Will The FDA Approve Iberdomide in Relapsed/Refractory Multiple Myeloma?

The approval of iberdomide might expand the “tool belt” of novel drugs and combination approaches that may help advance towards a cure in multiple myeloma, according to Sagar Lonial, MD, FACP, FASCO.

In February 2026, the FDA accepted a new drug application(NDA) seeking approval for iberdomide, a cereblon E3 ligase modulator (CELMoD) agent, in combination with daratumumab (Darzalex) and dexamethasone for patients with relapsed/refractory multiple myeloma.¹ Previous significant minimal residual disease (MRD) negativity data from the phase 3 EXCALIBER-RRMM trial (NCT04975997) supported the application for the iberdomide-based treatment in this patient population.²

In a conversation with CancerNetwork^®, Lonial discussed what the potential FDA approval of the iberdomide regimen would mean for patients with relapsed/refractory multiple myeloma. Additionally, he highlighted the advantages that iberdomide and other CELMoD agents may provide compared with immunomodulatory drugs (IMiDs) and other previous standards of care. Amid the “era of immune therapy” in multiple myeloma, he described how the “unique” attributes of the CELMoD class may open the door for more effective combination strategies later down the line.

Lonial is a professor and chair of the Department of Hematology and Medical Oncology and the Anne and Bernard Gray Family Chair in Cancer at Emory University School of Medicine, and the chief medical officer at Winship Cancer Institute of Emory University.

CancerNetwork: As a CELMoD agent, what mechanistic advantages might iberdomide offer in relapsed/refractory multiple myeloma compared with other treatment modalities?

Lonial: The CELMoD category is a group of agents that, while they bind to the same target as the IMiD class—lenalidomide [Revlimid], pomalidomide [Pomalyst], and thalidomide [Thalomid]—they all bind to cereblon. Their impacts are quite different. There are 3 features that distinguish iberdomide from the previous IMiD category. The first is potency. They bind with a much higher potency than we saw with [the IMiDs], and that results in more rapid degradation of some of those downstream transcription factors. This leads to cell death, as opposed to growth arrest, which is what we typically see with pomalidomide, lenalidomide, and thalidomide.

The second is that their adverse event profile is better as well. Many of those adverse events that patients talk about with lenalidomide are predominantly gastrointestinal [GI] toxicity; with pomalidomide, it’s that swimmy head, or unclear thinking. It's not zero with iberdomide or mezigdomide, but it's significantly lower.

The third is that these agents were chosen because not only do they target the myeloma cell with high potency, but they also target the immune system and activate T-cells and NK cells far more effectively than the predecessors in the IMiD category. Those 3 things are the main advantages of the CELMoD category.

The NDA for iberdomide plus daratumumab and dexamethasone is supported by findings from the phase 3 EXCALIBER-RRMM study. What do current data show about the potential efficacy of iberdomide-based treatment in this population?

What we know about EXCALIBER-RRMM is [that it] met its primary endpoint. I don't know if we have additional information beyond that. What EXCALIBER-RRMM was testing was [iberdomide plus daratumumab/dexamethasone] vs [daratumumab plus bortezomib/dexamethasone]. An established standard vs a new standard using iberdomide. The experimental arm was taking advantage of that synergy between an immune-targeted agent and an immune-enhancing agent like iberdomide.

What is exciting though is that this is the first test case for using MRD as an early end point for approval. We know that the i2TEAMM, along with the International Myeloma Foundation [IMF] and other investigators from all over the world, put together the case that MRD testing, particularly at fixed time points, should be used for accelerated approval. The Oncologic Drugs Advisory Committee [ODAC] met about this over a year ago and unanimously supported that. Iberdomide in EXCALIBER-RRMM is going to be the first test case for that approval.³ [This is] very exciting.

How does the safety profile of iberdomide compare with other anti-myeloma therapies?

When we think about common IMiD-associated toxicity and adverse events, the grade 3/4 toxicity is what's different between the CELMoDs and the IMiDs. There is very little grade 3/4 non-hematologic toxicity. We do see hematologic toxicity: myelosuppression and occasionally anemia or thrombocytopenia. But those are on-target effects. You support those as best you would for somebody on any kind of treatment. It's really the non-hematologic adverse events, where the reduction in grade 3/4 events is so different.

If approved, what would the availability of the iberdomide-based combination mean for patients with relapsed/refractory multiple myeloma?

When we think about [iberdomide plus daratumumab/dexamethasone] in the early relapse therapy setting, as we know, it is a very crowded space. To me, what it does is offer patients choices. We certainly know that CAR T-cell data in this space looks good. We also know from [the phase 3 MajesTEC-3 trial (NCT05083169)] that teclistamab-cqyv [Tecvayli] and [daratumumab] also look good in this space.⁴ But [not all] patients have access to all those treatments, necessarily. Having a highly effective treatment, particularly one that uses, at least in part, an oral approach, is certainly very favorable from a patient convenience perspective.

To me, this [potential approval] opens the door to using iberdomide with other immune agents. At the 2025 American Society of Hematology Annual Meeting & Exposition (ASH), we saw iberdomide in combination with elranatamab-bcmm [Elrexfio] in the [phase 1 MagnetisMM-30 trial (NCT04649359)].⁵ We also saw mezigdomide, the other CELMoD, in combination with elranatamab in the [phase 1/2 MELT-MM study (NCT06645678)].⁶ The T-cell engagers are perfect partners for the CELMoD class, potentially used either before the collection of T cells for a CAR or as short-duration maintenance after a CAR as well. It’s opening the field for these agents down the road.

What other potential developments or advancements in the multiple myeloma field are you anticipating?

Certainly, the movement of the CELMoDs to earlier lines of therapy. We know that there are trials designed already looking at iberdomide as part of frontline triplets or quadruplets, as well as in the maintenance setting. There are a couple of trials that are looking at iberdomide maintenance, as well as a randomized phase 3 trial going head-to-head against lenalidomide.

This is the era of immune therapy in multiple myeloma, between bispecifics, CAR T-cell [therapies], trispecifics, and antibody drug conjugates. Figuring out how to continue to sustain the activity of the immune system in the face of all these immune therapies is going to be important. That's where I think the CELMoD class brings a unique attribute. In addition to its direct anti-myeloma effect, it makes immune therapy better, and it is a great partner for all these approaches.

What do you hope others take away from this conversation?

I've been an investigator with iberdomide for over 5 years now, and we've been very excited about its activity and its potential. Recognizing that we have agents that can reset or augment immunity and partnering them [are important]. People always want to say it's a black and white world; you're either going to use this, or you're going to use this. To me, it's about combination therapy. Recently, we had a meeting with the International Myeloma Society about defining cure in myeloma. What does that definition look like? Having this tool belt with many drugs and putting them together in combinations is how we get to that cure.

References

1. U.S. 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 March 3, 2026. https://tinyurl.com/4c8mb6ex
2. 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 March 3, 2026. https://tinyurl.com/5n9768k5
3. April 12, 2024 Meeting of the Oncologic Drugs Advisory Committee (ODAC). Streamed live April 12, 2024. Accessed March 3, 2026. https://tinyurl.com/2tbe3f4k
4. Costa LJ, Bahlis NJ, Perrot A, et al. Teclistamab plus daratumumab in relapsed or refractory multiple myeloma. N Engl J Med. 2026;394(8):739-752. doi:10.1056/NEJMoa2514663
5. Suvannasankha A, Kaufman J, Badros A, et al. Safety and efficacy of elranatamab in combination with iberdomide in patients with relapsed or refractory multiple myeloma: results from the phase 1b MagnetisMM-30 trial. Blood. 2025;146(suppl 1):100. doi:10.1182/blood-2025-100
6. Byun JM, Min C-K, Kim K, et al. Phase I/II study of mezigdomide and elranatamab for relapsed/refractory multiple myeloma patients (MELT-MM): initial results from part 1. Blood. 2025;146(suppl 1):5835. doi:10.1182/blood-2025-5835