Extramedullary Multiple Myeloma: Challenges and Opportunities

Abstract

Extramedullary multiple myeloma (EMM), defined in this review as soft tissue plasmacytomas resulting from hematogenous spread, is characterized by the ability of MM cells to proliferate outside of the bone marrow microenvironment. It is aggressive, often associated with high-risk cytogenetics and early relapse, and independently portends significantly shorter progression-free and overall survival, even in the era of highly effective immunotherapies. The molecular and microenvironmental factors underlying extramedullary MM dissemination continue to be studied to inform the development of better treatments. In this review, we discuss our current understanding of the biology of EMM, focusing on its distinct molecular and microenvironmental characteristics vis-à-vis MM. We also review the current treatment strategies, acknowledging the paucity of large, randomized studies specific to this population.

Keywords: CAR-T; MAPK; bispecific antibodies; paraskeletal disease; relapsed myeloma.

Figure 1

Immunophenotype of MM (Left) and EMM (Right). Top: Flow cytometry and immunohistochemistry analyses reveal significant differences in the expression of chemotactic and adhesion receptors between EMM and MM. Bottom: Next-generation sequencing studies show increased expression of free light-chains and CD70 in EMM cells and decreased expression of therapeutic targets such as CD38, SLAMF7, GPRC5D, and FCRH5. There was also enrichment of CD8+ T cells and NK cells within the EMM microenvironment. (Created using Biorender).

Figure 2

Current understanding of the molecular pathogenesis of EMM: Extramedullary tumors are enriched in MAPK alterations that are frequently clonal, and a complex genomic profile with higher mutational burden and copy number abnormalities. The microenvironment is enriched in exhausted T-cells and the plasma cells demonstrated altered metabolic programming and less dependence on the bone marrow (Created using Biorender).