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Myeloma derives from the proliferation of a clone of malignant plasma cells that secretes a complete and/or partial monoclonal immunoglobulin protein. It originates in most, perhaps all, cases from an antecedent monoclonal gammopathy (essential monoclonal gammopathy) that progresses by clonal evolution (acquisition of additional mutations) to a malignant B-cell malignancy, often myeloma, at a rate of 1 percent per year. Myeloma cells accumulate in the marrow microenvironment, where contact with extracellular matrix and interaction with marrow accessory cells, such as osteoblasts, osteoclasts, and stromal cells, evokes cell growth and cell-survival signals and contributes to resistance to therapy. Myeloma cells show a complex genomic phenotype, with chromosomal translocations and small copy number variations that affect patient prognosis. Patients with myeloma have signs resulting from marrow infiltration (anemia), bone destruction (bone pain, pathologic fractures), excessive immunoglobulin production and deposition (renal failure and amyloidosis-related symptoms), and immunosuppression (e.g., infection). Clinical manifestations of myeloma vary as a result of the heterogeneous biology, spanning the entire spectrum from indolent to highly aggressive disease with extramedullary features. Diagnostic workup of myeloma should include serum protein electrophoresis together with immunoglobulin immunofixation; serum-free light-chain assay; a 24-hour urine collection to quantitate urinary protein; basic blood metabolic panel, including blood counts and renal function; and marrow aspirate or biopsy with fluorescence in situ hybridization and cytogenetic studies. Radiographic bone survey is used to detect osteopenia and bone lesions or impending fractures. Magnetic resonance imaging (MRI) is more sensitive than the bone survey, can identify early bone disease and extramedullary disease, and can distinguish myeloma from normal marrow, helping in quantifying the extent of the disease. Positron emission tomography coupled with computed tomography (PET-CT) detects metabolically active intramedullary or extramedullary myeloma foci and lytic bone lesions. The most common staging system for myeloma is the International Staging System, based on two parameters, serum β2-microglobulin (β2M) and albumin; three stages are defined and correlate with patient outcome. Serum levels of β2M, C-reactive protein, and number of circulating plasma cells and their labeling index are related to patient prognosis. Other prognostic factors include the presence of specific chromosomal abnormalities (deletion of chromosome 17p and loss of chromosome 1p/gain of chromosome 1q), altered gene-expression profiling, as well as MRI and PET-CT abnormalities. The introduction of the immunomodulatory drugs (IMiDs) thalidomide and lenalidomide and the proteasome inhibitor bortezomib have increased the 5-year relative survival rate to 45 percent, with some patients achieving long-term survival of more than 10 years. Melphalan-based autologous hematopoietic stem cell transplantation in combination with novel agents can achieve remarkable results in patients with good-risk myeloma; patients who are not eligible for autologous transplant have traditionally been treated with melphalan and prednisone; novel agents such as bortezomib and lenalidomide are also active and well tolerated in this population. Consolidation and maintenance regimens based on lenalidomide as a single agent or in combination with bortezomib have been evaluated to extend the duration of complete remission ...

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