CELMoDs and CAR T-Cell Therapies Show Promise in Multiple Myeloma Treatment
Novel CELMoD agents are being evaluated to address T-cell exhaustion in multiple myeloma patients, while CAR T-cell therapy CARVYKTI shows longer-term survival benefits. Nearly 200,000 people in the U.S. live with this blood cancer.
Nearly 200,000 people in the United States live with multiple myeloma, a cancer that occurs when a type of white blood cell grows out of control, causing low blood counts, bone and calcium problems, frequent infections and kidney damage. With the use of CAR T-cell therapies and bispecific antibodies expanding across the multiple myeloma treatment paradigm, a novel class of agents known as CELMoDs could help promote T-cell fitness for patients, along with delivering other antimyeloma effects.
CELMoDs are cereblon E3 ligase modulators and are currently being evaluated in clinical trials across multiple myeloma settings. They bind to cereblon, change its substrate specificity, and promote protein degradation via the transcription factors Ikaros and Aiolos. Their binding to cereblon is much stronger than earlier immunomodulatory drugs (IMiDs), and CELMoDs tend to have activity in patients who have IMiD-refractory disease.
Two CELMoDs currently being evaluated are iberdomide (CC-220) and mezigdomide (CC-92480). Both have been tested in preclinical and clinical studies and are currently in development in clinical trials. In February 2026, the FDA accepted a new drug application seeking the approval of iberdomide plus daratumumab (Darzalex) and dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma, based on data from the phase 3 EXCALIBER-RRMM study.
This class of agents could promote T-cell fitness, addressing T-cell exhaustion experienced by patients receiving immune-based therapy. More than ever, there is a need for novel agents—especially agents that can capture or rescue patients post–CAR T-cell therapy or post–bispecific antibody failure. CAR T-cell therapy is approved as early as the second line, so more and more patients are quad-exposed and quad-refractory after earlier lines of therapy.
One exciting aspect of CELMoDs is that they are able to restore immune fitness. The clinical efficacy data for both iberdomide and mezigdomide are impressive. Mezigdomide has shown efficacy in patients with extramedullary disease, which is an unmet need post–bispecific antibody and post–CAR T-cell therapy. Another area where CELMoDs could potentially be used is either pre–CAR T-cell therapy or pre–bispecific antibodies as a sort of priming mechanism, or even maintenance strategies.
According to the American Cancer Society, when traditional chemotherapy doesn't work, one treatment, called CAR T-cell therapy, uses genetically modified cells to fight the cancer. In 2024, the Food and Drug Administration eliminated some barriers to that care to increase patient access.
CARVYKTI is an option for multiple myeloma patients when traditional cancer treatments are no longer effective. It utilizes the patient's own immune cells to act against the cancer cells. The process involves collecting, genetically modifying and re-infusing white blood cells to attack the cancer. One treatment takes about two to three months to complete.
CARVYKTI has been approved for three years, and new longer-term data from a study show that CARVYKTI doesn't just slow the progression of the disease; it also helps patients live longer. Historically, the outcome of these patients is pretty poor, with the average survival of under a year. The average age of when a patient with multiple myeloma is diagnosed is about 70 years.
Multiple myeloma is a rare type of blood cancer that develops in plasma cells in bone marrow. It's treatable, but it's not curable. Ongoing trials evaluating CELMoDs include the phase 3 SUCCESSOR-1 and SUCCESSOR-2 studies for mezigdomide.