Multiple Myeloma: Heterogeneous in Every Way

SIMPLE SUMMARY: With the development of modern therapies in multiple myeloma, prognosis stratification is becoming an indispensable tool for the choice of treatment between patients. Many factors influence the prognosis in multiple myeloma; scores, mainly based on biochemical parameters and cytogenetics, have been proposed to discriminate patients. However, these scores are not perfect and fail to predict some patients’ outcomes. In this review, we describe current evaluated factors and their limitations. In the second part, we address factors with an impact on treatment escape and prognosis, but which are not available routinely yet. ABSTRACT: Multiple myeloma (MM) is a hematological malignancy characterized by the accumulation of tumor plasma cells (PCs) in the bone marrow (BM). Despite considerable advances in terms of treatment, patients’ prognosis is still very heterogeneous. Cytogenetics and minimal residual disease both have a major impact on prognosis. However, they do not explain all the heterogeneity seen in the outcomes. Their limitations are the result of the emergence of minor subclones missed at diagnosis, detected by sensible methods such as single-cell analysis, but also the non-exploration in the routine practice of the spatial heterogeneity between different clones according to the focal lesions. Moreover, biochemical parameters and cytogenetics do not reflect the whole complexity of MM. Gene expression is influenced by a tight collaboration between cytogenetic events and epigenetic regulation. The microenvironment also has an important impact on the development and the progression of the disease. Some of these determinants have been described as independent prognostic factors and could be used to more accurately predict patient prognosis and response to treatment.