Why CELMoDs Pair Synergistically With PIs and CD38 Antibodies in Multiple Myeloma

Paul Richardson, MD, and Muhamed Baljevic, MD, FACP, explained why CELMoDs such as mezigdomide pair more synergistically with proteasome inhibitors, including bortezomib (Velcade) and carfilzomib (Kyprolis), and CD38-directed antibodies, such as daratumumab (Darzalex), than older immunomodulatory drugs (IMiDs) like lenalidomide (Revlimid) and pomalidomide (Pomalyst) do for patients with multiple myeloma. They cite data from mezigdomide combination studies showing roughly 80% response rates even in patients previously exposed to or refractory to those backbone agents, regardless of the number of prior treatment lines.

Richardson is the 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. Baljevic is associate professor of medicine and Director of Plasma Cell Disorders Research at Vanderbilt-Ingram Cancer Center.

Transcript:

Richardson: The synergy lies in the potency of the cereblon E3 ligase closure, essentially, you’re achieving targeted degradation. We know the synergy between IMiDs and proteasome inhibitors is almost counterintuitive; mechanistically you might expect some antagonism, but that’s clearly not the case, and it’s even less the case with CELMoDs because of the potency of degradation. One of the most important and perhaps underappreciated factors is the immunogenic cell death signal triggered by proteasome inhibition. It’s very powerful. You’re seeing a whole constellation of effects on the tumor and, to [Baljevic’s] earlier point, on the tumor microenvironment, including the immune response. When we combined mezigdomide with either bortezomib or carfilzomib, even in patients who’d been exposed to or were refractory to those agents, we saw robust responses, solidly around 80%. What was so interesting is that across any number of prior lines of therapy, the response didn’t change, which points to this overdrive effect mezigdomide is able to confer.

Baljevic: Well, [Richardson], historically, proteasome inhibitors and CD38 monoclonal antibodies have represented cornerstones of myeloma therapy, and there’s been a lot of described synergy with agents that have powerful immune-modulating capacity. The way I’d frame it: anything IMiDs like [lenalidomide], thalidomide, and now pomalidomide can do, CELMoDs can do better, and then some. Particularly with CD38 monoclonal antibodies, we’ve learned how important they are in modulating regulatory T cells and myeloid-derived suppressor cells, including in combination with bispecific antibodies, so I wasn’t surprised by this synergy. We’re still elucidating the immunogenic pathways that improve T-cell function and lower T-cell exhaustion, while also engaging NK cells. One thing that’s stood out to me: even though the neutropenia signal was substantial as the main hematologic toxicity, the vast majority of those neutropenic patients did not develop serious infections. That, to me, points to the possibility that CELMoDs could eventually replace some frontline regimens still in use, particularly for frailer, more comorbid patients, given the more favorable adverse event profile in specific organ systems. I look forward to seeing how the regulatory process unfolds so we can take full advantage of these properties in routine practice.

Richardson: I agree completely, [Baljevic]. One clarification: iberdomide is being positioned earlier, for early relapse, upfront, and maintenance therapy, while mezigdomide is strictly in the relapsed/refractory space. I also want to echo [Baljevic’s] point about NK-cell access, because when you combine either iberdomide or mezigdomide with a CD38 antibody, the potency is clear. We also saw the combination of mezigdomide plus elotuzumab (Empliciti) work very well in CD38-refractory patients, since it isn’t entirely clear how beneficial elotuzumab is after CD38 therapy has already failed a patient. It can work, but it's inconsistent. Similarly, pomalidomide plus elotuzumab after CD38 failure is a bit hit-or-miss. In our study, we saw an almost 50% response rate in that group of patients.

Baljevic: I agree. In my practice, I’ve used elotuzumab mainly in combination with pomalidomide, and I feel strongly that a significant portion of the activity there is being driven by the IMiD itself. These are key drug classes.