Synergizing CELMoDs with T-Cell Engagers and CAR T-Cell Therapies

In a forward-looking interview with Targeted Oncology, Sagar Lonial, MD, professor and chair at Emory University School of Medicine, chief medical officer of the Winship Cancer Institute, discusses the expanding clinical utility of cereblon E3 ligase modulators (CELMoDs), specifically iberdomide and mezigdomide. Although much of his current focus is on the EXCALIBER-RRMM trial (NCT04975997) which is undergoing FDA priority review, Lonial highlights that the true potential of these agents lies in their ability to serve as ideal partners for advanced cellular and bispecific therapies.

Redefining Maintenance and Combination Therapy

Lonial first points to a critical shift in posttransplant care. The phase 3 EXCALIBER-Maintenance trial (NCT05827016) is currently evaluating iberdomide head-to-head against the current standard of care, lenalidomide, in the maintenance setting following autologous stem cell transplantation. This study is pivotal as it seeks to establish a more potent alternative for long-term disease control in newly diagnosed patients.

The Logic of Immune Synergism

Lonial’s primary enthusiasm, however, is directed toward the combination of CELMoDs with T-cell engagers. Because CELMoDs are engineered to enhance T-cell fitness and reduce exhaustion, they create a primed environment for T-cell engagers to function more effectively.

Lonial references the key ongoing MagnetisMM-30 study (NCT06215118), whose early data exploring iberdomide combined with the B-cell maturation antigen–directed bispecific antibody elranatamab (Elrexfio) has shown highly promising results, including an overall response rate exceeding 95% in certain cohorts. He also considers the MELT-MM trial (NCT06988488) investigating the next-generation CELMoD mezigdomide in combination with elranatamab, aiming to leverage mezigdomide's even greater potency in the relapsed/refractory setting.

Improving CAR T-Cell Persistence

Beyond bispecifics, Lonial envisions a “logical next step” involving chimeric antigen receptor (CAR) T-cell therapies. One of the primary limitations of current CAR T products is the eventual loss of T-cell persistence and the onset of exhaustion. By combining CELMoDs with CAR T cells, researchers hope to not only increase the initial tumor-killing capacity of the engineered cells but ensure persistence by preventing premature T-cell fatigue, allowing the CAR T product to remain active in the body for longer periods.

This synergistic approach aims to make these combinations significantly more powerful than the individual therapies alone, potentially offering more durable remissions for patients with limited options.