 2.5 mg film-coated tablets**, **Xarelto 2.5 mg film-coated tablets**, and **Warfarin Teva 0.5mg Tablets**. Aspirin, containing acetylsalicylic acid, is administered orally with a maximum daily dose of 75 mg. Clexane, containing enoxaparin sodium, is administered subcutaneously with a maximum daily dose of 40 mg. Eliquis, containing apixaban, and Xarelto, containing rivaroxaban, are both administered orally with maximum daily doses of 5 mg and 10 mg, respectively. Warfarin, containing warfarin sodium, is also administered orally with a maximum daily dose of 10 mg. These medications are used as auxiliary treatments and are provided by various pharmaceutical companies, including Clonmel Healthcare Ltd., Sanofi-Aventis Ireland Ltd., Bristol-Myers Squibb/Pfizer EEIG, Bayer AG, and Sun Pharmaceutical Industries Europe B.V.

The efficacy of the clinical trial will be assessed primarily through the measurement of **Progression-Free Survival (PFS)**. PFS is defined as the time from randomization to the first documentation of progressive disease according to the International Myeloma Working Group (IMWG) Uniform Response Criteria for Multiple Myeloma (MM) or death due to any cause, whichever occurs first. This endpoint will provide a direct measure of the treatment's effectiveness in delaying disease progression.

Secondary efficacy endpoints include achieving Minimal Residual Disease (MRD) negativity at a threshold of 10⁻⁵ by next-generation flow in participants who are in a response of Complete Response (CR) or better at 12 (±3) months post the start of maintenance treatment. Overall Survival (OS), defined as the time from randomization to death due to any cause, will also be evaluated. Additional secondary endpoints involve the recommended iberdomide dose for Stage 2, pharmacokinetics (PK) of iberdomide, and safety assessments, including the type, frequency, seriousness, and severity of adverse events (AEs) and their relationship to the study treatment.

Other secondary endpoints include PFS2, which is defined as the time from randomization to progression on the next anti-myeloma treatment or death due to any cause, and Time to Progression (TTP), defined as the time from randomization to the first documentation of disease progression according to IMWG criteria. Time to Next Treatment (TTNT) is defined as the time from randomization to the start of the participant receiving any anti-myeloma treatment other than the study treatment. The best response achieved, including Very Good Partial Response (VGPR), CR, and stringent Complete Response (sCR) prior to Progressive Disease (PD), will also be assessed.

Patient-reported outcomes will be measured using subscale and total scores in Health-Related Quality of Life (HRQoL) outcomes and multiple myeloma-related symptoms as measured by the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and EORTC QLQ-MY20. These assessments will provide insights into the impact of the treatment on patients' quality of life and symptom burden.