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CELMoDs in MM
CELMoDs: Answers to Your Questions on Immune-Based Combinations and Treatment Duration in Multiple Myeloma

Released: July 23, 2026

Francesca Gay
Francesca Gay, MD, PhD
Sagar Lonial
Sagar Lonial, MD, FACP, FASCO
Karthik Ramasamy
Karthik Ramasamy, MD, PhD
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Key Takeaways
  • Iberdomide and mezigdomide are being evaluated as part of emerging immune-based combination strategies in multiple myeloma, including combinations with bispecific antibodies and other T-cell–redirecting therapies, with particular interest in patients with high-risk features or extramedullary disease.
  • Key unanswered questions include how CELMoDs such as iberdomide and mezigdomide should be sequenced with BCMA- and GPRC5D-targeted therapies and whether sustained MRD negativity may help support fixed-duration or response-adapted treatment approaches.
  • Continued follow-up is needed to better define long-term safety, including infection risk, duration of response, and second primary malignancies, as well as other factors that contribute to risks.

In this commentary, Sagar Lonial, MD, FACP, FASCO; Karthik Ramasamy, MD, PhD; and Francesca Gay, MD, PhD, answer questions from an audience of healthcare professionals participating in a live symposium at the 2026 Controversies in Multiple Myeloma (COMy) conference in Paris, France.

What are your thoughts on combining mezigdomide with bispecific antibodies, particularly for patients with extramedullary disease?

Sagar Lonial, MD, FACP, FASCO:
CELMoD combinations represent a very exciting area of study that is quite actively being investigated. For example, the phase Ib MagnetisMM-30 study (NCT06215118) is evaluating elranatamab plus iberdomide in patients with relapsed/refractory (R/R) multiple myeloma (MM), and the combination of elranatamab plus mezigdomide is being evaluated in the phase I/II MELT-MM study (NCT06645678), both of which have reported interesting results. In preliminary Part 1 results from MagnetisMM-30, elranatamab plus iberdomide yielded an overall response rate (ORR) of 95.5%, with ≥ very good partial response (VGPR) of 77.3% and ≥ complete response (CR) of 45.5% at a median follow-up of 7.8 months. In initial Part 1 results from MELT-MM, elranatamab plus mezigdomide produced an ORR of 90%, with ≥ VGPR of 60% and ≥ CR of 50% among response-evaluable patients. Among patients treated for at least 3 cycles, the ORR was 100%, with ≥ VGPR of 100% and ≥ CR of 71.4%. These data remain early and based on small cohorts, but they support continued evaluation of CELMoD and BCMA bispecific antibody combinations in R/R MM.

When I think about patients with extramedullary disease, among other high-risk features (eg, high-risk cytogenetics such as del[17p], t[4;14], t[14;16], or gain/amplification of 1q; elevated LDH; plasma cell leukemia; aggressive relapse kinetics; or functional high-risk disease), combination strategies seem appropriate. These patients harbor a challenging disease course based on their initial genetics or other risk features. Of note, for MagnetisMM-30, extramedullary disease was reported as a baseline feature, but efficacy was not reported for that group alone.

Karthik Ramasamy, MD, PhD:
Because novel CELMoD agents may soon be approved, we need to start to think carefully about how to potentially integrate them in combination regimens. We have vast experience with lenalidomide and pomalidomide, and central concepts that emerged were tolerability, T-cell activation, and T-cell redirection. If we apply those concepts, the question becomes how to optimally integrate CELMoDs into immune-based approaches. In clinical trials, I would also look closely at the infection-related safety findings, evidence of antimyeloma activity, and duration of response. This is a nuanced question, but we also need a nuanced understanding as we begin to think about potentially combining CELMoDs with very effective immune therapies we have in place for MM.

Sagar Lonial, MD, FACP, FASCO:
A question that naturally arises is what is the better partner for T-cell engagers? There are compelling data with anti-CD38 antibodies as partners for T-cell engagers, but can CELMoDs match or exceed these outcomes, and what does the adverse event profile look like when we compare these approaches? I think that is something the field will need to evaluate in the coming years.

How do CELMoDs compare clinically with lenalidomide and pomalidomide?

Sagar Lonial, MD, FACP, FASCO:
In my opinion, a couple of ongoing trials will help answer this question. The international, randomized, phase III EXCALIBER-Maintenance study is comparing iberdomide with lenalidomide as maintenance therapy after primary MM treatment and autologous stem cell transplant. The primary endpoint is progression-free survival (PFS). Key secondary endpoints include MRD-negative rate, overall survival, and safety. This trial should help us better understand how iberdomide compares with lenalidomide in the maintenance setting. The multicenter, randomised, open-label phase III GEM21menos65 study conducted in Spain is evaluating iberdomide plus isatuximab, bortezomib, and dexamethasone for transplant-eligible patients 65 years of age or younger with newly diagnosed MM requiring treatment and an ECOG performance status ≤2. The primary endpoint is measurable residual disease (MRD)–negative rate; secondary endpoints include PFS and safety. We need data from both studies to better understand how these agents compare with historically used drugs.

What do you think is/are the most important question(s) related to how to sequence CELMoDs?

Karthik Ramasamy, MD, PhD:
When I think about the sequencing and duration of CELMoD-based therapy, I focus on 2 key concepts. First, has the myeloma clone been reduced to a very low level, such as MRD negativity at 10-6? Second, has the immune environment been sufficiently primed to help prevent clonal escape?

The goal is to reduce tumor burden to a level that is not measurable by standard MRD testing, whether by next-generation sequencing or next-generation flow cytometry, while also activating T-cells in a way that may help the immune system control residual disease. With this in mind, I would want to continue a combination long enough to prime the adaptive immune environment. I would not make the duration too short. In the newly diagnosed setting, I would probably consider 2-3 years of therapy to establish that level of adaptive immune control.

Emerging translational data in heavily pretreated patients suggest that antigen escape can occur after targeted immune therapies, including BCMA loss or alteration after BCMA-directed therapy and GPRC5D loss after GPRC5D-directed therapy. Although this may be less common in newly diagnosed disease, resistant subclones remain a concern. We do not want to find, years from now, that prolonged bispecific antibody therapy has been selected for more challenging disease. For that reason, I believe we need to study how to use CELMoDs more effectively in combinations and how best to sequence them with BCMA- and GPRC5D-targeted therapies.

Francesca Gay, MD, PhD:
I completely agree. The goal is not only to achieve MRD negativity, but also to maintain it over time. Sustained MRD negativity as an endpoint may be a marker of more durable disease control and better long-term outcomes, which support using a fixed-duration approach that is long enough to keep the disease suppressed. In that regard, a fixed duration that is not too short, probably 2-3 years, may make sense, particularly if immunomodulation after therapy can help.

What do we know about the long-term safety profile of CELMoDs, including the risk of second primary malignancies?

Karthik Ramasamy, MD, PhD:
This is an interesting question, but I want to note that this was also a major debate 10 years ago with immunomodulatory drugs. It is important to keep in mind that second primary malignancies (SPMs) have been reported in newly diagnosed MM trials, even in settings not driven by lenalidomide maintenance. For example, CASSIOPEIA evaluated daratumumab plus bortezomib, thalidomide, and dexamethasone (D-VTd) vs VTd before and after autologous stem cell transplant, followed by daratumumab maintenance or observation; in the long-term part 2 analysis, SPMs occurred in 11.4% of patients receiving D-VTd/daratumumab, 6.1% receiving D-VTd/observation, 12.3% receiving VTd/daratumumab, and 10.2% receiving VTd/observation. For CELMoDs, mature long-term SPM data remain limited. In SUCCESSOR-2, mezigdomide plus carfilzomib/dexamethasone was associated with SPMs in 7 of 288 patients (2%), compared with 4 of 186 patients (2%) receiving carfilzomib/dexamethasone. For iberdomide, detailed phase III SPM rates have not yet been fully reported; EXCALIBER-RRMM specifies long-term follow-up for SPMs every 4 months for at least 5 years.

Sagar Lonial, MD, FACP, FASCO:
I would reference an institutional analysis from our group evaluating patients who received bortezomib with lenalidomide and dexamethasone induction, autologous transplant, and risk-adapted maintenance. In that analysis, among patients who remained in remission for more than 10 years, the rate of second primary malignancies was no different from what was observed in patients who relapsed earlier. This finding indicates that if second primary malignancies were causative, 1 year may be enough. Being on therapy for 2-4 years does not necessarily increase the risk, which is still relatively low compared with the PFS benefit observed.

What is your broader perspective on where CELMoDs may fit in the treatment landscape as the field evolves from bispecific to trispecific antibodies and from single-antigen to dual-antigen CAR T-cell therapy?

Karthik Ramasamy, MD, PhD:
Although we are moving toward increasingly complex immune-based strategies, a foundation for improved survival in MM has been the use of immunomodulatory drugs in multiple combinations, including with proteasome inhibitors and daratumumab. It is important to continue building on that platform rather than assuming that targeting additional surface antigens through T-cell redirection is the only path forward. I hope that these trials will provide increasingly practice-informing data across different clinical settings and help guide how we integrate these approaches into patient care.

Sagar Lonial, MD, FACP, FASCO:
We are asking the immune system to do a lot with current therapeutic approaches. Anything we can do to improve immune health, improve immune responsiveness, and help the immune system be a better partner for bispecifics, trispecifics, and CAR T-cell therapies is important. CELMoDs clearly have single-agent activity, but they also have the added benefit of an immune-enhancing effect.

Your Thoughts
What are your questions related to CELMoD therapies and CELMoD-based combinations for patients with newly diagnosed or R/R MM? Leave a comment below and take our poll to join the conversation.
Access the overall program to download the slides and rewatch an on-demand webcast from the live meeting or listen to a podcast on where the experts think the field is going next. Also coming soon! Watch for our new Interactive Decision Support Tool for R/R MM. With just a few clicks to answer a few quick questions about your actual or hypothetical patient, we will show you how your approach compares with treatment recommendations from 5 experts!

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