Novel Combinations Showcase Post CAR T Myeloma Role For Mezigdomide

Paul G. Richardson, MD, director of Clinical Research and Clinical Program Leader at the Jerome Lipper Multiple Myeloma Center, the Dana-Farber Cancer Institute and RJ Corman Professor of Medicine, Harvard Medical School, outlined the strategic integration of mezigdomide into the immunotherapy landscape for multiple myeloma, emphasizing its versatile role alongside CAR T-cell therapy, bispecific antibodies, and antibody-drug conjugates (ADCs).

A primary mechanism of mezigdomide is its ability to reinvigorate, activate, and regenerate the immune system, effectively reversing T-cell exhaustion to restore immune function. Clinical data support these immunomodulatory effects, particularly in patients for whom B-cell maturation antigen (BCMA)-targeted therapies have failed. Richardson highlighted a trial led by Clifton C. Mo, MD, combining mezigdomide with selinexor (Xpovio), which demonstrated a remarkable reversal of T-cell exhaustion. This combination not only proved tolerable but also successfully prepared patients to receive subsequent lines of immunotherapy.

The therapeutic benefit of mezigdomide is also evident in highly refractory populations, including those with extramedullary disease who have failed both CAR T and bispecific therapies. Richardson specifically pointed to the "Novel-Novel" study (CA057-003; NCT05372354), where mezigdomide was paired with small molecule inhibitors tazemetostat (Tazverik) and trametinib (Mekinist).

This study reported impressive response rates, as mezigdomide plus tazemetostat had an over 50% response rate in patients refractory to CAR T and bispecifics, and mezigdomide plus trametinib had over 75% response rate in the same highly refractory population.

Looking toward future directions, Richardson expressed excitement regarding mezigdomide’s potential as a maintenance strategy following CAR T or bispecific treatment. Research is also expanding into combinations with ADCs; while iberdomide is currently being studied with belantamab mafodotin (Blenrep) in an ongoing Alliance trial, a similar combination featuring mezigdomide is planned as a next step. Ultimately, mezigdomide is emerging as an oral agent of choice for difficult-to-treat spaces due to its convenience and potent immune-restorative capabilities.