Medical Director Oncology Therapeutic Expertise FORTREA Buenos Aires, Buenos Aires, Argentina
Introduction: MM progression,dissemination,and relapse involve multiple driver lesions and exhibit high genomic complexity and heterogeneity. Early drivers,such as cytogenetic abnormalities,chromosomal translocations,and copy number variants (CNV), are detectable in premalignant stages. As the tumor evolves, secondary genomic lesions emerge in subclones,distinguishing them genetically from one another. We present here, the mutational landscape of MM, in cytogenetic,genetic,epigenetic, tumor microenvironment and immunoprofiling terms to identify areas of interest for drug development
Methods: n/a
Results: Primary events: two non-overlapping pathways initiate plasma cell proliferation: hyperdiploidy and non-hyperdiploidy. Hyperdiploidy, which rarely co-occurs with IgH translocations, generally indicates a better prognosis than IgH-translocated myeloma. Multiple myeloma SET domain protein (MMSET) becomes essential during MM progression with the t(4;14) translocation. Other translocations include t(11;14), t(12;14), t(6;14), t(14;16), and t(14;20), with the latter being less common and along with t(4;14) are associated with genetic instability.Two tumor progression models are proposed: the static progression model, where the malignant clone is defined at the SMM stage, and the spontaneous evolution model, where progression occurs through clonal evolution with secondary events like additional translocations,CNV,mutations,epigenetic changes, and microenvironmental alterations driving progression from MGUS/SMM to MM. Secondary events: the deletion of chromosome 13q, amplification of chromosome 1q ,and deletion of chromosome 1p are significant events.TP53 mutations combined with 17p loss result in poorer outcomes. Concerning the epigenetic changes, the key one in MM pathogenesis is global DNA hypomethylation and gene-specific hypermethylation during the transformation from MGUS to myeloma. On the other hand, the microenvironment: local “milieu” provides both suppressive and supportive signals to clonal plasma cells, such as increased IL-6 production and enhanced angiogenesis by VEGF. Not all MGUS/SMM patients with similar genetic alterations progress to MM, indicating the microenvironment's key role in disease initiation and progression. Immune evasion and MM progression are influenced by immune checkpoint molecules and immunosuppressive cytokines (IL-10 and TGF-β). Additional factors include bone disease (RANKL production), osteoclast activation,and metabolic changes (Warburg effect).
Conclusions: While our understanding of MM biology has improved, identifying molecular alterations, microenvironment, and cytokine abnormalities driving MM progression, has not yet fully translated into individualized targeted therapies with large and /or small molecules. On the other hand, promising results are seen with CAR-T cell therapy and developing clinical studies that combine this cell therapy with target drugs may become a game-changer in the natural history of high-risk MM
