Final Diagnosis -- Monoclonal gammopathy of undetermined signaficance (MGUS)


Follow up:

The patient's last two follow-up SPEP samples from this current year showed no significant change in the beta fraction; therefore, no new immunofixation characterization was sought. The beta fraction went from 1.29 g/dL (9/06) to 1.30 g/dL (1/08) to 1.36 g/dL (3/08) (nL range 0.60-1.10). Unfortunately, no urine protein electrophoresis or serum free light chain analysis were done to further characterize the patient's risk of malignant transformation. Currently, the patient remains stable with no evidence of malignant transformation. His weight loss and fatigue have resolved and his presenting symptoms were attributable primarily to his chronic alcohol abuse, anemia of chronic disease, and refractory hypertension.


When reading SPEP gels, one must be alert to the fact that an M-protein may be hiding in beta zone. These paraproteins are not limited to IgA monoclonality but may also be IgG or even IgM monoclonality. Definite diagnosis is derived with more sensitive testing via immunofixation electrophoresis. Given the patient's history of anemia, one must rule out elevated transferrin as a cause of the beta zone elevation; however, elevated transferrin is seen in iron deficiency anemia, and this patient's iron studies were within normal limits.

One must always keep in mind that fibrinogen may be a cause of a beta zone elevation. If a fibrinogen band is suspected, thrombin can be added to the serum sample. If a clot is formed then fibrinogen was in the sample and should be removed. Newer, simpler methods to remove fibrinogen are being investigated such as precipitation with ethanol.1 Other analytes that can increase the beta fraction include complement (C3), beta-liproprotein, and c-reactive protein (CRP). In practice, however, C3 is a liable protein that is usually degraded into components. Even with more sensitive testing using high resolution SPEP, the typical C3 band (which migrates in the beta-2 region) is usually not seen. Subsequently, there can be a concomitant increase in the beta-1 zone from these broken down components.2 Beta-lipoprotein should be distinguished by its distinctive shaped banding pattern, which can be found between alpha-2 to beta-2 regions.

Lastly on the differential of a beta zone elevation is a monoclonal immunoglobin, which can result from a number of diseases. The most notable malignancy is multiple myeloma, with Waldenström's Macroglobulinemia, other B-cell neoplasms, and systemic AL (Immunoglobulin Light Chain) amyloidosis included in the differential. Lastly, Monoclonal Gammopathy of Undetermined Significance (MGUS) is a disease of uncertain malignant potential, sometimes referred to as a "pre-malignant" condition that results in a low level monoclonal gammopathy.

Multiple myeloma (MM) is a malignant proliferation of plasma cells that produces a significant serum monoclonal protein (>2.5 g/dL). It is diagnosed by the combination of SPEP findings and bone marrow biopsy showing greater than 10% of plasma cells (expressing CD38 and CD138), along with predominant clinical symptoms of bone pain/fracture (from lytic bone lesions), fatigue (from anemia), and renal failure (from hypercalcemia and/or Bence Jones proteinuria).3 While our patient did experience weight loss and fatigue with anemia, there was no suggestion of lytic bone involvement (no bone pain or hypercalcemia), and he had a low level monoclonal protein of 0.52 g/dL. The patient's anemia was diagnosed as anemia of chronic disease and not attributed completely to his monoclonal gammopathy diagnosis.

Waldenström's Macroglobulinemia is also considered in the differential; however, this disease is usually characterized by a monoclonal IgM immunoglobulin produced by a clonal malignancy of well-differentiated lymphocytes that display plasmacytoid features.3 Clinical features include anemia, lymphadenopathy, and splenomegaly, with some patients also suffering from hyperviscosity syndrome and cryoglobulinemia with Raynaud's syndrome and vasculitis.3

Another cause of monoclonal immunoglobin production that can cause a beta zone elevation is systemic AL amyloidosis or primary amyloidosis. This type of amyloidosis is caused by a clonal disorder of plasma cells or lymphocytes that usually produce only a portion of a monoclonal light chain rather than an intact light chain, causing fibrillar protein deposition in various organs. Diagnosis is made by tissue biopsy or aspirate of subcutaneous fat showing Congo red staining, with confirmatory AL deposition by specific immunoperoxidase staining.4 Clinical symptoms/signs are related to end-organ damage due to deposition of the light chain amyloid, which includes nephrotic syndrome, axonal neuropathy, and restrictive cardiomyopathy. Some patients also show purpura and macroglossia.4 The exact mechanism of disease is not fully realized, but it may involve certain translocations of the IgH gene, which is seen in a majority of patients primary amyloidosis.4 Monoclonal Gammopathy of Undetermined Significance (MGUS) is the diagnosis of exclusion, based on a low level monoclonal gammopathy (a monoclonal peak below 3 g/dL) and no clinical symptoms or signs to suggest any of the aforementioned diseases. Usually a bone marrow is not performed for a low level monoclonal gammopathy, but when done, shows less than 10% plasma cells (median is approximately 3%5, with a normal marrow containing up to 4% of plasma cells6). MGUS is considered a pre-malignant disease, in that malignant transformation occurs in about 1.5% of MGUS patients per year, for which continued SPEP follow-up is necessary to monitor progression.

Specific risk factors beside age that increase progression to malignant disease are not fully realized. There has been mention in the literature that African-American race is a risk factor for transformation. However, a recent large-scale study of 2 million VA veterans, 2000 of which were MGUS patients, showed that there was no significant difference in the cumulative risk of developing multiple myeloma between Caucasian and African-American MGUS patients, over a 10-year period.7 There was, however, a 3-fold increase in the age-adjusted prevalence rate of MGUS in African-Americans as compared to Caucasians. This would suggest that race is not a risk factor per se for transformation but rather a risk factor for "pre-malignancy."7

Newer studies are now showing that additional risk factors, including larger size of the M-protein (>1.5 g/dL), type of M-protein (Non-IgG), bone marrow plasma cell percentage between 6-9%, and, most recently, abnormal serum free light chain (sFLC) ratio, are all important prognostic factors for malignant transformation (see table).8 An abnormal sFLC ratio of κ/λ was an independent risk factor for malignant progression (to MM, IgM lymphoma, primary amyloidosis, macroglobulinemia, CLL, and plasmacytoma) in a large scale study of over 1000 MGUS patients followed over a median of 15 years.9 Therefore, following the serum free light chain ratio, in addition to the M-protein size, seem to both have important prognostic information for predicting what patients have a higher likelihood of malignant transformation and therefore should be monitored more closely.

Table. Risk stratification to predict progression of MGUS8.


  1. Qiu L, et al. Convenient and Effective Method for Removing Fibrinogen from Serum Specimens before Protein Electrophoresis. Clinical Chemistry. 2003:49(6);868-872
  2. Keren D. Procedure for the Evaluation of Monoclonal Immunoglobulins. Arch of Pathol and Lab Med. 1999;123(2):126-132.
  3. Alexanian R et al. Differential Diagnosis of Monoclonal Gammopathies. Arch of Pathol and Lab Med. 1999;123(2):108-113.
  4. Mayo Medical Laboratories Education Department. Monoclonal Gammopathy of Undetermined Significance, Waldenström Macroglobulinemia, AL Amyloidosis, and Related Plasma Cell Disorders: Diagnosis and Treatment. 2006. URL: Accessed July 20, 2008.
  5. Reed M et al. Morphologic manifestations of monoclonal gammopathies. Am J Clin Pathol 1981;76:8-23.
  6. Attaelmannan. Understanding and Identifying Monoclonal Gammopathies. Clin Chem. 2000;46:8(B):1230-1238
  7. Landgren O et al. Risk of monoclonal gammopathy of undetermined significance (MGUS) and subsequent multiple myeloma among African American and white veterans in the United States. Blood. 2006;107(3):904-906.
  8. Rajkumar SV, et al. Presence of an abnormal serum free light chain ratio is an independent risk factor for the progression of MGUS. Br J Haematol. 2004;127(3):308-310.
  9. Rajkumar SV, et al. Serum free light chain is an independent risk factor for progression in monoclonal gammopathy of undetermined significance. Blood. 2005;106(3):812-817.
  10. Blade J, et al. Monoclonal gammopathies of undetermined significance. In: Myeloma Biology and Management. Eds: JS Malpas, DE Bergsagel, RA Kyle. Oxford University Press, 1995. New York.

Contributed by Jennifer Picarsic, MD and Dimitry Gutkin, MD, PhD

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