We therefore assessed established risk factors and explored novel risk factors for progression using a large independent cohort of 728 MGUS patients followed up to 30 years. == Patients and methods == == Study subjects == During the study period 1963 to 2000, there were 1202 individuals diagnosed with MGUS at Malm University Hospital (97.8%) or another local hospital (2.2%). abnormal free light-chain (FLC) ratio (<0.26 or >1.65), M-protein concentration (1.5 g/dL), and reduction of 1 or 2 2 noninvolved immunoglobulin isotype levels (immunoparesis). A prediction model with separate effects for these 3 factors and the M-protein isotype had higher discriminatory power than other models, although the differences were not statistically significant. The 30-year cumulative risk for myeloid malignancies was <2%. Our study confirms that abnormal FLC ratio and M-protein concentration >1.5 g/dL, factors previously considered by Mayo Clinic researchers, are predictors for MM progression and suggests that separate consideration of immunoparesis and the Mayo Clinic risk factors could improve identification of MGUS patients at high risk for progression. == Continuing Medical Education online == This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Medscape, LLC and the American Society of Hematology. Medscape, LLC is accredited by the ACCME to provide continuing medical education for physicians. Medscape, LLC designates this Journal-based CME activity for a maximum of 1.0AMA PRA Category 1 Credit(s).Physicians should claim only the credit commensurate with the extent of their participation in the activity. All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 70% minimum passing score and complete the evaluation athttp://www.medscape.org/journal/blood; and (4) view/print certificate. For CME questions, see page 457. == Disclosures == The authors, Associate Editor A. Keith Stewart, and CME questions author Laurie Barclay, freelance writer and reviewer, Medscape, LLC, declare no competing financial interests. == Learning 3-Methoxytyramine objectives == Describe the risk for hematologic disorders originating from lymphoid and myeloid lineages in patients with monoclonal gammopathy of undetermined significance (MGUS), based on a long-term follow-up study. List factors associated with progression of MGUS to hematologic disorders originating from lymphoid and myeloid lineages. Discuss a prediction model for progression of MGUS to hematologic disorders originating from lymphoid and myeloid lineages. Release date: January 16, 2014; Expiration date: January 16, 2015 == Introduction == Monoclonal gammopathies are disorders characterized by a homogeneous immunoglobulin (the M-protein) spike in serum or urine arising from the proliferation of an abnormal clone of a single plasma cell precursor. Multiple myeloma (MM) is the archetype of a malignant monoclonal plasma cell disorder. Benign monoclonal gammopathies, as first described by Waldenstrm, also occur and are much more common than MM.1Once it was observed that a substantial proportion of benign gammopathies develop into MM, the now universally accepted term monoclonal gammopathy of undetermined significance (MGUS) was introduced to describe the disorder.2 3-Methoxytyramine In 2003, the International Myeloma Working Group (IMWG) defined diagnostic criteria differentiating MGUS from MM, Waldenstrms macroglobulinemia (WM), and other non-Hodgkin lymphomas (NHLs), based on the type of M-protein, its concentration, degree Dig2 of bone marrow infiltration of plasma cells or lymphoplasmacytic cells, and presence of certain clinical manifestations (the CRAB 3-Methoxytyramine criteria).3The term smoldering MM (SMM) was introduced to distinguish a more advanced premalignant stage 3-Methoxytyramine with a higher risk of progression but still not requiring treatment.4There are 3 types of MGUS with distinct natural histories: non-IgM-(IgG or IgA)-MGUS, IgM-MGUS, and light-chain-MGUS.5,6Although IgG and IgA- and light-chain-MGUS typically progress to MM or develop light chain amyloidosis, IgM-MGUS cases more often progress to WM or other NHLs. Data from the Mayo Clinic suggest that MGUS is present in 3% of the general white population 50 years of age and is predominantly incidentally diagnosed.7,8Although 2 independent studies indicate that MGUS always precedes MM,9,10the majority of MGUS patients do not progress to a lymphoproliferative disorder. The average risk of progression is estimated to be 1%/yr, and the 25-year.