Efficacy and Safety of Etentamig and Daratumumab Versus Daratumumab and Combination Therapy in Transplant-Ineligible Patients With Newly Diagnosed Multiple Myeloma

The primary objective of this phase 2/3 study is to determine the recommended phase 2 dose (RP3D) of etentamig in combination with daratumumab and to evaluate the efficacy (5) of this combination in patients with newly diagnosed multiple myeloma who are not eligible for transplant. The investigation aims to establish therapeutic potential in a specific patient population through clinical assessment of disease response.

Secondary objectives include the assessment of safety (4) and tolerability (13) of the etentamig and daratumumab combination, as well as the determination of clinical activity. Additionally, the study will evaluate the pharmacokinetics (6) and immunogenicity of etentamig when co-administered with daratumumab.

This study involves 36 participants diagnosed with newly diagnosed multiple myeloma. The study population includes both male and female individuals within specific age ranges. Eligible participants must meet the International Myeloma Working Group diagnostic criteria and be deemed unsuitable for high-dose chemotherapy and autologous stem cell transplantation. Key requirements for inclusion include an International Myeloma Working Group Myeloma Frailty Index Score of 1 or greater and an Eastern Cooperative Oncology Group performance status of 1 or less. Additionally, participants must present with measurable disease, defined by specific thresholds of serum M-protein, urine M-protein, or serum free light chain levels as assessed by a central laboratory.

This Phase 2/3, multicenter, randomized, open-label study is designed to evaluate the efficacy and safety of etentamig combined with daratumumab compared to lenalidomide, dexamethasone, and daratumumab in subjects with newly diagnosed multiple myeloma who are not eligible for autologous stem cell transplantation. The Phase 2 component aims to determine the recommended phase 3 dose of etentamig in combination with daratumumab, while the Phase 3 component evaluates the efficacy of this combination therapy. Participants must meet specific criteria, including confirmed disease according to the International Myeloma Working Group diagnostic criteria, a Myeloma Frailty Index score of ≥ 1, and an Eastern Cooperative Oncology Group performance status of ≤ 1. The study involves measurable disease as defined by serum or urine M-protein or serum free light chain levels. Primary endpoints include overall response rate for Phase 2, and minimal residual disease negative complete response rate and progression-free survival for Phase 3. The estimated duration of the study spans from 2026 to 2042.

Etentamig is the investigational medicinal product administered as a solution for infusion via intravenous use. The specific dosage is not provided.

The comparator treatment includes daratumumab, which is administered via subcutaneous use. The specific dosage is not provided.

Lenalidomide is used as a comparator treatment through oral use. The specific dosage is not provided.

Dexamethasone is utilized as a comparator and is administered either via oral use or intravenous administration. The specific dosage is not provided.

In the Phase 2 portion of the study, efficacy is evaluated through clinical activity as defined by the International Myeloma Working Group response rates, including overall response rate, complete response or better, very good partial response, and partial response. Secondary endpoints for Phase 2 include the minimal residual disease negative complete response rate, progression-free survival, sustained minimal residual disease negativity at 12 months, and overall survival. Pharmacokinetic parameters such as maximum observed serum concentration, time to maximum observed concentration, and area under the serum concentration-time curve are also assessed, along with the presence of anti-drug antibodies and neutralizing anti-drug antibodies.

For the Phase 3 component, the primary efficacy endpoints are the minimal residual disease negative complete response rate and progression-free survival. Secondary endpoints include overall survival, sustained minimal residual disease negativity at 12 months, rate of complete response or better, rate of very good partial response or better, overall response rate, time to response, duration of response, time-to-progression, event free survival, and progression-free survival on subsequent therapy. Patient-reported outcomes are utilized to assess efficacy and quality of life, specifically through the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, patient-reported outcomes version of the common terminology criteria for adverse events, functional assessment of cancer therapy-general, patient global impression of severity, and European Quality of Life 5 Dimensions scores.