FDA Approves First CELMoD Therapy, Offering a New Treatment Option for People Living With Multiple Myeloma

The decision marks a milestone for a new class of cereblon‑modulating protein degraders (CELMoDs), with full approval contingent on confirmatory trials that validate the regimen’s clinical benefit.

CELMoDs represent a next‑generation approach to immune‑modulating therapy, offering an oral option designed to overcome resistance seen with earlier immunomodulatory drugs (IMiDs).

As Dr. Paul Richardson, one of the world’s leading myeloma experts, who serves as director of clinical research at the Jerome Lipper Multiple Myeloma Center at the Dana-Farber Cancer Institute, explains, these agents “target the cereblon E3 ligase complex—essentially the cell’s protein‑disposal system,” a central switchboard in myeloma biology that makes CELMoDs uniquely positioned to reshape treatment in the relapsed setting.

“By blocking the cerebral E3 ligase complex and closing it, there’s targeted degradation of key survival factors in myeloma: Ikaros and Aiolos (zinc-finger transcription factors essential for plasma cell/myeloma cell survival),” Dr. Richardson added.

“By obliterating these transcription factors, which is essentially what mezigdomide does, and also its close cousin iberdomide, although mezigdomide does it the most, it triggers not only the death of the myeloma cell, but most importantly it brings together the immune system within the patient to finish off what is left behind,” Dr. Richardson explained further.

The approval of ZENBEXUS is supported by results from the Phase 3 EXCALIBER‑RRMM clinical trial, which compared the combination of ZENBEXUS, daratumumab, and hyaluronidase‑fihj, plus dexamethasone (ZDd) against daratumumab, bortezomib, and dexamethasone in patients with relapsed or refractory multiple myeloma (RRMM) who had previously received one or two prior lines of therapy.

“This is such an important advance. I mean, an oral therapy can be given in community practices in the Midwest, in suburban settings, and in urban settings. This is very, very important. So, I think FDA will be looking to move this very quickly to full approval, and I certainly hope so,” Dr. Richardson said.

What the Trial Data Revealed

In the Phase 3 EXCALIBER-RRMM trial, researchers followed patients for about a year and a half (16 months on average) to see how well the new combination treatment, ZENBEXUS, daratumumab, and hyaluronidase-fihj, plus dexamethasone (ZDd), worked compared with the standard treatment DVd.

They looked closely at minimal residual disease (MRD), a very sensitive test that checks whether any trace of cancer is still left in the body, even at levels too small to detect with standard tests. Reaching “MRD-negative” status means no cancer could be found, even using this highly sensitive test, and it’s one of the strongest signs that a treatment is working well and is considered predictive of improved progression-free survival (PFS).

The trial results:

• About 41 out of every 100 patients who received ZDd reached this deep level of response (MRD-negative, with no signs of disease on scans or bloodwork)
• About 21 out of every 100 patients who received the standard treatment, DVd, reached that same deep level of response

In simple terms, patients on the new combination were about twice as likely to reach this deep level of response compared with those on the standard treatment. This marks the first FDA approval in relapsed or refractory multiple myeloma based on an MRD-negative complete response, the drug manufacturer, Bristol Myers Squibb, said in a news release.

Understanding What Mezigdomide Does

Mezigdomide is another medication on the pipeline from the same class of CELMoDs. These medicines are designed to work similarly to lenalidomide while overcoming some of the resistance that can develop over time.

Mezigdomide can help the immune system keep recognizing and fighting myeloma cells even when older therapies no longer work as well as they once did.

Dr. Richardson previously explained to SurvivorNet that he likes to use a Star Wars example as a metaphor for how the drugs work.

“Do you remember ‘Return of the Jedi’ and the Death Star sitting off of that lovely planet with the Ewok? Well, you may remember Han Solo and Chewbacca shoot something right into the center of the Death Star, and it goes to pieces, and then all the Federation ships come in,” he explains.

“…That’s exactly what mezigdomide does. It nails the Death Star, and then all the Federation starships come in to finish off the bad guys.”

Better Understanding Multiple Myeloma

Multiple myeloma is a rare and incurable type of blood cancer. When you have this cancer, white blood cells called plasma cells (the cells that make antibodies to fight infections) in your bone marrow grow out of proportion to healthy cells.

Those abnormal cells leave less room for your body’s healthy blood cells to fight infections. They can also spread to other parts of your body and cause problems with organs like your kidneys.

WATCH: Recognizing multiple myeloma symptoms.

Known risk factors for multiple myeloma include your age, family history of cancer, and whether you have monoclonal gammopathy of undetermined significance (MGUS). MGUS is a condition that occurs when you have too much monoclonal protein in your blood and bone marrow.

Most people diagnosed are in their 60s. However, people younger than 60 can also get this type of cancer, and if you have a close relative with multiple myeloma, that can increase your risk.

Questions To Ask Your Doctor

• Is there a benefit to using mezigdomide? Mezi is not FDA-approved and is only accessible through clinical trials or EAP access, over something like CAR T-cell therapy?
• Should I consider enrolling in a clinical trial?
• What are the potential side effects of CELMoDs?
• How will I be monitored for recurrence?

Learn more about SurvivorNet's rigorous medical review process.

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