A new kind of protein-degrading cancer drug has entered the multiple myeloma treatment landscape. The FDA granted accelerated approval to iberdomide, sold as Zenbexus, in combination with daratumumab and hyaluronidase-fihj plus dexamethasone for adults with multiple myeloma who have received at least one previous line of therapy that included a proteasome inhibitor and an immunomodulatory drug.
On September 25, investigators presented the first Phase 3 results from EXCALIBER-RRMM at the International Myeloma Society meeting, with the results published simultaneously in The Lancet Oncology. The iberdomide regimen produced an MRD-negative complete response in about 41% of patients in the primary analysis, compared with about 21% with a bortezomib-based comparator. The result is important, but it also comes with a major qualification: progression-free survival and overall survival data are not yet mature enough to establish whether the deeper responses translate into longer disease control or longer life.
What exactly did the FDA approve?
Multiple myeloma is a cancer of plasma cells, antibody-producing immune cells that normally live in the bone marrow. In myeloma, abnormal plasma cells expand and can crowd out healthy blood-forming cells, damage bone and produce abnormal proteins.
The new approval is not for iberdomide alone. It covers a three-drug regimen: oral iberdomide plus subcutaneous daratumumab and hyaluronidase-fihj, together with dexamethasone. Eligible adults must have received at least one previous line of therapy that included both a proteasome inhibitor and an immunomodulatory agent.
The recommended iberdomide dose is 1 mg once daily on days 1 through 21 of each 28-day cycle. Treatment continues until disease progression or unacceptable toxicity.
The Phase 3 result behind the approval
EXCALIBER-RRMM is an ongoing randomized, open-label Phase 3 trial in adults with relapsed or refractory multiple myeloma who had received one or two previous lines of therapy. Across its two stages, 939 patients were randomized. The FDA’s primary efficacy analysis used the first 420 patients assigned to either the selected 1 mg iberdomide regimen or the comparator regimen.
Patients received iberdomide, daratumumab and dexamethasone, often abbreviated IberDd, or daratumumab, bortezomib and dexamethasone, known as DVd. At a median follow-up of 15.7 months in the primary analysis, MRD-negative complete response was achieved by 41.1% of patients receiving IberDd and 20.7% receiving DVd. The odds ratio was 2.75, and the difference was statistically significant.
That is a substantial difference in depth of response. But “MRD-negative” needs careful interpretation.
What does MRD-negative complete response mean?
A complete response means conventional tests no longer detect the usual signs used to measure multiple myeloma. Minimal, or measurable, residual disease testing goes further. It uses highly sensitive methods to search for very small numbers of cancer cells that can remain after treatment.
In EXCALIBER-RRMM, MRD was assessed by next-generation flow cytometry at a sensitivity of 10-5, meaning the assay was designed to detect roughly one myeloma cell among 100,000 cells. An MRD-negative complete response therefore represents a particularly deep treatment response. It does not prove that every cancer cell has been eliminated or that the disease is cured.
The FDA has been developing a framework for using MRD-negative complete response as an endpoint that can support accelerated approval in multiple myeloma. The advantage is speed: waiting for enough patients to experience disease progression or death can take considerably longer.
The trade-off is uncertainty. A surrogate endpoint is expected to predict clinical benefit, but it is not itself direct evidence that patients live longer or remain progression-free longer. That is why the FDA lists Zenbexus as an ongoing accelerated approval and requires continued evaluation of progression-free survival, with overall survival and overall response rate among the confirmatory outcomes.
How iberdomide turns the cell’s disposal machinery against myeloma
The most interesting part of iberdomide is its mechanism. Iberdomide belongs to a class called cereblon E3 ligase modulators, or CELMoDs. To understand the name, it helps to think of the cell as having a controlled waste-disposal system for proteins.
Proteins that are no longer needed can be tagged with a small molecule called ubiquitin. Chains of ubiquitin act like a disposal label, directing the tagged protein to the proteasome, a molecular machine that breaks proteins down. E3 ubiquitin ligases help decide which proteins receive that tag.
Iberdomide binds cereblon, the substrate-recognition component of one such E3 ligase complex. That interaction changes which proteins the complex recognizes. Two important targets are the transcription factors Ikaros, also called IKZF1, and Aiolos, or IKZF3. Iberdomide promotes their ubiquitination and subsequent destruction by the proteasome.
Removing Ikaros and Aiolos changes gene regulation inside myeloma and immune cells. Experimental work has linked this degradation to direct anti-myeloma activity and immune stimulation, including changes in T-cell signaling. It is a form of targeted protein degradation: rather than simply blocking the activity of a protein, the drug recruits the cell’s own machinery to remove selected proteins.
This broader idea, exploiting specific molecular vulnerabilities rather than treating every tumor the same way, is also central to newer targeted approaches such as the KRAS inhibitors being developed for pancreatic cancer.
How is a CELMoD different from older immunomodulatory drugs?
Iberdomide did not emerge from nowhere. Multiple myeloma has long been treated with immunomodulatory drugs such as lenalidomide and pomalidomide, which also act through cereblon and promote degradation of Ikaros and Aiolos.
CELMoDs were designed to interact with cereblon more strongly and drive deeper, more efficient degradation of these substrates. Preclinical studies found that iberdomide remained active in some myeloma models resistant to lenalidomide or pomalidomide, including models with altered cereblon biology. Those laboratory findings helped motivate clinical development, but they should not be interpreted to mean iberdomide overcomes every form of resistance in patients.
The distinction matters because many patients entering later lines of myeloma therapy have already been exposed to an immunomodulatory agent. In the FDA’s primary efficacy population, about 90% had previously received an immunomodulatory drug, including 70% who had received lenalidomide.
Why combine iberdomide with daratumumab?
Daratumumab is an antibody directed against CD38, a protein highly expressed on myeloma cells. The combination therefore attacks the disease through different biological routes: daratumumab helps target CD38-positive cells, while iberdomide alters cereblon-dependent protein degradation and immune signaling.
The comparator in EXCALIBER-RRMM also contained daratumumab, but paired it with the proteasome inhibitor bortezomib rather than iberdomide. That design makes the difference in MRD-negative complete response particularly informative because both groups received daratumumab and dexamethasone.
There are limits to who was represented, however. Patients whose disease was refractory to previous anti-CD38 antibody therapy or refractory to bortezomib were excluded. The FDA label specifically notes that data are limited for patients previously treated with or refractory to anti-CD38 therapy.
The safety trade-offs are substantial
The deeper response came with significant hematologic and infectious toxicity. In the safety population receiving the approved iberdomide combination, neutropenia occurred in 90.2% of patients. Grade 3 neutropenia occurred in 30.9% and Grade 4 neutropenia in 53.4%. Febrile neutropenia occurred in 5.4%.
Infections were also common. The prescribing information reports infections in 78.9% of patients, with serious infections in 40% and fatal infections in 2%. Pneumonia was among the most frequent serious adverse reactions.
Zenbexus carries boxed warnings for embryo-fetal toxicity and serious venous and arterial thromboembolism. Because of the embryo-fetal risk, the drug is available only through a restricted Risk Evaluation and Mitigation Strategy, or REMS, program. The label also warns about secondary primary malignancies.
These risks are a reminder that a higher response rate does not automatically make a regimen appropriate for every patient. Treatment decisions in relapsed multiple myeloma depend on previous therapies, resistance patterns, comorbidities, infection risk and other individual factors.
What we still do not know
The biggest unanswered question is whether the deeper MRD responses translate into better long-term outcomes. Progression-free survival is the other primary endpoint of EXCALIBER-RRMM, but those results are not yet mature. Overall survival also remains under evaluation.
That distinction is especially important because this is an accelerated approval. The FDA can allow earlier access to therapies for serious diseases based on endpoints reasonably likely to predict clinical benefit, while requiring additional evidence afterward. For Zenbexus, the FDA’s ongoing accelerated-approval database lists completion of the randomized trial, with progression-free survival as the primary confirmatory endpoint and overall survival and overall response rate as secondary endpoints.
So the September Phase 3 presentation strengthens the evidence that iberdomide can drive unusually deep responses in previously treated multiple myeloma. It does not yet answer the longer-term question patients care about most: how much longer the disease can be controlled, and whether that ultimately extends survival.
Why this approval matters beyond one drug
Iberdomide’s approval is notable not only because another treatment option has reached patients with relapsed multiple myeloma. It is the first FDA approval of a CELMoD, bringing a deliberately engineered form of cereblon-directed protein degradation into routine cancer treatment.
That makes the drug a useful example of where modern pharmacology is heading. Instead of only searching for molecules that block enzymes or receptors, researchers are increasingly learning how to redirect the cell’s own protein-control systems. Iberdomide shows that the concept can move from molecular biology to a randomized Phase 3 trial and an FDA approval.
The next test is more clinical than molecular: whether the impressive depth of response seen so far translates into durable benefit as EXCALIBER-RRMM continues.
References
- U.S. Food and Drug Administration. FDA grants accelerated approval to iberdomide with daratumumab and hyaluronidase-fihj and dexamethasone for multiple myeloma. August 13, 2026. FDA approval announcement.
- Lonial S, Dimopoulos MA, Gavriatopoulou M, et al. Iberdomide plus daratumumab and dexamethasone versus daratumumab, bortezomib, and dexamethasone in patients with relapsed or refractory multiple myeloma (EXCALIBER-RRMM): an open-label, randomised, controlled, phase 3 trial. Lancet Oncology. Published online September 25, 2026. doi:10.1016/S1470-2045(26)00450-X.
- U.S. Food and Drug Administration. Zenbexus (iberdomide) prescribing information. 2026. Prescribing information.
- Bjorklund CC, Kang J, Amatangelo M, et al. Iberdomide (CC-220) is a potent cereblon E3 ligase modulator with antitumor and immunostimulatory activities in lenalidomide- and pomalidomide-resistant multiple myeloma cells with dysregulated CRBN. Leukemia. 2020;34:1197-1201. doi:10.1038/s41375-019-0620-8.