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Abstract
Multiple Myeloma (MM) is characterized by uncontrolled proliferation and accumulation of clonal plasma cells within the bone marrow. However, the cell of origin is a B-lymphocyte acquiring aberrant genomic events in the germinal center of a lymph node as off-target events during somatichypermutation and class-switch recombination driven by activation-induced-deaminase. Whether pre-germinal center events are also required for transformation, and which additional events are required for disease progression is still matter of debate. As early treatment in asymptomatic phases is gaining traction in the clinic, a better understanding of the molecular pathogenesis of myeloma progression would allow stratification of patients based on their risk of progression, thus rationalizing efficacy and cost of clinical interventions. In this review, we will discuss the development of MM, from the cell of origin through asymptomatic stages such as monoclonal gammopathy of undetermined significance and smoldering MM, to the development of symptomatic disease. We will explain the genetic heterogeneity of MM, one of the major drivers of disease recurrence. In this context, moreover, we will propose how this knowledge may influence future diagnostic and therapeutic interventions.
Highlights
Random mutagenesis is a frequent and likely ubiquitous phenomenon in replicating tissues, stemming from slight intrinsic infidelity of DNA replication and repair processes, and enzymatic modification of DNA bases.[1]
Further acquisition of additional variants may dictate evolution from these small clonal proliferations, never recognized in clinical practice, to a clinically evident cancer following natural selection acting on the resulting phenotypic diversity.[3]
Active MM in turn is diagnosed in presence of clonal BM plasma cells >10% and/or a biopsy proven bony or extra- medullary plasmacytoma, and one or more myeloma-defining events: end-organ damage, ≥60% bone marrow clonal plasma cells, serum free lightchain (FLC) ratio ≥100 or 1 focal lesion on MRI.[6]
Summary
Random mutagenesis is a frequent and likely ubiquitous phenomenon in replicating tissues, stemming from slight intrinsic infidelity of DNA replication and repair processes, and enzymatic modification of DNA bases.[1]. Active MM in turn is diagnosed in presence of clonal BM plasma cells >10% and/or a biopsy proven bony or extra- medullary plasmacytoma, and one or more myeloma-defining events: end-organ damage (hypercalcemia, renal failure, anemia, lytic bone lesions), ≥60% bone marrow clonal plasma cells, serum free lightchain (FLC) ratio ≥100 (for kappa) or 1 focal lesion on MRI.[6] These categories reflect differences in management to prevent the development of end-organ damage, or its prompt recognition and treatment.[6] From a genomic point of view, the question is whether this clinical evolution is paralleled by a similar biological evolution of the neoplastic clone, from initiating lesions to those associated with progression and development of an aggressive disease, and whether this can be exploited clinically. We will focus on the different patterns of evolution from asymptomatic to aggressive stages of disease and the impact MM heterogeneity has in this process
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