New developments and Treatment in multiple: New insights on molecular biology

Abstract

During the past decade, new insights into the molecular pathology of MM have been obtained recognizing the importance of both the malignant clone and the BM microenvironment for disease evolution and propagation. It appears that progressive genetic changes are associated with the development of various stages of monoclonal gammopathies [2]. Translocations involving 14q32 with consecutive activation of an oncogene at one of the various translocation partners may be considered as a primary event leading to immortalization of a plasma cell clone and to the development of MGUS. Chromosomal instability becomes apparent and even more pronounced as soon as the disease progresses. Transformation to MM is associated with such additional chromosomal events, with a deletion of chromosome 13 occurring in about 50% of cases. Further expansion of the malignant clone is supported by factors provided by the BM microenvironment, which in turn is influenced by products of the malignant plasma cells. During this phase of the disease, MM cells remain growth factor-dependent and therefore are restricted to the BM itself. Late occurring genetic and molecular events (secondary translocations, dysregulation of additional oncogenes) characterize myeloma cell growth that is stroma independent, which clinically gives rise to a terminal, aggressive phase of the disease with development of extramedullary manifestations. It is expected that the use of novel techniques, in particular global gene expression profiling, will further contribute to a molecular classification of MM [52]. Characterization of such critical events in the development of monoclonal gammopathies may be the basis for future therapeutic approaches. Agents targeting the BM microenvironment instead of the tumor cell (e.g. immunomodulatory drugs, proteasome inhibitors) are already being investigated in clinical trials and may be particularly active in combination with conventional cytotoxic drugs. Identification of MM subtypes with tumor-specific alterations, such as mutations of fgfr3, overexpression of cyclins and activation of specific kinases, provides the background for novel therapeutic targets. Delineation of the molecular pathway that causes bone destruction in MM will also improve our ability to treat and prevent osseous complications of the disease.