Expanding Horizons for Iberdomide With Trials as Maintenance and Other Myeloma Settings

Surbhi Sidana, MD, associate professor of medicine at Stanford University and chair of the American Society of Hematology (ASH) Committee on Communication, details the expanding clinical footprint of iberdomide (Zenbexus) following its FDA approval, highlighting its versatility across relapsed, frontline, and post-transplant maintenance settings in multiple myeloma. Although currently approved for use as first relapse in combination with daratumumab (Darzalex) and dexamethasone, the drug's favorable pharmacological profile enables clinicians to explore off-label combinations in real-world practice even as formal clinical trials systematically evaluate its broader utility.

A major focus of ongoing investigation is evaluating iberdomide as post-autologous stem cell transplant (ASCT) maintenance. Standard post-transplant care currently relies on lenalidomide (Revlimid) maintenance, an immunomodulatory drug (IMiD) frequently associated with chronic fatigue and gastrointestinal toxicities like diarrhea. Because iberdomide is a cereblon E3 ligase modulator (CELMoD) with a similar mechanism but higher target specificity, it offers the potential for enhanced potency with improved tolerability. EXCALIBER-Maintenance (NCT05827016), a randomized clinical trial comparing post-ASCT iberdomide maintenance directly against standard lenalidomide maintenance is currently enrolling to determine if this target specificity translates into superior quality of life and sustained disease control.

In addition to post-transplant surveillance, researchers are advancing iberdomide into earlier treatment lines and cellular therapy paradigms: development of clinical trials evaluating iberdomide maintenance following chimeric antigen receptor T-cell therapy in the relapsed setting to prolong immune-mediated disease control and prevent relapse, investigating iberdomide alongside bispecific antibodies to exploit potential immunomodulatory synergies and bolster T-cell activity, and exploring multi-agent iberdomide combinations in newly diagnosed multiple myeloma, are of key interest, following the established oncology paradigm of moving effective agents from the relapsed setting into frontline management.

Ultimately, iberdomide is poised to evolve from an early-relapse option into a foundational agent across the entire multiple myeloma continuum, offering a better-tolerated, target-specific backbone for combination and maintenance therapies.