الفهرس 
Introduction
Clinical features of MMOnly 14 pages are availabe for public view
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Abstract
Multiple myeloma is a prototype of a differentiated clonal B-cell tumor usually comprising slowly proliferating plasma cells. The disease is mainly contained within the bone marrow with tendency of the malignant plasma cells to invade peripheral blood only in the terminal stage. The disorder is frequently accompanied by monoclonal (M) protein production and either diffuse osteoporosis or lytic bone lesions.
The average 5-year survival in MM is about 15–20% with a wide range of survival between some few years to 10 years or more. It is primarily a disease of the elderly, with a median age range at diagnosis from 65 to 70 years. The disease does not occur in children. MM generally occurs equally in males and females with male predominance. MM accounts for approximately 15-20 % of hematologic cancers and 0. 8% of all cancers.
Most of MM patients present denovo but some documented as arising from monoclonal gammopathy of undetermined significance (MGUS). Weak associations have been reported with farm working and exposure to radiation, benzene, or pesticides. Infections with HIV and hepatitis C appear related to an elevated multiple myeloma risk. Familial clusters have been reported suggesting a possible genetic element.
Clinical manifestations of MM are related to malignant behavior of plasma cells and abnormalities produced by M protein. Plasma cell proliferation causes multiple osteolytic bone lesions, hypercalcemia and bone marrow suppression ( pancytopenia ). Monoclonal M protein causes decreased level of normal immunoglobulins and hyperviscosity. So most of MM cases presents with bone pains, pathologic fractures, weakness, fatigue, serious infection, renal failure and bleeding diathesis .
Diagnosis of MM needs three criteria according to The Mayo Clinic and the International Myeloma Working Group criteria for the diagnosis of symptomatic MM. Presence of an M-protein in serum and/or urine but in true non-secretory MM, an M protein will not be detectable in the serum or urine. Presence of clonal bone marrow plasma cells (no minimum level, 5% have <5% plasma cells) or after histopathologic confirmation of a soft tissue or bony plasmacytoma. Presence of related organ or tissue impairment by Specification of CRAB which include hypercalcemia, renal insufficiency, anemia and Bone lesions.
The BM microenvironment is composed of a variety of extracellular matrix (ECM) proteins, such as fibronectin, collagen, laminin, and osteopontin, as well as cell components including hematopoetic stem cells, progenitor and precursor cells, immune cells, erythrocytes, BMSCs, bone marrow (BM) endothelial cells, as well as osteoclasts and osteoblasts. The close interaction between MM cells and both ECM proteins and accessory cells in the BM milieu plays a crucial role in MM pathogenesis, both by tumor cell adhesion to the ECM and accessory cells, and by secretion of cytokines, growth factors, and chemokines by tumor cells (autocrine loop) or BM cells (paracrine loop). Interactions between MM cells and their microenvironment activate signaling pathways mediating growth, survival, drug resistance, and migration of MM cells, as well as osteoblastogenesis and angiogenesis in the BM.
There has been a huge expansion in research in myeloma molecular biology in the last decade which has led to a long list of potential drug targets within the cell. Increasing understanding of the role that the bone marrow microenvironment plays in promoting myeloma cell survival and drug resistance has also led to the definition of targets outside the myeloma cell.
Until we have better technology to define dysregulated pathways within the individual patient, drugs which have multiple targets such as heat shock protein 90 (HSP90) inhibitors are most likely be clinically effective in a group of patients. Novel agents that do find their way into clinical practise are likely to do so because they demonstrate synergism with existing agents or uncouple drug resistance mechanisms to existing agents. In the future, gene and protein profiling will enable patient-specific selection of targeted therapies and will also provide the framework for development of more potent and less toxic targeted therapies
Early intervention has shown no benefit in the treatment of asymptomatic MM. Patients with symptomatic MM should be treated immediately as without effective therapy, symptomatic patients die within a median of six months. Aim of therapy in newly diagnosed young myeloma patients which are not only people younger than 65 or 70 years old, but also those fit enough (that is, without severe comorbidities) ideally it should be to provide a cure or at least ensure long-term survival (> 10 or 20 years) with good quality of life.
The initial evaluation of a patient with MM should include testing for specific cytogenetic abnormalities that may help predict response to chemotherapy .MM patients are classified into high and standard risk groups according to mSMART. Although the favorable results obtained with long-term treatment with novel combinations in myeloma are challenging the role of ASCT to be done upfront or at time of relapse, ASCT is considered a cost effective therapy compared with cost of novel agents. As such, all patients should be evaluated at diagnosis for transplant eligibility so that the risks and benefits of ASCT can be reviewed with those eligible.