Monoclonal gammopathy of undetermined significance
Encyclopedia
Monoclonal gammopathy of undetermined significance (MGUS, unknown or uncertain may be substituted for undetermined), formerly benign monoclonal gammopathy, is a condition in which a paraprotein
is found in the blood during standard laboratory tests. It resembles multiple myeloma
and similar diseases, but the levels of antibody are lower, the number of plasma cells (white blood cells that secrete antibodies) in the bone marrow is lower, it has no symptoms or problems, and no treatment is indicated. However, multiple myeloma
develops at the rate of about 1-2% a year, so doctors recommend monitoring it yearly. In rare cases, it may also be related with a slowly progressive symmetric distal sensorimotor neuropathy.
Increased serum protein with M spike.
Other typical features seen in multiple myeloma
are absent, such as hypercalcemia, lytic bone lesions, Bence Jones
proteinuria, and AL amyloid.
Commonly seen in elderly.
plasma cell
s in the bone marrow
with an abnormal immunophenotype (CD38
+ CD56+ CD19
−) mixed in with cells of a normal phenotype (CD38+ CD56− CD19+); in MGUS, on average more than 3% of the clonal plasma cells have the normal phenotype, whereas in multiple myeloma, less than 3% of the cells have the normal phenotype. What causes MGUS to transform into multiple myeloma is as yet unknown.
Kyle studied the prevalence of myeloma in the population as a whole (not clinic patients) in Olmsted County, Minnesota
. They found that the prevalence of MGUS was 3.2% in people above 50, with a slight male predominance (4.0% vs. 2.7%). Prevalence increased with age: of people over 70 up to 5.3% had MGUS, while in the over-85 age group the prevalence was 7.5%. In the majority of cases (63.5%), the paraprotein level was <1 g/dl, while only a very small group had levels over 2 g/dl. A study of monoclonal protein levels conducted in Ghana
showed a prevalence of MGUS of approximately 5.9% in African men over the age of 50.
In 2009, prospective data demonstrated that all or almost all cases of Multiple Myeloma are preceded by MGUS. In addition to multiple myeloma, MGUS may also progress to Waldenström's macroglobulinemia, primary amyloidosis
, B-cell lymphoma
, or chronic lymphocytic leukemia
.
test should be repeated annually, and if there is any concern for a rise in the level of monoclonal protein, then prompt referral to a hematologist is required. The hematologist, when first evaluating a case of MGUS, will usually perform a skeletal survey
(X-rays of the proximal skeleton), check the blood for hypercalcemia and deterioration in renal function
, check the urine for Bence Jones
protein and perform a bone marrow biopsy
. If none of these tests are abnormal, a patient with MGUS is followed up once every 6 months to a year with a blood test (serum protein electrophoresis).
Brendan W. Weiss & Michael Kuehl. Expert Rev Hematol. 3(2), 165-174 (2010)
myeloma based on multiparameter flow cytometry analisis of bone marrow plasma cells.
Ernesto Perez-Persona et al. Blood, 1 October 2007. Vol 110. N 7, 2586–2592
earlier salvage therapy for symptomatic disease. Bart Barlogie et al. Blood 15 October 2008. Vol 112. N 8, 3122-3125
Francesca Rossi et al. Clin Cancer Res 2009; 15 (13), July 1, 2009, 4439-4445
Paraproteinemia and the Urinary N-Telopeptide of Tyoe I Collagen Bone Turnover Marker. Terry Golombick et al.
Clin Cancer Res 2009; 15(18), September 15, 2009, 5917-5922
Res 2009; 15(18), September 15, 2009, 5606-5608
perspectives risk factors for progression and Guidelines for monitoring and management. R A Kyle et al. Leukemia (2010, 1-7
Paraprotein
A paraprotein is an immunoglobulin or immunoglobulin light-chain that is produced in excess by the clonal proliferation of plasma cells. Detection of paraproteins in the urine or blood is most often associated with benign MGUS , where they remain "silent", and multiple myeloma. An excess in the...
is found in the blood during standard laboratory tests. It resembles multiple myeloma
Multiple myeloma
Multiple myeloma , also known as plasma cell myeloma or Kahler's disease , is a cancer of plasma cells, a type of white blood cell normally responsible for the production of antibodies...
and similar diseases, but the levels of antibody are lower, the number of plasma cells (white blood cells that secrete antibodies) in the bone marrow is lower, it has no symptoms or problems, and no treatment is indicated. However, multiple myeloma
Multiple myeloma
Multiple myeloma , also known as plasma cell myeloma or Kahler's disease , is a cancer of plasma cells, a type of white blood cell normally responsible for the production of antibodies...
develops at the rate of about 1-2% a year, so doctors recommend monitoring it yearly. In rare cases, it may also be related with a slowly progressive symmetric distal sensorimotor neuropathy.
Increased serum protein with M spike.
Other typical features seen in multiple myeloma
Multiple myeloma
Multiple myeloma , also known as plasma cell myeloma or Kahler's disease , is a cancer of plasma cells, a type of white blood cell normally responsible for the production of antibodies...
are absent, such as hypercalcemia, lytic bone lesions, Bence Jones
Bence Jones protein
A Bence Jones protein is a monoclonal globulin protein found in the blood or urine, with a molecular weight of 22-24 kDa.Finding this protein is often suggestive of multiple myeloma or Waldenstrom's macroglobulinemia....
proteinuria, and AL amyloid.
Commonly seen in elderly.
Diagnosis
MGUS is a common, age-related medical condition characterized by an accumulation of bone marrow plasma cells derived from a single abnormal clone. Patients may be diagnosed with MGUS if they fulfill the following three criteria:- A monoclonal paraprotein band less than 30 g/L (< 3g/dL);
- Plasma cellPlasma cellPlasma cells, also called plasma B cells, plasmocytes, and effector B cells, are white blood cells which produce large volumes of antibodies. They are transported by the blood plasma and the lymphatic system...
s less than 10% on bone marrow examination; and - No evidence of bone lesions, anemiaAnemiaAnemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
, hypercalcemia, or renal insufficiency related to the paraprotein.
Differential diagnosis
Several other illnesses can present with a monoclonal gammopathy, and the monoclonal protein may be the first discovery before a formal diagnosis is made:- Multiple myelomaMultiple myelomaMultiple myeloma , also known as plasma cell myeloma or Kahler's disease , is a cancer of plasma cells, a type of white blood cell normally responsible for the production of antibodies...
- AIDSAIDSAcquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus...
- Chronic lymphocytic leukemiaChronic lymphocytic leukemiaB-cell chronic lymphocytic leukemia , also known as chronic lymphoid leukemia , is the most common type of leukemia. Leukemias are cancers of the white blood cells . CLL affects B cell lymphocytes. B cells originate in the bone marrow, develop in the lymph nodes, and normally fight infection by...
- Non-Hodgkin LymphomaNon-Hodgkin lymphomaThe non-Hodgkin lymphomas are a diverse group of blood cancers that include any kind of lymphoma except Hodgkin's lymphomas. Types of NHL vary significantly in their severity, from indolent to very aggressive....
, particularly Splenic marginal zone lymphomaSplenic marginal zone lymphomaSplenic marginal zone lymphoma is a lymphoma made up of B-cells that replace the normal architecture of the white pulp of the spleen. The neoplastic cells are both small lymphocytes and larger, transformed blasts, and they invade the mantle zone of splenic follicles and erode the marginal zone,...
and Lymphoplasmocytic lymphoma - Hepatitis CHepatitis CHepatitis C is an infectious disease primarily affecting the liver, caused by the hepatitis C virus . The infection is often asymptomatic, but chronic infection can lead to scarring of the liver and ultimately to cirrhosis, which is generally apparent after many years...
- Connective tissue diseaseConnective tissue diseaseA connective tissue disease is any disease that has the connective tissues of the body as a target of pathology. Connective tissue is any type of biological tissue with an extensive extracellular matrix that supports, binds together, and protects organs...
such as lupusSystemic lupus erythematosusSystemic lupus erythematosus , often abbreviated to SLE or lupus, is a systemic autoimmune disease that can affect any part of the body. As occurs in other autoimmune diseases, the immune system attacks the body's cells and tissue, resulting in inflammation and tissue damage... - Immunosuppression following organ transplantation
- Waldenström macroglobulinemiaWaldenström macroglobulinemiaWaldenström's macroglobulinemia is cancer involving a subtype of white blood cells called lymphocytes. The main attributing antibody is Immunoglobulin M . WM is an "indolent lymphoma,"...
- Guillain-Barre syndromeGuillain-Barré syndromeGuillain–Barré syndrome , sometimes called Landry's paralysis, is an acute inflammatory demyelinating polyneuropathy , a disorder affecting the peripheral nervous system. Ascending paralysis, weakness beginning in the feet and hands and migrating towards the trunk, is the most typical symptom...
Pathology
Pathologically, the lesion in MGUS is in fact very similar to that in multiple myeloma. There is a predominance of clonalClone (B-cell biology)
The process of immunological B-cell maturation involves transformation from an undifferentiated B cell to one that secretes antibodies with particular specificity...
plasma cell
Plasma cell
Plasma cells, also called plasma B cells, plasmocytes, and effector B cells, are white blood cells which produce large volumes of antibodies. They are transported by the blood plasma and the lymphatic system...
s in the bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
with an abnormal immunophenotype (CD38
CD38
CD38 , also known as cyclic ADP ribose hydrolase is a glycoprotein found on the surface of many immune cells , including CD4+, CD8+, B and natural killer cells...
+ CD56+ CD19
CD19
B-lymphocyte antigen CD19 also known as CD19 , is a protein that in humans is encoded by the CD19 gene.- Function :...
−) mixed in with cells of a normal phenotype (CD38+ CD56− CD19+); in MGUS, on average more than 3% of the clonal plasma cells have the normal phenotype, whereas in multiple myeloma, less than 3% of the cells have the normal phenotype. What causes MGUS to transform into multiple myeloma is as yet unknown.
Prognosis
At the Mayo Clinic, MGUS transformed into multiple myeloma or similar myeloproliferative disorder at the rate of about 1-2% a year, or 17%, 34%, and 39% at 10, 20, and 25 years, respectively, of follow-up—among surviving patients. However, because they were elderly, most patients with MGUS died of something else and did not go on to develop multiple myeloma. When this was taken into account, only 11.2% developed myeloproliferative disorders.Kyle studied the prevalence of myeloma in the population as a whole (not clinic patients) in Olmsted County, Minnesota
Olmsted County, Minnesota
As of the census of 2000, there were 124,277 people, 47,807 households, and 32,317 families residing in the county. The population density was 190 people per square mile . There were 49,422 housing units at an average density of 76 per square mile...
. They found that the prevalence of MGUS was 3.2% in people above 50, with a slight male predominance (4.0% vs. 2.7%). Prevalence increased with age: of people over 70 up to 5.3% had MGUS, while in the over-85 age group the prevalence was 7.5%. In the majority of cases (63.5%), the paraprotein level was <1 g/dl, while only a very small group had levels over 2 g/dl. A study of monoclonal protein levels conducted in Ghana
Ghana
Ghana , officially the Republic of Ghana, is a country located in West Africa. It is bordered by Côte d'Ivoire to the west, Burkina Faso to the north, Togo to the east, and the Gulf of Guinea to the south...
showed a prevalence of MGUS of approximately 5.9% in African men over the age of 50.
In 2009, prospective data demonstrated that all or almost all cases of Multiple Myeloma are preceded by MGUS. In addition to multiple myeloma, MGUS may also progress to Waldenström's macroglobulinemia, primary amyloidosis
Amyloidosis
In medicine, amyloidosis refers to a variety of conditions whereby the body produces "bad proteins", denoted as amyloid proteins, which are abnormally deposited in organs and/or tissues and cause harm. A protein is described as being amyloid if, due to an alteration in its secondary structure, it...
, B-cell lymphoma
B-cell lymphoma
The B-cell lymphomas are types of lymphoma affecting B cells. Lymphomas are "blood cancers" in the lymph glands. They develop more frequently in older adults and in immunocompromised individuals ....
, or chronic lymphocytic leukemia
Chronic lymphocytic leukemia
B-cell chronic lymphocytic leukemia , also known as chronic lymphoid leukemia , is the most common type of leukemia. Leukemias are cancers of the white blood cells . CLL affects B cell lymphocytes. B cells originate in the bone marrow, develop in the lymph nodes, and normally fight infection by...
.
Management
The protein electrophoresisProtein electrophoresis
Protein electrophoresis is a method for analysing the proteins in a fluid or an extract. The electrophoresis may be performed with a small volume of sample in a number of alternative ways with or without a supporting medium: SDS polyacrylamide gel electrophoresis Protein electrophoresis is a method...
test should be repeated annually, and if there is any concern for a rise in the level of monoclonal protein, then prompt referral to a hematologist is required. The hematologist, when first evaluating a case of MGUS, will usually perform a skeletal survey
Skeletal survey
A skeletal survey is a series of X-rays of all the bones in the body, or at least the axial skeleton and the large cortical bones. A very common use is the diagnosis of multiple myeloma, where tumour deposits appear as "punched-out" lesions...
(X-rays of the proximal skeleton), check the blood for hypercalcemia and deterioration in renal function
Renal function
Renal function, in nephrology, is an indication of the state of the kidney and its role in renal physiology. Glomerular filtration rate describes the flow rate of filtered fluid through the kidney...
, check the urine for Bence Jones
Bence Jones protein
A Bence Jones protein is a monoclonal globulin protein found in the blood or urine, with a molecular weight of 22-24 kDa.Finding this protein is often suggestive of multiple myeloma or Waldenstrom's macroglobulinemia....
protein and perform a bone marrow biopsy
Bone marrow biopsy
Bone marrow examination refers to the pathologic analysis of samples of bone marrow obtained by bone marrow biopsy and bone marrow aspiration. Bone marrow examination is used in the diagnosis of a number of conditions, including leukemia, multiple myeloma, lymphoma, anemia, and pancytopenia...
. If none of these tests are abnormal, a patient with MGUS is followed up once every 6 months to a year with a blood test (serum protein electrophoresis).
Further reading
- Advances in understanding monoclonal gammopathy of undetermined significance as a precursor of multiple myeloma.
Brendan W. Weiss & Michael Kuehl. Expert Rev Hematol. 3(2), 165-174 (2010)
- New criteria to identify risk of progression in monoclonal gammopathy of uncertain significance and smoldering multiple
myeloma based on multiparameter flow cytometry analisis of bone marrow plasma cells.
Ernesto Perez-Persona et al. Blood, 1 October 2007. Vol 110. N 7, 2586–2592
- Seven-year median time to progression with thalidomide for smoldering myeloma: partial response identifies subset requiring
earlier salvage therapy for symptomatic disease. Bart Barlogie et al. Blood 15 October 2008. Vol 112. N 8, 3122-3125
- Proposal and Validation of Prognostic Scoring Systems for IgG and IgA Monoclonal Gammopathies of Undetermined Significance.
Francesca Rossi et al. Clin Cancer Res 2009; 15 (13), July 1, 2009, 4439-4445
- The potential Role of Curcumin in Patients with Monoclonal Gammopathy of Undetermined Significance-Its effect on
Paraproteinemia and the Urinary N-Telopeptide of Tyoe I Collagen Bone Turnover Marker. Terry Golombick et al.
Clin Cancer Res 2009; 15(18), September 15, 2009, 5917-5922
- Prevention of Progression in Monoclonal Gammopathy of Undetermined Significance. S. Vincent Rajkumar. Clin Cancer
Res 2009; 15(18), September 15, 2009, 5606-5608
- Monoclonal Gammopathy of Undetermined Significance: a consensus statement. James R. Berenson et al. Brit J Hematol, 2010, 150, 28-38
- Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering (asymptomatic) Multiple Myeloma: IMWG consensus
perspectives risk factors for progression and Guidelines for monitoring and management. R A Kyle et al. Leukemia (2010, 1-7