A new oral drug for multiple myeloma, mezigdomide, has shown a ‘modest’ survival benefit in a phase 1 trial involving patients who had received at least three prior lines of treatment, including Revlimid and Pomalyst. The trial results were published in the New England Journal of Medicine on Wednesday.
Mezigdomide is a novel drug that belongs to the class of cereblon E3 ligase modulators, which are designed to exploit the mechanism of action of thalidomide analogues such as Revlimid and Pomalyst. These drugs work by binding to a protein called cereblon, which is involved in regulating the degradation of other proteins in the cell. By altering the activity of cereblon, these drugs can trigger the destruction of certain proteins that are essential for the survival of multiple myeloma cells.
The phase 1 trial enrolled 92 patients with relapsed or refractory multiple myeloma who had received at least three prior lines of therapy, including Revlimid and Pomalyst. The patients were given mezigdomide in combination with dexamethasone, a steroid that is commonly used to treat multiple myeloma. The trial assessed the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of mezigdomide at different doses.
The trial results showed that mezigdomide was well tolerated and had a manageable safety profile. The most common adverse events were fatigue, diarrhea, nausea, and constipation. The most common serious adverse events were infections, such as pneumonia and sepsis.
The trial also showed that mezigdomide had some anti-myeloma activity in this heavily pretreated population. The overall response rate was 41%, meaning that 41% of the patients had a reduction in their disease burden by at least 50%. The median duration of response was 7.6 months, meaning that half of the responders maintained their response for at least 7.6 months. The median progression-free survival was 4.4 months, meaning that half of the patients did not experience disease progression or death for at least 4.4 months. The overall survival data were not mature enough to be reported at the time of the publication.
In an editorial accompanying the paper, Jake Shortt, a professor at Monash University, called the progression-free survival ‘modest’. He also noted that the treatment landscape for multiple myeloma has changed significantly since the trial was initiated in 2018. Several new therapies have emerged for patients who have received four or more lines of therapy, such as CAR-T cell therapy (Carvykti), bispecific T-cell engagers (Tecvayli and Talvey), and antibody-drug conjugates (Blencar). These therapies have shown impressive response rates of over 65% and remarkable progression-free survival outcomes in clinical trials.
However, the authors of the paper argued that mezigdomide still has a role to play in the treatment of multiple myeloma, especially in combination with other agents. They pointed out that cell therapies and bispecifics may not be suitable or accessible for all patients, due to their high cost, complexity, toxicity, and availability. They also highlighted that oral regimens such as mezigdomide and dexamethasone are convenient and easy to administer in any setting, without requiring hospitalization or specialized facilities.
Bristol Myers Squibb, the developer of mezigdomide, is currently testing the drug in two phase 3 trials in patients who have received one to three lines of therapy, including Revlimid. One trial is evaluating mezigdomide as a replacement for Pomalyst in combination with dexamethasone and daratumumab (Darzalex), an antibody that targets a protein called CD38 on multiple myeloma cells. The other trial is assessing mezigdomide as an addition to Kyprolis (carfilzomib) and dexamethasone, a proteasome inhibitor that blocks the degradation of unwanted proteins in multiple myeloma cells. The results of these trials are expected to shed more light on the potential of mezigdomide as a new oral option for multiple myeloma patients.
