Mezigdomide Drives 41% ORR in Triple-Class Refractory Multiple Myeloma

Paul Richardson, MD, director of Clinical Research and Clinical Program Leader at the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute and RJ Corman Professor of Medicine at Harvard Medical School, and Muhamed Baljevic, MD, FACP, associate professor of medicine and Director of Plasma Cell Disorders Research at Vanderbilt-Ingram Cancer Center, discussed the biological underpinnings of mezigdomide, an investigational CELMoD being studied in the phase 1/2 CC-92480-MM-001 trial (NCT03374085). The pair explain how mezigdomide's structure allows it to fully engage the cereblon E3 ligase complex, unlike older immunomodulatory drugs (IMiDs) such as lenalidomide (Revlimid) and pomalidomide (Pomalyst).

Transcript:

Richardson: It’s important to understand that CELMoDs are quite distinct from IMiDs. They’re in the broad category of molecular glues and degraders, but their engagement of the cereblon E3 ligase complex, specifically with mezigdomide, is key to understanding their pharmacological potency. That engagement closes the cereblon E3 ligase complex by 100%. For comparison, IMiDs, which have an importantly different molecular structure, close it between 15% and 20% at best. What CELMoDs share with IMiDs is a glutarimide ring, but the rest of the molecule is completely different, and it’s designed to do several things. In the case of mezigdomide, complete closure of the ligase complex massively accelerates degradation of Ikaros and Aiolos, which has enormous downstream effects, not only on killing the tumor, but also on activating the immune system.

Another key aspect of mezigdomide is its ability to penetrate extramedullary tissue; it was designed at the molecular level specifically to do this. In the… mezigdomide-dexamethasone combination study, we were gratified to see a 30% response rate in patients with extramedullary disease, which for an oral therapy alone is remarkable. The overall response rate in this very heavily pretreated population was 41%, and in the BCMA-exposed and/or -refractory population, it was 50%. We were very pleased with that single-agent signal.

Baljevic: I’d only reinforce that, since this is specifically a question about potency, these are agents with a significantly different structure, the binding pocket is very well covered by mezigdomide, so there’s essentially no room for other engagement. Structurally, in terms of binding affinity, mezigdomide works at an IC50 of 0.03 micromolar, compared with about 1.2 for pomalidomide. That’s orders of magnitude that are more potent. That can also help with toxicity and off-target effects. We’ve seen in the data Paul referenced that some of the neurologic toxicities, like fatigue, have been somewhat better with CELMoDs than with IMiDs, and that’s something that matters to our patients. What’s especially interesting to me… is the impact on the tumor microenvironment and immunity, and how that interplay makes CELMoDs, in my opinion, probably the most attractive companion drugs for the immune therapies we already have access to.

Richardson: [Baljevic] raises a good point about how completely the molecule occupies the binding pocket, which limits off-target effects. When we look at iberdomide, for example, which closes the complex by about 50%, what’s striking is the absence of non-hematologic toxicity, an important positive to share. While mezigdomide is more potent, the off-target effects are still less than with IMiDs, which is conceptually important for our audience, since IMiDs have their own spectrum of [adverse] effects. There are other molecular glues under study with different structures, and we’ll have to see whether that translates into differences in tolerability. It’s important to recognize that this class’s unique positive attribute is engaging the pocket and staying there, because patients tolerate these drugs without the [gastrointestinal adverse] effects, cardiac [adverse] effects, or fatigue that IMiDs can cause. Another piece worth noting is the absence of central nervous system effects, with IMiDs we sometimes see brain fog, especially with prolonged use. At least to date, I personally haven’t seen that with either mezigdomide or iberdomide.

Reference

Richardson PG, Trudel S, Popat R, et al. Mezigdomide plus dexamethasone in relapsed and refractory multiple myeloma. N Engl J Med. 2023;389(11):1009-1022. doi:10.1056/NEJMoa2303194