Monoclonal Gammopathy of Undetermined Significance and Smoldering Myeloma: New Insights into Pathophysiology and Epidemiology

Abstract

Routine screening for monoclonal gammopathy of undetermined significance (MGUS) is not indicated. Despite this fact, MGUS is a common finding in medical practice. Almost all individuals diagnosed with MGUS represent incidental cases diagnosed when physicians order serum protein electrophoresis, immunofixation, or both, as part of the work-up of a number of common symptoms and laboratory abnormalities. In the absence of reliable molecular predictors of outcome, the detection of an early precursor state typically imposes a complex situation for the patient and the responsible physician-usually, it leads to a lot of questions that lack clear answers. In the past years, several novel insights have been gained in the area of multiple myeloma (MM) precursor disease. This review focuses on results from recent investigations and discusses implications for diagnostic work-up, clinical management, and patient counseling. More specifically, it sheds light on the following commonly asked questions by patients and physicians: i) what is the risk of progression from precursor to full-blown MM, and are there ways to risk-stratify patients?; ii) is MM always preceded by a precursor state, and is there anything that could or should be done to delay or prevent progression?; and iii) why do some individuals develop MM precursor diseases, and is there a reason to screen the family? Definitions and Epidemiology From 'Benign Monoclonal Protein' to Monoclonal Gammopathy of Undetermined SignificanceThe concept of monoclonal versus polyclonal gammopathies was initially raised in 1960 by Jan Waldenström, 1 who described patients with a narrow band of hypergammaglobulinemia on electrophoresis as having a monoclonal-or M-protein. Many of these patients had multiple myeloma (MM) or macroglobulinemia, while others had no evidence of malignancy. Waldenström considered these patients to have "essential hypergammaglobulinemia" or a "benign monoclonal protein."Based on the observation that otherwise healthy individuals with these protein abnormalities turned out to have an excess risk of developing MM, Waldenströ m's macroglobulinemia, light-chain amyloidosis, or related disorders, Robert Kyle coined the term "monoclonal gammopathy of undetermined significance" (MGUS) in 1978. 2 According to diagnostic criteria provided by the International Myeloma Working Group (IMWG) in 2010, 3 MGUS is defined as follows (and all three criteria must be met): i) serum monoclonal protein under 3 g/dL; ii) clonal bone marrow plasma cells under 10%; and iii) absence of end-organ damage such as hypercalcemia, renal insufficiency, anemia, and bone lesions that can be attributed to the plasma-cellproliferative disorder.Screening studies have found MGUS to be present in approximately 3.2% of Caucasians above the age of 50 years. 4 Prevalence appears to be roughly twice as high among African men, African-American women, and obese individuals. 5,6 Chronic antigen stimulation 7-11 and pesticide exposure have also been associated with an excess risk of MGUS/MM. 12,13 Rece...

Monoclonal gammopathy related to Sjögren syndrome: A key marker of disease prognosis and outcomes

“…Previous studies have estimated that as many as 10% of patients with SS and monoclonal gammopathy develop hematological neoplasia [20]. This association depends on the mIg isotype, with IgM being the most common class associated with B-cell lymphoma and IgG with MM (in other series) [38], as reported in patients with MGUS [13]. However, strikingly, no patient developed MM in our series.…”

“…Therefore, monoclonal gammopathy should be considered as a frequent immunological marker of primary SS. Recent studies of patients with MGUS have suggested a prognostic role for the isotype of the monoclonal band, and the Mayo Clinic prognostic model has included a non-IgG isotype as a risk factor for multiple myeloma [13]. The predominant isotype in our primary SS patients was IgGk, as was also found in the abovementioned meta-analysis [20] and in large series of patients with MGUS [35].…”

“…The prevalence of MGUS increases with age, from <2% in people aged <40 years to 5% in those aged >70 years and 9% in those aged >85 years [5,7e11]. Recent reviews [4,12,13] of MGUS pay very little attention to the non-hematological causes, especially systemic autoimmune diseases, which is surprising taking into account the close association between monoclonal gammopathy and some of these diseases, such as cryoglobulinemia [14] or SS [15]. In the 1980s, Moutsopoulos et al…”

Paraproteinemic neuropathy

“…10 Approximately 1% of patients with MGUS transform into symptomatic plasma cell disorders annually. 11 An initial paraprotein or M-protein concentration of >15 g/L, the detection of an IgM or IgA paraprotein, and an abnormal free-lightchain ratio (free kappa/lambda ratio; normal range = 0.26-1.65) are related to an increased risk of a malignant evolution. 8,12 In patients with MGUS presenting with peripheral neuropathy, progressive weight loss, progression of the neuropathy, and an M-protein level of >1 g/L also have been identified as independent predictors for a malignant transformation.…”

“…51 The diagnosis of MM is usually based on the following clinical findings: (1) serum M-protein, (2) BenceJones proteinuria, (3) increased bone-marrow plasma cells (≥10%), and (4) evidence of end-organ damage, such as hypercalcemia (serum calcium ≥ 11.5 mg/dL), renal insufficiency (serum creatine >1.73 mmol/L), anemia (normochromic, normocytic with a hemoglobin level of >2 g/dL below the lower limit of normal, or a hemoglobin level of <10 g/dL), or osteolytic bone lesions. 8,11 About 50% of patients have an…”