S26 EXABS-121-MM MGUS/SMM: Incidence, Evaluation and Follow-up Timothy Schmidt, MD1, and Natalie S Callander, MD1,* University of Wisconsin, Madison, USA *Corresponding author: nsc@medicine.wisc.edu Keywords MGUS, smoldering myeloma, evaluation Abstract Monoclonal proteins are common, with a prevalence in the United States around 5% that increases with age. Although most patients are asymptomatic, the vast majority of cases are caused by a clonal plasma cell disorder. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are asymptomatic precursor conditions with variable risk of progression to multiple myeloma (MM). In recent years, significant progress has been made to better understand the factors that lead to the development of symptoms and progression to MM. Monoclonal Gammopathy of Undetermined Significance Background The International Myeloma Working Group defines MGUS as the presence of a monoclonal protein (M protein) detected by either serum or urine protein electrophoresis, or unexplained free light chain (FLC) excess in the absence of a monoclonal IgH heavy chain, with the monoclonal protein <3g/dl and fewer than 10% clonal plasma cells on bone marrow biopsy.1 In addition, the definition of MGUS requires that the individual have no symptoms of clinical myeloma (CRAB criteria, e.g. hypercalcemia, renal dysfunction, anemia, and/or lytic bone disease). MGUS incidence varies greatly based on ethnicity and age, with the lower levels encountered in Asia, approximately 0.4–2%2,3 compared to Northern Europe and North America, where one study found an MGUS incidence of 6.1% in the US.4 MGUS incidence increases with age,5 e.g. 3–4% of the population aged 50–60, compared to approximately 10% of octogenarians. Landgren et al found that African American subjects in the NHANES study developed MGUS at a higher level but also an earlier age, compared to Caucasian and Mexican American individuals.6 Obesity has also been associated with an increased risk of MGUS,7 as well as progression to MM.8 Search for a genetic cause of MGUS led to the discovery of hyperphosphorylated Paratarg-7 (pP-7), a protein that may serve as an autoantigen driving chronic antigen stimulation and has been found in both familial and sporadic MGUS. The inheritance of pP-7 was associated with nearly 8-fold increased risk of developing MGUS9 and appeared to be detected more frequently in African-Americans than Caucasians with MGUS.1 Other loci that may be important in the development of MGUS and MM have been found in GWAS studies, including 3p22.1 (rs1052501), 6p21.33 (rs2285803), 7p15.3 (rs4487645), and 17p11.2 (rs4273077).11 Certain environmental exposures have also been associated with the development of MGUS, include Agent Orange,12 pesticides,13 and most recently participation in the 9/11 rescue operation.14 Because the majority of individuals found to have MGUS will never go on to develop a symptomatic plasma cell disorder, routine screening for MGUS is not recommended. However, previous studies have found an increased risk of MGUS in first-degree relatives of patients with MM or other blood disorders.15–18 This risk seems even greater in first-degree relatives of African American MM patients. Two large studies are underway to see if screening of such individuals will ultimately reduce the MM burden through early detection of precursor states – the iSTOPMM (Iceland Screens, Treats or Prevents Multiple Myeloma, has found the incidence of MGUS to be 4.9% in 75,422 adults over the age of 5019 and the US study, PROMISE which investigated rates of MGUS using mass spectrometry and found a staggering 43% of individuals had some sort of monoclonal protein, most of which were insignificant. These efforts are important because it is clear that MGUS nearly always precedes the development of MM.21,22 Diagnosis and Evaluation The diagnosis of MGUS requires demonstration of a monoclonal protein, which is typically determined by serum protein electrophoresis (SPEP) or less often by urine protein electrophoresis (UPEP) and classified by immunofixation (IFE). MGUS is generally divided into three types – non-IgM MGUS (i.e. IgG or IgA, or rarely IgD and IgE), IgM MGUS and light chain MGUS. Light chain MGUS is defined as an abnormal free light chain ratio, elevation in appropriate light chain and absence of Ig heavy chain on immunofixation.23 Once a patient is found to have a monoclonal protein, the patient must be evaluated with attention to any symptoms or other clinical elements that would potentially change management strategy. The presence of such symptoms may indicate that the patient has underlying MM but can also be associated with conditions such as AL amyloidosis, POEMS, or MGCS. MGUS patients with
RkJQdWJsaXNoZXIy MTk3NTQxMg==