Mezigdomide-Based Triplet Highlights Potential of CELMoDs in Myeloma Management

The oral CELMoD mezigdomide (CC-92480) given in combination with dexamethasone and carfilzomib (Kyprolis) or bortezomib (Velcade) induced responses across different lines of therapy in patients with relapsed/refractory multiple myeloma, highlighting the potential of CELMoDs within the treatment paradigm, according to Rahul Banerjee, MD, FACP.

Findings from the phase 1/2 CC-92480-MM-002 trial (NCT03989414) presented during the 22nd Annual International Myeloma Society Meeting and Exposition revealed that patients achieved an overall response rate (ORR) of greater than 70%, irrespective of line of therapy.¹ The ORRs were 83.9% for patients who received 1 prior line of therapy (n = 31), 88.4% for those given 2 prior lines of therapy (n = 43), 73.9% for patients who received 3 prior lines of therapy (n = 23), and 71.4% for those given 4 prior lines of therapy (n = 7).

“CELMoDs are coming, and when they come, I encourage patients and physicians to consider using them because they work better myeloma-wise [compared with immunomodulatory drugs (IMiDs)]. They trigger T cells better for the long haul, and they're generally better tolerated for patients,” Banerjee explained in an interview with OncLive®.

Banerjee is an assistant professor in the Clinical Research Division at Fred Hutch Cancer Center and an assistant professor in the Division of Hematology and Oncology at the University of Washington in Seattle.

In the interview, Banerjee discussed the differences between CELMoDs and currently available IMiDs; highlighted key findings from the CC-92480-MM-002 trial; and outlined where CELMoDs could ultimately fit into the multiple myeloma treatment paradigm.

OncLive: How do CELMoDs differ from currently existing IMiDs that are used within the myeloma treatment paradigm?

Banerjee: I used to believe [CELMoDs] were just next-generation IMiDs; I now think that they are more. I was a doubter, and I’ve become a believer. If you look at the preclinical and translational data, they work powerfully both on myeloma and T cells.

With CELMoDs, I would argue that both the preclinical data and the [clinical] data we have so far strongly suggest they make T cells work better. Not only do they work better on myeloma cells than IMiDs do, and not only do they work in IMiD-refractory patients from a myeloma perspective, but independently of this, [CELMoDs] make T cells work better.

We’ll see a lot in future years about adding iberdomide [CC-220] after CAR T-cell therapy, or adding mezigdomide in combination with bispecific antibodies. We’re already seeing some of those data. At the 2025 ASH Annual Meeting and Exposition, for example, Attaya Suvannasankha, MD, [of Indiana University Health], presented data for elranatamab-bcmm [Elrexfio] plus iberdomide.² The combination is really appealing. Preclinically and translationally, you could make a strong case that [CELMoDs] are different [from IMiDs].

Clinical trials of mezigdomide plus dexamethasone, for example—just as an example that was published [in 2023] in the New England Journal of Medicine by Paul Richardson, MD, [of Dana-Farber Cancer Institute], and colleagues—you saw a lot of data and a lot of good, solid responses of heavily IMiD-refractory patients. In the future, this is the heuristic that I use in my mind: are [CELMoDs] next-generation IMiDs, or are they a new class of drugs for therapies of the future once iberdomide and mezigdomide become available? Because [CELMoDs] work so much better in lenalidomide [Revlimid]-refractory patients than any other [IMiD] because they can induce deep responses.

I’ll want to know what percent of patients were exposed to lenalidomide and pomalidomide [Pomalyst] vs those exposed to mezigdomide and iberdomide. I’ll put this another way: in a study 10 years from now, as a reader, going to want to know what percent of patients had been exposed to mezigdomide and iberdomide before going on to CAR T-cell therapy or something new? If the answer is yes, then you believe also that mezigdomide and iberdomide are fundamentally a different class of drugs than the older IMiDs. That’s the big point to really double down on.

In the future, CELMoDs will be used almost as much for the pro–T-cell effect as for the myeloma effect. That’s really interesting, and certainly some important notes to differentiate these from IMiDs.

What were the key efficacy and safety data from CC-92480-MM-002?

These were data of mezigdomide plus bortezomib [Velcade] and dexamethasone, or mezigdomide plus carfilzomib [Kyprolis] and dexamethasone. We have [prior] data for mezigdomide plus dexamethasone as a doublet, but I think all of us like the idea of a triplet, and there may very well be some synergy between proteasome inhibitors and these [CELMoDs].

The high-level efficacy data [from CC-92480-MM-002] all looked really good. Most of these patients were refractory to prior treatments. With [both mezigdomide-based combinations], you saw good outcomes. It was an 84% ORR for patients with 1 prior line of treatment, down to 71% ORR for patients with 4 prior lines of treatment. Unsurprisingly, these drugs tend to not work as well [in later lines of therapy], one because myeloma disease biology has changed, but two, because it was always more aggressive.

If you look at our bispecific antibodies [tested in later-line clinical trials], a 71% ORR is maybe a little bit higher than what you sometimes see with these bispecific antibodies. And the bispecific antibodies have a lot of adverse effects [AEs].

Pivoting to safety, the most important part about these, we have found is that because these drugs are much more targeted on myeloma cells and boosting T cells, they tend not to have as many off-target immune AEs or off-target hematopoietic AEs. For anyone who has either prescribed lenalidomide or taken lenalidomide, you know that it is one of the messiest drugs we have in myeloma. Most of my patients have a rash, fatigue, or arthralgias. There's risk of blood clots [with lenalidomide] as well, and there’s the financial toxicity that comes with it. IMiDs—lenalidomide in particular—can induce a TP53-mutated myeloid neoplasm down the line. We don't necessarily have [long-term follow-up with CELMoDs yet], but what I can say for sure is that the non-hematologic AE profile is so much better. The most common AE in the [CC-92480-MM-002] study was not fatigue or diarrhea, which is what we typically see in these patients, but neutropenia.

Where could CELMoDs ultimately fit into the multiple myeloma treatment paradigm if data from prospective trials continue to be positive?

To quote Daft Punk, CELMoDs work harder, faster, better, stronger…than the traditional IMiD. Anything an IMiD can do, a CELMoD can do better, and that's not just efficacy. That is also in terms of safety and tolerability as well, and that is supremely important for our patients. [CELMoDs] will replace IMiDs, I think there's no doubt about that.

We can't prove this right now, but there have been preclinical data suggesting, for example, that the risk of secondary malignancies, which has been an Achilles heel for lenalidomide since the dawn of time…don't seem to be the case with CELMoDs at all. Will there be a future that these also have a better long-term safety profile [vs IMiDs]? I think it's very reasonable, because they're more targeted. What I don't know, for example, is whether CELMoDs require a Risk Evaluation and Mitigation Strategy [REMS] program. My guess is probably not, but regulatory wise, they may still require REMS. That's okay, but I think if they can make it simpler for patients, that would be amazing. And importantly, again, if you don't have that risk of second malignancies, which I don't think these will have to the same extent, and if they work better and they have fewer AEs, I would see no reason to keep using lenalidomide when we have CELMoDs available.

What would be your advice for someone who is considering a patient for a CELMoD-based clinical trial?

It depends on the trial. I always encourage clinical trials because of how we answer important questions. Anecdotally, I've only been able to treat patients with CELMoDs on clinical trials [as they’re not] FDA-approved in the US or anywhere else, but they work. These are patients who are refractory to just about everything. [Even for patients] running out of options, CELMoDs seem to work quite well for them. It's a very reasonable discussion point for patients. [CELMoDs] are oral drugs. The first couple of cycles, I'll admit, can be a rough ride, and it has been a rough ride for my patients in terms of neutropenia, dose holds, growth factor injections, etc. However, even though a lot of patients require growth factors while on a CELMoD, it tends to be front loaded. It tends to be in the beginning of treatment, and over time, as the marrow clears out and the bone marrow starts to recover, and if you adjust the dose, give growth factor, etc, things start to smooth out.

I would encourage physicians and patients in this category to consider the trial, because again, these drugs work extremely well. CELMoDs can hit the myeloma, but again, they can make T cells work much better, much more resiliently than before. We can reduce T-cell exhaustion, get the T cells going, and get CAR T cells to persist for longer. I would encourage these trials for all patients, but in particular, for anyone…in the setting of CAR T or bispecifc antibody failure. I think these are really intriguing data, and CELMoDs certainly seem to work. Obviously, we need the trials to find out if they really work in a large setting. The trials are important, and I encourage people to consider them—certainly an important note at any point for any tumor type.

References

1. Efficacy of Mezigdomide Plus Dexamethasone and Bortezomib or Carfilzomib in Patients with Relapsed/Refractory Multiple Myeloma by Line of Therapy: Results from the Phase 1/2 CC-92480-MM-002 Trial. Presented at: 22nd Annual International Myeloma Society Meeting and Exposition; September 17-20, 2025; Toronto, Canada. Abstract OA-54.
2. Suvannasankha A, Kaufman J, Badros A, et al. Safety and efficacy of elranatamab in combination with iberdomide in patients with relapsed or refractory multiple myeloma: Results from the phase 1b MagnetisMM-30 trial. Blood; 2025;146(suppl 1):100. doi:10.1182/blood-2025-100