Mezigdomide Data Show CELMoD Potential

A next-generation cereblon-targeting drug that functions like other approved immunomodulatory agents—but with enhanced cancer-killing and immune-stimulatory effects—shows early signs of efficacy in patients with multiple myeloma who have already received several therapies.

In the dose-expansion portion of a phase I/II study, 41 of 101 patients with triple-class refractory disease—meaning resistance to at least one proteasome inhibitor, one anti-CD38 antibody, and one immunomodulatory agent—responded to the combination of mezigdomide (CC-92480; Bristol Myers Squibb [BMS]) and dexamethasone (N Engl J Med 2023;389:1009–22).

The oral regimen was well tolerated and yielded a median progression-free survival of 4.4 months and a median duration of response of 7.6 months.

Encouragingly, benefits were observed in clinically challenging situations, including among patients with extramedullary disease and in individuals who experienced disease relapse following treatment with a BCMA-directed therapy.

“We saw dramatic responses,” says trial investigator Nizar Bahlis, MD, of the University of Calgary in Canada. “I'm excited about the potency of this molecule.”

The study looked at mezigdomide–dexamethasone doublet therapy; clinicians are now testing the drugs in combination with proteasome inhibitors—an approach that Bahlis expects will amplify response rates—in phase III trials.

According to data from a separate phase I/II trial presented at the International Myeloma Society's 2022 annual meeting, around 70% to 80% of patients—all of whom had previously received two or more therapies, but only a minority of whom had triple-refractory disease—benefited from three-drug regimens comprised of mezigdomide, dexamethasone, and either bortezomib (Velcade; Takeda) or carfilzomib (Kyprolis; Amgen).

Phase III trial results are not expected for a few years, however, and some clinicians don't want to wait that long to see mezigdomide made available for patients with multiple myeloma with no other treatment options. “There's a really good case here to argue for accelerated approval,” says trial investigator Paul Richardson, MD, of Dana-Farber Cancer Institute in Boston, MA.

Mezigdomide is a chemical relative of lenalidomide (Revlimid; BMS) and pomalidomide (Pomalyst; BMS), two immunomodulatory imide drugs (IMiD) derived from thalidomide. Like the IMiDs, mezigdomide functions as a molecular glue between cereblon, part of the E3 ubiquitin ligase complex, which marks proteins for degradation, and two transcription factors—Ikaros (IKZF1) and Aiolos (IKZF3)—that promote the survival of myeloma cells.

Yet, whereas lenalidomide and pomalidomide were developed before this mechanism of action was known, mezigdomide was rationally designed. Scientists leveraged insights from structural biology to identify molecules with enhanced ability to degrade Ikaros and Aiolos while minimizing off-target binding.

The related phase III drug candidate iberdomide (CC-220; BMS) was similarly developed. Both are cereblon E3 ligase modulatory drugs (CELMoD).

Judging by early trial data, iberdomide may be more tolerable, with lower rates of severe neutropenia. But mezigdomide is the more potent agent, with superior degradation efficiency of its targets and higher response rates in phase II trials involving patients with IMiD-resistant disease. That may make it more effective in refractory cases, says Richardson.

The degradation of Ikaros and Aiolos by mezigdomide and other CELMoDs also elicits immune-stimulatory effects, raising the possibility for combination strategies with T cell–directed treatments, notes Sarah Holstein, MD, PhD, of the University of Nebraska Medical Center in Omaha. “This is just the first step,” she says. “There's a lot of potential with these drugs.” –Elie Dolgin

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