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Prashant Kapoor, MD, FACP


Targeting EZH2 to Counter Resistance to Anti-CD38 Immunotherapies in Myeloma

By: Celeste L. Dixon
Posted: Monday, October 23, 2023

In a letter published in Leukemia, Jerome Moreaux, PhD, of the Institute of Human Genetics, Montpellier, France, and colleagues described details of their work pointing to the possibility of inhibition of the EZH2 gene as a strategy to resensitize myeloma cells to anti-CD38 monoclonal antibodies and overcome resistance. Anti-CD38 monoclonal antibodies are among the newest class of targeted immunotherapies and have “promising clinical efficacy and safety,” but patients with multiple myeloma who improve with them still ultimately relapse, the team reported.

“Overcoming drug resistance mechanisms remains of major therapeutic interest,” the investigators said. Inhibition of EZH2—a histone methyltransferase—is already approved for the treatment of B-cell lymphoma, they added.

An important finding described in the letter is that treating multiple myeloma cells with the EZH2 inhibitor EPZ-6438 may lead “to significant upregulation of membrane CD38 expression, both in heterogeneous human myeloma cell lines and primary multiple myeloma cells. Furthermore, CD38 re-expression significantly improved daratumumab and isatuximab antibody-dependent cellular cytotoxicity efficiency” in those lines and cells. Further supporting their research trajectory was the finding that in a cohort of 97 patients at relapse who had been treated with daratumumab, significantly higher EZH2 expression was seen in the nonresponder patient subgroup compared with the responders (P < .01).

Of those 97 patients, gene-expression profiling data of purified multiple myeloma cells were available for 51 individuals. Within that subgroup, Dr. Moreaux and co-investigators found that high EZH2 expression was associated with significantly shorter event-free survival after treatment with an anti-CD38 monoclonal antibody (P = .02).

Disclosure: The study authors reported no conflicts of interest.

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