Analyzing the Role of CELMoDs in the Relapsed/Refractory Myeloma Space

Expert consensus highlights a critical need to refine treatment sequencing for relapsed/refractory multiple myeloma, particularly as the field transitions toward T-cell–redirecting therapies and next-generation cereblon E3 ligase modulators (CELMoDs). In a Frontline Forum program, myeloma specialists gathered to discuss the landscape surrounding these novel agents, particularly iberdomide and mezigdomide in trials such as the phase 1b/2 CC-220-MM-01(NCT02773030) and phase 1/2 CC-92480-MM-002 (NCT03989414) trial, respectively, while comparing them with current standards such as bispecific antibodies and CAR T-cell therapies.^1,2

The panel was hosted by Sagar Lonial, MD, FACP, FASCO, professor and chair of the Department of Hematology and Medical Oncology at Emory University School of Medicine and chief medical officer at Winship Cancer Institute of Emory University. Panelists included Faith Davies, MD, director of the Clinical Myeloma Program at NYU Langone Perlmutter Cancer Center; Shahzad Raza, MD, hematologist/medical oncologist at the Cleveland Clinic; Adam Binder, MD, quality officer in the Division of Hematologic Malignancies and associate professor at Thomas Jefferson University Hospital; James Berenson, MD president and medical director at Berenson Cancer Center and the founder and president of the Institute for Myeloma & Bone Cancer Research; Hans Lee, MD, director of Myeloma Research at Sarah Cannon Research Institute; Carol Ann Huff, MD, medical director for the Johns Hopkins Kimmel Cancer Center and associate professor of Oncology and Medicine at the Johns Hopkins University School of Medicine; Peter Forsberg, MD, hematologist/medical oncologist at the Colorado Blood Cancer Institute; Alfred Garfall, MD, MS, director of Autologous Hematopoietic Stem Cell Transplantation and section chief of Myeloma, Hematology-Oncology at the University of Pennsylvania Abramson Cancer Center; Mansi Shah, MD, clinical director of Multiple Myeloma at Rutgers Cancer Institute and associate assistant professor of Medicine at Rutgers Robert Wood Johnson Medical School; and Jeffrey Zonder, MD, medical oncologist and hematologist at the Karmanos Cancer Institute.

Outlining the Standards in Relapsed/Refractory Multiple Myeloma

First, the investigators highlighted inadequacies within the NCCN guidelines for the relapsed/refractory patient population, emphasizing a need for better recommendations for treatment selection and sequencing. Specifically, they first discussed the use of CAR T cells in this patient population upon first relapse, with Lee being a proponent of cilta-cel (Carvykti)–based triplet therapy use in patients with high-risk cytogenetics and a daratumumab (Darzalex)-based triplet regimen for patients without, even among patients who were previously exposed. Davies took an alternative stance, relegating daratumumab to the maintenance setting for patients with previous exposure.

Regarding the use of CAR T products, they also emphasized a reluctance to administer CAR T-cell treatment given their toxicities, with many patients expressing unwillingness to undergo later lines with CAR T-cell therapies if they did not do so in the frontline or second-line setting. When considering the use of immunomodulatory drugs (IMiDs), Hans expressed an affinity for combinations with these agents prior to apheresis.

They also discussed the importance of considering the nature of prior relapse as well as the class of drugs previously used, particularly regarding the use of carfilzomib (Kyprolis) therapy for patients who experience rapid progression following lenalidomide (Revlimid). The experts deliberated over the use of carfilzomib- or CAR-based interventions in the second-line setting based on a patient’s goals for efficacy and the burden of treatment.

Raza brought up several points regarding therapy based on the number of prior treatments, specifically outlining his use of bispecific bridging therapy.

“We are frequently doing talquetamab-tgvs [Talvey] bridging now. This is because we have options now; we have data to support that,” Raza explained. “We give 3 ramp-up doses, 1 dose as an outpatient, and then it [stabilizes] the disease. If you asked me the same question 6 months ago, I would have been using the same things: [daratumumab, carfilzomib, pomalidomide (Pomalyst), and dexamethasone] and [CELMoD-based] regimens.”

Next, Berenson opined on the development of BCL2 inhibition for t(11;14) translocation, calling it a “home run.” He also alluded to the efficacy of isatuximab-irfc (Sarclisa) and elotuzumab (Empliciti). He further explained that for most older patients in his clinic, he saves IMiDs for second-line therapy, usually as part of a lenalidomide-based regimen.

Unmet Needs in the Management of Late Relapses

Regarding unmet needs in this space, the experts identified patients previously exposed to therapies targeting both BCMA and GRPC5D, as these patients lack options in later lines of therapy. Additionally, understanding resistance patterns among patients who receive T-cell–engaging therapies was noted as an unmet need, which may help to better inform subsequent lines of treatment, such as rechallenge with a BCMA-targeted therapy. Finally, a need for safer CAR T agents was posited, with experts noting the possibility of rare, debilitating, or fatal toxicities that may emerge with agents like cilta-cel.

Lee also added that in the community setting, many patients may not have the ability to access T-cell–redirecting therapies at all, which presents considerations surrounding barriers to access for this patient population. Raza added that many patients with a higher degree of comorbidities or frailty symptoms may prefer orally available therapies to avoid coming into the clinic, which he will often employ for later lines of therapy. Finally, Berenson highlighted a need to better manage toxicities with bispecific antibodies, noting an elevated risk of infection and suggesting intermittent treatment with these therapies.

Examining Disparate Treatment Profiles in CELMoDs

When considering CELMoDs, Lonial outlined their characteristics as cytotoxic agents that can be administered in a shorter treatment window. Highlighting the potency between agents, he suggested that mezigdomide confers greater potency vs iberdomide for this patient population, although their adverse effect (AE) profiles differ significantly. Notably, contrasting with the AE profile of iMiDs, iberdomide conferred limited grade 3 or 4 non-hematologic toxicities.

When analyzing the phase 1b/2 CC-220-MM-01 data, Lonial suggested that based on the efficacy, shorter duration of therapy, and lower non-hematologic toxicities, iberdomide may be advantageous over iMiDs.

“[T]hese are going to be far more effective partners with immune therapy,” Lonial explained. “[T]he upside of that combination is shortening the duration of therapy… If you give [elranatamab-bcmm (Elrexfio) with iberdomide,] can you give it for 12 or 18 months and walk away depending upon sustained MRD negativity? Here are the AEs…what you'll see is that the [non-hematologic toxicities] that many of you brought up as bugaboos of giving long-term lenalidomide occur much less frequently in the iberdomide expansion cohort.”

Next, touching upon the phase 1/2 CC-92480-MM-002 data examining mezigdomide in this relapsed/refractory group, he noted activity across all dose levels of the agent in a less heavily pretreated population. He also highlighted high response rates in combination with carfilzomib and dexamethasone (Kd), particularly in the pomalidomide- and lenalidomide/CD38-refractory groups. Moreover, Lonial emphasized a similarly low rate of non-hematologic grade 3/4 AEs with mezigdomide.

The panel then discussed the rationale behind adding dexamethasone to each of the CELMoD regimens, with Lonial noting better symptom management with the agent, as well as observed synergy in efficacy. Raza then raised the question regarding how the drug is sequenced, with a particular need to establish early-line efficacy. Other panelists concurred, noting how the integration of these CELMoD combinations is unclear, but that they may have utility in centers were CAR T therapies may not be feasible, particularly in the community setting.

Regarding the integration into the treatment paradigm, Lonial explained that a near doubling was observed with the iberdomide/dexamethasone combination vs what was observed in the phase 3 MAIA study (NCT02252172).³ Moreover, the panel discussed the application of CELMoDs across a variety of patient groups, particularly for those who cannot access bispecifics or those who want a reduced infection risk, as well as for patients who need treatment between bispecific or CAR T-cell agents.

Exploring CELMoD Utility in High-Risk/Extramedullary Settings

Contextualized by an overall response rate (ORR) of about 40% among patients with extramedullary disease, Lonial identified an opportunity for CELMoD therapy to synergize with bispecifics in a population where bispecifics alone do not confer optimal outcomes. Raza expanded upon this idea, suggesting that he found the most profound benefit in patients with extramedullary disease using a bispecific combination with an iMiD in addition to mezigdomide. Moreover, Lee highlighted a patient who was treated with mezigdomide prior to apheresis, who subsequently attained a durable response to treatment on idecabtagene vicleucel (ide-cel; Abecma).

The Impact of Future Trials in the Relapsed/Refractory Setting

Next, the KOLs discussed future trials that may inform practice for this relapsed/refractory population, particularly how the availability of CELMoDs would impact their practice. They touched upon considerations for the use of potent CELMoDs with elotuzumab, as well as using these agents to potentiate responses for newly diagnosed patients after CAR T-cell therapy and mitigate the effects of cytokine release syndrome. Moreover, they discussed the potential for fixed-duration CELMoD use, underscored by the fact that many of these trials are registrational in nature.

Regarding upcoming data from the phase 3 EXCALIBER-Maintenance trial (NCT05827016), which is comparing maintenance therapy with iberdomide vs lenalidomide, the experts discussed if subsequent trials would compare a CELMoD with a lenalidomide/daratumumab combination, which is a common maintenance regimen post-autologous stem cell transplant (ASCT).⁴

Next, the panelists further explored the potential of fixed-duration therapy, specifically for potential reutilization as well as for quality-of-life considerations. Moreover, they discussed a further potential for CELMoDs to bolster remission durability post-CAR T infusion. However, they suggested that more data on the use of these agents post-BCMA in earlier lines of therapy will be warranted.

Furthermore, Lee identified a potential gap in the phase 3 EXCALIBER-RRMM data (NCT04975997), as the comparative efficacy of pomalidomide vs iberdomide will need to be parsed out for patients who can’t access or are ineligible for bispecific antibodies or CAR T cells.⁵

Regarding CELMoD rechallenge, Lonial highlighted previous findings showing modest response rates but short progression-free survival (PFS).

“If you have a patient who's progressing on pomalidomide, would you go back to lenalidomide? Probably not,” he explained. “Unless you're looking for a different mechanism of action—you're thinking about synergy with something else—it's probably going to be similar.”

He further highlighted where he might see CELMoDs being integrated into the treatment paradigm.

“Iberdomide is going to replace lenalidomide, and mezigdomide is going to replace pomalidomide. That's my sense of it,” Lonial stated. “Where would I think about mezigdomide? The [patient with] high-risk extramedullary [disease] is where I may want to think about [it] early on.”

Fitting CELMoDs Into Community Practice

Lee began by outlining the potential use of CELMoDs in the community by pointing to the higher uptake of oral regimens, even in spite of efficacy. Moreover, they highlighted a desire for community oncologists to keep a patient close to home for as long as possible, often exhausting all available options before referring them to a center specializing in CAR T-cell therapies. Notably, the experts pointed out that many sites that participated in the EXCALIBER trials were community centers.

However, they debated how the integration of bispecifics into the community setting will come into play when considering CELMoDs. Raza suggested that for many, it may be a point of access issue, with many older patients resistant to traveling to the doctor’s office, making bispecifics a less preferable option given more intensive monitoring.

Finally, regarding CELMoDs in community practice, they concluded by spotlighting a need to better educate those in the community, especially oncologists who are comfortable using older generations of therapies, to understand and acknowledge differences with emerging therapeutics to offer the best options for their patients.

Closing Remarks

Berenson, in his conclusion, highlighted the ability for CELMoDs to reduce fatigue while conferring efficacy in the relapsed/refractory population, potentially to replace ruxolitinib (Jakafi) and pomalidomide.

“The key takeaway for me is truly…this fatigue, this quality-of-life thing. It’s gigantic, and the population that you're targeting is [older], where all the pomalidomide toxicity occurs. If you don't see that, that's going to be huge,” he stated.

Other panelists highlighted a greater number of questions than answers that emerged during the discussion, as well as a note that these patients are diverse, with CELMoDs displaying efficacy across a wide spectrum of disease phenotypes. They collectively highlighted greater access to therapy and a benefit in having a plurality of options. Finally, they expressed further interest in exploring fixed-duration CELMoD administration to help reduce healthcare costs for patients.

References

1. Lonial S, Popat R, Hulin C, et al. Iberdomide plus dexamethasone in heavily pretreated late-line relapsed or refractory multiple myeloma (CC-220-MM-001): a multicentre, multicohort, open-label, phase 1/2 trial. Lancet Hematol. 2022;9(11):822-832. doi:10.1016/S2352-3026(22)00290-3
2. Richardson PG, Ocio E, Raje NS, et al. CC-92480, a potent, novel cereblon E3 ligase modulator (CELMoD) agent, in combination with dexamethasone (DEX) and bortezomib (BORT) in patients (pts) with relapsed/refractory multiple myeloma (RRMM): preliminary results from the phase 1/2 study CC-92480-MM-002. Blood. 2021;138(suppl 1):2731. doi:10.1182/blood-2021-147812
3. Facon T, Moreau P, Weisel K, et al. Daratumumab/lenalidomide/dexamethasone in transplant-ineligible newly diagnosed myeloma: MAIA long-term outcomes. Leukemia. 2025;39:942-950. doi:10.1038/s41375-024-02505-2
4. A study to compare iberdomide maintenance versus lenalidomide maintenance therapy following autologous stem cell transplant in participants with newly diagnosed multiple myeloma. ClinicalTrials.gov. Updated March 13, 2026. Accessed April 17, 2026. https://tinyurl.com/mtyyawzz
5. Open-label study comparing iberdomide, daratumumab and dexamethasone (IberDd) versus daratumumab, bortezomib, and dexamethasone (DVd) in participants with relapsed or refractory multiple myeloma (RRMM) (EXCALIBER-RRMM). ClinicalTrials.gov. Updated April 3, 2026. Accessed April 17, 2026. https://tinyurl.com/34kcsdm3