What are CELMoDs for Multiple Myeloma? : Mezigdomide and Iberdomide Explained

Treatment for multiple myeloma has improved over time, but many patients still face relapse, especially after several lines of therapy. Newer approaches are now focusing not only on killing myeloma cells but also on strengthening the immune system. One of the most promising developments in this area is a class of drugs called CELMoDs, which are being studied across different stages of the disease.

What are CELMoDs and how do they work?

CELMoDs is short for cereblon E3 ligase modulators. They are a newer generation of immune-based therapies designed to enhance the body’s ability to eliminate myeloma cells. 

They work by activating the immune system, particularly T cells, to target and destroy cancer cells more effectively. At the same time, they can directly interfere with the growth and survival of myeloma cells. Compared to other therapies like lenalidomide, CELMoDs are designed to be more potent and may still work even when the disease becomes resistant to standard treatments.

What is mezigdomide?

Mezigdomide is a CELMoD. It is being studied in patients with more advanced disease who have already received many prior treatments, including immunotherapies like CAR T-cell therapy or bispecific antibodies. It is designed to be very potent, especially in myeloma that has become resistant to earlier therapies, and has shown strong activity even in high-risk and heavily pre-treated patients. Because of this, mezigdomide is often seen as an option for later stages of the disease when fewer treatments remain.

Using mezigdomide for heavily pre-treated relapsed multiple myeloma

In heavily pre-treated multiple myeloma, where patients often face limited options. Studies have opened the possibility of bringing newer therapies like mezigdomide, designed to boost the immune system’s ability to target myeloma cells. 

In a small real-world study from Italy, mezigdomide and dexamethasone were given to patients who had already received many prior treatments, including immunotherapies and stem cell transplants. 

80% of patients responded to treatment, with some achieving deep responses within just a few months. The overall survival rate was 69%. While side effects, particularly infections and low blood counts, were common and required careful management. 

Although more research is required to prove the safety for patients with kidney damage or other health problems, these findings suggest that mezigdomide could help people with multiple myeloma who have exhausted many therapies and even those with high-risk disease.

Can CELMoD-based combinations help the immune system recover after CAR-T or bispecific antibodies?

After treatments like CAR T-cell therapy and bispecific antibodies T cells can become exhausted. This means there is the possibility of relapse. In an early-phase clinical trial, this all-oral combination showed encouraging results in heavily pre-treated patients, including those who had already received or could not receive T cell–redirecting therapies. 

About 40% of patients responded to treatment, and all patients experienced at least some disease control. Importantly, the therapy appeared to increase active, healthy T cells while reducing signs of immune exhaustion. While side effects like low blood counts were common, they were generally manageable with supportive care. 

What is iberdomide? 

Iberdomide is another CELMoD. It is being studied more broadly across different stages of myeloma, including newly diagnosed patients, early relapse, and maintenance strategies. While it is also a powerful immune-modulating drug, its development focuses more on combining it with other treatments early in the disease course or even using it alone after initial therapy to maintain response. 

In contrast to mezigdomide’s role in more advanced settings, iberdomide may help extend treatment options earlier and allow for adjustments in treatment intensity over time, potentially improving long-term disease control and quality of life. 

Watch how iberdomide and mezigdomide are boosting CAR-T therapies

Can iberdomide-based combinations improve first-line treatment for older adults with myeloma?

Older adults with newly diagnosed multiple myeloma are not always eligible for a stem cell transplant. 

In a small clinical trial, the combination of iberdomide, bortezomib, and dexamethasone was given to older patients with a median age of 77 years, 60% had high-risk genetic features. 

All patients responded to treatment, with many achieving deep remissions. Responses occurred quickly, often within the first month, and continued to deepen over time. While side effects such as infections and low blood counts were common, they were manageable with dose adjustments and supportive care. 

Iberdomide-based quadruplet therapy to improve outcomes after early myeloma relapse

In this study, patients with early relapsed multiple myeloma received a four-drug combination of iberdomide, carfilzomib (Kyprolis), daratumumab (Darzalex), and dexamethasone. This was followed by the option to continue with iberdomide alone. Most of the patients were already resistant to lenalidomide (Revlimid) and had received one to three prior treatments. 

About 92% of patients responded to treatment. Most patients remained on treatment, suggesting durable disease control, and some transitioned to iberdomide alone, reducing treatment intensity. While side effects such as low blood counts and infections were common, they were manageable with supportive care and dose adjustments.

The rise of CELMoDs opens accessible therapies for those whose options were limited

These studies suggest that CELMoDs like mezigdomide and iberdomide could play an important role in the future of multiple myeloma care. They offer a new way to treat the disease by combining direct anti-cancer effects with immune system support, even in patients who have run out of other options. While more research is still needed, especially to better understand long-term safety, these therapies are opening the door to more effective and adaptable treatment strategies. For patients, this means more opportunities to control myeloma at every stage.

Watch the latest myeloma roundtable, where experts gather to inform patients about CELMoDs, blenrep and beyond, where Dr. Gayathri Ravi explains how new myeloma therapies could potentially change the treatment landscape for many people. 

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Sources: 

• Real-world efficacy and safety of mezigdomide-dexamethasone in heavily pre-treatred multiple myeloma patients: An Italian case series
• Selinexor, mezigdomide, and dexamethasone in patients with Relapsed/Refractory multiple myeloma who relapsed or are ineligible for T-cell–redirecting therapy: Stomp Phase 1 results
• Iberdomide, bortezomib, and dexamethasone (IberVd) in transplant-ineligible (TNE) newly diagnosed multiple myeloma (NDMM): Updated results from the CC-220-MM-001 trial.
• A phase 2 trial of iberdomide, carfilzomib, daratumumab and dexamethasone quadruplet therapy for relapsed/refractory multiple myeloma: The rekindle study