Can Mezigdomide Help Elranatamab Work Better? Early Results From the MELT-MM Trial

A small, early study suggests that combining two myeloma drugs, elranatamab (Elrexfio, Pfizer) and mezigdomide (BMS), may produce deep responses in people whose myeloma has come back after several treatments. The results were presented at the 23rd International Myeloma Society (IMS) Annual Meeting by Dr. Ja Min Byun of Seoul National University Hospital in Seoul, South Korea. Only 13 patients were treated so far, so these findings are promising but preliminary.

What problem is the MELT-MM study trying to solve?

T-cell engagers have changed treatment for relapsed and refractory multiple myeloma. Relapsed means the myeloma came back after treatment. Refractory means the myeloma stopped responding to a treatment. T-cell engagers, also called bispecific antibodies, are drugs that grab onto a myeloma cell with one arm and a T-cell with the other. T-cells are immune cells that can find and kill cancer cells. By bringing the two together, the drug helps the immune system attack the myeloma.

These drugs work well, but they don't cure myeloma, especially when used alone. One reason is T-cell exhaustion. When T-cells are kept "switched on" for a long time, they can wear out and stop fighting as well. Over time, this can let the myeloma grow again. The researchers also noted that a large amount of myeloma in the body can make these drugs less effective.

What are the two drugs being studied?

Elranatamab is an approved T-cell engager. It targets B-cell maturation antigen (BCMA), a protein found on the surface of myeloma cells, and CD3, a protein on T-cells. It is given as a shot under the skin.

Mezigdomide is an investigational treatment. Investigational means it is still being studied and is not yet approved by the U.S. Food and Drug Administration (FDA). Mezigdomide belongs to a newer class of drugs called cereblon E3 ligase modulators (CELMoDs). CELMoDs are related to familiar drugs like lenalidomide (Revlimid, Bristol Myers Squibb) but are designed to be more powerful. They work by breaking down two proteins, called Ikaros and Aiolos, that myeloma cells need to survive. Breaking down these proteins also boosts the immune system.

In July 2026, the FDA accepted an application to review mezigdomide in a different combination, with carfilzomib and dexamethasone. The FDA's target date for a decision is May 13, 2027. The combination with elranatamab described in this article is not approved and is being studied only in clinical trials.

Why combine mezigdomide and elrantamab?

The researchers believed mezigdomide could do more than attack myeloma directly. Based on lab research, they thought it might also help "refresh" T-cells and prevent or reverse the exhaustion that elranatamab can cause. If that works, patients might get deeper responses that last longer.

How was the study designed?

MELT-MM (NCT06645678) is a phase 1/2 clinical trial being run in South Korea and Singapore. It has two parts:

• Part 1, reported here, was a phase 1 safety study. Its main goal was to see how well people tolerated the combination and to find the right dose of mezigdomide for the next part. This is called the recommended phase 2 dose (RP2D).

• Part 2 is a larger expansion study that is now enrolling patients.

Part 1 used a common approach called a "3+3" design. Groups of three patients (sometimes expanded to six) receive a dose, and doctors watch closely for serious side effects before moving to a higher dose.

To join, patients needed to have:

• Relapsed or refractory multiple myeloma after at least two prior lines of therapy, including a proteasome inhibitor (such as bortezomib or carfilzomib) and lenalidomide

• No prior treatment that targeted BCMA

• Be able to care for themselves and up and about more than half the day (ECOG performance status of 0 to 2)

• Measurable disease

How was the treatment given?

Treatment started with a lead-in period, called Cycle 0. During this cycle, patients received only elranatamab. Doses were gradually increased over the first week. This "step-up dosing" helps lower the risk of a side effect called cytokine release syndrome (CRS), described below.

After that, treatment was given in 28-day cycles:

• Elranatamab was given once a week for cycles 1 to 6. Patients with a good response could then move to every two weeks, and later to once a month.

• Mezigdomide was taken by mouth on days 1 to 21 of each cycle, followed by a week off. Patients received either 0.3 mg or 0.6 mg.

All patients also received medicines to help prevent infections. They also received growth factor support, which are shots that help the body make more white blood cells. Patients whose antibody levels dropped too low received intravenous immunoglobulin (IVIG), an infusion of antibodies from donated blood that helps protect against infection.

Who took part?

Fifteen patients enrolled between December 2024 and October 2025. Two did not receive mezigdomide, so 13 patients were included in the results. Seven received 0.3 mg of mezigdomide and six received 0.6 mg.

• The median age was 69, ranging from 51 to 76.

• Patients had received a median of four prior lines of therapy, with a range of two to seven. The median is the middle value. This means half had received less than four lines of therapy and half had received more.

• About half had been treated with an anti-CD38 antibody, such as daratumumab.

• Four patients had already received a T-cell engager that did not target BCMA.

• About 3 in 10 had extramedullary disease, which means myeloma growing outside the bone marrow, such as in soft tissue.

What were the results?

The data were collected through July 31, 2026*. Patients had been followed for a median of about 13.7 months after starting treatment.

• Every patient responded. All 13 patients (100%) had a response. This means the amount of myeloma protein in their blood or urine dropped. 

• Most responses were very deep. Twelve of 13 patients (92.3%) reached a stringent complete response (sCR). This means no signs of myeloma could be found on standard blood, urine, and bone marrow tests, plus additional lab checks. The remaining patient had a very good partial response (VGPR), meaning the myeloma decreased by at least 90%.

• Many patients were MRD negative. Minimal residual disease (MRD) testing looks for tiny amounts of myeloma that standard tests can miss. MRD data were available for 11 patients. Of those, 10 (90.9%) were MRD negative. That means fewer than 1 myeloma cell was found in every 100,000 cells tested.

• Responses came quickly. The median time to a first response was 17 days. The median time to reach each patient's best response was about 5.6 months.

• Responses have held so far. At the time of the data cutoff, all patients were still responding. Because of this, the researchers could not yet calculate how long responses last. The median progression-free survival, or the time before the myeloma gets worse, has not yet been reached.

Responses looked similar at both mezigdomide doses. They were also similar across groups of patients, including those who had received a T-cell engager before, those with triple-class or penta-refractory myeloma, and those with extramedullary disease in soft tissue. However, each of these groups included only a handful of patients, so these comparisons should be seen as early signals.

* This article includes updated data presented at IMS that are not included in the abstract.

What side effects did patients have?

Every patient had at least one side effect that doctors considered related to treatment, and every patient had at least one serious (grade 3 or 4) side effect. Side effects are graded from 1 (mild) to 5, with grades 3 and 4 being severe or potentially life-threatening.

Blood count side effects

• Low white blood cell counts (neutropenia): 11 of 13 patients (84.6%), all grade 3 or 4. Neutrophils are white blood cells that fight infection. According to the researchers, low counts were short-lived and managed with growth factor support.

• Low platelet counts (thrombocytopenia): 7 of 13 patients (53.8%), all grade 3 or 4. Platelets are cells that help blood clot.

• No patients had febrile neutropenia, which is a fever when white blood cell counts are low and can be a medical emergency.

Immune-related side effects

• Cytokine release syndrome (CRS) happened in 10 of 13 patients (76.9%). CRS is a reaction that can happen when the immune system is strongly activated and releases a flood of inflammatory proteins called cytokines. It can cause fever, chills, low blood pressure, and trouble breathing. In this study, all CRS was mild to moderate (grade 1 or 2). No one had grade 3 or higher CRS.

• No cases of immune effector cell-associated neurotoxicity syndrome (ICANS) were seen. ICANS is a side effect of some immune therapies that affects the nervous system and can cause confusion, trouble speaking, or seizures.

Other common side effects

• Tiredness or weakness: 84.6%, mostly mild (one patient had grade 3)

• Decreased appetite: 53.8%

• Nausea: 38.5%

• Higher levels of liver enzymes on blood tests: 38.5%, including 3 patients with grade 3 or 4

• Fever: 38.5%

• Skin rash: 30.8%

• Joint or bone pain: 30.8%

Two dose-limiting toxicities occurred in the 0.6 mg group. A dose-limiting toxicity is a side effect serious enough that it can limit how high a dose can safely go. One patient had severe low platelets (grade 4) and one had a sudden drop in kidney function (grade 3 acute kidney injury). Both improved.

When asked about stopping treatment, Dr. Byun said patients generally paused treatment when needed and recovered after about a week off. She said she did not have exact numbers on hand for how many people stopped treatment permanently.

Infections

Infections are a known concern with BCMA-targeted treatments, which can weaken the immune system. Six of 13 patients (46.2%) had an infection, and four of those were serious (grade 3 or higher).

• Lung and lower airway infections, including pneumonia, were the most common (4 patients).

• Two patients developed cytomegalovirus (CMV) retinitis. CMV is a common virus that usually causes no problems in healthy people but can cause serious illness when the immune system is weakened. Retinitis is an infection of the retina, the light-sensing layer at the back of the eye. It can damage vision, so patients should tell their care team right away about eye changes such as blurry vision, floaters or blind spots.

• One patient had influenza A (the flu) and one had a fungal infection.

What did the lab studies show?

The researchers also studied blood samples from all 13 patients to understand how the two drugs work together. After mezigdomide was added, they saw signs that patients' T-cells were healthier and more active:

• More T-cells were actively multiplying, a sign they were ready to fight.

• There were fewer worn-out, late-stage T-cells.

• There was less of PD-1 and TIGIT, two "brake" proteins on T-cells that are signs of exhaustion.

• Levels of interferon gamma, a protein T-cells release when attacking cancer, went up.

Interestingly, these signs of stronger immune activity did not come with a similar rise in the inflammatory markers linked to CRS. The researchers said this may explain why no severe CRS was seen. This lab work suggests mezigdomide may help "recharge" T-cells, but more research is needed to confirm what it means for patients over time.

What happens next?

Because the two doses worked similarly, the researchers chose both 0.3 mg and 0.6 mg of mezigdomide to study further. Part 2 of MELT-MM will randomly assign patients to one of the two doses. About 34 patients are planned for each group. Patients will be grouped by frailty, using a tool from the International Myeloma Working Group (IMWG), to make the comparison fair. The researchers also adjusted the elranatamab schedule for Part 2 based on what they learned in Part 1. After 24 cycles of the combination, patients will continue taking mezigdomide alone until their myeloma progresses.

Dr. Byun said the dose results likely reflected differences among patients rather than the dose itself, which is part of why a randomized comparison is the next step.

What does this mean for patients?

These early results are encouraging. Every patient in this small group responded, most very deeply, and there was no severe CRS. Still, it is important to keep them in perspective:

• Only 13 patients were treated, and there was no comparison group.

• Follow-up is just over a year, so it is not yet known how long responses will last.

• Serious side effects, especially low blood counts and infections, were common.

• The combination is investigational and available only through clinical trials.

Larger studies, including Part 2 of MELT-MM, will help show whether these results hold up in more patients.

Talk to your care team

If you have relapsed or refractory multiple myeloma, ask your care team whether a clinical trial like MELT-MM might be an option for you. While phase 2 of MELT-MM is currently recruiting new patients in South Korea and Singapore, another clinical trial is currently recruiting for this same combination at multiple locations worldwide (NCT06988488). They can help you weigh the possible benefits and risks based on your own health and treatment history. Never start, stop, or change a treatment without talking to your doctor first.

Sources:

• Byun JM, Cho H, Min CK, et al. Phase I/II Study of Mezigdomide and Elranatamab for Relapsed/Refractory Multiple Myeloma Patients (MELT-MM): Updated Results From Part 1. Abstract and oral presentation, 23rd International Myeloma Society Annual Meeting, 2026.

• Byun JM, Min CK, 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. November 3, 2025: https://doi.org/10.1182/blood-2025-5835  

• MELT-MM trial listing (NCT06645678), ClinicalTrials.gov: https://clinicaltrials.gov/study/NCT06645678

• Bristol Myers Squibb. U.S. Food and Drug Administration Accepts Bristol Myers Squibb's New Drug Application for Mezigdomide in Patients with Relapsed or Refractory Multiple Myeloma. July 13, 2026: https://news.bms.com/news/corporate-financial/2026/U-S--Food-and-Drug-Administration-Accepts-Bristol-Myers-Squibbs-New-Drug-Application-for-Mezigdomide-in-Patients-with-Relapsed-or-Refractory-Multiple-Myeloma