Insights on CELMoDs in Multiple Myeloma From the EXCALIBER-RRMM Trial

One of the most exciting trends on the horizon in multiple myeloma is the development of CELMoDs (cereblon E3 ligase modulators), a distinct class of agents that bind cereblon more potently than traditional immunomodulatory imide drugs (IMiDs). The phase 3 EXCALIBER-RRMM trial (NCT04975997) is evaluating the CELMoD iberdomide plus daratumumab (Darzalex) and dexamethasone vs daratumumab, bortezomib (Velcade), and dexamethasone in early relapsed multiple myeloma, leading to the FDA priority review acceptance of iberdomide.¹

In this interview, Sagar Lonial, MD, professor and chair at Emory University School of Medicine, chief medical officer of the Winship Cancer Institute, and member of the International Myeloma Foundation’s Scientific Advisory Board, discussed the trial design and the evolving therapeutic landscape of multiple myeloma. He explained the advantages of CELMoDs over IMiDs and highlighted the trial’s use of minimal residual disease (MRD) at a fixed 9- to 12-month time point as a coprimary end point for accelerated FDA approval, a landmark shift aimed at bringing active treatments to patients sooner than traditional progression-free survival (PFS) metrics allow. Lonial also discussed the future of CELMoDs, emphasizing their potential as maintenance therapy and their promising combination with bispecific T-cell engagers and chimeric antigen receptor (CAR) T-cell products.

Targeted Oncology: Could you explain the background for using CELMoDs in multiple myeloma?

Sagar Lonial, MD: The CELMoDs are a new, distinct class of agents, and although they share in common binding to cereblon with the older category of IMiD drugs that include thalidomide, lenalidomide [Revlimid], and pomalidomide [Pomalyst], what the CELMoDs do is 3 things. The first is that they bind cereblon far more potently and result in degradation of the transcription factors Ikaros and Aiolos much faster than the IMiD class does, and by doing it faster, it results in cell death, as opposed to just growth arrest, which is what you see with the IMiD class.

The second thing they do is they were engineered to be more effective at activating immune function, increasing T cell activation, reducing exhaustion, and activating [natural killer] cells, which makes them perfect partners for immune therapy.

The third thing is that their adverse event profile is quite different from lenalidomide and pomalidomide—not that there are no adverse events, but the frequency of grade 3 [and] grade 4 nonhematologic adverse events is significantly lower than what we see with the previous IMiD class. There are differences in what I think the CELMoDs iberdomide and mezigdomide bring to the table.

What was the background for the EXCALIBER-RRMM trial?

The EXCALIBER-RRMM trial followed up on early phase 1 studies that demonstrated iberdomide plus dexamethasone had activity, and in fact, when you combined iberdomide plus dexamethasone with daratumumab, based on some of the immune effects that iberdomide has, you could, in some cases, overcome daratumumab resistance or enhance the efficacy of daratumumab.² That’s not terribly dissimilar from what we saw, for instance, in MAIA [phase 3; NCT02252172], where daratumumab plus lenalidomide was better than either of those 2 drugs together. But what we've noticed when you combine iberdomide plus daratumumab, particularly in newly diagnosed [multiple myeloma], you see a deeper response, and you see more MRD negativity. That's what gave rise to the [iberdomide, daratumumab, and dexamethasone] vs bortezomib, daratumumab, [and] dexamethasone in early relapse with the goal of trying to achieve deeper responses and longer PFS in early relapsed myeloma.

What stood out about the design of this trial?

There were coprimary end points; one was MRD negativity at about a year, and that was part of the FDA guidance on when MRD could be used potentially as an accelerated approval end point. It wasn't MRD anytime; it was looking at fixed time points, so between months 9 and 12 is what was used for this. The coprimary end point was PFS. But what was unique about the way this trial was designed is it was the first test of using MRD as an early accelerated approval mechanism, then allowing PFS to be followed in terms of the full approval for iberdomide in relapsed myeloma.

What is the significance of MRD being used as an approval end point in myeloma?

What I think it does is bring breakthrough treatments to patients sooner. Historically in myeloma, we have not used overall survival, we've used PFS, but often, waiting for median PFS can end up taking a long time, and that time is preventing patients from having access to these drugs when we have a strong signal, particularly by MRD at a fixed time point, that these drugs can offer benefit. What I'm most excited about is that we now have a test case. I'm hopeful that this will get approved in August 2026 and, as a consequence of that, we will begin to see earlier approvals for drugs that clearly have activity in different disease states.

What are the next steps for this particular combination using iberdomide?

The trial is under review at the FDA, so I think we're going to have to wait a few months to get a sense of what their view of the data is, given the need for PFS as the full approval end point. A lot of data will not be released based on the primary end point…until the FDA finishes evaluating it, because they don't want to bias the trial one way or the other based on early end points. We do need to be truthful to the actual end points of the study and not reveal too much information. But certainly, this is a very encouraging step forward, not just for iberdomide, but for patients in the field who need access to effective therapy sooner than the typical end points; this would allow them to get access.

In what other disease settings do you see the most potential for iberdomide?

There is another randomized phase 3 [trial] looking at iberdomide vs lenalidomide head-to-head in posttransplant maintenance [phase 3 EXCALIBER-Maintenance; NCT05827016]. I think that's an important study. But what I'm most excited about is the combinations of iberdomide and mezigdomide, the other CELMoD, with the T-cell engagers, and we've seen early data now combining iberdomide with elranatamab [Elrexfio] in the MagnetisMM-30 study [phase 1; NCT06215118].³ We've also seen combinations of mezigdomide plus elranatamab in the MELT-MM trial [phase 1/2; NCT06645678]. So to me, this is a logical next step, to be able to combine the CELMoDs with T-cell engagers [or] with CAR T cells to try to improve the efficacy of the product, perhaps the persistence of the CAR T product, and make those combinations even more powerful than either of them separately.

REFERENCES

1. U.S. Food and Drug Administration accepts Bristol Myers Squibb's new drug application for iberdomide in patients with relapsed or refractory multiple myeloma. News release. Bristol Myers Squibb. February 17, 2026. Accessed February 17, 2026. https://tinyurl.com/46jxfsjs

2. Lonial S, Richardson PG, Popat R, et al. Iberdomide in combination with dexamethasone and daratumumab, bortezomib, or carfilzomib in patients with relapsed/refractory multiple myeloma. Presented at: European Hematology Association Congress; June 9-17, 2021; Virtual.

3. Suvannasankha A, Kaufman JL, 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 MagentisMM-30 trial. Presented at: 2025 American Society of Hematology Annual Meeting and Exposition; December 6-9, 2025; Orlando, FL. Abstract #100.