Spectrum of the possible progression of MGUS. Acquisition of somatic genetic and epigenetic abnormalities in the tumor cells and changes in the bone marrow microenvironment lead to the transformation of non-IgM MGUS into SMM, to MM, extramedullary myeloma (EMM), and plasma cell leukemia (PCL). IgM-MGUS can progress to smoldering Waldenström macroglobulinemia (WM), to WM, lymphoma, or other chronic lymphoproliferative disorders (not shown in the figure). The stages of progression are differentiated using biomarkers (⁠⁠) and imaging. Recently, the diagnosis of “active myeloma” has been proposed, a condition anticipating the occurrence of end-organ damage (CRAB).⁵  The clone may also produce end-organ damage through the M-protein. The protein may target the kidney in monoclonal gammopathy of renal significance (MGRS), including, among others, monoclonal immunoglobulin deposition disease (MIDD), immunotactoid glomerulopathy (ITG), and Fanconi syndrome (FS). The monoclonal light chains may deposit in tissues, causing progressive organ dysfunction; the most notable condition is AL amyloidosis. Biomarkers may help to anticipate the diagnosis of these conditions, before irreversible organ damage has occurred. Other M-protein–related conditions, such as autoimmune neuropathies and chronic cold agglutinin disease, are caused by the autoantibody activity of the M-protein.