Mezigdomide Triplet Cuts Progression Risk by 52% in Relapsed Myeloma

Patients with relapsed or refractory multiple myeloma lived significantly longer without their disease worsening when treated with mezigdomide, Kyprolis (carfilzomib) and dexamethasone compared with Kyprolis and dexamethasone alone, according to findings from the phase 3 SUCCESSOR-2 trial presented at the 2026 ASCO Annual Meeting.

The study showed that adding mezigdomide reduced the risk of disease progression or death by 52%. Patients who received the three-drug combination went a median of 18 months before their cancer worsened, compared with 8.3 months for those who received Kyprolis and dexamethasone alone.

“These findings are highly encouraging,” said Dr. Paul G. Richardson of Dana-Farber Cancer Institute, who presented the study. “In this setting, we can reasonably conclude that oral mezigdomide combined with weekly intravenous [Kyprolis] is a potential new standard of care in relapsed/refractory disease.”

What Is Mezigdomide?

Mezigdomide is an investigational oral therapy known as a CELMoD, a newer type of immune-modulating drug designed to help the body's immune system identify and destroy multiple myeloma cells. Researchers believe mezigdomide may work even in patients whose disease has stopped responding to other commonly used treatments, including Revlimid (lenalidomide).

The SUCCESSOR-2 study was designed to evaluate whether adding mezigdomide to Kyprolis and dexamethasone could improve outcomes for patients whose multiple myeloma had returned or stopped responding to treatment.

Who Participated in the Study?

The trial enrolled 479 patients with relapsed or refractory multiple myeloma who had received at least one prior line of therapy. Patients were randomly assigned to receive either mezigdomide plus Kyprolis and dexamethasone or Kyprolis and dexamethasone alone.

The patient population represented a particularly difficult-to-treat group. Patients had received a median of two prior lines of therapy, with some receiving as many as nine. More than 92% had previously been exposed to three major classes of myeloma treatment, nearly 86% were resistant to anti-CD38 antibody therapy and approximately 76% were resistant to Revlimid.

“These patients represent a growing population with poor outcomes and few validated treatment options,” Richardson explained during his presentation.

More Patients Responded to Treatment With Mezigdomide

In addition to improving progression-free survival, the mezigdomide combination produced higher response rates than the two-drug regimen.

More than 80% of patients treated with mezigdomide experienced tumor reduction or disease response compared with 53.4% of patients who received kyprolis and dexamethasone alone.

Researchers also reported deeper responses with the three-drug combination. Approximately 27% of patients receiving mezigdomide achieved a complete response or better, compared with 8.9% of patients treated with Kyprolis and dexamethasone alone.

A deeper response means fewer detectable cancer cells remain in the body and may help improve long-term disease control.

The benefits were also seen across a wide range of patients, including those who had received multiple prior treatments, patients with high-risk genetic abnormalities, individuals with disease outside the bone marrow and patients age 75 years and older.

Benefits Continued Beyond Initial Disease Progression

Researchers also looked at progression-free survival two (PFS2), a measure that evaluates how long patients live before their disease worsens a second time or they die.

Patients who received mezigdomide continued to show benefit even after their initial treatment stopped working. Median PFS2 was 23.6 months in the mezigdomide group compared with 13 months in the control group.

According to investigators, this finding suggests the treatment may provide lasting benefits beyond the first response.

Researchers also conducted an early analysis of overall survival. Although the data are not yet mature, results showed a positive trend favoring the mezigdomide combination. Additional follow-up is ongoing.

What Side Effects Were Reported?

The safety profile of the mezigdomide combination was considered predictable and manageable, with no new safety concerns identified.

The most common serious side effect was neutropenia, a condition involving low levels of infection-fighting white blood cells. Severe neutropenia occurred in 61.1% of patients treated with mezigdomide compared with 9.1% of patients receiving Kyprolis and dexamethasone alone.

Researchers noted that neutropenia was generally managed with dose adjustments or medications that help stimulate white blood cell production.

Serious infections occurred in 34.1% of patients receiving mezigdomide compared with 15.6% of those receiving the two-drug regimen. However, fatal infections were uncommon in both groups.

“Neutropenia was the most common grade 3/4 adverse event and was manageable with dose modifications and/or G-CSF,” Richardson said.

What the Findings Mean for Patients

Many patients with relapsed or refractory multiple myeloma eventually become resistant to available therapies, creating a need for new treatment options that can continue to control the disease.

The SUCCESSOR-2 results suggest that adding mezigdomide to Kyprolis and dexamethasone may help patients stay in remission longer while producing deeper responses than standard treatment alone. The combination also uses an oral medication and a once-weekly infusion schedule, which investigators said could make it easier to use in both academic and community cancer centers.

Richardson said the findings support the potential role of the regimen in routine care.

“Oral mezigdomide plus weekly IV [Kyprolis] is a potential new standard of care for relapsed/refractory multiple myeloma that can be easily used across diverse care settings, including community practice,” he said.

References

1. Mezigdomide, Carfilzomib, and Dexamethasone (MeziKd) vs Carfilzomib and Dexamethasone (Kd) in Relapsed/Refractory Multiple Myeloma (RRMM): Results From the Phase 3 SUCCESSOR-2 Trial. Paul G. Richardson. Presented at the 2026 American Society of Clinical Oncology Annual Meeting; May 29-June 2, 2026; Chicago, Illinois.
2. A Study to Evaluate Mezigdomide in Combination With Carfilzomib and Dexamethasone (MeziKD) Versus Carfilzomib and Dexamethasone (Kd) in Participants With Relapsed or Refractory Multiple Myeloma (SUCCESSOR-2). ClinicalTrials.gov. Updated April 1, 2026.