SUMMARY: Multiple Myeloma (MM) is a clonal disorder of plasma cells in the bone marrow. It evolves from a precursor stage called Monoclonal Gammopathy of Undetermined Significance (MGUS) to MM. Smoldering Multiple Myeloma (SMM) is an intermediate stage in this process of disease evolution. MGUS is defined as the presence of a serum monoclonal protein (M protein) at a concentration of 3 g/dl or less, urine with none or only modest amounts of monoclonal light chains, absence of CRAB features that are related to the M protein (Hypercalcemia, Renal insufficiency, Anemia, and Bone lesions) and 10% or fewer monoclonal plasma cells in the bone marrow. MGUS occurs in approximately 3% of individuals 50 years of age or older and in 5.3% of those 70 years of age or older.
MGUS is classified into two major subtypes, IgM and non-IgM. This is because the clonal cell that is involved and the nature of progression, differ between these two types. The origin of IgM MGUS is typically from a CD20 positive Lymphoplasmacytic cell that has not undergone Switch Recombination (Class-Switch Recombination or CSR, is a biological mechanism that changes a B cell production of immunoglobulin from one type to another, such as from the isotype IgM to the isotype IgG.), and this disease type is associated with a risk of progression to Lymphoma or Waldenström’s macroglobulinemia. In contrast, non-IgM MGUS typically arises from mature plasma cells that have undergone Switch Recombination and is associated with a risk of progression to Multiple Myeloma. Both disease types can progress to AL Amyloidosis.
There is limited information regarding malignant transformation of MGUS to Multiple Myeloma as well as Overall Survival, after diagnosis is made. Further, the risk of progression to Multiple Myeloma among the two major biologic subtypes of MGUS, IgM and non-IgM, is different, and data regarding the prognosis and risk stratification associated with these entities have not been well characterized. The authors in this publication, which is a longer follow up of previously reported findings, studied 1384 patients with MGUS, who were identified in a well-defined geographic area, from 1960-1994. The median follow up was 34.1 years. The Primary end point was progression to Multiple Myeloma or another Plasma-cell or Lymphoid disorder.
During 14,130 person-years of follow up, the rate of progression of MGUS to Multiple Myeloma was 6.5 times as high as the rate in the control population. The risk of progression to Multiple Myeloma was 10% at 10 years, 18% at 20 years, 28% at 30 years, 36% at 35 years, and 36% at 40 years. The risk of progression varied depending on the biologic subtypes of MGUS and other adverse risk factors. Among patients with IgM MGUS, the presence of two adverse risk factors – an abnormal serum free light chain ratio (ratio of kappa to lambda free light chains) and a high serum monoclonal protein level (1.5 g/dl or greater), was associated with a risk of progression at 20 years of 55%, as compared with 41% among patients who had one adverse risk factor and 19% among patients who had neither risk factor. Among patients with non-IgM MGUS, the risk of progression to Multiple Myeloma at 20 years was 30% among those who had the two risk factors, 20% among those who had one risk factor, and 7% among those who had neither risk factor. More importantly, patients with MGUS had shorter survival compared to age and sex matched control population (median 8.1 versus 12.4 years, P<0.001).
It was concluded that there were significant differences noted in the risk of progression between patients with IgM MGUS and those with non-IgM MGUS and Overall Survival was shorter among patients with MGUS than was expected in a matched control population. Long-Term Follow-up of Monoclonal Gammopathy of Undetermined Significance. Kyle RA, Larson DR, Therneau TM, et al. N Engl J Med 2018; 378:241-249
