How Will Iberdomide’s Approval and Other CELMoDs Impact Multiple Myeloma?

CancerNetwork® spoke with Surbhi Sidana, MD, an associate professor of medicine at Stanford University, where she leads the myeloma cellular immunotherapy program and chairs the American Society of Hematology (ASH) Committee on Communications, about the FDA’s accelerated approval of iberdomide (Zenbexus) plus daratumumab and hyaluronidase-fihj (Darzalex Faspro) and dexamethasone for patients with relapsed/refractory multiple myeloma.¹ The approval marks the first based on a minimal residual disease (MRD) end point in multiple myeloma, as well as the first for any CELMoD, a drug class that Sidana described as more potent, more target-specific successors to immunomodulatory drugs (IMiDs) such as lenalidomide (Revlimid) and pomalidomide (Pomalyst). The decision was supported by the phase 3 EXCALIBER-RRMM trial (NCT04975997), which enrolled patients with 1 to 2 prior lines of therapy and randomly assigned them to iberdomide plus daratumumab/dexamethasone or daratumumab plus bortezomib (Velcade) and dexamethasone (DVd).²

Sidana discussed what the approval means for patients, how the combination fits into current treatment sequencing, its boxed warning and REMS requirements, and how its toxicity profile compares with older IMiDs. She also touched upon how CELMoDs differ mechanistically from IMiDs, where CELMoDs may fit alongside CAR T-cell agents and bispecific antibody therapy, and where the field is headed.

CancerNetwork: What does this accelerated approval of iberdomide-based treatment mean for patients with relapsed/refractory multiple myeloma?

Sidana: This approval is a landmark approval for several reasons, the first of which is it’s our first approval in multiple myeloma based on an MRD end point. MRD, or measurable residual disease, or minimal residual disease, is looking at myeloma plasma cells at very low levels: 1 in 100,000 or 1 in a million. [In 2024], we heard from the FDA, based on the recommendations of the Oncologic Drugs Advisory Committee (ODAC), that they were open to using MRD as an end point for drug approval.³ This was years in the making. A lot of effort from academic myeloma practice, our industry sponsors, organizations that work in myeloma like the International Myeloma Foundation, and several ASH members. We got together, got the data that MRD is a surrogate for survival outcomes, and the FDA accepted it. This is the first approval based on that. Drug agnostic, it’s historic for our field in general, because progression-free survival [PFS] now takes several years. We can’t wait several years to get these drugs into our patients’ hands. We want to get them to our patients early, and so this is a trailblazer in that sense.

Coming back to iberdomide, having that as an option, which is an oral drug and easy to give, is tremendous for our patients. Iberdomide is a CELMoD, which for those who are familiar with myeloma practice, I think of as IMiDs, but better: 2.0. They’re oral, they have a REMS program, which we can talk about that’s very similar, and they’re given on a very similar schedule, but they’re more targeted, which means more target specific [with fewer] adverse effects [AEs].

EXCALIBER-RRMM enrolled patients with 1 to 2 prior lines. Where does this combination fit in your current sequencing for relapsed/refractory myeloma, particularly relative to other daratumumab-based or triplet regimens already available in that setting?

Just to summarize, EXCALIBER-RRMM, allowed 1 to 2 prior lines of therapy for these relapsed patients.² The majority were enrolled after 1 prior line of therapy; that was two-thirds of the patients. A third had 2 prior lines. They could not be daratumumab refractory or bortezomib refractory because they were randomly assigned to either iberdomide plus daratumumab/dexamethasone or DVd, and only 5% of the patient population was daratumumab exposed, which is a little different than the way we practice right now; we are using daratumumab in the upfront setting. That’s something for us to keep in mind.

Having said that, iberdomide is now approved after 1 prior line of therapy. It’s approved in combination with daratumumab, but of course, in clinical practice in the US, we often use things off label, so I expect it may be combined with other drugs. There’s a very long track record of combining IMiDs with other drugs like proteasome inhibitors and so on.

Now, where do I see it in my practice? We have a plethora of options for first relapse, which is great news for our patients. We have CAR T cells and bispecific antibodies with the recent approval of teclistamab-tgvs [Tecvayli]/daratumumab, so that’s the immunotherapy.⁴ We have belantamab mafodotin-blmf [Blenrep]–based combinations for early relapse, we now have iberdomide, and we already had daratumumab plus pomalidomide/dexamethasone and carfilzomib [Kyprolis]–based combinations. The good news: we have an option that suits every patient. The challenging news: how do you decide?

For patients who can get immunotherapy, CAR T or bispecific, that’s a higher response rate and a higher MRD-negativity rate; that’s a great option. But many of our patients don’t live close to centers because CAR T and bispecifics are given at academic centers; they live in the community, get treatment in the community, and may not be able to relocate for many reasons. For those patients, especially those who are older or frailer, or who cannot go to a center that offers immunotherapy, this offers a very convenient option that can be given at every oncologist’s office, not just very expert centers with lots of logistical requirements.

I’m at an academic center, so I can offer all these therapies. For CAR T, there’s a period of time between manufacturing, apheresis, and infusion; that’s the bridging period. We need to give patients something to bring their disease burden down because we know bringing disease burden down leads to safer CAR T, fewer AEs, and more effectiveness in the long term. This can be a great bridging regimen, which can be given in partnership with our community oncologists. This is also being investigated in combination with bispecifics, although those trials aren’t done yet. In the future, we might even be able to combine it with bispecifics.

Because we have so many immunotherapy options, this is also a great sandwich approach. What if someone started teclistamab closer to home, and now their T cells are exhausted? You want to get them to CAR T. There are encouraging data from small trials that this might be able to rejuvenate, or revive, the CAR T cells. We may be able to sandwich this approach between 2 immunotherapies.

For some patients, if they need maintenance after CAR T…because they’re high risk or don’t have an MRD-negative complete response, this can be an excellent drug. In fact, we’re developing a trial through Stanford using iberdomide as maintenance. There are many approaches because it’s such a flexible drug to combine with different strategies.

Iberdomide carries a boxed warning for embryo-fetal toxicity and thromboembolism, and it is only available through a REMS program. How does that REMS requirement change counseling and logistics compared with existing IMiD-based regimens you’re already managing REMS for?

You bring up an excellent point: the REMS program requirement that comes with iberdomide, along with the thromboembolism risk. The good news is we’ve been doing this for 20 years for lenalidomide and pomalidomide. It’s the same manufacturer, so I expect the REMS program will be very similar. The patient needs to enroll in the REMS program with monthly questionnaires; the doctors need to enroll as well. Because we’re so used to doing this and have processes in place, and it’s the same manufacturer, I honestly don’t think this will be a practical concern at all for access to these drugs.

We know there’s an increased risk of thrombosis. Most patients just get aspirin. If you’re combining iberdomide in high-risk patients with other regimens that can increase risk of thrombosis, like carfilzomib, or if someone has other risk factors, we’ll often give a DOAC [direct oral anticoagulant]. This is, again, something we’re very used to doing in our clinical practice.

How does the toxicity profile of iberdomide-based treatment compare to what you’ve seen with pomalidomide- or lenalidomide-based combinations?

CELMoDs are more target specific, so they have less off-target toxicity. I will say you might see less fatigue and less diarrhea with iberdomide than with lenalidomide, which becomes a challenge for our patients who are on lenalidomide for years. After a year of being on it, they often have fatigue, brain fog, and some low-grade diarrhea. There’s less of a signal for that with iberdomide.

Some of the AEs are very similar, especially neutropenia; a majority of patients will get severe neutropenia with iberdomide. It is something to watch out for. Most of this happens in the first 2 or 3 cycles, so when that happens, hold the drug and give G-CSF. It settles down over time, but that’s something to be aware of. There’s also an infection signal, with both upper and lower respiratory tract infections, including severe infections, being common. It is something to be aware of, though we’re very used to managing this with our patients with multiple myeloma.

There’s very little neuropathy; we see some of that as a class effect even, but much less than the control arm of the trial, which included bortezomib-based treatment.

This is the first FDA approval for any CELMoD. How would you explain to a community oncologist what distinguishes a CELMoD from an IMiD like lenalidomide or pomalidomide beyond just being “more potent”?

For practical purposes, IMiD and CELMoD administration is very similar. We talked about it being an oral drug given on a 3-week-on, 1-week-off schedule in this trial. Some of the toxicities are very similar, too: low blood counts and an increased risk of blood clots, [which are] very familiar. The REMS program is also very similar to what’s in place for lenalidomide and pomalidomide, so there’s a lot of familiarity there, which is helpful for our community partners because they’re dealing with so many drugs and so many diseases; familiarity helps.

The advantages here are that CELMoDs are more potent and more specific, so there’s fewer off-target AEs, less diarrhea, and less fatigue with iberdomide compared with what we might see in clinical trials with lenalidomide, so it’s easier to tolerate, but still a very convenient oral drug.⁵ It’s a very similar practice for community oncologists to develop for administering this.

Given your own focus on CAR T-cell therapy and bispecifics, where do you see CELMoDs fitting relative to T-cell–redirecting therapies? Do you see it as a bridge, a post-relapse option, a combination partner to boost immune effects, or fulfilling another role?

Where do we see the role of this in academic centers, in a practice like mine, where we’re giving CAR T and bispecifics that have very high MRD-negative rates? It’s a complement. It’s available in the community for patients who can’t travel or come here, but for [patients who receive] CAR T, if I do CAR T as their first relapse, they need bridging; they can get this as bridging therapy for the 2 or 3 months while we want them to get a response.

Then, in some patients where we want to give maintenance [therapy], and we’re studying that in clinical trials, it’s becoming more commonplace. If they’re still MRD positive after CAR T, we know these patients don’t do well; if they’re functionally high risk or have extramedullary disease [EMD], we know they won’t get years [of benefit]. We want to give them some easy maintenance that doesn’t require coming back for injections or infusions. [CELMoDs] can play a very complementary role.

Then, post-relapse, it’s a great option. Just a couple of days ago, I had a patient who was relapsing and had everything under the sun. Before this approval, that would have been a very difficult conversation; they’d had all CAR T and bispecifics and weren’t eligible for a trial. I said, “Guess what, we have a new drug you might be eligible for that’s oral.” This is [also] an older patient, so this brings hope as a relapse option as well.

While patients get a lot of durable disease control, many still relapse. [It is a] relapse option, maintenance option, and bridging option. As we sequence these immunotherapies between bispecifics and CAR T, if someone got a bispecific first, we have concerns about T-cell exhaustion. We know these CELMoDs can reverse T-cell exhaustion to a level, so we can perhaps put someone on one of these CELMoDs, iberdomide right now, give them 2 or 3 months of it, get myeloma control, and then manufacture for CAR T. Those clinical trials are also ongoing. Even in academic practice, where we’re using CAR T and bispecifics, CELMoDs have a huge role to play. Of course, they’re also being tested in combination with bispecifics.

Looking ahead, do you think CELMoDs will eventually move into earlier lines, including maintenance or newly diagnosed settings, and what data would you want to see first?

Just like with every drug that is first tested in late relapse and early relapse, this will eventually move to the front line. Those clinical trials are already ongoing. You mentioned maintenance—lenalidomide maintenance is our standard of care after stem cell transplant. There’s a large, randomized trial ongoing looking at iberdomide vs lenalidomide maintenance. The challenge with lenalidomide maintenance is tolerability; patients get diarrhea, as I mentioned, and fatigue, so it becomes a little more challenging the longer they’re on it. If you have a drug that’s more tolerable, of course you want to see the data, but if that trial truly shows it’s more tolerable and perhaps more effective, or even just as effective, it becomes a great option for maintenance treatment. There are also trials ongoing to integrate it into combination approaches for the newly diagnosed setting.

Was there anything else you wanted to discuss?

I want to make you aware of an initiative with ASH. We’re fortunate to have all of these approvals for CAR T, bispecifics, and CELMoDs, but a lot of these approvals started 10 or 20 years ago, with someone working on the bench for research that didn’t clearly have a path to approval at that time. It takes a long time, so we need to continue investing in research funding and NIH funding. This is a very topical issue for our time; every few months we’re talking about NIH budget cuts.

ASH has an initiative called Fight4Hematology.⁶ ASH members and hematologists are advocating to our legislators and making the public aware of how important it is to continue funding blood disorder research and hematology research so we can have all of these new approvals for our patients.

References

1. FDA grants accelerated approval to iberdomide with daratumumab and hyaluronidase-fihj and dexamethasone for multiple myeloma. News release. FDA. August 13, 2026. Accessed August 25, 2026. https://tinyurl.com/38258auk
2. 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 August 25, 2026. https://tinyurl.com/mstweynn
3. April 12, 2024 Meeting of the Oncologic Drugs Advisory Committee (ODAC). Streamed live April 12, 2024. Accessed August 25, 2026. https://tinyurl.com/2tbe3f4k
4. FDA grants third approval under the National Priority Voucher Program. News release. FDA. March 5, 2026. Accessed August 25, 2026. https://tinyurl.com/45hhbpau
5. van de Donk NWCJ, Bahlis NJ, Pawlyn C, et al. The role of CELMoD agents in multiple myeloma. Onco Targets Ther. 2025;18:921-933. doi:10.2147/OTT.S398118
6. #Fight4Hematology Action Hub. American Society of Hematology. Accessed August 25, 2026. https://tinyurl.com/ms94frk9