Abstract
BACKGROUND/OBJECTIVES: In recent years, efforts by the scientific community to elucidate the underlying mechanisms of clonal expansion and selection within tumors have led to the theory of "tumor ecosystems", implicating, among other factors, the role of the microenvironment in therapy resistance and tumor progression. In this context, the contribution of the microenvironment in the development of multiple myeloma (MM) is being investigated, imparting great emphasis on continuous clonal evolution. This process gives rise to aggressive clones with the potential to spread to extramedullary sites, rendering any treatment strategy practically ineffective. This systematic review aimed to gather knowledge about the immune microenvironment (IME) of extramedullary plasma cell myeloma and the differences in immune synthesis between medullary and extramedullary disease (EMD). METHODS: A search strategy according to PRISMA guidelines was conducted in seven databases, and six articles meeting the inclusion criteria were encompassed in the study. RESULTS: Results obtained from molecular analysis as well as flow cytometry and immunofluorescence indicated profound genetic instability at EMD sites along with spatial and temporal heterogeneity of the IME, implying a possible correlation between them. Both genetic and microenvironment variability were notably greater in EMD compared to medullary disease. The establishment of an immunosuppressive microenvironment was the rule, with exhausted CD8+ and natural killer (NK) cells, M2 macrophages, and inactivated dendritic cells found co-localized with neoplastic plasma cells, whereas cytotoxic CD8+ cells, M1 macrophages, and active dendritic cells congregated in tumor-free areas. Post-therapy alterations in the immune milieu were also noted and were concerned mostly the percentages of Tregs and MDSCs. CONCLUSIONS: The recognition of the microenvironment-myeloma cell interplay is essential for designing specific therapeutic strategies and ameliorating disease prognosis.