Monoclonal gammopathy of undetermined significance

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Monoclonal gammopathy of undetermined significance
Other namesBenign monoclonal gammopathy, monoclonal gammopathy of unknown significance, monoclonal gammopathy of renal significance, [1] unknown or uncertain may be substituted for undetermined
Electrophoresis.png
Schematic representation of a normal protein electrophoresis gel. A small spike would be present in the gamma (γ) band in MGUS

Monoclonal gammopathy of undetermined significance (MGUS) is a plasma cell dyscrasia in which plasma cells or other types of antibody-producing cells secrete a myeloma protein, i.e. an abnormal antibody, into the blood; this abnormal protein is usually found during standard laboratory blood or urine tests. MGUS resembles multiple myeloma and similar diseases, but the levels of antibodies are lower, [2] the number of plasma cells (white blood cells that secrete antibodies) in the bone marrow is lower, and it rarely has symptoms or major problems. However, since MGUS can lead to multiple myeloma, which develops at the rate of about 1.5% a year, or other symptomatic conditions, yearly monitoring is recommended.

Contents

The progression from MGUS to multiple myeloma usually involves several steps. In rare cases, it may also be related with a slowly progressive symmetric distal sensorimotor neuropathy. [3]

Signs and symptoms

People with monoclonal gammopathy generally do not experience signs or symptoms. [1] Some people may experience a rash or nerve problems, such as numbness or tingling. [1] MGUS is usually detected by chance when the patient has a blood test for another condition or as part of standard screening. [1]

Pathophysiology

Pathologically, the lesion in MGUS is in fact very similar to that in multiple myeloma. There is a predominance of clonal plasma cells in the bone marrow with an abnormal immunophenotype (CD38+ CD56+ CD19−) mixed in with cells of a normal phenotype (CD38+ CD56− CD19+); [4] [5] 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. [6]

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 four criteria: [7]

  1. A monoclonal paraprotein band less than 30 g/L (< 3g/dL);
  2. Plasma cells less than 10% on bone marrow examination;
  3. No evidence of bone lesions, anemia, hypercalcemia, or chronic kidney disease related to the paraprotein, and
  4. No evidence of another B-cell proliferative disorder.

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:

Management

MGUS occurs in over 3 percent of the White population over the age of 50, and is typically detected as an incidental finding when patients undergo a protein electrophoresis as part of an evaluation for a wide variety of clinical symptoms and disorders (e.g., peripheral neuropathy, vasculitis, hemolytic anemia, skin rashes, hypercalcemia, or elevated erythrocyte sedimentation rate). Although patients with MGUS have sometimes been reported to have peripheral neuropathy, a debilitating condition which causes bizarre sensory problems to painful sensory problems, [13] no treatment is indicated.[ citation needed ]

The protein electrophoresis 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).[ citation needed ]

Prognosis

At the Mayo Clinic, MGUS transformed into multiple myeloma or similar lymphoproliferative disorders 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 lymphoproliferative disorders. [14]

Kyle et al. 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. [15]

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. [16]

In 2009, prospective data demonstrated that all or almost all cases of multiple myeloma are preceded by MGUS. [17]

In addition to multiple myeloma, MGUS may also progress to Waldenström's macroglobulinemia or primary amyloidosis. [12]

See also

Related Research Articles

<span class="mw-page-title-main">Serum protein electrophoresis</span> Laboratory test

Serum protein electrophoresis is a laboratory test that examines specific proteins in the blood called globulins. The most common indications for a serum protein electrophoresis test are to diagnose or monitor multiple myeloma, a monoclonal gammopathy of uncertain significance (MGUS), or further investigate a discrepancy between a low albumin and a relatively high total protein. Unexplained bone pain, anemia, proteinuria, chronic kidney disease, and hypercalcemia are also signs of multiple myeloma, and indications for SPE. Blood must first be collected, usually into an airtight vial or syringe. Electrophoresis is a laboratory technique in which the blood serum is applied to either an acetate membrane soaked in a liquid buffer, or to a buffered agarose gel matrix, or into liquid in a capillary tube, and exposed to an electric current to separate the serum protein components into five major fractions by size and electrical charge: serum albumin, alpha-1 globulins, alpha-2 globulins, beta 1 and 2 globulins, and gamma globulins.

<span class="mw-page-title-main">Multiple myeloma</span> Cancer of plasma cells

Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibodies. Often, no symptoms are noticed initially. As it progresses, bone pain, anemia, renal insufficiency, and infections may occur. Complications may include hypercalcemia and amyloidosis.

<span class="mw-page-title-main">Plasma cell</span> White blood cell that secretes large volumes of antibodies

Plasma cells, also called plasma B cells or effector B cells, are white blood cells that originate in the lymphoid organs as B cells and secrete large quantities of proteins called antibodies in response to being presented specific substances called antigens. These antibodies are transported from the plasma cells by the blood plasma and the lymphatic system to the site of the target antigen, where they initiate its neutralization or destruction. B cells differentiate into plasma cells that produce antibody molecules closely modeled after the receptors of the precursor B cell.

<span class="mw-page-title-main">Cryoglobulinemia</span> Presence of cold-sensitive antibodies in the blood

Cryoglobulinemia is a medical condition in which the blood contains large amounts of pathological cold sensitive antibodies called cryoglobulins – proteins that become insoluble at reduced temperatures. This should be contrasted with cold agglutinins, which cause agglutination of red blood cells.

<span class="mw-page-title-main">Precancerous condition</span> Condition or cell change indicating increased cancer risk

A precancerous condition is a condition, tumor or lesion involving abnormal cells which are associated with an increased risk of developing into cancer. Clinically, precancerous conditions encompass a variety of abnormal tissues with an increased risk of developing into cancer. Some of the most common precancerous conditions include certain colon polyps, which can progress into colon cancer, monoclonal gammopathy of undetermined significance, which can progress into multiple myeloma or myelodysplastic syndrome. and cervical dysplasia, which can progress into cervical cancer. Bronchial premalignant lesions can progress to squamous cell carcinoma of the lung.

Waldenström macroglobulinemia is a type of cancer affecting two types of B cells: lymphoplasmacytoid cells and plasma cells. Both cell types are white blood cells. It is characterized by having high levels of a circulating antibody, immunoglobulin M (IgM), which is made and secreted by the cells involved in the disease. Waldenström macroglobulinemia is an "indolent lymphoma" and a type of lymphoproliferative disease which shares clinical characteristics with the indolent non-Hodgkin lymphomas. It is commonly classified as a form of plasma cell dyscrasia, similar to other plasma cell dyscrasias that, for example, lead to multiple myeloma. Waldenström macroglobulinemia is commonly preceded by two clinically asymptomatic but progressively more pre-malignant phases, IgM monoclonal gammopathy of undetermined significance and smoldering Waldenström macroglobulinemia. The Waldenström macroglobulinemia spectrum of dysplasias differs from other spectrums of plasma cell dyscrasias in that it involves not only aberrant plasma cells but also aberrant lymphoplasmacytoid cells and that it involves IgM while other plasma dyscrasias involve other antibody isoforms.

<span class="mw-page-title-main">Plasmacytoma</span> Growth of a plasma cell tumour within soft tissue or the axial skeleton

Plasmacytoma is a plasma cell dyscrasia in which a plasma cell tumour grows within soft tissue or within the axial skeleton.

<span class="mw-page-title-main">Monoclonal gammopathy</span> Excess myeloma protein or monoclonal gamma globulin in the blood

Monoclonal gammopathy, also known as paraproteinemia, is the presence of excessive amounts of myeloma protein or monoclonal gamma globulin in the blood. It is usually due to an underlying immunoproliferative disorder or hematologic neoplasms, especially multiple myeloma. It is sometimes considered equivalent to plasma cell dyscrasia. The most common form of the disease is monoclonal gammopathy of undetermined significance.

<span class="mw-page-title-main">Beta-2 microglobulin</span> Component of MHC class I molecules

β2 microglobulin (B2M) is a component of MHC class I molecules. MHC class I molecules have α1, α2, and α3 proteins which are present on all nucleated cells. In humans, the β2 microglobulin protein is encoded by the B2M gene.

<span class="mw-page-title-main">Myeloma protein</span> Abnormal immunoglobulin fragment

A myeloma protein is an abnormal antibody (immunoglobulin) or a fragment thereof, such as an immunoglobulin light chain, that is produced in excess by an abnormal monoclonal proliferation of plasma cells, typically in multiple myeloma or Monoclonal gammopathy of undetermined significance. Other terms for such a protein are monoclonal protein, M protein, M component, M spike, spike protein, or paraprotein. This proliferation of the myeloma protein has several deleterious effects on the body, including impaired immune function, abnormally high blood viscosity, and kidney damage.

In hematology, plasma cell dyscrasias are a spectrum of progressively more severe monoclonal gammopathies in which a clone or multiple clones of pre-malignant or malignant plasma cells over-produce and secrete into the blood stream a myeloma protein, i.e. an abnormal monoclonal antibody or portion thereof. The exception to this rule is the disorder termed non-secretory multiple myeloma; this disorder is a form of plasma cell dyscrasia in which no myeloma protein is detected in serum or urine of individuals who have clear evidence of an increase in clonal bone marrow plasma cells and/or evidence of clonal plasma cell-mediated tissue injury. Here, a clone of plasma cells refers to group of plasma cells that are abnormal in that they have an identical genetic identity and therefore are descendants of a single genetically distinct ancestor cell.

<span class="mw-page-title-main">Plasma cell leukemia</span> Medical condition

Plasma cell leukemia (PCL) is a plasma cell dyscrasia, i.e. a disease involving the malignant degeneration of a subtype of white blood cells called plasma cells. It is the terminal stage and most aggressive form of these dyscrasias, constituting 2% to 4% of all cases of plasma cell malignancies. PCL may present as primary plasma cell leukemia, i.e. in patients without prior history of a plasma cell dyscrasia or as secondary plasma cell dyscrasia, i.e. in patients previously diagnosed with a history of its predecessor dyscrasia, multiple myeloma. The two forms of PCL appear to be at least partially distinct from each other. In all cases, however, PCL is an extremely serious, life-threatening, and therapeutically challenging disease.

Free light chains (FLCs) are immunoglobulin light chains that are found in the serum (blood) in an unbound (free) state. In recent decades, measuring the amount of free light chains (FLCs) in the blood has become a practical clinical test. FLC tests can be used to diagnose and monitor diseases like multiple myeloma and amyloidosis.

<span class="mw-page-title-main">Light chain deposition disease</span> Medical condition

Light chain deposition disease (LCDD) is a rare blood cell disease which is characterized by deposition of fragments of infection-fighting immunoglobulins, called light chains (LCs), in the body. LCs are normally cleared by the kidneys, but in LCDD, these light chain deposits damage organs and cause disease. The kidneys are almost always affected and this often leads to kidney failure. About half of people with light chain deposition disease also have a plasma cell dyscrasia, a spectrum of diseases that includes multiple myeloma, Waldenström's macroglobulinemia, and the monoclonal gammopathy of undetermined significance premalignant stages of these two diseases. Unlike in AL amyloidosis, in which light chains are laid down in characteristic amyloid deposits, in LCDD, light chains are deposited in non-amyloid granules.

Smouldering myeloma is a disease classified as intermediate in a spectrum of step-wise progressive diseases termed plasma cell dyscrasias. In this spectrum of diseases, a clone of plasma cells secreting monoclonal paraprotein causes the relatively benign disease of monoclonal gammopathy of undetermined significance. This clone proliferates and may slowly evolve into more aggressive sub-clones that cause smouldering multiple myeloma. Further and more rapid evolution causes the overtly malignant stage of multiple myeloma and can subsequently lead to the extremely malignant stage of secondary plasma cell leukemia. Thus, some patients with smouldering myeloma progress to multiple myeloma and plasma cell leukemia. Smouldering myeloma, however, is not a malignant disease. It is characterised as a pre-malignant disease that lacks symptoms but is associated with bone marrow biopsy showing the presence of an abnormal number of clonal myeloma cells, blood and/or urine containing a myeloma protein, and a significant risk of developing into a malignant disease.

<span class="mw-page-title-main">Serum B-cell maturation antigen</span> Cleaved form of B-cell maturation antigen

Serum B-cell maturation antigen (sBCMA) is the cleaved form of B-cell maturation antigen (BCMA), found at low levels in the serum of normal patients and generally elevated in patients with multiple myeloma (MM). Changes in sBCMA levels have been found to correlate with a MM patient’s clinical status in response to treatment.

Monoclonal immunoglobulin deposition disease, or MIDD, is a disease characterised by the deposition of monoclonal immunoglobulins on the basement membrane of the kidney. Monoclonal immunoglobulins are produced by monoclonal plasma cells, which are found in a variety of plasma cell dyscrasias. The deposition of monoclonal immunoglobulins on the basement membrane of the kidney causes renal impairment. As well as the kidney, MIDD may also affect the liver, heart, peripheral nerves, lung and skin.

Crystal-storing histiocytosis is a form of histiocytosis that mostly occurs in people with monoclonal gammopathies. Histiocytosis is an excessive number of histiocytes. In the vast majority of crystal-storing histiocytosis cases, immunoglobulins accumulate within the cytoplasm of histiocytes; in rare cases clofazimine, cystine, silica, or Charcot–Leyden crystals may be found in the histiocytes instead. Non-immunoglobulin crystal-storing histiocytosis is mostly associated with non-malignant disorders, such as chronic inflammation or autoimmune abnormality conditions such as rheumatoid arthritis, Crohn's disease, or Helicobacter pylori gastritis. It may be a localised or generalised disease. Examples of locations where histiocytosis may occur include the lungs, pleura, stomach, kidney, bone marrow, thyroid, thymus, and parotid gland. The disease is described as generalised if two or more unrelated sites are involved.

Monoclonal gammopathy of renal significance (MGRS) are a group of kidney disorders that present with kidney damage due to nephrotoxic monoclonal immunoglobulins secreted by clonal plasma cells or B cells. By definition, people with MGRS do not meet criteria for multiple myeloma or other hematologic malignancies. The term MGRS was introduced in 2012 by the International Kidney and Monoclonal Gammopathy Research Group (IKMG). MGRS is associated with monoclonal gammopathy of undetermined significance (MGUS). People with MGUS have a monoclonal gammopathy but does not meet the criteria for the clonal burden nor the presence of end organ damage seen in hematologic malignancies. In a population based study based on the NHANES III health survey; 6% of patients with MGUS were subsequently classified as having MGRS. The prevalence and incidence of MGRS in the general population or in specific populations is not known but it is more prevalent in those over the age of 50 as there is a monoclonal protein (M-protein) present in 3% of those 50 and years older and 5% of those 70 years and older, placing those 50 and older at increased risk of MGRS.

Irene Ghobrial is an American-Egyptian physician who is a professor at the Dana–Farber Cancer Institute and Harvard Medical School, where her research investigates early detection, mechanisms of disease progression and early interception of multiple myeloma. She is interested in why certain patients with monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) develop multiple myeloma.

References

  1. 1 2 3 4 Kaushansky, Kenneth (2016). Williams Hematology. United States: McGraw Hill. pp. 1723–1727. ISBN   9780071833011.
  2. ↑ Agarwal, A; Ghobrial, IM (1 March 2013). "Monoclonal gammopathy of undetermined significance and smoldering multiple myeloma: a review of the current understanding of epidemiology, biology, risk stratification, and management of myeloma precursor disease". Clinical Cancer Research. 19 (5): 985–94. doi:10.1158/1078-0432.CCR-12-2922. PMC   3593941 . PMID   23224402.
  3. ↑ Kahn S. N.; Riches P. G.; Kohn J. (1980). "Paraproteinaemia in neurological disease: incidence, associations, and classification of monoclonal immunoglobulins". Journal of Clinical Pathology. 33 (7): 617–621. doi:10.1136/jcp.33.7.617. PMC   1146171 . PMID   6253529.
  4. ↑ Zhan F, Hardin J, Kordsmeier B, Bumm K, Zheng M, Tian E, Sanderson R, Yang Y, Wilson C, Zangari M, Anaissie E, Morris C, Muwalla F, van Rhee F, Fassas A, Crowley J, Tricot G, Barlogie B, Shaughnessy J (2002). "Global gene expression profiling of multiple myeloma, monoclonal gammopathy of undetermined significance, and normal bone marrow plasma cells". Blood. 99 (5): 1745–1757. doi: 10.1182/blood.V99.5.1745 . PMID   11861292.
  5. ↑ Magrangeas F, Nasser V, Avet-Loiseau H, Loriod B, Decaux O, Granjeaud S, Bertucci F, Birnbaum D, Nguyen C, Harousseau J, Bataille R, Houlgatte R, Minvielle S (2003). "Gene expression profiling of multiple myeloma reveals molecular portraits in relation to the pathogenesis of the disease". Blood. 101 (12): 4998–5006. doi: 10.1182/blood-2002-11-3385 . PMID   12623842.
  6. ↑ Ocqueteau M, Orfao A, Almeida J, Bladé J, González M, García-Sanz R, López-Berges C, Moro M, Hernández J, Escribano L, Caballero D, Rozman M, San Miguel J (1998). "Immunophenotypic characterization of plasma cells from monoclonal gammopathy of undetermined significance patients. Implications for the differential diagnosis between MGUS and multiple myeloma". Am J Pathol. 152 (6): 1655–65. PMC   1858455 . PMID   9626070.
  7. ↑ International Myeloma Working Group (2003). "Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group". Br J Haematol. 121 (5): 749–757. doi: 10.1046/j.1365-2141.2003.04355.x . PMID   12780789. S2CID   3195084.
  8. ↑ Murakami H, Irisawa H, Saitoh T, Matsushima T, Tamura J, Sawamura M, Karasawa M, Hosomura Y, Kojima M (1997). "Immunological abnormalities in splenic marginal zone cell lymphoma". Am. J. Hematol. 56 (3): 173–178. doi: 10.1002/(SICI)1096-8652(199711)56:3<173::AID-AJH7>3.0.CO;2-V . PMID   9371530.
  9. ↑ Larking-Pettigrew M, Ranich T, Kelly R (1999). "Rapid onset monoclonal gammopathy in cutaneous lupus erythematosus: interference with complement C3 and C4 measurement". Immunol. Invest. 28 (4): 269–276. doi:10.3109/08820139909060861. PMID   10454004.
  10. ↑ Czaplinski A, Steck A (2004). "Immune mediated neuropathies--an update on therapeutic strategies". J. Neurol. 251 (2): 127–137. doi:10.1007/s00415-004-0323-5. PMID   14991345. S2CID   13218864.
  11. ↑ Sykes, David B.; Schroyens, Wilfried; O'Connell, Casey (2011). "TEMPI Syndrome – A Novel Multisystem Disease". N Engl J Med . 365 (5): 475–477. doi: 10.1056/NEJMc1106670 . PMID   21812700. S2CID   35990145.
  12. 1 2 Go, Ronald S.; Rajkumar, S. Vincent (2018-01-11). "How I manage monoclonal gammopathy of undetermined significance". Blood. 131 (2): 163–173. doi: 10.1182/blood-2017-09-807560 . ISSN   0006-4971. PMC   5757684 . PMID   29183887.
  13. ↑ Nobile-Orazio E.; et al. (June 1992). "Peripheral neuropathy in monoclonal gammopathy of undetermined significance: prevalence and immunopathogenetic studies". Acta Neurologica Scandinavica. 85 (6): 383–390. doi:10.1111/j.1600-0404.1992.tb06033.x. PMID   1379409. S2CID   30788715.
  14. ↑ Bladé J (2006). "Clinical practice. Monoclonal gammopathy of undetermined significance". N Engl J Med. 355 (26): 2765–2770. doi:10.1056/NEJMcp052790. PMID   17192542.
  15. ↑ Kyle RA, Therneau TM, Rajkumar SV, Larson DR, Plevak MF, Offord JR, Dispenzieri A, Katzmann JA, Melton LJ 3rd (28 December 2006). "Prevalence of monoclonal gammopathy of undetermined significance". N Engl J Med. 354 (13): 1362–1369. doi: 10.1056/NEJMoa054494 . PMID   16571879.
  16. ↑ Landgren O, Katzmann JA, Hsing AW, Pfeiffer RM, Kyle RA, Yeboah ED, Biritwum RB, Tettey Y, Adjei AA, Larson DR, Dispenzieri A, Melton LJ 3rd, Goldin LR, McMaster ML, Caporaso NE, Rajkumar SV (Dec 2007). "Prevalence of monoclonal gammopathy of undetermined significance among men in Ghana". Mayo Clin Proc. 82 (12): 1468–1473. doi:10.4065/82.12.1468. PMID   18053453.
  17. ↑ Landgren O, Kyle RA, Pfeiffer RM, Katzmann JA, Caporaso NE, Hayes RB, Dispenzieri A, Kumar S, Clark RJ, Baris D, Hoover R, Rajkumar SV (28 May 2009). "Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study". Blood. 113 (22): 5412–7. doi:10.1182/blood-2008-12-194241. PMC   2689042 . PMID   19179464.

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