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Abstract
الملخص Multiple myeloma (MM) is the most common hematologic malignancy. It constitutes 1% of all cancers, and accounts for 10% of hematological malignancies. Multiple myeloma is a plasma cell dyscrasia. Plasma cell dyscrasias are disorders begin with the mere presence of monoclonal protein (M-protein) in the serum, progressing through both asymptomatic and symptomatic forms of MM, and ending with the presence of monoclonal plasma cells in the peripheral blood.
The pathogenesis of MM is believed to be a multistep process that includes the progressive occurance of multiple structural chromosomal changes. There is a strong evidence to believe that chromosome translocations are an important initiating event in the pathogenesis of MM. Also, the survival advantage of MM is further enhanced by a number of pathophysiologically relevant cytokines and growth factors such as interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), and hepatocyte growth factor (HGF).
Bone marrow angiogenesis is a constant hallmark of multiple myeloma progression and has prognostic potential. The pathophysiology of MM-induced angiogenesis is complex and involves both direct production of angiogenic cytokines by plasma cells and their induction within the microenvironment.
The selective localization of MM in the bone marrow reflects the expression of chemotactic receptors on MM cells that directs their migration to the bone marrow. Also, homing of myeloma cells into the bone marrow seems to involve selective adhesion to the bone marrow endothelial cells, transendothelial migration, and adhesion to stromal cells through the production of stromal derived factor -1 (SDF-1). Another important mediator in localization of myeloma cells to the bone marrow is macrophage inflammatory protein-1 alpha MIP-1?., which is produced by myeloma cells and directly stimulates osteoclast formation and differentiation in a dose dependent way.
Multiple myeloma is a disease of adults. Only 2% of patients are diagnosed before age 40 years. Presenting symptoms include persistent bone pain, fatigue usually related to anemia, weight loss, paresthesias, and rarely fever due to MM. In up to one third of patients, a plasma cell proliferative process may be recognized before the diagnosis of MM.
There are a number of laboratory tests that can be made to determine which criteria are present for initial diagnosis and to determine the extent of the disease. The most important are complete blood count, bone marrow aspirate, serum protein electrophoresis, immunofixation, flow cytometric analysis and biochemical markers.
The outcome of myeloma patients is highly heterogenous, with survival ranging from a few months to more than 10 years. Accordingly, investigation of prognostic factors may contribute to identification of risk categories and to provision of more accurate information about individual disease outcome. A number of prognostic indices have been proposed to date using different risk factors. In all these ?2 microglobulin remains the most powerful prognostic marker, while CRP, albumin, LDH, and chromosome 13q loss have also shown to be of prognostic value.
Accordingly, a new international staging system (ISS) has recently been proposed, based on the levels of ?2M and albumin. The new system allows delineation of three risk groups regardless of age, geographic region or standard or transplant therapy.
The negative prognostic impact of specific IgH translocations as the t(4;14), t(14;16), and chromosome 13 deletions are now established. Preliminary gene expression profiling studies have also demonstrated that individual genes or groups of genes can define prognosis with greater accuracy than conventional genetic markers.
The degree of bone marrow angiogenesis is a powerful prognostic factor for survival of multiple myeloma. A high number of plasma cells in bone marrow, as well as a diffuse pattern of infiltration, are generally associated with a poor prognosis.
In conclusion, Patients with MM can develop signs and symptoms involving multiple organ systems; therefore, it is essential that physicians of all disciplines be able to recognize its manifestations. A thorough understanding of the disease process will help guide physical examination and laboratory evaluation. Conventional and molecular cytogenetics should now be used to guide therapeutic strategies and prognostic stratification of myeloma. Further more, using a single GEP platform, IgH translocation status, chromosomal ploidy, deletion of chromosome 13 and high risk genetic signatures can be used not only to diagnose but also to provide pharmacogenomic and biologic insight into the pathophysiology of the disease, and future targets of myeloma.