Thalidomide analogue in ‘encouraging’ trials for MM


By Geir O'Rourke

4 Sep 2023

An all-oral combination of mezigdomide plus dexamethasone has shown promising efficacy in patients with heavily pretreated multiple myeloma  in a phase 1-2 study.

A novel cereblon E3 ubiquitin ligase modulator, the drug has molecular similarities with thalidomide and had already demonstrated potent antiproliferative and tumoricidal activity in preclinical models of MM, including those resistant to lenalidomide and pomalidomide, researchers say.

Over a median follow-up of 6.3 months, the 77 patients in the phase 1 dose-escalation cohort had an overall response rate of 25% (95% CI, 16%-36%). This comprised a complete response rate of 1%, and “very good partial” and “partial” response rates of 12% respectively.

Some 101 patients were enrolled in the phase 2 study, receiving 1mg mezigdomide once daily in combination with dexamethasone for 21 days, followed by seven days off in each cycle, as per the phase 1 findings.

At a median 7.5 month follow-up, these patients achieved an overall response rate of 41%. These included a stringent complete response in 2%, complete response in 3%, very good partial response in 20%, and partial response in 16%.

The median duration of response was 7.6 months, although the data here were not mature, according to the researchers.

And the median progression-free survival was 4.4 months, they reported in NEJM (link here).

“This study confirmed that the potent substrate degradation observed in preclinical studies of mezigdomide translated into clinical efficacy among patients with relapsed and refractory myeloma, even in patients with disease that was refractory to lenalidomide  and pomalidomide,” the authors noted.

“The expected median overall survival is 3-9 months among patients with disease that is refractory to at least three previous drug classes; thus, the results achieved with mezigdomide are promising.”

Safety was another positive, said the investigators led by Professor Paul Richards, of Harvard Medical School and the Dana-Farber Cancer Centre.

The most common adverse events, almost all of which “proved the be reversible”, included neutropenia (in 77% of the patients) and infection (in 65%; grade 3, 29%; grade 4, 6%), they noted.

In addition, no unexpected toxic effects were encountered, they said.

In a linked editorial, Professor Jake Shortt, Monash Haematology research head and clinical lead for myeloid leukaemia, myelodysplasia and T-cell lymphoma agreed the results were “encouraging” (link here) for an “all-oral dexamethasone doublet.”

Professor Shortt noted thalidomide had famously been withdrawn from clinical use in the 1960s due to its teratogenicity, but results of more recent trials had shown “unprecedented therapeutic activity against myeloma”, triggering a search for related therapies.

He said mezigdomide – like thalidomide and its analogue pomalidomide – worked by binding to a protein in myeloma cells called cereblon.

However, the former was more effective because it acted on certain substrates of the protein, which led to the lead to the death of myeloma cells, activation of T cells, and reduced granulocyte maturation.

“However, the effect on median progression-free survival (4.4 months) was modest,” he noted.

“Although mezigdomide is active in cells with low levels of cereblon, it cannot work in the complete absence of cereblon or overcome cereblon-independent resistance mechanisms.”

“Further studies will determine the safety and efficacy of mezigdomide concomitant with other antimyeloma therapies.”

Professor Shortt concluded: “Concurrently, the myeloma field is being revolutionised by immunotherapies such as bispecific antibodies and chimeric antigen receptor T cells.”

“Because mezigdomide bears the same immunostimulatory hallmarks as its IMiD forebears, it may also partner well with these immune effector cell–based approaches.”

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