Insights into Multiple Myeloma: Immune Microenvironment, Disease Mechanisms, and Therapeutic Innovations
- 1Department of Blood and Marrow Transplantation and Cellular Therapy, Fujita Health University, Toyoake 470-1192, Aichi, Japan
- 2International Center for Cell and Gene Therapy, Fujita Health University, Toyoake 470-1192, Aichi, Japan
- 3Graduate School of Medicine, Department of Cellular Immunotherapies for Cancer, Fujita Health University, Toyoake 470-1192, Aichi, Japan
Abstract
Multiple myeloma (MM) remains a hematologic malignancy characterized by progressive immune dysfunction and the emergence of therapeutic resistance despite substantial recent advances in treatment. The transition from monoclonal gammopathy of undetermined significance (MGUS) to symptomatic MM is associated with coordinated immune dysfunction across innate and adaptive immune compartments. Single-cell and spatial profiling technologies reveal that immune abnormalities emerge at precursor stages and intensify during progression, including T-cell exhaustion, expansion of regulatory T cells, natural killer cell dysfunction, and impaired antigen presentation by dendritic cells. The cancer immunoediting framework, encompassing elimination, equilibrium, and escape phases, provides a unifying paradigm for understanding tumor-immune coevolution in MM. Disease complexity is further compounded by pronounced spatial and temporal heterogeneity. Multi-region sequencing studies demonstrate anatomically distinct clonal architectures and immune microenvironments within individual patients, contributing to variable therapeutic responses and facilitating immune escape. Current immunotherapies, including immunomodulatory drugs, proteasome inhibitors, monoclonal antibodies, chimeric antigen receptor (CAR) T-cell therapies, and bispecific antibodies, have transformed the therapeutic landscape of MM. Nevertheless, durable disease control remains limited by convergent resistance mechanisms, including antigen modulation, T-cell dysfunction, and persistent microenvironmental immunosuppression. A comprehensive understanding of the immune-mediated resistance mechanisms, extending beyond tumor-intrinsic genetic alterations, is essential for the rational design of next-generation therapies. Accumulating evidence suggests that immune dysfunction is closely associated with disease evolution and treatment resistance in MM and may represent a potentially targetable contributor to these processes.
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BibTeX
@article{miyama2026insights,
title = {{Insights into Multiple Myeloma: Immune Microenvironment, Disease Mechanisms, and Therapeutic Innovations}},
author = {Takahiko Miyama and Keichiro Mihara},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = nov,
doi = {10.3390/ijms272210183},
url = {https://www.mdpi.com/1422-0067/27/22/10183},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Insights into Multiple Myeloma: Immune Microenvironment, Disease Mechanisms, and Therapeutic Innovations
AU - Takahiko Miyama
AU - Keichiro Mihara
PY - 2026
DA - 2026/11/13
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms272210183
UR - https://www.mdpi.com/1422-0067/27/22/10183
AB - Multiple myeloma (MM) remains a hematologic malignancy characterized by progressive immune dysfunction and the emergence of therapeutic resistance despite substantial recent advances in treatment. The transition from monoclonal gammopathy of undetermined significance (MGUS) to symptomatic MM is associated with coordinated immune dysfunction across innate and adaptive immune compartments. Single-cell and spatial profiling technologies reveal that immune abnormalities emerge at precursor stages and intensify during progression, including T-cell exhaustion, expansion of regulatory T cells, natural killer cell dysfunction, and impaired antigen presentation by dendritic cells. The cancer immunoediting framework, encompassing elimination, equilibrium, and escape phases, provides a unifying paradigm for understanding tumor-immune coevolution in MM. Disease complexity is further compounded by pronounced spatial and temporal heterogeneity. Multi-region sequencing studies demonstrate anatomically distinct clonal architectures and immune microenvironments within individual patients, contributing to variable therapeutic responses and facilitating immune escape. Current immunotherapies, including immunomodulatory drugs, proteasome inhibitors, monoclonal antibodies, chimeric antigen receptor (CAR) T-cell therapies, and bispecific antibodies, have transformed the therapeutic landscape of MM. Nevertheless, durable disease control remains limited by convergent resistance mechanisms, including antigen modulation, T-cell dysfunction, and persistent microenvironmental immunosuppression. A comprehensive understanding of the immune-mediated resistance mechanisms, extending beyond tumor-intrinsic genetic alterations, is essential for the rational design of next-generation therapies. Accumulating evidence suggests that immune dysfunction is closely associated with disease evolution and treatment resistance in MM and may represent a potentially targetable contributor to these processes.
SN - 1422-0067
ER -