Novel CELMoD Agents for Multiple Myeloma: Iberdomide and Mezigdomide

At the 2022 Lymphoma, Leukemia & Myeloma Congress in New York, Paul Richardson, MD, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, MA, provides insights into treatment with novel CELMoD agents iberdomide and mezigdomide for patients with multiple myeloma (MM).

Transcript:

Hello everyone. It is my pleasure to join you here at the Lymphoma, Leukemia and Myeloma Congress here in New York at the 2022 in-person meeting. It is an absolute pleasure to be here, so nice to see everyone and be interacting in the way that we used to, pre-pandemic. It's a very productive and exciting meeting. The myeloma session today I thought was extraordinary. Really remarkable spectrum of different conversations about where we are and where we're going. I think one of the most encouraging sessions of the whole day was the immunotherapy session towards the end of the day's activities. In that, we had wonderful presentations about cellular therapy bispecifics and new immunotherapeutic approaches, as well as, critically, the management of important toxicities that we see with these approaches. In that same segment, it was a privilege on my part to present, on behalf of my co-investigators, our work with the so-called “CELMoDs.”

These are very important oral agents easily administered on a 3-weeks-on, 1-week-off schedule, with the simplicity of that approach, but with the real power of being extremely powerful new small molecules that target the cereblon e3 ligase complex and generate downstream effects that set them firmly apart from their cousins, the immunomodulators. As we think about thalidomide, lenalidomide, and pomalidomide, we then move into the space of the so-called CELMoDs, which are much larger synthetic molecules or synthesized molecules that are larger and designed to get into a key pocket in the cereblon e3 ligase complex. [When that happens], this results in profound and rapid degradation of Aiolos and Ikaros, which are the key transcription factors that are modulated by this mechanism that downstream influence so much in myeloma pathobiology, from direct effects on the myeloma cell to profound immune effects as well.

What is interesting is there are basically 2 [CELMoDs]. There is iberdomide, or CC220 as it was known, and now mezigdomide, which is the original CC92480. Mezigdomide is much more potent pre-clinically than iberdomide, which in turn is significantly up to 20 to 40 times more potent than pomalidomide or lenalidomide in the same model systems. Pre-clinically, these drugs clearly overdrive pomalidomide and lenalidomide resistance and are highly synergistic with classical partners like dexamethasone, daratumumab, and the proteasome inhibitors, both bortezomib and carfilzomib. Translating these characteristics to the clinic has been a real priority for us. We have been able to do just that and to show—not only in these studies—that clinically, the drugs are very powerful. In the context of very comprehensively run trials with wonderful participation from patients and providers alike, we have lots of correlative samples, and the qualitative science has been very informative. In a nutshell, many of the effects that were anticipated pre-clinically from these drugs were confirmed clinically in terms of effects on natural killer cells, T-cell subsets, and other markers of activity in patients.

We saw safety for patients on the one hand, and on the other hand, promising activity. In iberdomide we saw response rates of around 30% from the monotherapy approach, which we also saw mirrored in patients who were not only triple class refractory, but also BCMA refractory, so that was very encouraging. And then when you combine this backbone with other drugs, be they proteasome inhibitors or CD38 targeting antibodies, we see a big jump in efficacy. We saw, with iberdomide, response rates of around 50% to 60% in combination with these various platforms. Mezigdomide is in a different league, and it combines powerfully with the other drugs, but it is a sort of step up. With mezigdomide, which is particularly active in extramedullary disease, we have seen response rates over 50% with monotherapy. And we'll be presenting data at ASH (American Society of Hematology Annual Meeting and Exposition) to show its activity not only in triple class disease, but also in BCMA exposed patients. We’re excited to be doing this.

Combining mezigdomide with other combinations has been equally rewarding. We have response rates in excess of 70% combined with both proteasome inhibitors and, of course, monoclonal antibodies.

If one can think of these as the 2 next big players in the space of oral therapies as they apply to immunotherapy, this is a very reasonable way to think of them. In that context, iberdomide is being moved up into the upfront setting. It has even been explored as part of small disease and is already under study as a maintenance strategy. Mezigdomide is coming into the relapsed/refractory space, where we're testing it as a go-to oral approach combined with other drugs in relapsed/refractory disease. One of the most interesting things is how this will play with CAR-T and bispecifics. What is exciting is that these agents could provide very rational partners to optimizing the benefit that we can see potentially either from CAR-T or, for that matter, from a bispecific.

I think in terms of side effects, a couple of points to make. The good news about iberdomide, is it is very well tolerated, and the side effect profile is very manageable. The grade 3 and 4 toxicities are very limited. So that's extremely good news for patients. Mezigdomide is more powerful, so we see a little more in the way of myeloma suppression. We also see some occasionally non-hematologic toxicities that are meaningful such as dyskinesia, fatigue, and so on. But they are, again, manageable. What is also particularly attractive about both approaches is the relatively low rates of infection. This is important obviously in the era of Covid-19, and especially of course with the immune suppression that is intrinsic to bispecifics, as well as, for that matter, the immune dysfunction that can occur from CAR-T.

In that context, it is important to have agents that do not have that kind of issue. In that spirit, we didn't see, or rather we saw very few, minimal, 1 or 2 only, cases of lethal Covid in the various studies that we've done, compared to significantly higher signals in other settings, which I think from a patient perspective, of course, is incredibly important. We think the future is good, and we'll look to complement the existing platforms of lenalidomide and pomalidomide with iberdomide and mezigdomide.

You may say, "Well, how on earth is that all going to work?" I think probably on the basis that we need all these drugs, not just one versus the other. One theoretical advantage, especially for Iberdomide, early in the disease and as a maintenance strategy, is that there is reason to expect them to not to be so associated with second cancers. That is an important point, and it is built on a mechanism and the way these drugs can engender that second primary risk. It is clear that risk is real for lenalidomide, especially if it is combined with melphalan, for example, but that is not the case, it seems, with some of these newer molecules, which may have a lower risk by virtue of some of their pharmacology.

Source:

Richardson, P. Iberdomide- Combinations- New Directions. Presented at Lymphoma, Leukemia & Myeloma Congress; October 18-22, 2022. New York, NY.