Addition of Mezigdomide to Standard Therapy Significantly Improves Outcomes in Relapsed Refractory Multiple Myeloma

For patients with relapsed or refractory multiple myeloma (RRMM), the addition of the oral drug mezigdomide to standard treatment with carfilzomib and dexamethasone markedly improved progression-free survival over standard treatment alone, according to results from a phase 3 clinical trial led by investigators at Dana-Farber Cancer Institute.

“There are relatively few accessible therapeutic options for patients whose multiple myeloma has returned or stopped responding to current standard treatments,” said Paul G. Richardson, M.D., Director of Clinical Research at the Jerome Lipper Multiple Myeloma Center at Dana-Farber and the R.J. Corman Professor of Medicine at Harvard Medical School. “These results support mezigdomide, a potent and novel oral therapy, as a new standard of care for RRMM across multiple settings.”

The findings were presented as a late-breaking abstract at the 2026 ASCO annual meeting, held May 29-June 2 in Chicago, and will be published in The Lancet imminently. 

Mezigdomide is in a new class of oral drugs with powerful effects on the immune system. Known as CELMoDs (Cereblon E3 Ligase Modulatory Drugs), these drugs work through a dual process of targeted protein degradation and immune system activation.

Mezigdomide binds to a protein called cereblon, altering its shape to promote the recruitment and destruction of proteins that myeloma cells need to survive. By wiping out these cancer-promoting proteins, mezigdomide also stimulates the body’s immune system to attack and kill any remaining cancer cells. 

Because these newer drugs bind more tightly to cereblon than other immunomodulatory drugs, such as lenalidomide and pomalidomide, they produce much deeper responses and are effective at overcoming drug resistance. 

“Mezigdomide closes the cerablon-3 ligase complex completely, by 100% in laboratory models, as compared to 15-20% at best with lenalidomide and pomalidomide,” says Dr. Richardson. “This has dramatic downstream effects on the myeloma cell and the immune system pre-clinically, which has translated to remarkable clinical benefit in patients.”

“As an oral agent, this has the convenience of outpatient use and has a manageable and predictable safety profile,” he continued. “It also combines readily with other agents and has shown impressive synergy in RRMM.”

In the SUCCESSOR-2 trial, Dr. Richardson and his colleagues evaluated the addition of mezigdomide to the standard treatment of carfilzomib and dexamethasone to see if the triplet combination improves outcomes, such as how long people live without the disease getting worse (progression-free survival), over standard treatment alone. 

In the trial, 479 adult patients with RRMM were randomly assigned to receive either mezigdomide, carfilzomib, and dexamethasone (288 patients), or carfilzomib and dexamethasone (191 patients). Patients had previously been treated with at least one, and up to 8, prior lines of treatment, including lenalidomide, pomalidomide, proteasome inhibitors, anti-CD38 monoclonal antibody drugs, and BCMA-targeting agents. Their disease had either returned or stopped responding to therapy.  

After a median follow-up of 10.6 months, patients in the mezigdomide group achieved a median of 18 months without their disease progressing, compared with 8.3 months for patients who received standard treatment. This improvement was seen across multiple subgroups of patients, including those with more aggressive disease. 

A substantial majority of the patients in the mezigdomide group (80.2%) had some response to treatment, compared with just half of patients (53.4%) in the standard treatment group. Among patients in the mezigdomide group, 26.7% achieved a complete response, meaning there was no evidence of disease, compared with only 8.9% of patients in the group that received standard treatment alone. 

Because they were on treatment substantially longer, patients in the mezigdomide group had a higher rate of treatment-related side effects (83.7%) compared with those in the standard treatment group (56.5%). The side effects, which included low white blood counts (known as neutropenia) and some infections, proved manageable and readily reversible. There were no unexpected side effects, and rates of discontinuation due to toxicity were notably low.

The researchers are continuing to evaluate patients on SUCCESSOR-2 for overall survival, as well as benefits in specific subgroups. They are also conducting correlative science to inform the optimal use of mezigdomide in this and other settings.   

“There are several pivotal studies with mezigdomide in RRMM exploring its use in combination with other standard treatments, such as bortezomib and dexamethasone, to confirm its value in real-world practice, as well as providing a broad platform for regulatory approval,” Dr. Richardson said. “In addition, its ability to reverse immune exhaustion and enhance immune activity makes it an ideal partner to current immunotherapies as well as other novel oral agents, and numerous trials are now underway.” 

Since 2017, Dr. Richardson and his colleagues at Dana-Farber have led the development of mezigdomide, starting with phase I studies and multiple subsequent and ongoing trials. To date, they have treated over 120 patients with mezigdomide at Dana-Farber, and the team are considered leaders with this approach, which in turn has the promise to improve treatment options for RRMM globally.