Phase 3 Randomized Study of Elranatamab, Daratumumab, and Lenalidomide in Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma

The primary objective of this study is to assess **dose limiting toxicities** (DLTs) of the combination of Elranatamab (EDR) with Daratumumab and Lenalidomide or Elranatamab with Lenalidomide, in order to select a recommended Phase 3 dose (RP3D) for use in Part 2 of the study. This is clinically relevant as it aims to establish a safe and effective dosage regimen for patients with newly diagnosed **multiple myeloma** who are ineligible for transplant, thereby optimizing therapeutic outcomes and minimizing adverse effects.

Secondary objectives include: - Evaluating the overall safety profile of EDR or ER to select an RP3D for the combination to be used in Part 2 of the study. - Evaluating the efficacy of EDR or ER to select an RP3D for the combination to be used in Part 2. - Evaluating the pharmacokinetics (PK) of Elranatamab when used in the EDR or ER combinations. - Evaluating the immunogenicity of Elranatamab when used in the EDR or ER combinations. - Evaluating the PK of Daratumumab and Lenalidomide when used in EDR or ER combinations. - Comparing the efficacy of Arm A (EDR or ER) versus Arm B (DRd) as measured by overall survival (OS).

The clinical trial involves a total of **558 participants** diagnosed with **multiple myeloma**. The study population includes both male and female subjects, aged 18 years and older, with a specific focus on those who are transplant-ineligible due to age or comorbidities. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, indicating a relatively stable general health status. The selection criteria ensure that participants have adequate hepatic, renal, and bone marrow function, as well as resolved acute effects of any prior therapy. The trial includes individuals with measurable disease based on International Myeloma Working Group (IMWG) criteria. Lifestyle considerations such as diet and physical activity are not specified in the available data. The trial population was selected based on specific inclusion criteria, including age, sex, and disease characteristics, ensuring a representative sample of the target patient population.

The clinical trial is designed as a **randomized**, open-label, multicenter, Phase 3 study to evaluate the efficacy and safety of **elranatamab** in combination with **daratumumab** and **lenalidomide**, or elranatamab with lenalidomide, versus daratumumab, lenalidomide, and **dexamethasone** in participants with newly diagnosed **multiple myeloma** who are ineligible for transplant. The trial is structured into two parts, with Part 1 focusing on assessing dose-limiting toxicities to select a recommended Phase 3 dose for Part 2, which aims to compare the efficacy of the treatment arms based on minimal residual disease (MRD) status and progression-free survival (PFS).

The trial is expected to last until November 29, 2031, with recruitment having commenced on November 10, 2022. Participants will be involved in the study for a maximum treatment period of 73 weeks. The study includes several key visits: an initial screening visit to confirm eligibility based on criteria such as age, performance status, and adequate organ function; regular follow-up visits to monitor treatment response and adverse events; and an end-of-study visit to assess overall outcomes and collect final data. Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent.

Inclusion criteria require participants to be at least 18 years old, with a diagnosis of multiple myeloma as per International Myeloma Working Group (IMWG) criteria, and to have measurable disease. Exclusion criteria are not specified in the provided data. The primary endpoints include dose-limiting toxicities during the observation period for Part 1 and sustained MRD negativity rate for at least 12 months for Part 2. Secondary endpoints encompass adverse events, laboratory abnormalities, objective response rates, and overall survival, among others. The trial employs a combination of oral and subcutaneous administration routes for the investigational products, with specific dosing regimens tailored to each treatment arm.

The clinical trial involves the administration of several experimental and non-experimental treatments to evaluate their efficacy and safety in participants with newly diagnosed **multiple myeloma**. The experimental medication **Elranatamab** is provided as a solution for injection, with a maximum daily dose of 76 mg. It is administered subcutaneously and is classified as a biologic product. The treatment period for Elranatamab is up to 73 days.

**Lenalidomide** is used in various dosages as part of the trial. It is available in hard capsule form with dosages of 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, and 25 mg. The maximum daily dose for Lenalidomide is 25 mg, administered orally. The treatment duration is also up to 73 days. Lenalidomide is a chemical substance and is provided by ADALVO LIMITED.

**Dexamethasone** is included as a comparator treatment in the form of tablets, with a dosage of 20 mg. The maximum daily dose is 40 mg, administered orally. The treatment period for Dexamethasone is up to 73 days. It is a chemical substance provided by NORAMEDA UAB.

**Daratumumab** is another comparator treatment, provided as a solution for injection with a dosage of 1800 mg. It is administered subcutaneously, with a maximum daily dose of 1800 mg. The treatment period is up to 73 days. Daratumumab is a protein-based substance provided by JANSSEN-CILAG INTERNATIONAL NV.

**Human Normal Immunoglobulin** is used as an auxiliary treatment in the form of a solution for infusion. It is administered intravenously with a concentration of 100 mg/ml and a maximum daily dose of 4.8 ml. The treatment period is up to 73 days. This product is provided by CSL BEHRING GMBH and is derived from blood.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment regimen. The trial aims to assess the dose-limiting toxicities and compare the efficacy of different treatment arms, as measured by minimal residual disease status and progression-free survival.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints for Part 1 include the evaluation of dose-limiting toxicities (DLTs) during the DLT observation period. For Part 2, the primary endpoints are the sustained minimal residual disease (MRD) negativity rate for at least 12 months, as assessed via next-generation sequencing (NGS), and progression-free survival (PFS) by blinded independent central review (BICR) according to the International Myeloma Working Group (IMWG) criteria.

Secondary endpoints encompass a range of measures, including adverse events (AEs) characterized by type, frequency, severity, timing, seriousness, and relationship to study treatment. The severity of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) will be graded according to the American Society for Transplantation and Cellular Therapy (ASTCT) criteria. Additional secondary endpoints include laboratory abnormalities, objective response rate (ORR), complete response rate (CRR), time to response (TTR), duration of response (DOR), duration of complete response (DOCR), overall survival (OS), and MRD negativity rate per IMWG sequencing criteria. The study will also measure predose and post-dose concentrations of **elranatamab**, anti-drug antibodies (ADAs), and neutralizing antibodies (NAbs) against **elranatamab**, as well as predose concentrations of **daratumumab** and **lenalidomide**.

The efficacy assessments will be conducted at specified intervals throughout the trial, with data collection and analysis performed using validated methodologies. The trial will utilize tools such as the European Organisation for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire (QLQ-C30) and Myeloma Module 20 (MY20) to evaluate patient-reported outcomes. The trial is designed to ensure rigorous and comprehensive evaluation of the efficacy of the treatment regimens in participants with newly diagnosed multiple myeloma who are transplant-ineligible.