In two complementary preclinical studies published in Blood, investigators reported that mezigdomide, a cereblon E3 ligase modulator, may help overcome T-cell dysfunction in multiple myeloma, thereby enhancing the activity of BCMA-directed CAR T-cell and bispecific T-cell engager therapies. These studies were published by Chen et al and Chu et al.
T cell–based therapies, including chimeric antigen receptor (CAR)-T cells and bispecific antibodies, have improved outcomes for patients with multiple myeloma. However, many patients eventually experience relapse, in part because their T cells become dysfuntional, or “exhausted” and less capable of facilitating an effective antitumor response.
“Our findings show that mezigdomide can reinvigorate exhausted T cells and enhance the activity of immunotherapies that are already changing the standard of care for multiple myeloma,” said Samir Parekh, MD, Professor of Medicine (Hematology and Medical Oncology) at the Icahn School of Medicine at Mount Sinai, and senior author of the studies. “This approach addresses one of the fundamental challenges in treating patients whose disease has returned after multiple lines of therapy.”
In analyses of bone marrow samples from patients with relapsed multiple myeloma, the researchers found that treatment with mezigdomide significantly reduced populations of dysfunctional T cells expressing key exhaustion markers, which include PD-1 and TIGIT. At the same time, the drug enhanced the cytotoxicity activity of both CAR-T cells and bispecific T-cell engagers in preclinical models, leading to deeper tumor clearance and improved survival. The studies also uncover the biological mechanism behind these effects.
Mezigdomide Mechanism of Action
Mezigdomide targets two transcription factors, IKZF1 (Ikaros) and IKZF3 (Aiolos), which the researchers identified as central regulators of T-cell dysfunction. Using advanced multiomic approaches, including gene-expression profiling and analysis of three-dimensional genome organization, the team showed that these proteins help sustain the genetic and epigenetic programs that keep T cells in an exhausted state.
“Whilst the effects of immunomodulatory imide drugs and cereblon E3 ligase modulators on myeloma cells are understood, it was really exciting to instead focus on how these drugs affect the surrounding immune cells,” said first author Lucia Y. Chen, a hematology clinician at Oxford University Hospitals NHS Foundation Trust and PhD candidate at the University of Oxford.
He added that “We found that they can reprogram nearby T cells into a more active, cancer-fighting state by removing key gene regulators Ikaros and Aiolos. The role of these gene regulatory factors in T-cell dysfunction is understudied. Understanding these epigenetic pathways could have implications for immune therapies in myeloma and other cancers.”
“By removing these key regulators, mezigdomide effectively rewires the immune system,” said Dr. Parekh. “It shifts T cells from a dysfunctional state to a more active, tumor-fighting state, allowing them to produce critical signaling molecules and mount a stronger response against cancer.”
The findings provide a scientific rationale for combining mezigdomide with T cell–based therapies in clinical settings. Early-phase clinical trials evaluating these combinations are underway.
For patients, particularly those with relapsed disease who have limited treatment options, this strategy could represent a meaningful advance.
“Patients who have undergone multiple therapies often have a weakened immune system, which can limit how well newer treatments work,” Dr. Parekh said. “Reversing T-cell dysfunction has the potential to improve both the depth and durability of response.”
DISCLOSURE: The research was conducted in collaboration with investigators from Bristol Myers Squibb, the University of Oxford, and the University of Navarra in Spain. Funding support was provided by the International Myeloma Society Career Development Award, the Paula and Rodger Riney Foundation, the CRUK Cancer Sciences DPhil Programme, Bristol Myers Squibb, and the National Cancer Institute. For full disclosures of the study authors, visit ashpublications.org/blood.
