Ask AI
Back Back

Experts Discuss HCP Questions on CELMoD Agent Therapy for Multiple Myeloma

Clinical Thought
Clinical Thought
See Activity Information

Released: August 21, 2026

See Activity Collection

Step 1 of 2

1 ClinicalThought 2 Complete Activity

In this commentary, experts address key questions on CELMoD agent therapy for multiple myeloma, including a new approval, combination strategies, adverse event management, and potential use in extramedullary disease.

Sagar Lonial
Sagar Lonial, MD, FACP, FASCO
Fredrik Schjesvold
Fredrik Schjesvold, MD, PhD
Niels van de Donk
Niels van de Donk, MD, PhD
FAQs on CELMoD Agents for MM


Continue to Activity
Key Takeaways
  • Iberdomide received accelerated FDA approval in combination with daratumumab/hyaluronidase and dexamethasone for adults with multiple myeloma who have received ≥1 prior line of therapy including a proteasome inhibitor and an immunomodulatory agent, marking the first FDA approval of a CELMoD agent.
  • Emerging data support the potential for CELMoD agents in managing difficult-to-treat disease, including extramedullary myeloma.
  • Practical management with CELMoD agents includes proactive growth factor support for neutropenia, a class effect with these drugs.

In this commentary, experts address key questions on CELMoD agent therapy for multiple myeloma (MM), including a new approval, combination strategies, adverse event management, and potential use in extramedullary disease.

Can you describe the new FDA approval for iberdomide?

Sagar Lonial, MD, FACP, FASCO:
On August 13, 2026, accelerated approval was granted by the FDA for the CELMoD agent iberdomide plus daratumumab and hyaluronidase-fihj and dexamethasone for adults with MM who have received ≥1 prior line of therapy including a proteasome inhibitor and an immunomodulatory drug (IMiD). This approval was based on data from the phase III EXCALIBER-RRMM trial, in which patients with relapsed/refractory MM with prior 1-2 lines of therapy with progressive disease not refractory to bortezomib or anti-CD38 therapy were randomized to the iberdomide combination described above or daratumumab and hyaluronidase-fihj, bortezomib, and dexamethasone. This is the first FDA approval of a CELMoD agent.

Are CELMoD agents active against extramedullary disease?

Fredrik Schjesvold, MD, PhD:
Initially, I was cautious about the activity of CELMoD agents in extramedullary disease because early-phase signals do not always hold up in randomized studies. However, data from the phase III SUCCESSOR-2 study of the CELMoD agent mezigdomide plus carfilzomib plus dexamethasone were encouraging. Patients with plasmacytomas and other soft tissue disease appeared to derive benefit from this combination, with favorable progression-free survival HRs vs carfilzomib plus dexamethasone despite the traditionally poor outcomes associated with extramedullary MM. I think this is one of the clearest signals we have seen that mezigdomide may have meaningful activity in this population with difficult-to-treat disease.

Niels van de Donk, MD, PhD:
I agree. Extramedullary disease may respond to treatment, but responses are often brief. Seeing a progression-free survival benefit in SUCCESSOR-2 is clinically relevant and provides an important foundation for further investigation.

Sagar Lonial, MD, FACP, FASCO:
There may also be a pharmacologic explanation. When extramedullary lesions are biopsied, lenalidomide or pomalidomide may not be readily detectable within those lesions, whereas mezigdomide can be detected. Its structure may allow better penetration into plasmacytomas, potentially helping explain the activity we are seeing clinically.

Could CELMoD agents enhance immune activation when combined with CAR T-cell therapy or bispecific antibodies (BsAbs)?

Niels van de Donk, MD, PhD:
CELMoD agents are very interesting combination partners because their effects extend beyond direct anti-MM activity. Preclinical studies demonstrate increased T-cell activation, proliferation, and cytotoxic capacity vs IMiDs, which may improve the ability of BsAbs to eliminate MM cells. Several phase I studies are now evaluating BsAbs in combination with iberdomide or mezigdomide, and early combinations have produced promising response rates. The follow-up remains short, however, so we need to determine whether those responses translate into greater durability.

I think these combinations may be particularly relevant in daratumumab-refractory disease, where we still need effective immune-based combinations. Another intriguing strategy is using CELMoD agents after CAR T-cell therapy, particularly in patients with high-risk disease, to potentially deepen or maintain responses.

Fredrik Schjesvold, MD, PhD:
We have known for some time that CELMoD agents and IMiDs stimulate T-cells, but whether that immune activation translates into meaningful clinical benefit when these agents are combined with BsAbs remains an open question. The mechanism of resistance matters. If progression is primarily related to T-cell exhaustion or dysfunction, adding a CELMoD agent could be important. If progression results predominantly from target loss or downregulation, such as BCMA loss, restoring T-cell function may accomplish less. An interesting future strategy might be to use BsAbs for a shorter period and then maintain T-cell activity with a CELMoD agent, potentially reducing the challenges associated with prolonged BsAb therapy.

Sagar Lonial, MD, FACP, FASCO:
I think resistance to BsAbs can broadly reflect either impaired immune function or target loss. Clinically, I have seen patients progressing on BCMA- or GPRC5D-directed bispecific therapy recapture durable responses after adding an IMiD. That tells us that restoring immune function can matter, depending on the mechanism driving resistance.

Should or could CELMoD agents replace IMiDs?

Sagar Lonial, MD, FACP, FASCO:
One lesson we have learned repeatedly in MM is that our most effective drugs eventually move earlier in the treatment course and become part of combination therapy. CELMoD agents have the potential to follow that trajectory. Their greater potency and immune activation, together with potentially improved tolerability compared with traditional IMiDs, make the possibility of moving them earlier very compelling.

Fredrik Schjesvold, MD, PhD:
I think they should replace IMiDs. The remaining question is whether the clinical trials will establish that they can. Iberdomide appears more active and better tolerated than lenalidomide, whereas mezigdomide appears more potent than pomalidomide in relapsed disease. The clinical studies now need to confirm whether those advantages justify moving CELMoD agents into earlier treatment settings.

Niels van de Donk, MD, PhD:
Efficacy is only one part of this discussion. For our patients, long-term tolerability is extremely important. In the EMN26 maintenance study, prolonged iberdomide treatment was well tolerated. Aside from neutropenia, we saw relatively few grade ≥3 nonhematologic adverse events, including less diarrhea and fatigue, which are commonly associated with lenalidomide. If CELMoD agents can provide both greater efficacy and improved tolerability, that makes them particularly attractive for earlier-line and maintenance strategies.

What is the best way to manage neutropenia and other adverse events associated with CELMoD agents?

Sagar Lonial, MD, FACP, FASCO:
Neutropenia is an expected on-target effect of cereblon modulation and is particularly important during the first several treatment cycles when we are trying to achieve a deep response and marrow reserve may already be compromised by significant disease burden. My approach with mezigdomide has been to use granulocyte colony–stimulating factor (G-CSF) liberally early in treatment rather than immediately reducing the CELMoD agent dose. As patients respond and marrow function improves, growth factor support can often be reduced.

Fredrik Schjesvold, MD, PhD:
I strongly favor growth factor support over dose reduction for neutropenia because reducing the CELMoD agent dose may compromise efficacy. Dose reductions make more sense for toxicities such as fatigue or diarrhea. For neutropenia, I prefer pegylated G-CSF, which is convenient and reduces the number of injections patients require. Many patients need this support primarily during early treatment, although some continue to require it longer term.

The clinical context also matters. For aggressive disease, maintaining dose intensity may be particularly important, and I will continue growth factor support. In a more indolent situation, dose reduction may eventually become reasonable if ongoing G-CSF becomes burdensome for the patient.

Sagar Lonial, MD, FACP, FASCO:
The practical message is to support the marrow, particularly early in therapy. Patients with heavy marrow involvement may have limited myeloid reserve initially, but once disease burden falls, many no longer require the same degree of growth factor support.

Why is dexamethasone typically chosen as the first combination partner for CELMoD agents?

Sagar Lonial, MD, FACP, FASCO:
Cereblon-binding agents have substantial synergy with corticosteroids, and that is not unique to iberdomide or mezigdomide. Early studies showed that even among patients whose disease was considered dexamethasone-resistant, adding dexamethasone meaningfully increased the activity of CELMoD agent therapy. That provides a strong biologic and clinical rationale for using dexamethasone as an initial combination partner.

Fredrik Schjesvold, MD, PhD:
At the same time, more dexamethasone is not necessarily better. Across MM studies, dexamethasone frequently enhances efficacy when added to monotherapy, but trials evaluating reduced steroid doses have generally shown that lower doses can maintain—and sometimes improve—outcomes. My practical view is that dexamethasone is useful initially, but it is also often the first component we should reduce or discontinue when possible.

Niels van de Donk, MD, PhD:
I agree. I routinely reduce dexamethasone as treatment progresses and will ultimately discontinue it when patients achieve a deep response. The goal is to preserve the therapeutic contribution of the CELMoD agent-based regimen while minimizing the cumulative toxicity associated with prolonged corticosteroid exposure.

Your Thoughts
With the FDA approval of iberdomide, how will you integrate this CELMoD agent into your treatment armamentarium for MM? Please answer the polling question or leave a comment to join the discussion.

Continue to Activity

Poll

1.

With the FDA approval of iberdomide, how do you anticipate primarily incorporating this CELMoD agent into your treatment approach for patients with MM?

Submit