Multiple myeloma (MM) is the second most common hematologic malignancy, characterized by the uncontrolled growth of plasma cells and progressive damage to multiple organs. Over the past two decades, advances in immunotherapy—including immunomodulatory drugs, monoclonal antibodies, and emerging cellular therapies—have transformed MM treatment and significantly extended patient survival. Despite these achievements, MM remains incurable and almost always relapses. Patients with multidrug-resistant forms of the disease face limited options. Therefore, understanding how immune dysfunction drives disease progression and exploring new therapies for MM with novel targets are urgently needed to improve clinical responses and avoid disease relapse.
To address these challenges, Professor Mu Hao and Professor Lugui Qiu from the State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, China, together with their research team, conducted a comprehensive review of recent advances in immunotherapy for MM. Their article systematically summarizes current therapeutic strategies, highlights the discovery of emerging immune targets, and discusses future directions for overcoming resistance and improving long-term outcomes. The review was made available online in Chinese Medical Journal on October 31, 2025.
"Although current immunotherapies have improved survival rates for many patients, relapse and resistance remain major challenges," says Prof. Mu Hao, corresponding author of the study. MM progression is driven not only by genetic mutations but also by profound immune dysfunction within the bone marrow microenvironment. Immunosuppressive cells, cytokine imbalances, and immune checkpoint activation collectively enable tumor cells to evade immune surveillance. Key findings discussed include the roles of regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages in promoting MM growth and drug resistance. Targeting these immune evasion pathways may enhance the efficacy of existing treatments and delay relapses.
Over recent decades, immune-based treatments have reshaped MM management. Immunomodulatory imid drugs, such as thalidomide and its derivatives lenalidomide and pomalidomide, enhance anti-tumor immunity through cereblon-mediated degradation of transcription factors and stimulation of T and NK cell activity. Next-generation cereblon E3-ligase modulators, including iberdomide and mezigdomide, exhibit stronger affinity and improved safety profiles. Monoclonal antibodies targeting CD38 (daratumumab, isatuximab) and SLAMF7 (elotuzumab) have become foundational components of therapy, offering durable survival benefits.
Beyond conventional immunotherapy, the review explores advanced immunotherapies that harness the immune system more directly, such as antibody–drug conjugates (ADCs), chimeric antigen receptor (CAR)-T cell therapies, and bispecific T cell engagers. Among these, ADCs harness antibodies to deliver cytotoxic payloads with precision, exemplified by belantamab mafodotin targeting B cell maturation antigen (BCMA). CAR-T cell therapies directed against BCMA, GPRC5D, and Fc receptor-like 5 (FcRL5) have produced unprecedented response rates in relapsed/refractory MM, while novel bispecific antibodies, such as teclistamab, elranatamab, and talquetamab, demonstrate potent anti-myeloma activity by redirecting T cells toward tumor cells.
Despite these advances, challenges persist—particularly antigen loss, immune exhaustion, and treatment-related toxicity. The identification of new immunotherapeutic targets, such as GPRC5D, FcRL5, CD229, and LILRB4, provides critical opportunities to overcome drug resistance and improve the durability of response. Integration of multi-omics analyses and combination regimens may further enhance precision and efficacy.
"We are entering an era where personalized immunotherapy will become a reality for MM," concludes Prof. Hao. "Our ongoing mission is to translate these biological insights into durable and accessible treatments for patients worldwide."
Reference
DOI: https://doi.org/10.1097/CM9.0000000000003869
About Professor Hao Mu from
Professor Hao Mu, Ph.D., Principal Investigator at the State Key Laboratory of Experimental Hematology, has over 20 years of research experience in multiple myeloma immunotherapy. She has published 50+ SCI papers, led national projects, holds two invention patents, and received major honors including the Tianjin Science and Technology Progress Award.
About Professor Lugui Qiu from the State Key Laboratory of Experimental Hematology
Professor Lugui Qiu, M.D., Ph.D., Level-I Principal Investigator at the State Key Laboratory of Experimental Hematology, has over 30 years of experience in multiple myeloma and lymphoma research. He has published 600+ papers (180 in top journals) and leads major national projects and 30+ clinical trials.
Funding information
This study was funded by the Noncommunicable Chronic Diseases-National Science and Technology Major Project (No. 2023ZD0501300), the National Natural Science Foundation of China (Nos. 82370210, 82341211, and 82170194), Tianjin Natural Science Foundation Key Project (No. 25JCZDJC00530), and the CAMS Innovation Fund for Medical Sciences (Nos. CIFM 2023-I2M-2-007, CIFMS 2021-I2M1-040, and CIFMS 2022-I2M1-022).
