MajesTEC-3 and the Future of Combination Regimens in Multiple Myeloma

Krina Patel, MD, MSc, associate professor in the Department of Lymphoma/Myeloma in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discusses key implications of late-breaking MajesTEC-3 trial data presented at ASH 2025, focusing on the evolving role of bispecific antibody combinations, treatment sequencing, toxicity management, and payer considerations in multiple myeloma. The conversation highlights how combination bispecific approaches may further elevate response rates and depth of response, approaching those historically achieved with CAR T-cell therapy, including higher rates of minimal residual disease (MRD) negativity. While single-agent bispecifics have already demonstrated strong efficacy as continuous therapies, combination strategies appear to expand the proportion of patients who achieve deep and durable responses.

A central theme of the discussion is toxicity, particularly infection risk, which remains a major challenge with BCMA-directed therapies and anti-CD38 combinations. Both classes are associated with hypogammaglobulinemia and immune dysfunction, including impaired T-cell function, leading to increased rates of serious infections. Although supportive measures such as intravenous immunoglobulin replacement and Pneumocystis jirovecii pneumonia prophylaxis are routinely used, they do not fully mitigate immune suppression, and patients often have suboptimal vaccine responses. As a result, long-term management strategies—including fixed-duration therapy, alternative combination partners, or agents that may improve immune markers—are increasingly important considerations to balance efficacy with safety.

The interview also explores how these clinical advances may influence payer perspectives. With MajesTEC-3 demonstrating a pronounced progression-free survival advantage, questions arise regarding cost-effectiveness, particularly given the high upfront and ongoing costs of continuous bispecific therapy. Payers are likely to weigh drug acquisition costs against prolonged disease control, quality-of-life improvements, and reduced downstream healthcare utilization. Comparisons with CAR T-cell therapy, which carries a substantial upfront cost but offers treatment-free intervals, will be central to these evaluations.

Overall, MajesTEC-3 signals a meaningful step forward for combination bispecific therapies in multiple myeloma, while underscoring the need for strategies that optimize long-term tolerability, immune recovery, and economic sustainability as these regimens move closer to routine clinical use.