For Physicians

Monoclonal Gammopathy of Undetermined Significance (MGUS) (2009)

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It is not rare that a routine screening protein electrophoresis in asymptomatic individuals uncovers an incidental monoclonal gamma globulin, or "M protein spike". The source of this abnormal protein is a clonal population of plasma cells in the bone marrow which secretes a specific type of monoclonal globulin. In about 45% of patients the M protein, or monoclonal gammopathy, is a marker for an already serious underlying disease, mainly multiple myeloma/plasmacytoma , but also AL amyloidosis, macroglobulinemia, and lymphoproliferative disorders. On the other hand, about 55% of cases have no symptoms and no signs of an obvious underlying disease. This group has been designated "monoclonal gammopathy of undetermined significance", abbreviated as MGUS. Although historically thought of as a benign condition, MGUS is in fact a marker of a lifelong risk for the development of any one of the serious diseases mentioned above1.

Definition, Incidence, and Characteristics

The contemporary definition of MGUS is: serum M protein of 3 g/dL or less, absence of end-organ disease, anemia, or hypercalcemia, and <10% clonal plasma cells in the bone marrow4. This definition is consistent with that proposed by the International Myeloma Working Group. Furthermore, in the normal population the detection of MGUS correlates with age; it was found in 1.7% at ages 50-59, 3% at ages 60-69, and 6.6% at age > 804.

The prevalence of MGUS in the general healthy population has varied widely from 0.3 to 6.1%. This variation mainly is due to lack of a precise definition, over-sampling certain ethnic and geographic groups, and the use of old-fashioned screening methods. Using the precise criteria described above, in a healthy well-defined U.S. population the overall incidence of MGUS was 3.2%4. Almost 70% were IgG, 17% IgM, 11% IgA, and 3% biclonal. Light chains were kappa in 62% and lambda in 38%. M protein was < 1 g/dL in almost two-thirds of cases, too low to measure in 13%, and the highest value was 2.94 g/dL. The concentration of uninvolved immunoglobulins was reduced in 28%. Light chains (Bence-Jones protein) were found in 22% of the urines tested. IgM MGUS frequently predicted subsequent progression to lymphoma or Waldenstom's macroglobulinemia. Progression of non-IgM MGUS usually resulted in plasma cell disorders or amyloidosis4.

Significance of MGUS

MGUS is one of the most prevalent premalignant disorders in the world for individuals age 50 and older. Two recent studies have provided evidence of premalignancy since virtually all cases of overt multiple myeloma (MM) were preceded by a MGUS precursor state. Both studies assessed blood samples collected and stored many years before myeloma became overt, and found an M protein in virtually every case, and as well as an abnormal free light chain ratio (FLC)(see below) in up to 85%2,3. In some cases the M protein and FLC ratios showed year-by-year increases, while in others these abnormalities remained largely stable right up to the abrupt diagnosis of myeloma. Thus, stable tests do not exclude ultimate transformation to malignancy3. Furthermore, first degree relatives of individuals with MGUS have a 3-fold increased risk for myeloma or MGUS. This suggests a role for susceptibility genes and/or immune-related factors in causation of MGUS and multiple myeloma.

Detection Procedures

The intact gamma globulin molecule is comprised of two light chains (either kappa or lambda) attached to a single heavy chain. Each plasma cell produces only one type of heavy and one type of light chains; thus the normal situation is a mixture of different gamma globulin molecules (G,A,M,D,E) secreted by a variety of plasma cells. However, with monoclonal gammopathies a single clone of plasma cells over-secretes one type of immunoglobulin. To detect this, current recommendations advise serum protein electrophoresis (SPEP), and if a discrete band is identified, this is followed by immunofixation electrophoresis (IFE), which identifies the specific immunoglobulin causing the M protein4.

A third test, which has become increasing important, is the measurement and analysis of к and λ serum free light chains (FLC) by immunonephelometry (FREELYTE assay). For unknown reasons, plasma cells typically produce more light chains than are required to form intact immunoglobulin molecules and the excess к and λ FLC enter the blood where they can be measured as free or unbound light chains. The normal к/λ ratio is 0.26-1.65 although usually there are approximately twice as many free к as free λ light chains. SPEP and IFE tests are fairly insensitive to FLC, since the levels must be quite high (50 to 15 times normal respectively) to be detected as an abnormal band. Although excellent for serum testing, the FLC test is inaccurate for 24 urine light chain testing, which still has to be performed by protein electrophoresis.

Excessive secretion of FLC may occur in the presence of an abnormal clone of plasma cells. Therefore, in patients with MGUS, FLC testing has become a very important addition to screening and follow-up. The concentration of free light chains and the ratio of к to λ initially is normal in two-thirds of patients and is abnormally increased in about one-third6. If the level of one light chain type increases steadily over time and the ratio of к to λ is altered, this is predictive for possible malignant transformation. Therefore, following the concentration and ratio of serum free light chains provides useful prognostic information and should be added to SPEP and IFE as part of the evaluation and follow-up of MGUS patients5,6.

Progression To Malignancy

A very reliable study of 241 patients with MGUS had a median follow-up of 13.7 years (range 0-39). 27% developed multiple myeloma, macroglobulinemia, amyloidosis, lymphoproliferative disease, or related disorders, with an actuarial rate of progression of approximately 1.5% per year. 69% of the malignancies were multiple myeloma1. Other studies from Spain, Denmark, and Iceland reported similar results confirming that the risk of progression from MGUS to myeloma or a related disorder is about 1% per year 1.

Two major patterns of evolution to myeloma have been described. In about half the cases there was a year-by-year increase in M protein and FLC ratio, while the other half remained largely stable for long periods until a sudden transformation to myeloma occurred2. In an attempt to separate high risk from low risk MGUS, the Mayo Clinic classification has identified the following adverse risk factors: non-IgG gammopathy, > 1.5 g/dL M protein concentration, and abnormal FLC ratio. Spanish investigators instead use flow cytometry of bone marrow aspirates to identify "aberrant plasma cells" with abnormal cell surface phenotypes. The flow findings, in combination with total marrow plasma cells at diagnosis, and DNA aneuploidy, comprise three risk factors that have been successfully used to predict progression7.

Although it has not been absolutely proved that annual follow-up of the M protein of MGUS patients is of value, it seems reasonable to do so since myeloma with its attendant complications may emerge suddenly in patients with intermediate/high risk MGUS. This is supported by the International Myeloma Working Group (IMWG) guidelines which state that after initial diagnosis, low-risk MGUS should be evaluated by SPEP, IFE, and FLC assay again in 6 months, and if there is no change, every 2 or 3 years unless symptoms arise. For high risk MGUS, the guidelines state that a bone marrow should be performed at diagnosis and re-evaluation of the M protein should take place in 6 months, then if stable, annually for life6,8. The combination of these three serum screening tests negates the need for 24 hour urine studies when screening for plasma cell disorders (with the exception of AL amyloidosis).

Unfortunately, at present there are no comletely reliable immunophenotypic, molecular, or genetic markers to differentiate plasma cells destined to progress to smoldering or overt multiple myeloma. Progression is suspected to result from intrinsic changes within the plasma cells as well as extrinsic influences of cytokines, stromal cells, and immunologic factors, but the precise mechanism is not understood. In the meantime, MGUS remains an exceedingly common premalignant condition that requires lifelong follow-up.

References:

  1. Kyle R., Br J Haem, 2007, 139:730
  2. Landgren O., Blood, 2009, 113(22):5412
  3. Weiss B., Blood, 2009, 113(22):5418
  4. Kyle R., NEJM, 2006, 354:13
  5. Bakker A., Clin Chem Lab Med,2009, 47(12):1507
  6. Dispenzieri A., Leukemia, 2009,23:215
  7. Perez-Persona E., Blood, 2007, 110(7):2586
  8. IMWG Criteria for Classification, 2003,Br J Haematol, 121(5):749

This newsletter is meant as a review and not as a guideline for medical treatment.

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