Monoclonal gammopathy of undetermined significance

Monoclonal gammopathy of undetermined significance

What every physician needs to know about monoclonal gammopathy of undetermined significance:

Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant asymptomatic disorder, characterized by the presence of a monoclonal protein (M-protein) in the absence of end-organ damage, that can be attributable to plasma cell proliferation.

It is defined by the presence of a serum monoclonal immunoglobulin level under 3g/dl and less than 10% clonal plasma cells in the bone marrow, with no features related to other malignancy.

It is important for clinicians to distinguish MGUS from other plasma cell disorders in order to determine prognosis, and disease management. The International Myeloma Working Group (IMWG) established the guidelines of diagnostic criteria for plasma cell disorders in 2010. (See Table I)

Table I.

Diagnostic criteria for plasma cell disorders
Disease entity Disease definition Clinical characteristics
MGUS Serum monoclonal protein level less than 3g/dlLess than 10% bone marrow clonal plasma cellsNo evidence of other B-cell lymphoproliferative disorder Absence of end organ damage defined by lytic bone lesions, anemia, hypercalcemia and renal insufficiency that can be attributed to a plasma cell disorder
Smoldering multiple myeloma Serum monoclonal protein greater than or equal to 3g/dl (immunoglobulin G [IgG] or IgA) and/orbone marrow clonal plasma cells greater than or equal to 10% Absence of end organ damage defined by lytic bone lesions, anemia, hypercalcemia, and renal insufficiency
Multiple myeloma Presence of serum and/or urine monoclonal protein (except in patients with nonsecretory myeloma), or abnormal serum free light chain ratio plusany % of marrow plasma cells or presence of plasmacytoma Evidence of end organ damage secondary to a plasma cell disorder defined by the (CRAB) criteria:    •  Hypercalcemia (serum calcium greater than 11.5mg/dl)    •  Renal insufficiency (serum creatinine greater than 2mg/dl or an estimated glomerular filtration rate less than 40mL/min    •  Anemia (hemoglobin less than 10g/dl or greater than 2g/dl below the normal reference value)    •  Lytic bone lesions, pathalogic fractures or severe osteopenia

The annual rate of transformation from MGUS to multiple myeloma (MM), or another related disorder such as B-cell lymphoma, Waldenstrom's macroglobulinemia and immunoglobulin light chain amyloidosis (AL), is approximately 1%. The rate of progression does not decrease over time, with a probability of progression at 25 years follow-up of approximately 25 to 30%. Patients with smoldering multiple myeloma (SMM) have a higher degree of disease involvement, characterized by an increase in the serum M-protein and a higher percentage of clonal plasma cells in the marrow. The annual rate of transformation from SMM to MM is approximately 10% in the first 5 years following diagnosis, with a median time to progression of 2 to 3 years.

The prevalence of MGUS increases with age. A screening population study found MGUS to be present in 3.2% of a population of 21,463 residents older than 50 years in Olmstead Country, Minnesota. The prevalence of MGUS was 5.3% among those older than 70 years of age.

There have been reports of familial predisposition of plasma cell disorders. A large population study found a two fold increased relative risk for MM, among 37,838 first degree relatives of 13,896 MM patients, compared with 151,068 first degree relatives of 54,365 matched controls. A prospective study found that the relative risk of MGUS was three fold higher than in the general population. These differences in frequency of MGUS by race, ethnicity, and familial predisposition, suggest that genetic and environmental factors likely play a role in the pathogenesis of these disorders.

It is more common in men (4% over age 50) than women (2.7% over age 50). African Americans have a two to three fold higher prevalence of MGUS compared to Caucasians. The risk is lower in Mexicans and Asians of Japanese descendent. Obesity and exposure to pesticides have also been associated with an increased risk of developing MGUS.

Immunoglobulin G (IgG) is the most common immunophenotype, followed by immunoglobulin A (IgA). Immunoglobulin M (IgM) MGUS which occurs in approximately 15% of cases, is usually associated with lymphoplasmacytoid histology and can involve extramedullary sites, such as lymph nodes and spleen. Up to 20% of MGUS patients have immunoglobulin light chain disease, that may be detected only by the serum free light chain assay.

What features of the presentation will guide me toward possible causes and next treatment steps:

Discovering MGUS

MGUS is typically discovered unexpectedly after a routine blood test reveals the presence of an elevated total protein concentration, and a follow-up serum protein electrophoresis reveals a monoclonal spike. Patients with MGUS are asymptomatic and do not show physical signs related to their condition. It is commonly found by primary care physicians while investigating a broad-spectrum of symptoms and disorders such as fatigue, vasculitis, hemolytic anemia, arthralgias, neuropathies, and skin rashes.

Transformation of MGUS to MM

We currently lack the ability to predict the risk of progression for individual patients with MGUS to symptomatic MM. However, there are several laboratory parameters that are useful at predicting the likelihood of transformation.

Retrospective epidemiologic studies have reported that patients with a serum M-protein concentration greater than 1.5g/dl, non-IgG MGUS, and abnormal serum free kappa/lambda light chain ratio, defined as below 0.26 or above 1.65, are at higher risk to progress to MM.

Two major models of risk stratification have been proposed:

  • The Mayo Clinic model

- The Mayo Clinic model is based on these three parameters (serum M-protein concentration, non-IgG MGUS, and abnormal serum free kappa/lambda light chain ratio). In this model, patients with all three factors had a 58% absolute risk of progression to MM, over a follow-up period of 20 years. For patients with two, one or zero risk factors, the likelihood of transformation was reduced to 37%, 21%, and 5%, respectively.

  • The Spanish PETHEMA (Programa para el Estudio de la Terapeutica en Hemopatia Maligna) group model

- The Spanish PETHEMA (Programa para el Estudio de la Terapeutica en Hemopatia Maligna) group model is based on the total number of plasma cells in the bone marrow aspirate at diagnosis, and the percentage of phenotypically aberrant plasma cells, which is determined by flow cytometric analysis. In 93 SMM patients and 407 MGUS patients, the percentage of aberrant plasma cells equal or greater than 95% of the total plasma cell population, and DNA aneuploidy, were recognized as independent risk factors for progression to MM. In the MGUS group, patients with zero, one or two risk factors, the risk of progression was 2%, 10% and 46%, respectively.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

Laboratory studies required:

  • Complete blood count with differential

  • Serum creatinine concentration

  • Calcium level

  • Protein studies:

- Serum protein electrophoresis (SPEP), is the preferred method used to detect serum monoclonal protein concentration.

- Serum immunofixation (IFE), distinguishes the immunoglobulin class and type of light chain.

- Serum free light chain assay, allows for quantification of free, unbound light chain. Clonal production of either kappa or lambda light chain by the clonal plasma cells disrupts the normal ratio between these two proteins. It should be obtained in all patients with newly diagnosed MGUS, due to its prognostic value.

- 24 hour urine protein excretion and urine electrophoresis (UPEP) with immunofixation, to detect and quantify M-protein in the urine.

  • Bone marrow biopsy and aspirate:

- These should be obtained in patients with a monoclonal protein greater than 1.5g/dl, an abnormal serum free light chain ratio, in non IgG MGUS, and in patients with any evidence of CRAB criteria. The biopsy may show a minimal increase in plasma cells that are interstitial or scattered throughout the marrow. The plasma cells are generally mature appearing with occasional changes, such as cytoplasmic inclusions and nucleoli.

  • Cytogenetic analysis

- This is performed using methaphase karyotype and fluorescence in situ hybridization (FISH) for the most common mutations seen in MM including deletion 13q, deletion 17p, t(11;14), and t(14;16). Karyotype is usually normal in MGUS, because of the small number of plasma cells with a low proliferative rate. FISH studies have demonstrated abnormalities in the majority of MGUS patients while the prevalence may vary in comparison to MM. These genetic abnormalities lack clinical correlation and none have yet been found to predict progression from MGUS to MM.

What conditions can underlie monoclonal gammopathy of undetermined significance:


When do you need to get more aggressive tests:


What imaging studies (if any) will be helpful?

A skeletal survery is not a standard procedure, but it is recommended in patients with intermediate and high risk MGUS, and in any patient with signs and symptoms concerning for MM. In patients with IgM MGUS, a computed tomography (CT) scan should be considered, to evaluate for lymphadenopathy and organomegaly.

What therapies should you initiate immediately and under what circumstances – even if root cause is unidentified?

Patients with MGUS are relatively healthy and asymptomatic from their condition. We should emphasize that these patients have a low lifelong risk of progression.

At this time, there are no known interventions or chemotherapy agents proven to delay progression of MGUS to symptomatic disease, or to prolong survival, therefore treatment is not indicated. Based on the International Myeloma Working Group recommendations, patients with MGUS should not be treated outside of clinical trials.

Some studies are currently investigating the effect of medications to decrease the risk of progression, including the immunomodulatory agent lenalidomide, biphosphonates and the cyclooxygenase-2 (COX-2) inhibitor, celecoxib. The efficacy of these medications is currently unknown.

What other therapies are helpful for reducing complications?


What should you tell the patient and the family about prognosis?

MGUS is a common finding in clinical practice. Patients newly diagnosed with MGUS should be counseled that this is not considered a neoplastic condition, since the majority of patients will not evolve to MM or lymphoproliferative neoplasms. However, the risk of transformation is lifelong, and patients should be educated to report any concerning symptoms to their physicians.

Patients should be followed appropriately to detect early disease progression, prior to the development of complications such as renal insufficiency and pathologic fractures. The M-spike usually remains stable with small fluctuations in its concentration, until MM develops.

Patients are at higher risk for developing venous thromboembolism, osteoporosis, and fractures, even in the absence of progression to MM. There has also been an association of reduced life expectancy, increased risk of bacterial infections, and heart, liver and renal diseases. However, this higher rate of complications may be due to the underlying comorbid conditions that led to the detection of monoclonal gammopathy.

Recent studies have reported familial aggregation patterns in plasma cell dyscrasias. Nonetheless, the risk of a first degree relative of developing any of these conditions is low. Since no therapeutic interventions have demonstrated to prolong survival, it is not recommended screening family members outside of research studies.

“What if” scenarios.



The pathogenesis of MGUS is not clearly understood. It is thought that MGUS arises from a malignant clone of plasma cells or lymphocytes. MGUS has been reported to be associated with other diseases.

It is occasionally seen in other hematologic malignancies such as chronic lymphocytic leukemia, B and T-cell lymphomas, hairy cell leukemia, and chronic neutrophilic leukemia.

It has also been related to autoimmune disorders such as systemic lupus erythematosus and rheumatoid arthritis, acquired immunodeficiency syndromes, peripheral neuropathies, acquired angioedema, lichen myxedematosus, and pyoderma gangrenosum.

MGUS also occurs as a result of chronic liver diseases, in particular hepatitis C infection.

Transient oligoclonal and monoclonal gammopathies have been observed in immunosuppressed patients following hematopoietic stem cell and solid organ transplants.

What other clinical manifestations may help me to diagnose monoclonal gammopathy of undetermined significance?

Presenting symptoms related to anemia such as fatigue, generalized weakness and dyspnea, bone or back pain, are suggestive of multiple myeloma.

Patients with constitutional symptoms including fever, night sweats, and unintentional weight loss, in the presence of lymphadenopathy and/or hepatosplenomegaly suggest lymphoma.

The manifestation of coagulopathy, purpura, peripheral neuropathy, and signs of heart failure such as lower extremity edema would suggest amyloidosis. In addition to these findings, patients with IgM MGUS in association with hyperviscosity syndrome would be suspicious of having Waldenstrom's macroglobulinemia.

In patients who presents with symptomatic disease with any of the CRAB criteria, additional testing to evaluate for malignancy is warranted and should include a bone marrow biopsy and appropriate imaging studies. It is moreover important to exclude other common conditions that could explain these abnormalities, for example, anemia secondary to chronic gastrointestinal bleeding or nutritional deficiencies like B12 or folate deficiency, renal dysfunction secondary to hypertensive or diabetic nephropathy, or hypercalcemia due to hyperparathyroidism.

What other additional laboratory studies may be ordered?

How should patients with MGUS be followed?

There are no enough data to guide optimal frequency for assessment. In 2010, the IMWG defined two risk categories and determined the following guidelines for patient management:

Low risk MGUS

Patients with a serum monoclonal protein less than 1.5g/dl, IgG type and normal free light chain (FLC) ratio. If at diagnosis the physical examination, blood counts, calcium levels, and kidney function are normal, a bone marrow biopsy of skeletal survey are not indicated. Patients should have a serum protein electrophoresis (SPEP) in 6 months and if stable, they can be followed every 2 to 3 years, while they remain asymptomatic.

Intermediate and high risk MGUS

Patients with a serum monoclonal protein greater than 1.5g/dl, IgA or IgM type, and or abnormal FLC ratio. These patients should have a bone marrow biopsy and aspirate and a skeletal survey at baseline. If there is concern of MM or Waldenstrom's macroglobulinemia, lactate dehydrogenase, B2-microglobulin, and C-reactive should be obtained. Patients should be followed with SPEP and complete blood count in 6 months, and then yearly.

What’s the evidence?

Kyle, RA, Durie, BJ, Rajkumar, SV. "Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management". Leukemia.. vol. 24. 2010. pp. 1121-1127.

[Summary of the International Myeloma Group recommendations on the diagnosis, prognosis, and management of monoclonal gammopathy of unknown significance and smoldering multiple myeloma.]

Kyle, RA, Therneau, TM, Rajkumar, SV. "Prevalence of monoclonal gammopathy of undetermined significance". N Engl J Med.. vol. 354. 2006. pp. 1362-1369.

[Population-based study that used serum protein electrophoresis to ascertain the prevalence of monoclonal gammopathies in a large geographically defined population that is well representative of the white population of the United States.]

Landgren, O, Weiss, B. "Patterns of monoclonal gammopathy of undetermined significance and multiple myeloma in various ethnic/racial groups: support for genetic factors and pathogenesis". Leukemia.. vol. 23. 2009. pp. 1691-7.

[Review of epidemiologic studies that examined the prevalence of MGUS in different ethnic and racial groups.]

Blade, J. "Monoclonal gammopathy of unknown significance". N Engl J Med. vol. 355. 2006. pp. 2765-2770.

[A clinical review on MGUS.]

Kyle, RA, Rajkumar, SV. "Monoclonal gammopathy of undetermined significance and smouldering multiple myeloma: emphasis on risk factors for progression". Br J Haematol. vol. 139. 2007. pp. 730-743.

[A clinical review on MGUS.]

Rajkumar, SV, Kyle, RA, Therneau, TM. "Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance". Blood.. vol. 106. 2005. pp. 812-817.

[Study that demonstrated that the risk of progression of patients with an abnormal serum free light chain ratio is significantly higher, compared with patients with a normal ratio at diagnosis. It also showed that non IgG MGUS and a high serum M-protein level greater than 1.5g/dl are adverse risk factors for progression.]

Perez-Persona, E, Vidriales, MB, Mateo, G. "New criteria to identify risk of progression in monoclonal gammopathy of uncertain significance and smoldering multiple myeloma based on multiparameter flow cytometry analysis of bone marrow plasma cells". Blood.. vol. 110. 2007. pp. 2586-92.

[The PETHEMA Study investigated the use of multiparameter flow cytometry analysis to determine the proportion of aberrant plasma cells in the bone marrow of patients with MGUS and SMM at diagnosis. Results suggested that the percentage of aberrant plasma cells and aneuploidy are valuable markers in the risk stratification of these disorders, and may help individualize therapeutic strategies and follow-up of MGUS patients.]

Vachon, CM, Kyle, RA, Therneau, TM. "Increased risk of monoclonal gammopathy in first-degree relatives of patients with multiple myeloma or monoclonal gammopathy of undetermined significance". Blood. vol. 114. 2009. pp. 785-90.

[Study that demonstrated a statistically significant increase in the prevalence of MGUS among first-degree relatives of patients with MGUS and multiple myeloma compared to a reference population.]

Landgren, O. "Monoclonal gammopathy of undetermined significance and smoldering myeloma: new insights into pathophysiology and epidemiology". Hematology Am Soc Hematol Educ Program.. vol. 2010. 2010. pp. 295-302.

[Review of MGUS and SMM presented at the American Society of Hematology meeting in 2010.]

Rajkumar, SV, Dispenzieri, A, Kyle, R. "Monoclonal Gammopathy of Undetermined Significance, Waldenstrom Macroglobulinemia, AL Amyloidosis, and Related Plasma Cell Disorders: Diagnosis and Treatment". Mayo Clin Proc.. vol. 81. 2006. pp. 693-703.

[Classification and diagnosis of plasma cell disorders.]
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