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INTRODUCTION

SUMMARY

Myeloma derives from the proliferation of a clone of malignant plasma cells that secrete a complete monoclonal immunoglobulin protein or a free light chain. It originates in most, perhaps all, cases from an antecedent monoclonal gammopathy (monoclonal gammopathy of undetermined significance) that progresses by clonal evolution (acquisition of additional mutations) and microenvironment changes to a B-cell malignancy, at a rate of 1% 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, supports cell growth and cell-survival 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. Often, patients with myeloma have signs resulting from marrow infiltration (anemia), bone destruction (bone pain, pathologic fractures), excessive immunoglobulin production and deposition (renal failure, Fanconi syndrome, hyperviscosity), and immunosuppression (eg, 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 and characterize proteinuria; blood cell counts a complete metabolic panel; and marrow aspirate or biopsy with fluorescence in situ hybridization and cytogenetic studies. The use of either positron emission tomography–computed tomography, low-dose whole-body computed tomography, or magnetic resonance imaging of the whole body or spine has replaced the use of skeletal survey to assess myeloma-related bone involvement, given its superior sensitivity in identifying early bone disease and better quantification of disease burden by taking into account extramedullary disease. The most common staging system for myeloma is the International Staging System (ISS), which is based on two parameters: serum β2-microglobulin and albumin; 3 stages are defined and correlate with patient outcome. A revised ISS (R-ISS) incorporating lactic dehydrogenase and cytogenetic abnormalities has superior prognostic power compared to ISS. Adverse cytogenetics in myeloma are del(17/17p), t(4;14), t(14;20), t(14;16), 1q+, and any nonhyperdiploid karyotype. Other prognostic factors include altered gene expression profiling and circulating plasma cells. The clinical use of a combination of immunomodulatory drugs (IMiDs) such as thalidomide, lenalidomide and pomalidomide with proteasome inhibitors (PIs) including bortezomib, carfilzomib, and ixazomib have progressively increased the median overall survival to longer than 5 years, with some patients achieving long-term survival of longer than 10 years. The monoclonal antibodies (MoAbs) elotuzumab and daratumumab and the histone deacetylase inhibitor panobinostat are FDA-approved options for myeloma and contribute to further prolongation of survival. Melphalan-based autologous hematopoietic stem cell transplantation (HSCT) in combination with novel agents results in long-term control of disease in patients with favorable myeloma biology; patients who are not eligible for autologous transplantation derive substantial benefit from therapy integrating PIs, IMiDs and MoAbs, and the impact of autologous HSCT on survival, in the era of novel agents, is currently under scrutiny. Risk-stratified consolidation and maintenance strategies using IMiDs ...

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