Unveiling Extramedullary Myeloma Immune Microenvironment: A Systematic Review
by
, , , and
Kassiani Boulogeorgou
1,
Maria Papaioannou
2,
Sofia Chatzileontiadou
2,
Elisavet Georgiou
3,
Amalia Fola
2,
Sofia-Eleni Tzorakoleftheraki
1,
Evdoxia Hatjiharissi
2,† and
Triantafyllia Koletsa
1,*,† 1
Department of Pathology, School of Medicine, Aristotle University of Thessaloniki, University Campus, 54124 Thessaloniki, Greece
2
Hematology Unit, 1st Department of Internal Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
3
Department of Biological Chemistry, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cancers 2025, 17(7), 1081; https://doi.org/10.3390/cancers17071081
Submission received: 31 January 2025
/
Revised: 1 March 2025
/
Accepted: 21 March 2025
/
Published: 24 March 2025
(This article belongs to the Special Issue Multiple Myeloma—Biology, Diagnosis, Treatment and Prognosis (2nd Edition))
Simple Summary
Extramedullary disease (EMD) is an advanced-stage disease and is typically characterized by poor clinical outcome. Numerous therapeutic strategies have been applied at times, with insufficient results so far. The current systematic review investigates the composition of the immune microenvironment (IME) at EMD sites and its possible differences between medullary and extramedullary milieu. Six studies meeting our inclusion criteria were analyzed and highlighted the establishment of an immunosuppressive state across the extramedullary niche. A profound spatial and temporal heterogeneity of IME was reported and possibly correlated with defined genetic instability at EMD. Differences were noted between medullary disease and EMD concerning both molecular and microenvironment findings. IME synthesis endured also post-therapy alterations concerning mostly the percentages of T-regulatory cells (Tregs) and Myeloid-derived suppressor cells (MDSCs). Grasping the heterogeneity of IME provides strategic avenues for tailored therapeutic options in EMD.
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.
