AN OPEN-LABEL, RANDOMIZED, PHASE 3 STUDY OF LINVOSELTAMAB (REGN5458; ANTI-BCMA X ANTI-CD3 BISPECIFIC ANTIBODY) VERSUS THE COMBINATION OF ELOTUZUMAB, POMALIDOMIDE, AND DEXAMETHASONE (EPd), IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA (LINKER-MM3)

The primary objective of this study is to compare **Progression-Free Survival** (PFS) as assessed by an Independent Review Committee (IRC) between linvoseltamab monotherapy and the combination of elotuzumab, pomalidomide, and dexamethasone (EPd) in patients with relapsed/refractory multiple myeloma who have been previously treated with CD38 antibodies. This comparison is clinically relevant as it aims to determine the efficacy of linvoseltamab, a bispecific antibody, in prolonging the time patients live without disease progression compared to the standard EPd regimen.

Secondary objectives include:

• Comparing PFS per IRC between linvoseltamab monotherapy and EPd in all study participants.
• Comparing the anti-tumor activity of linvoseltamab monotherapy versus EPd as measured by objective response, ≥VGPR (Very Good Partial Response), and ≥CR (Complete Response).
• Comparing the incidence of minimal residual disease (MRD) negative status (10^-5) in the bone marrow between the two treatment groups.
• Comparing the treatment effects on overall survival (OS) between linvoseltamab monotherapy and EPd.
• Evaluating the treatment effects on pain symptoms between the two treatment groups.
• Evaluating the safety and tolerability of linvoseltamab monotherapy compared to EPd.
• Comparing the anti-tumor activity of linvoseltamab monotherapy versus EPd as measured by PFS per investigator.
• Evaluating the duration of response (DOR) per investigator and IRC for participants achieving objective response on both treatments.
• Evaluating the time to response for participants achieving objective response on both treatments.
• Evaluating the pharmacokinetics (PK) of linvoseltamab in an earlier line of therapy than previously studied.
• Evaluating the immunogenicity of linvoseltamab.
• Evaluating the effects on patient-reported quality of life (QoL), functioning, and symptoms in participants receiving linvoseltamab monotherapy and EPd.

The clinical trial involves a total of **192 participants** diagnosed with **Relapsed Refractory Multiple Myeloma**. The study population includes both male and female subjects, aged 18 years or older, with an **Eastern Cooperative Oncology Group (ECOG) performance status** of 1 or less. Participants are required to have received between one and four prior lines of anti-neoplastic therapies, including lenalidomide and a proteasome inhibitor, and must have demonstrated disease progression as per the 2016 International Myeloma Working Group (IMWG) criteria. The trial excludes vulnerable populations and requires participants to have adequate hematologic, hepatic, renal, and cardiac function, as well as a life expectancy of at least six months. The selection process ensures that participants have measurable disease for response assessment and adequate bone marrow reserves. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The sponsor has not provided additional information regarding the selection process or specific lifestyle factors.

The clinical trial is designed as an open-label, **randomized**, Phase 3 study comparing the efficacy of **linvoseltamab** monotherapy against a combination therapy of **elotuzumab**, **pomalidomide**, and **dexamethasone** in patients with **relapsed refractory multiple myeloma**. The primary objective is to evaluate **progression-free survival** as determined by an Independent Review Committee, with secondary endpoints including overall survival, objective response rates, and incidence of adverse events. The trial is expected to run until December 26, 2032, with recruitment having commenced on May 31, 2023.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, performance status, and prior treatment history. Following randomization, participants will attend regular follow-up visits to monitor treatment efficacy and safety, with assessments conducted according to the International Myeloma Working Group response criteria. The end-of-study visit will conclude the participant's involvement, with a comprehensive evaluation of their health status and treatment outcomes.

The expected duration of participant involvement is up to 60 months, contingent upon individual response to treatment and overall health status. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. The trial's methodology ensures rigorous data collection and analysis, adhering to ethical standards and regulatory requirements to provide robust evidence on the comparative effectiveness of the treatment regimens under investigation.

The clinical trial involves the administration of several treatments, including both experimental and comparator medications. **Linvoseltamab** is the primary experimental medication in this study. It is administered as a **solution for infusion** with a maximum daily dose of 200 mg. The route of administration is via infusion, and the treatment period is up to 60 days. Linvoseltamab is a protein-based substance developed by Regeneron Pharmaceuticals, Inc.

**Empliciti**, containing the active substance **elotuzumab**, is used as a comparator treatment. It is available in two formulations: 300 mg and 400 mg powder for concentrate for solution for infusion. The pharmaceutical form is a solution for infusion, administered intravenously. The maximum daily dose is 20 mg/kg, with a treatment period of up to 60 days. Elotuzumab is a protein-based substance provided by Bristol-Myers Squibb Pharma EEIG.

**Imnovid**, with the active substance **pomalidomide**, is another comparator treatment. It is available in hard capsule form with dosages of 1 mg, 2 mg, 3 mg, and 4 mg. The route of administration is oral, with a maximum daily dose of 4 mg. The treatment period is up to 60 days. Pomalidomide is a chemical substance also provided by Bristol-Myers Squibb Pharma EEIG.

**Dexamethasone** is used as a standard-of-care therapy in this trial. It is available in two forms: 4 mg tablets and 8 mg solution for injection. The tablets are administered orally, while the solution is administered via injection. The maximum daily dose for the tablets is 40 mg, and for the injection, it is 8 mg. The treatment period is up to 60 days. Dexamethasone is a chemical substance provided by Mercury Pharmaceuticals Ltd. and MIBE GmbH Arzneimittel.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial aims to compare the efficacy of Linvoseltamab monotherapy against the combination of elotuzumab, pomalidomide, and dexamethasone in patients with relapsed/refractory multiple myeloma.

Efficacy in this clinical trial will be assessed primarily through **Progression-Free Survival (PFS)** as determined by the Independent Review Committee (IRC) using the International Myeloma Working Group (IMWG) response criteria. This primary endpoint will be evaluated in participants who have been previously treated with CD38 antibodies. Secondary endpoints include PFS in all study participants, Objective Response (OR) rates of Partial Response (PR) or better, and Complete Response (CR) or better, as well as the incidence of minimal residual disease (MRD) negative status, overall survival (OS), and changes in patient-reported outcomes such as pain and quality of life.

The efficacy parameters will be measured and analyzed at various timepoints throughout the study. The IRC will conduct separate analyses for participants previously exposed to CD38 antibodies and for all study participants. The study will also assess the duration of response, time to objective response, and the concentration of linvoseltamab in the serum over time. Patient-reported outcomes will be evaluated using validated instruments such as the Brief Pain Inventory-Short Form (BPI-SF), the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), and the EuroQoL-5 Dimension-5 Level Scale (EQ-5D-5L).