Phase 3 Randomized Trial of Teclistamab and Talquetamab Combinations Versus Standard Regimen in Newly Diagnosed Multiple Myeloma Ineligible for Transplant

The primary objective of this Phase 3 randomized study is to compare the **efficacy** of two treatment combinations, Teclistamab in combination with Daratumumab SC and Lenalidomide (Tec-DR) and Talquetamab in combination with Daratumumab SC and Lenalidomide (Tal-DR), against the standard regimen of Daratumumab SC, Lenalidomide, and Dexamethasone (DRd) in participants with newly diagnosed **Multiple Myeloma** who are either ineligible or not intended for autologous stem cell transplant as initial therapy. This comparison is clinically relevant as it aims to identify potentially more effective treatment options for patients who cannot undergo stem cell transplantation, thereby improving therapeutic outcomes and quality of life for this patient population.

The clinical trial involves a total of **937 participants** diagnosed with **Multiple Myeloma**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, indicating a middle-aged to older adult demographic. Participants were selected based on their diagnosis according to the International Myeloma Working Group (IMWG) criteria and are newly diagnosed individuals not considered candidates for high-dose chemotherapy with autologous stem cell transplant (ASCT) due to advanced age or comorbid conditions. The trial includes individuals with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 to 2, ensuring a general health status that allows participation. Lifestyle considerations such as pregnancy and plans for parenthood are addressed, with participants agreeing not to become pregnant or father a child during and shortly after the study. The trial also includes a vulnerable population, ensuring comprehensive representation within the study cohort.

The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy of different drug combinations in participants with newly diagnosed **multiple myeloma** who are either ineligible or not intended for autologous stem cell transplant as initial therapy. The trial will compare the efficacy of teclistamab in combination with daratumumab SC and lenalidomide (Tec-DR) and talquetamab in combination with daratumumab SC and lenalidomide (Tal-DR) versus daratumumab SC, lenalidomide, and dexamethasone (DRd). The primary endpoints are progression-free survival (PFS) and complete response (CR) or better. The estimated duration of the trial is from September 28, 2022, to June 28, 2033.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a diagnosis of multiple myeloma according to the International Myeloma Working Group diagnostic criteria, and an Eastern Cooperative Oncology Group performance status score of 0 to 2. Follow-up visits will be scheduled to monitor the participants' response to treatment and any adverse effects. The end-of-study visit will conclude the trial for each participant, assessing the final outcomes and any long-term effects of the treatment.

The expected length of participant involvement in the study is approximately 11 years, depending on the date of enrollment. Conditions that may lead to early termination from the study include the participant's withdrawal of consent, significant adverse events, or any other medical condition that, in the opinion of the investigator, would make continued participation in the study unsafe. The trial aims to provide valuable insights into the treatment of multiple myeloma, potentially improving therapeutic strategies for patients who are not candidates for high-dose chemotherapy with autologous stem cell transplant.

The clinical trial involves several experimental medications and treatments for participants with newly diagnosed **multiple myeloma**. The study compares different combinations of medications to evaluate their efficacy. The experimental medications include **Lenalidomide**, **Talquetamab**, **Teclistamab**, and **Daratumumab**, each with specific pharmaceutical forms, dosages, and administration routes.

**Lenalidomide** is administered in the form of hard capsules, available in dosages of 5 mg, 10 mg, 15 mg, and 25 mg. The capsules are taken orally. The brands involved in the trial include Lenalidomide Mylan and Lenalidomide Accord, both of which are chemical in origin. The administration frequency and dosing schedule are determined by the study protocol, with compliance monitored throughout the trial.

**Talquetamab** is provided as a solution for injection, administered subcutaneously. The dosing is based on the participant's body weight, measured in milligrams per kilogram (mg/kg). Talquetamab is a protein-based substance, and its administration is carefully monitored to ensure participant safety and adherence to the dosing schedule.

**Teclistamab** is also a solution for injection, administered subcutaneously. The dosing is calculated in micrograms per kilogram (µg/kg) of body weight. As a protein-based medication, Teclistamab requires precise administration and monitoring to maintain compliance and evaluate its efficacy in combination with other treatments.

**Daratumumab**, marketed as DARZALEX, is administered as a solution for injection, given subcutaneously. The dosage is standardized at 1800 mg per injection. Daratumumab is a protein-based medication, and its administration is part of the combination therapy being evaluated in the trial.

In addition to the experimental medications, **Dexamethasone** is used as a non-experimental treatment in the study. It is available in tablet form, with dosages of 2 mg, 4 mg, and 8 mg. Dexamethasone is administered orally and serves as a standard-of-care therapy in the trial. Participant compliance with Dexamethasone administration is monitored to ensure accurate assessment of the treatment combinations.

The efficacy of the clinical trial will be assessed using dual primary endpoints: progression-free survival (PFS) and complete response (CR) or better. These endpoints are critical in evaluating the effectiveness of the treatment regimens being compared. The trial involves a Phase 3 randomized study comparing two combinations: Teclistamab in combination with Daratumumab SC and Lenalidomide (Tec-DR) and Talquetamab in combination with Daratumumab SC and Lenalidomide (Tal-DR) versus Daratumumab SC, Lenalidomide, and Dexamethasone (DRd) in participants with newly diagnosed **Multiple Myeloma** who are either ineligible or not intended for autologous stem cell transplant as initial therapy.

The measurement and collection of these efficacy parameters will be conducted at specified intervals throughout the trial duration, with the primary focus on the time to disease progression and the rate of achieving a complete response or better. The analysis will be performed using validated scales and laboratory tests to ensure the accuracy and reliability of the results. The trial is designed to provide a comprehensive evaluation of the efficacy of the drug combinations in improving patient outcomes in the context of **Multiple Myeloma** treatment.