CELMoDs May Represent Next Wave of Immunomodulation Approaches in Multiple Myeloma

The therapeutic landscape continues to rapidly evolve in multiple myeloma management, with quadruplet induction regimens, CAR T-cell therapies, and bispecific antibodies driving expectations for deep and durable responses. On top of that progress, another novel class of agents known as CELMoDs are poised to again alter the space.

At a recent OncLive^® Ask the Expert program, Sagar Lonial, MD, FACP, FASCO, a professor and chair of the Department of Hematology and Medical Oncology at Emory University School of Medicine and chief medical officer of the Winship Cancer Institute of Emory University in Atlanta, Georgia, outlined the ongoing research evolving CELMoDs in multiple myeloma, what sets these agents apart from earlier-generation immunomodulatory drugs (IMiDs), and how they may reshape treatment algorithms across lines of therapy.¹

What sets CELMoDs apart from IMiDs?

IMiDs such as lenalidomide (Revlimid) and pomalidomide (Pomalyst) transformed myeloma therapy and are staples across current lines of treatment; however, Lonial explained that these agents bind to cereblon with much lower affinity compared with investigational CELMoDs.

“[CELMoDs] not only change the conformation of cereblon, moving it more toward a closed conformation, [but they also] bind it with such potency that it rapidly degrades Ikaros and Aiolos,” Lonial explains. “The more rapidly it degrades these, the more impact it has on cell survival. Unlike many of the other drugs in this category like thalidomide, lenalidomide, or pomalidomide, which are thought to be cytostatic, CELMoDs such as iberdomide [CC-220] and mezigdomide [CC-92480] are actually cytotoxic because the effects [on] downstream [regulation] are so rapid that you get cell death.”

In addition to direct tumor cytotoxicity, CELMoDs demonstrate enhanced immunostimulatory capacity, with greater activation of T cells and natural killer cells compared with earlier-generation IMiDs. In an era increasingly defined by T-cell–redirecting strategies, this immune potentiation may represent a critical differentiator.

“If you look at the effect on immune stimulation, you'll see that mezigdomide and iberdomide are significantly more potent at activating immune function,” he explained. “And this to me is one of the key parts that make them so critical in this wave of immune therapy that we're going through in myeloma right now.”

What have clinical trial data shown regarding CELMoD use in multiple myeloma?

Lonial highlighted findings from the phase 1/2 CC-220-MM-001 trial (NCT02773030), which evaluated iberdomide-based therapy across cohorts of patients with relapsed/refractory and newly diagnosed disease, including combinations with daratumumab (Darazalex) and dexamethasone.²

Findings presented at the 18th Annual International Myeloma Society Annual Meeting in 2021 showed that in cohort E, which featured patients (n = 43) with relapsed/refractory multiple myeloma who had received a median of 4 prior lines of therapy (range, 2-13), iberdomide plus daratumumab and dexamethasone produced an overall response rate (ORR) of 45.9%, a clinical benefit rate of 54.1%, and a disease control rate of 89.2%.³

“What struck me was not only the activity…but the fact that many of the grade 3 and grade 4 adverse effects [AEs] that we've come to know with the IMiD class basically didn't happen,” Lonial said. “The only toxicity that [was seen] both in the IMiDs and in the CELMoDs was hematologic toxicity, and that is in fact an on-target effect of binding cereblon.”

In cohort K of the study, which evaluated the same combination in patients with newly diagnosed disease (n = 75), patients achieved an ORR of 94.7%, including a complete response (CR) or better rate of 68.0%, with a trend of responses deepening over time.²

The subsequent phase 3 EXCALIBER-RRMM trial (NCT04975997) evaluated iberdomide plus daratumumab and dexamethasone in patients with relapsed/refractory multiple myeloma who had received 1 to 2 prior lines of therapy. After it was announced that patients treated with the experimental combination experienced improved rates of minimal residual disease (MRD)–negativity rates compared with those given daratumumab, bortezomib (Velcade), and dexamethasone, the FDA accepted for review a new drug application seeking the approval of iberdomide plus daratumumab and dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma.^4,5

Regarding mezigdomide, findings from the phase 1/2 CC-92480-MM-002 trial (NCT03374085) presented during the 22nd Annual International Myeloma Society Meeting and Exposition revealed that patients treated with mezigdomide in combination with dexamethasone and carfilzomib (Kyprolis) or bortezomib (Velcade) achieved an ORR of greater than 70%, irrespective of line of therapy.⁶ The ORRs were 83.9% for patients who had received 1 prior line of therapy (n = 31), 88.4% for those who had been given 2 prior lines of therapy (n = 43), 73.9% for patients who had received 3 prior lines of therapy (n = 23), and 71.4% for those who had been given 4 prior lines of therapy (n = 7).

“These [responses] were very encouraging and suggested that the potency associated with mezigdomide appears to be…the highest in terms of potency overall [among cereblon-binding agents],” Lonial said. “If we look at safety again, [we saw] mostly hematologic toxicity. You do see a little bit of infectious complications; [however], these are patients who have had myeloma for a long time. What I think is encouraging is that the incidence of asthenia, fatigue, and diarrhea [was] significantly lower than we see with lenalidomide or pomalidomide, suggesting a differential AE profile that really favors mezigdomide and iberdomide over lenalidomide and pomalidomide.”

Ongoing phase 3 trials are further investigating mezigdomide-based therapy in relapsed/refractory multiple myeloma, including SUCCESSOR-1 (NCT05519085), evaluating mezigdomide plus bortezomib and dexamethasone, and SUCCESSOR-2 (NCT05552976), investigating mezigdomide plus carfilzomib and dexamethasone.

Other studies are looking at CELMoD and bispecific antibody combination approaches in the relapsed/refractory setting, Lonial highlighted, pointing to the phase 1 MagnetisMM-30 trial ​(NCT06215118)​ evaluating iberdomide plus elranatamab-bcmm (Elrexfio). and the phase 1/2 MELT-MM3 trial ​(NCT06645678)​ looking at iberdomide plus elranatamab and dexamethasone.

How may CELMoDs affect real-world multiple myeloma management?

In audience polling during the program, clinicians favored potentially using CELMoDs as oral alternatives when CAR T-cell therapy or bispecific antibody administration is not feasible.¹ Others expressed interest in early relapse settings following lenalidomide-based frontline therapy.

“In terms of key considerations as you're talking about where to use these agents and when, there certainly are patient factors, practice factors, system factors, and ongoing questions,” Lonial said. “And as we begin to think about these, one of the things that I'm most excited about is using [CELMoDs] potentially as part of a pre-apheresis for patients getting CAR T-cell therapy, as well as potentially for limited-duration maintenance after CAR T-cell therapy to try [to] keep the CARs going longer.”

The ultimate aspiration in multiple myeloma remains cure, or at a minimum, durable treatment-free intervals. Long-term follow-up from modern regimens and cellular therapies suggests that a subset of patients may achieve sustained remission.

CELMoDs may contribute to this trajectory by enabling deeper responses, enhancing MRD negativity rates, and potentiating T-cell–redirecting therapies. As regulatory agencies increasingly consider MRD as a surrogate end point for accelerated approval, depth of response may gain even greater prominence in development programs.

“To me, [CELMoDs] represent a way not only to kill myeloma, but also to augment the efficacy of the bispecific antibodies and perhaps to reduce T-cell exhaustion and enhance T-cell activation that may make the efficacy of a bispecific antibody better, allow us to spread the doses out more, or even give patients long-term treatment holidays after they've achieved deep and sustainable remissions,” Lonial concluded.

References

1. Lonial S. Next-generation immunomodulation: emerging role of CELMoDs in multiple myeloma care. OncLive Ask the Expert. January 21, 2026. Accessed February 26, 2026.
2. Balarí AS, Khan A, Oriol A, et al. Iberdomide plus daratumumab and dexamethasone (IberDd) in patients with newly diagnosed multiple myeloma by renal function: a subgroup analysis of the CC-220-MM-001 trial. Blood. 2025;146(suppl 1):5810. doi:10.1182/blood-2025-5810
3. 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: 18th Annual International Myeloma Society Annual Meeting; September 8-11, 2021; Vienna, Austria. Abstract 1087033.
4. Bristol Myers Squibb announces phase 3 EXCALIBER-RRMM study evaluating iberdomide in combination with standard therapies demonstrated a significant improvement in minimal residual disease negativity rates in relapsed or refractory multiple myeloma. News release. Bristol Myers Squibb. September 23, 2025. Accessed February 26, 2026. https://news.bms.com/news/details/2025/Bristol-Myers-Squibb-Announces-Phase-3-EXCALIBER-RRMM-Study-Evaluating-Iberdomide-in-Combination-with-Standard-Therapies-Demonstrated-a-Significant-Improvement-in-Minimal-Residual-Disease-Negativity-Rates-in-Relapsed-or-Refractory-Multiple-Myeloma/default.aspx
5. US 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 26, 2026. https://news.bms.com/news/corporate-financial/2026/U-S--Food-and-Drug-Administration-Accepts-Bristol-Myers-Squibbs-New-Drug-Application-for-Iberdomide-in-Patients-with-Relapsed-or-Refractory-Multiple-Myeloma/default.aspx
6. 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.