Paul Richardson, MD, discusses the background and design of the CC-92480-MM-002 trial in multiple myeloma.
Paul Richardson, MD, director of clinical research at the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute in Boston, Massachusetts, RJ Corman professor of medicine at Harvard Medical School, discusses the background and design of the CC-92480-MM-002 trial (NCT03989414).
The ongoing phase 1/2 study evaluated mezigdomide (CC-92480) with dexamethasone and daratumumab (Darzalex) or elotuzumab (Empliciti0 in patients with relapsed/refractory multiple myeloma.
0:09 | Hello everyone. My name is Paul Richardson, MD, and I serve as the director of clinical research at the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute in Boston, Massachusetts. I am also the RJ Corman professor of medicine at Harvard Medical School. It was my privilege to present on behalf of my colleagues and co investigators the preliminary results of our combination study of mezigdomide combined with dexamethasone and daratumumab, or with dexamethasone and elotuzumab. There have been patients with relapsed/refractory myeloma, so these are results from the so-called CC-92480-MM-002 trial. I especially want to acknowledge my co investigators and co authors listed here.
0:50 | Now, by way of introduction, it's important to recognize that mezigdomide is a potent, novel, oral cereblon E3 ligase modulator, and these are classically described as CELMoDs for short. In preclinical studies, these drugs are remarkably powerful in terms tumoricidal and immune modulatory effects compared with traditional IMiDs [immunomodulatory drugs], so it's important to recognize that mezigdomide induces rapid degradation of target proteins and apoptosis and shows synergy, but not only with steroids and proteasome inhibitors, but also with CD38, monoclonal antibodies, as illustrated here.
1:34 | What's important to understand about how mezigdomide works is that it binds tightly into the cerebral E3 ligase pocket, and the cerebellum binding is absolutely key, because it leads to the disclosure of the complex, which is incredibly important to trigger and dramatic apoptosis. This degrader effect is particularly powerful with mezigdomide, by virtue it is a 100% engagement with the cerebral E3 ligase, the complex is shutting that down. To give people a sense of proportion, mezigdomide is 100%, pomalidomide for example, is just 20%. Mezigdomide constitutes the most powerful in this space, in terms of its effects on the cerebral E3 ligase modulator complex.
2:26 | Now, what was the design of the study? Basically, we were building on our experience with mezigdomide and dexamethasone in relapsed/refractory disease where we established a dose and schedule of mezigdomide 3 weeks on 1 week off, combined with weekly dexamethasone. In this particular study, we then went next steps further and combined mezigdomide with bortezomib and dexamethasone, which showed dramatically enhanced activity with that combination, suggesting profound synergy between proteasome inhibition and CELMoDs, and at the same time with similarly powerful results was mezigdomide with carfilzomib and dexamethasone.
3:03 | The cohorts that I want to share with you today are cohort B and cohort H. Here we looked at mezigdomide, daratumumab, and dexamethasone, or mezigdomide, elotuzumab, and dexamethasone. This was subcohort B1, B2, and B3 in the daratumumab space because we looked at different schedules, 3 weeks on, 1 week off, 2 weeks on, 1 week off, and 7 days on 14 days off, but syncopated so that patients got a total of 14 days of on treatment, and 14 days off. This was an important schedule approach that was designed to optimize outcomes and improve, hopefully, tolerability.