MGUS is of clinical significance
What is MGUS?
Monoclonal gammopathy of undetermined significance (MGUS) is characterised by the presence of a monoclonal protein in the serum of asymptomatic individuals who do not meet the diagnostic criteria for Multiple Myeloma, AL amyloidosis, Waldenström's macroglobulinaemia (WM), lymphoproliferative disorders, plasmacytoma or related conditions.
It was first described in 1978¹. The name was chosen as some patients with MGUS would go on to develop Multiple Myeloma but not all. Since then, many publications have demonstrated that MGUS is of clinical significance, even in patients who do not go on to develop Multiple Myeloma².
What are the three types of MGUS?
MGUS is categorized into three types, depending on the type of monoclonal protein produced by the underlying clone. For all three types, the monoclonal protein must be present, at the concentrations presented in the table below, along with <10% clonal bone marrow cells, and an absence of the symptoms described in the bodily symptoms column3.
Diagnostic criteria |
||||||
% of MGUS patients |
Monclonal protein |
Tumour cells |
Bodily symptoms |
Primary progression |
Progression rate per year |
|
IgG MGUS and IgA MGUS (referred to as non-IgM MGUS) |
66% | Serum IgG or IgA M-protein <30g/L |
<10% BMPC |
No CRAB or amyloidosis | Multiple myeloma, solitary plasmacytoma, immunoglobulin related amyloidosis | 1% |
IgM MGUS |
12% | Serum IgM M-protein <30g/L |
<10% Lympho-plasmactic infiltration |
No anaemia, constitutional symptoms, hyperviscosity, LO, HSM, or other end-organ damage |
Waldenström’s macroglobulinaemia, Immunoglobulin related amyloidosis | 1.5% |
Who is at greater risk of developing MGUS?
Certain populations are at a higher risk of developing MGUS, such as older individuals, males, African Americans, and those with a family history of monoclonal gammopathy.
Age4,5
MGUS prevalence increases with age. It is rare in people younger that 40, but about 3-4% of individuals over the age of 50 and 5-7% over the age of 70 have MGUS.
Sex4
Men are slightly more likely to develop MGUS than women.
Race6,7
MGUS is more common in African Americans.
Family History8
People with a family history of MGUS or related conditions, such as Multiple Myeloma, are at higher risk.
What tests should be performed when a monoclonal gammopathy is suspected?
MGUS is frequently discovered as an incidental finding during laboratory tests that are conducted for other reasons9. This is because MGUS typically does not present with some specific symptoms that would lead to testing specifically for this condition.
The same initial testing is used no matter which monoclonal gammopathy is suspected. The initial testing aims to identify the presence of a monoclonal protein. Guidelines recommend use of sFLC testing plus SPE plus sIFE10.
Figure adapted from Dispenzieri et al. 10
Once a monoclonal protein is identified, the patient is further characterized to determine whether they have MGUS, SMM or MM (or another, rarer, monoclonal gammopathy). This includes tests for renal function, anemia, calcium levels, imaging to look for bone lesions and bone marrow biopsy to determine percentage of clonal bone marrow plasma cells3,11-13.
Why is serum free light chain measurement useful in patients with MGUS?
"A rise in serum free light chain concentration may precede an increase in intact immunoglobulin concentrations and may be the first sign that a patient is progressing from MGUS to Multiple Myeloma14."
- MGUS can evolve to Multiple Myeloma
- The monoclonal protein can also cause organ damage without progression
- Evaluation of MGUS during follow up enables better care for MGUS patients
- Evaluation of previous diagnosed MGUS should including measurement of the monoclonal protein. Adding sFLC to SPE measurement allows evaluation of free light chains as well as intact immunoglobulins.
"An increasingly abnormal sFLC ratio may be a harbinger of symptomatic myeloma"
Weiss, B.M., et al., A monoclonal gammopathy precedes multiple myeloma in most patients. Blood, 2009. 113(22): p. 5418-5422.
Why is MGUS important?
MGUS can progress to Myeloma and can also cause organ damage
As well as progression to Multiple Myeloma or another lymphoproliferative disorder, patients with MGUS may develop monoclonal protein-related disorders, these may include autoantibody activity by the monoclonal protein or deposition of the monoclonal protein in tissues and the associated organ dysfunction, or conditions associated with changes in the bone marrow microenvironment caused by the underlying tumour.
These changes can lead to increased infection, osteoporosis, fractures and thrombosis15. Patients with MGUS have an increased risk of death, not just through progression to Multiple Myeloma and other lymphoproliferative diseases but also bacterial infections, heart disease, liver diseases and kidney diseases2. This is why it is important to evaluate patients with MGUS to detect these comorbidities and manage them.
What is Multiple Myeloma?
Progression of MGUS to myeloma
Evaluation of patients with MGUS enables supportive care to be given if they develop any symptoms related to their monoclonal protein production, and also means that progression to Multiple Myeloma is detected earlier.
If progression to Multiple Myeloma is detected earlier, treatment can be given earlier, reducing the end organ damage the disease can cause, and improving patient outcome.
Patients with MGUS who are followed up and progress have fewer comorbidities at progression than patients first identified once they already have Multiple Myeloma15,16. They also have a longer median overall survival17.
Monoclonal Gammopathy of Clinical Significance
A monoclonal gammopathy that does not reach the diagnostic criteria of an active malignancy such as multiple myeloma, AL amyloidosis or Waldenström’s macroglobulinemia but does affect organ function are called monoclonal gammopathy of clinical significance. The most common of these are monoclonal gammopathy of renal significance (MGRS)18-20 and monoclonal gammopathy of neurological significance (MGNS)21.
It is important for clinicians who evaluate patients with MGUS to be aware of the monoclonal gammopathies of clinical significance, so that symptoms can be identified if they occur, and treatment can be given if needed.
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References
- Kyle RA: Monoclonal gammopathy of undetermined significance. Natural history in 241 cases. Am J Med 1978, 64(5):814-826.
- Kristinsson SY, Bjorkholm M, Andersson TML, Eloranta S, Dickman PW, Goldin LR, Blimark C, Mellqvist UH, Wahlin A, Turesson I et al: Patterns of survival and causes of death following a diagnosis of monoclonal gammopathy of undetermined significance: a population-based study. Haematologica 2009, 94(12):1714-1720.
- Rajkumar SV, Dimopolous MA, Palumbo A, Blade J, Merlini G, Mateos MV, Kumar S, Hillengass J, Kastritis E, Richardson P et al: International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol 2014, 15(12):e538-e548.
- Kyle RA, Therneau TM, Rajkumar SV, Larson DR, Plevak MF, Offord JR, Dispenzieri A, Katzmann JA, Melton LJ, III: Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med 2006, 354(13):1362-1369.
- Dispenzieri A, Katzmann JA, Kyle RA, Larson DR, Melton LJ, III, Colby CL, Therneau TM, Clark R, Kumar SK, Bradwell A et al: Prevalence and risk of progression of light-chain monoclonal gammopathy of undetermined significance: a retrospective population-based cohort study. Lancet 2010, 375(9727):1721-1728.
- Landgren O, Gridley G, Turesson I, Caporaso NE, Goldin LR, Baris D, Fears TR, Hoover RN, Linet MS: 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.
- Landgren O, Weiss BM: Patterns of monoclonal gammopathy of undetermined significance and multiple myeloma in various ethnic/racial groups: support for genetic factors in pathogenesis. Leukemia 2009, 23(10):1691-1697.
- Vachon CM, Kyle RA, Therneau TM, Foreman BJ, Larson DR, Colby CL, Phelps TK, Dispenzieri A, Kumar SK, Katzmann JA et al: Increased risk of monoclonal gammopathy in first-degree relatives of patients with multiple myeloma or monoclonal gammopathy of undetermined significance. Blood 2009, 114(4):785-790.
- Rajkumar SV: Updated diagnostic criteria and staging system for multiple myeloma. Am Soc Clin Oncol Educ Book 2016, 35:e418-423.
- Dispenzieri A, Kyle R, Merlini G, Miguel JS, Ludwig H, Hajek R, Palumbo A, Jagannath S, Blade J, Lonial S et al: International Myeloma Working Group guidelines for serum-free light chain analysis in multiple myeloma and related disorders. Leukemia 2009, 23(2):215-224.
- Kumar SK, Callander NS, Adekola K, Anderson LD, Baljevic M, Campagnaro E, Castillo JJ, Costello C, D'Angelo C, Devarakonda S et al: NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Multiple Myeloma - Version 3.2023. 2023.
- Keren DF, Bocsi G, Billman BL, Etzell J, Faix JD, Kumar S, Lipe B, McCudden C, Montgomery R, Murray DL et al: Laboratory Detection and Initial Diagnosis of Monoclonal Gammopathies: Guideline From the College of American Pathologists in Collaboration With the American Association for Clinical Chemistry and the American Society for Clinical Pathology. Arch Pathol Lab Med 2021, 146(5):575-590.
- NICE: Myeloma: diagnosis and management. NICE guideline [NG35]. 2016.
- Weiss BM, Abadie J, Verma P, Howard RS, Kuehl WM: A monoclonal gammopathy precedes multiple myeloma in most patients. Blood 2009, 113(22):5418-5422.
- van de Donk NW, Palumbo A, Johnsen HE, Engelhardt M, Gay F, Gregersen H, Hajek R, Kleber M, Ludwig H, Morgan G et al: The clinical relevance and management of monoclonal gammopathy of undetermined significance and related disorders: recommendations from the European Myeloma Network. Haematologica 2014, 99(6):984-996.
- Go RS, Gundrum JD, Neuner JM: Determining the clinical significance of monoclonal gammopathy of undetermined significance: a SEER-medicare population analysis. Clin Lymphoma Myeloma Leuk 2015, 15(3):177-186.
- Sigurdardottir E, Turesson I, Lund S, Lindqvist E, Mailankody S, Korde N, Bjorkholm M, Landgren O, Kristinsson S: The role of diagnosis and clinical follow-up of monoclonal gammopathy of undetermined significance on survival in multiple myeloma. JAMA Oncology 2015, 1(2):168-174.
- Leung N, Bridoux F, Hutchison CA, Nasr SH, Cockwell P, Fermand JP, Dispenzieri A, Song KW, Kyle RA: Monoclonal gammopathy of renal significance (MGRS): when MGUS is no longer undetermined or insignificant. Blood 2012, 120(22):4292-4295.
- Leung N, Barnidge DR, Hutchison CA: Laboratory testing in monoclonal gammopathy of renal significance (MGRS). Clin Chem Lab Med 2016, 54(6):929-937.
- Leung N, Bridoux F, Batuman V, Chaidos A, Cockwell P, D'Agati VD, Dispenzieri A, Fervenza FC, Fermand JP, Gibbs S et al: The evaluation of monoclonal gammopathy of renal significance: a consensus report of the International Kidney and Monoclonal Gammopathy Research Group. Nat Rev Nephrol 2018, 15(1):45-59.
- Castillo JJ, Callander NS, Sborov DW, Kumar S: The evaluation and management of monoclonal gammopathy of renal significance and monoclonal gammopathy of neurological significance. Am J Hematol 2021.