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What is igg kappa: Types of Multiple Myeloma | International Myeloma Foundation

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Types of Multiple Myeloma | International Myeloma Foundation

Multiple myeloma has different types and subtypes. These types are based on the immunoglobulin (protein) produced by the myeloma cell. The various immunoglobulins have different functions in the body. Each immunoglobulin is made up of two heavy chains and two light chains.

The five types of heavy protein chains are G, A, D, E, and M.
The two types of light protein chains are kappa (κ) and lambda (λ).

Furthermore, there are different subtypes of myeloma. 

Subtypes of immunoglobulins

IgG kappa
IgA kappa
IgD kappa
IgE kappa
IgM kappa
IgG lambda
IgA lambda
IgD lambda
IgE lambda
IgM lambda
  • Normal plasma cells secrete immunoglobulins (antibodies) to fight infections. Immunoglobulins are proteins that attach to substances entering the body that the body recognizes as foreign. Normal immunoglobulins are called “polyclonal protein.” Myeloma cells, which are cancerous plasma cells, secrete monoclonal protein. Monoclonal protein is an abnormal immunoglobulin that cannot properly fight infection.
  • Healthy plasma cells or myeloma cells can produce immunoglobulins. These immunoglobulins made up of two heavy chains and two light chains that are bound together. 
  • The five possible types of immunoglobulin (abbreviated “Ig”) are heavy chains: IgG, IgA, IgD, IgE, and IgM.
  • The possible types of light chains are either kappa (κ) or lambda (λ).
  • Myeloma cells make immunoglobulins. These immunoglobulins are made up of only one type of heavy chain (G, A, D, E, or M) and one type of light chain (kappa or lambda). The most common type of myeloma is IgG kappa. In IgG kappa myeloma, the myeloma cells produce an immunoglobulin made from two IgG heavy chains bound to two kappa light chains.
  • About 15% of patients have light chain myeloma. In this type of myeloma, the myeloma cells secrete only light chain protein and no heavy chains. It is also known as “Bence-Jones myeloma” (after the doctor who discovered it).
  • One to two-percent of patients have “non-secretory myeloma.” In non-secretory myeloma, the myeloma cells produce very little or no monoclonal protein of any type.
  • Your doctor will order tests to identify your type of myeloma. It’s important to know which type you have as you will be able to better understand your test results.You will be able to determine if your level of monoclonal protein is stable, increasing, or decreasing.

See the IMF’s Patient Handbook if you have been diagnosed with any of the following:

  • AL amyloidosis
  • Light chain deposition disease (LCDD)
  • Waldenström’s macroglobulinemia
  • POEMS syndrome

Types of Myeloma

Disease Type Description
Myeloma
IgG k or λ
IgA k or λ
Rarer subtypes:
IgD, E, or M
  • Typical myeloma: majority of patients.
  • Monitored by tracking monoclonal protein in serum using SPEP (IgG) and/or quantitative immunoglobulin (QIG) measurement (IgA/D/E). For IgA myeloma quantitative immunoglobulin measurement is often more reliable.
Light Chain only or
Bence Jones (BJ) myeloma:

k or λ types
  • Bence Jones myeloma: approximately 15%–20% of patients.
  • Monitored by tracking monoclonal light chains in urine using UPEP and/or with serum free light chain measurements (Freelite®) in the serum.
  • May lead to deposits of light chains in the kidneys and/or nerves.
Non-secretory myeloma:
  • Less common myeloma: 1%–2% of patients.
  • Since both SPEP and UPEP are negative (no monoclonal spike in serum or urine), disease is monitored using Freelite® testing.
IgM myeloma:
k or λ subtypes
  • IgM myeloma is a very rare subtype.
  • Typically, IgM production occurs in a disease called Waldenström’s macrgoglobulinemia, which is more like a lymphoma (lymph node cancer) versus myeloma, which is a bone marrow cancer.

 

What’s Next?

 

Types of myeloma | Cancer Research UK

There are different types of myeloma. The treatment you need is usually the same whichever type you have but the type can change how it affects you.

There are also some other conditions related to myeloma that affect plasma cells. 

Immunoglobulins and your type of myeloma

Most people have a type of myeloma that causes the abnormal plasma cells to produce abnormal proteins. These proteins are called immunoglobulin (also called abnormal protein, paraprotein, monoclonal protein or monoclonal spike). As well as the whole immunoglobulin, often a small part called the free light chain (called Bence Jones protein in urine) is made in big amounts by the plasma cells.  

Each immunoglobulin is made up of 2 long protein chains (called heavy chains) and 2 shorter protein chains (called light chains). 

Immunoglobulins can be classified into one of 5 types depending on their heavy chains. These are A, G, M, D and E. Your type of myeloma is named after the abnormal immunoglobulin it is making.

Only one type of immunoglobulin (Ig) is overproduced when you have myeloma. The type of immunoglobulin this is varies from person to person. IgG is the most common. The next most common is IgA and light chain only. IgM, IgD and IgE are very rare. 

Light chain myeloma sometimes called Bence Jones myeloma

About 20 out of 100  people with myeloma (20%) do not produce complete immunoglobulins. They only produce part of the immunoglobulin called the light chain. 

There are 2 types of light chains – called kappa and lambda. The light chains can show up in the urine. Doctors call this the Bence Jones protein (BJP).

A blood test called a serum free light chain test can pick up small increases in the amount of free light chains in the blood. Doctors use this test to:

  • measure the amount of each of the light chains in the blood
  • to compare the amount of kappa light chains to the amount of lambda light chains, known as the ratio

Your doctor can use the test to diagnose and monitor your myeloma.

Non secretory myeloma

In about 3 out of every 100 people with myeloma (3%), the myeloma cells produce little or no immunoglobulin (also called paraprotein). This makes it harder to diagnose.

Doctors use bone marrow tests and scans (such as PET-CT) to diagnose and monitor non secretory myeloma.

Types of myeloma depending on gene changes

Myeloma develops because of changes in genes that become abnormal. Genes are the instruction manuals for cells ‘telling’ them how to behave. There are subtypes of myeloma based on the changes in their genes. Your genetic subtype depends on the changes there are in the genes of the myeloma cells.

Knowing the genetic subtype can help doctors know how your myeloma might progress.

Doctors are researching how particular genetic subtypes of myeloma might be treated differently in the future.

Other conditions related to myeloma

Monoclonal gammopathy of undetermined significance (MGUS)

If you have MGUS your plasma cells make too many large protein molecules known as immunoglobulins or paraproteins (also called abnormal protein, monoclonal protein or monoclonal spike). These show up in the blood.

MGUS is often found by chance, in blood tests for a routine check up, or tests for a different medical problem. This is because MGUS does not cause any symptoms, and does not generally affect your health.

MGUS is diagnosed if you have:

  • a low level of abnormal paraprotein in your blood (less than 30 g/l)
  • a low level of abnormal plasma cells in your bone marrow (less than 10%)
  • no evidence of certain other related conditions
  • no related problems with organs or tissues

Because it doesn’t usually cause any symptoms or cause problems, MGUS does not usually need treatment. Some people with MGUS go on to develop myeloma, so your specialist or GP will see you regularly for check ups. About 1 out of 100 people with MGUS (1%) develop myeloma each year.

Plasmacytoma

A plasmacytoma is a tumour made up of plasma cells together in a lump. They can be found in bone or soft tissue. You might have one area of plasmacytoma and this is called solitary plasmacytoma. Some people have more than one plasmacytoma and this is called multiple solitary plasmacytoma.

The areas of plasmacytoma are similar to the areas of plasma cells found in people with multiple myeloma.

More than half of people with bone plasmacytoma go on to develop myeloma later in life. Soft tissue (or extramedullary) plasmacytoma can also develop into myeloma but is less common.

Doctors usually treat plasmacytoma with radiotherapy.

Amyloidosis

This is a rare conditon. The plasma cells make an abnormal protein called amyloid. The amyloid collects in body organs, such as the kidneys or heart, and gradually causes damage.

About 10 to 15 out of every 100 people with myeloma (10 to 15%) develop amyloidosis. But it doesn’t always cause problems. However, it is rare for people with amyloidosis to develop myeloma. Doctors usually treat amyloidosis with chemotherapy, and use the same drugs that you would have for myeloma.

Monoclonal Gammopathies of Undetermined Significance (MGUS): Practice Essentials, Pathophysiology, Epidemiology

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  • Leung N, Bridoux F, Hutchison CA, Nasr SH, Cockwell P, Fermand JP, et al. Monoclonal gammopathy of renal significance: when MGUS is no longer undetermined or insignificant. Blood. 2012 Nov 22. 120 (22):4292-5. [Medline].

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  • Chang WJ, Van Wier SA, Ahmann GJ, et al. A validated FISH trisomy index demonstrates the hyperdiploid and nonhyperdiploid dichotomy in MGUS. Blood. 2005 Sep 15. 106(6):2156-61.

  • Ogmundsdottir HM, Einarsdottir HK, Steingrimsdottir H, Haraldsdottir V. Familial predisposition to monoclonal gammopathy of unknown significance, Waldenstrom’s macroglobulinemia, and multiple myeloma. Clin Lymphoma Myeloma. 2009 Mar. 9(1):27-9. [Medline].

  • Fenhuang Z, Barlogie B, Arzoumanian, et al. Gene-expression signature of benign monoclonal gammopathy evident in multiple myelom is linked to good prognosis. Blood. 2007. 109:1692-1700.

  • Nagoshi H, Taki T, Chinen Y, Tatekawa S, Tsukamoto T, Maegawa S, et al. Transcriptional dysregulation of the deleted in colorectal carcinoma gene in multiple myeloma and monoclonal gammopathy of undetermined significance. Genes Chromosomes Cancer. 2015 Dec. 54 (12):788-95. [Medline].

  • Mullikin TC, Rajkumar SV, Dispenzieri A, Buadi FK, Lacy MQ, Lin Y, et al. Clinical characteristics and outcomes in biclonal gammopathies. Am J Hematol. 2016 May. 91 (5):473-5. [Medline].

  • Kyle RA, Therneau TM, Rajkumar SV, Larson DR, Plevak MF, Offord JR, et al. Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med. 2006 Mar 30. 354 (13):1362-9. [Medline]. [Full Text].

  • Murray D, Kumar SK, Kyle RA, Dispenzieri A, Dasari S, Larson DR, et al. Detection and prevalence of monoclonal gammopathy of undetermined significance: a study utilizing mass spectrometry-based monoclonal immunoglobulin rapid accurate mass measurement. Blood Cancer J. 2019 Dec 13. 9 (12):102. [Medline]. [Full Text].

  • Genet P, Sutton L, Chaoui D, Al Jijakli A, Gerbe J, Masse V, et al. Prevalence of monoclonal gammopathy in HIV patients in 2014. J Int AIDS Soc. 2014. 17(4 Suppl 3):19649. [Medline]. [Full Text].

  • Landgren O, Shim YK, Michalek J, Costello R, Burton D, Ketchum N, et al. Agent Orange Exposure and Monoclonal Gammopathy of Undetermined Significance: An Operation Ranch Hand Veteran Cohort Study. JAMA Oncol. 2015 Nov 1. 1 (8):1061-8. [Medline].

  • Landgren O, Zeig-Owens R, Giricz O, Goldfarb D, Murata K, Thoren K, et al. Multiple Myeloma and Its Precursor Disease Among Firefighters Exposed to the World Trade Center Disaster. JAMA Oncol. 2018 Jun 1. 4 (6):821-827. [Medline].

  • Kristinsson SY, Björkholm M, Landgren O. Survival in monoclonal gammopathy of undetermined significance and waldenström macroglobulinemia. Clin Lymphoma Myeloma Leuk. 2013 Apr. 13(2):187-90. [Medline].

  • Kristinsson SY, Bjorkholm M, Andersson TM, et al. Patterns of survival and causes of death following a diagnosis of monoclonal gammopathy of undetermined significance (MGUS): a population-based study. Haematologica. 2009 Jul 16. epub ahead of print. [Medline]. [Full Text].

  • Landgren O, Gridley G, Turesson I, 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 Feb 1. 107(3):904-6.

  • 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 Jul 9. [Medline].

  • Rajkumar SV, Kyle RA, Therneau TM, Melton LJ 3rd, Bradwell AR, Clark RJ, et al. Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance. Blood. 2005 Aug 1. 106 (3):812-7. [Medline]. [Full Text].

  • Pelzer BW, Arendt M, Moebus S, Eisele L, Jöckel KH, Dührsen U, et al. Light chain monoclonal gammopathy of undetermined significance is characterized by a high disappearance rate and low risk of progression on longitudinal analysis. Ann Hematol. 2018 Aug. 97 (8):1463-1469. [Medline].

  • Turesson I, Kovalchik SA, Pfeiffer RM, Kristinsson SY, Goldin LR, Drayson MT, et al. Monoclonal gammopathy of undetermined significance and risk of lymphoid and myeloid malignancies: 728 cases followed up to 30 years in Sweden. Blood. 2014 Jan 16. 123(3):338-45. [Medline]. [Full Text].

  • Cohen AL, Sarid R. The relationship between monoclonal gammopathy of undetermined significance and venous thromboembolic disease. Thromb Res. 2009 Feb 2. [Medline].

  • Srkalovic G, Cameron MG, Rybicki L, et al. Monoclonal gammopathy of undetermined significance and multiple myeloma are associated with an increased incidence of venothromboembolic disease. Cancer. 2004 Aug 1. 101(3):558-66.

  • Kristinsson SY, Tang M, Pfeiffer RM, et al. Monoclonal gammopathy of undetermined significance and risk of skeletal fractures: a population-based study. Blood. 2010 Oct 14. 116(15):2651-5. [Medline].

  • Piot JM, Royer M, Schmidt-Tanguy A, Hoppé E, Gardembas M, Bourrée T, et al. Factors associated with an increased risk of vertebral fracture in monoclonal gammopathies of undetermined significance. Blood Cancer J. 2015 Aug 28. 5:e345. [Medline].

  • Kristinsson SY, Tang M, Pfeiffer RM, Björkholm M, Goldin LR, Blimark C, et al. Monoclonal gammopathy of undetermined significance and risk of infections: a population-based study. Haematologica. 2012 Jun. 97 (6):854-8. [Medline]. [Full Text].

  • Rison RA, Beydoun SR. Paraproteinemic neuropathy: a practical review. BMC Neurol. 2016 Jan 28. 16:13. [Medline]. [Full Text].

  • [Guideline] Kyle RA, et al; International Myeloma Working Group. 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. 2010 Jun. 24 (6):1121-7. [Medline].

  • Swerdlow SH, Campro E, Harris NL, et al. World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: IARC; 2008.

  • Katzmann JA, Kyle RA, Benson J, et al. Screening panels for detection of monoclonal gammopathies. Clin Chem. 2009 Aug. 55(8):1517-22. [Medline].

  • Greenberg AJ, Cousin M, Kumar S, Ketterling RP, Knudson RA, Larson D, et al. Differences in the distribution of cytogenetic subtypes between multiple myeloma patients with and without a family history of monoclonal gammopathy and multiple myeloma. Eur J Haematol. 2013 May 6. [Medline].

  • Ng AP, Wei A, Bhurani D, et al. The sensitivity of CD138 immunostaining of bone marrow trephine specimens for quantifying marrow involvement in MGUS and myeloma, including samples with a low percentage of plasma cells. Haematologica. 2006. 91:972-975.

  • Jerez A, Ortuno FJ, Osma MD, et al. Bone-marrow immunophenotypic analysis allows the identification of high risk of progression and immune condition-related monoclonal gammopathy of undetermined significance. Ann Med. 2009 Jul 26. 1-12. [Medline].

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  • Mikhael J. Ask the Hematologist: A Diagnostic Approach to Patients with an IgM monoclonal protein. American Society of Hematology. Available at http://www.hematology.org/Thehematologist/Ask/3186.aspx. August 3, 2016; Accessed: December 27, 2019.

  • Niermeijer JM, Eurelings M, Lokhorst HL, et al. Rituximab for polyneuropathy with IgM monoclonal gammopathy. J Neurol Neurosurg Psychiatry. 2009 Sep. 80(9):1036-9. [Medline].

  • Kappa and Lambda Light Chains

    Kappa/Lambda Light Chains in Multiple Myeloma

    Multiple myeloma is a blood cancer of white blood cells called plasma cells. Plasma cells come from the bone marrow and they produce antibodies (also called immunoglobulins) that fight wide variety of infections. In myeloma, one of these antibodies grows out of control in the bone marrow, crowding out the other antibodies. This is called a monoclonal protein (also called M-protein or M-spike). 

    Antibodies are made up of two parts: heavy chains and light chains. When myeloma progresses, the myeloma cells start to produce more light chains than heavy chains. This can be measured by the Free Light Chain Assay test on a blood specimen. In general, the higher the free light chains, the more aggressive the disease is. Therefore, the serum free light chain test is a better predictor of outcome than the amount of M-protein in the blood.

    What are light chains? 

    There are two types of light chains: kappa and lambda. If a patient has kappa myeloma, their doctor will watch for a rise in the kappa numbers. Likewise, if a patient has lambda myeloma, the lambda number will be watched. This balance of kappa and lambda together is called the kappa/lambda ratio which can also indicate a change in levels of disease. “The ratio or proportion between the kappa and lambda light chains indicates an excess production of one chain over the other, and therefore can be used as an indication of disease progression or remission,” said Dr. Christina Gasparetto of Duke University. 

    What are heavy chains? 

    There are five types of immunoglobulins: IgG, IgA, IgM, IgE and IgD. Approximately 60-70% of patients have IgG myeloma and about 20% have IgA myeloma. 

    Heavy and light chain combinations

    In total, there are 10 variations of these immunoglobulins for myeloma patients: IgA kappa, IgG kappa, IgM kappa, IgD kappa, IgE kappa, IgA lambda, IgG lambda, IgM lambda, IgD lambda, and IgE lambda.

    Presence of heavy and light chains

    There are instances where patients can lose the heavy chain and have “light chain only” myeloma. There are also instances where patients no longer produce light chains in the blood and their disease must then be monitored through a bone marrow biopsy. 

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    Making sense of serum protein bands

    Serum protein bands (monoclonal gammopathy) will sometimes be found following serum protein
    electrophoresis in patients presenting with classic signs or symptoms of multiple myeloma, e.g. bone pain. In other cases,
    patients may have non-specific symptoms, meaning the discovery is more unexpected. Irrespective of how the band is discovered,
    there are additional tests that can be performed to provide more information to help with the diagnosis and to guide management.
    These tests include; immunofixation, Bence-Jones protein and serum free light chains.

    While we may recognise the names of some of the tests, it can be confusing to know the situations in which they should
    be requested, and even what the results mean. This article provides an overview of the clinical situations in which a
    patient may have a monoclonal gammopathy in their serum, what these results mean, and the role of other related laboratory
    tests.

    In a general practice setting, test results showing increased protein in serum or urine are often incidental findings
    when investigations have been requested for other reasons. Patients with clinical conditions such as multiple myeloma,
    that increase the levels of protein in serum or urine, may present with a wide range of symptoms or may be asymptomatic.
    In these patients serum protein electrophoresis may have been requested as part of the initial work-up.

    Levels of protein in the serum change in a predictable way in response to many clinical conditions, such as inflammation,
    trauma (including burns and chemical injury), malignancy, infarction and necrosis. 1 Serum protein electrophoresis
    is a laboratory test used to help identify patients with multiple myeloma and other serum protein disorders, by separating
    serum proteins into their various components. Indications for serum protein electrophoresis are numerous and are based
    on clinical, laboratory and occasionally radiological findings (see “Indications for requesting serum protein electrophoresis”).

    Indications for requesting serum protein electrophoresis

    1,2,3

    Indications based on clinical findings:

    • Suspected multiple myeloma, Waldenström’s macroglobulinemia, primary amyloidosis or other related disorders
    • Unexplained bone pain or fracture
    • Recurrent infections
    • Unexplained peripheral neuropathy (not able to be attributed to another condition, e.g. type 2 diabetes, chemotherapy)

    Indications based on laboratory findings:

    • High (or low) total serum globulin or immunoglobulin
    • Extremely high percentage of lymphocytes
    • Incidental finding of an increased total protein level
    • Unexplained anaemia (multiple myeloma is a recognised cause of non-iron deficiency anaemia) or other persisting cytopaenias
      for which there is no other explanation
    • Unexplained high ESR (>50) with a normal CRP
    • Unexplained hypercalcaemia or renal impairment
    • Red cell rouleaux formations noted on the peripheral blood smear
    • Unexplained high urine protein with relatively low or normal urine albumin
    • Presence of urine free light chains (Bence-Jones proteinuria)

    Indications based on radiological findings:

    • Lytic lesions in bone
    • Unexplained osteopaenia (as not all patients with multiple myeloma will have osteolytic lesions)

    Electrophoresis fractions

    Serum protein electrophoresis separates serum proteins into the following fractions: albumin, alpha, beta and gamma
    globulins. Approximately 60% of the total protein in the serum is albumin, while the remaining fractions are composed
    mainly of globulins, predominantly immunoglobulins. The gamma fraction contains the largest portion of immunoglobulins,
    hence an increase in gamma globulin is referred to as a gammopathy.

    Gammopathies can be either polyclonal, characterised by a broad diffuse band in the electrophoresis pattern, or monoclonal
    where the band is sharp and well defined. Making the distinction between a monoclonal and polyclonal gammopathy is important.

    Monoclonal gammopathies are associated with excessive production of immunoglobulins from a single clone of cells that
    is malignant or potentially malignant, whereas polyclonal gammopathies are characterised by a generalised increase in
    immunoglobulins.1 A polyclonal gammopathy can be caused by various infections, haematologic diseases, liver
    disease, some malignancies and inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus, temporal
    arteritis and sarcoidosis.

    This article focuses on monoclonal gammopathies, and provides guidance on the laboratory management of conditions associated
    with these.

    Monoclonal gammopathy

    Monoclonal gammopathy is the name given to a “band” in serum protein electrophoresis, caused by the overproduction
    of a population of plasma cells, which in turn produce a single immunoglobulin (the so-called “plasma cell dyscrasias”).
    As there is a finite capacity in the bone marrow, an enlarging clone of plasma cells expands at the expense of other cells.
    Levels of other normal immunoglobulins eventually fall, referred to as immune paresis. While this is most often associated
    with multiple myeloma, it is quite frequently an unexpected discovery, and may be related to a number of conditions.

    Conditions associated with monoclonal gammopathy

    There are a number of conditions associated with monoclonal gammopathy. In the first instance, most GPs will think of
    multiple myeloma, but this is less common, and most people will be found to have a monoclonal gammopathy of undetermined
    significance (MGUS). Table 1 compares the incidence of these conditions.







    Table 1: Conditions with monoclonal gammopathies6,7,8
    Condition Clinical Effect Incidence
    Monoclonal gammopathy of undetermined significance (MGUS) Asymptomatic with risk of progression 1% >50 years, rising up to 8% >70 years
    Multiple myeloma Severe 40 per million, but increases to 300 per million for people >80 years
    Waldenström’s macroglobulinaemia Moderate 0. 1 per million at age <45 years and 36.3 per million at age >75 years.
    Amyloidosis Severe 8 per million

    Monoclonal gammopathy of undetermined significance (MGUS)

    MGUS is the most common monoclonal gammopathy. It describes the presence of a monoclonal protein without sufficient
    clinical or laboratory evidence to diagnose one of the other associated conditions. It is the most frequent diagnosis
    of a monoclonal gammopathy, and has an incidence approximately 60 times greater than multiple myeloma (1% in people aged
    over 50 years, rising to up to 8% of people aged over 70 years).4,5

    Approximately 1% of patients per year with MGUS will progress to multiple myeloma, therefore periodic (usually annual)
    monitoring should be done (with serum protein electrophoresis, immunoglobulins and complete blood count). There is no
    plateau time, beyond which development of a condition such as multiple myeloma will not occur. However, reactive bands,
    which can occur as part of the immune response to an inflammatory stimulus, often reduce or disappear when followed.

    Multiple myeloma

    Multiple myeloma is uncommon and has an incidence of approximately 40 per million people. It is rare under the age 40
    years, but its incidence rises to over 300 per million in people aged over 80 years. The median age at diagnosis is 69
    years with a slight male predominance.3

    Patients with multiple myeloma can be classified as having asymptomatic (formerly known as smouldering) or symptomatic
    (active) disease.

    Anaemia and bone marrow failure, infections, renal impairment, bone pain and pathological fractures are common clinical
    features. The differential diagnosis of multiple myeloma is shown in Table 2.







    Table 2: Differential diagnosis of multiple myeloma (adapted from O’Connell, et
    al 2005)1
    Disease Distinctive features
    Multiple myeloma (active)

    Monoclonal gammopathy in serum or urine – plasma concentration >30 g/L (IgG or A) or lower
    concentration of monoclonal IgD or light chain band

    and

    ≥10% plasma cells in bone marrow

    and

    evidence of organ dysfunction involving one or more of: lytic bone lesions or osteoporosis, anaemia, hypercalcaemia
    or renal disease

    Asymptomatic myeloma (smouldering)

    Monoclonal gammopathy ≥30 g/L (IgG) and/or ≥10% plasma cells in bone marrow

    but

    no evidence of disease-specific end-organ damage – no lytic bone lesions, anaemia, hypercalcaemia or renal disease

    Monoclonal gammopathy of undetermined significance

    Monoclonal gammopathy <30 g/L and <10% plasma cell in bone marrow

    and

    no evidence of disease-specific end-organ damage – no lytic lesions, anaemia, hypercalcaemia or renal disease

    Waldenström’s macroglobulinaemia

    IgM monoclonal gammopathy, and ≥10% bone marrow infiltration with lymphoplasmacytic cells (with
    characteristic immune phenotype)

    Clinical features include hyperviscosity, anaemia, and enlargement of liver, spleen and lymph nodes

    Less common associations of monoclonal gammopathies

    Lymphomas: monoclonal gammopathy is a common feature of primary lymphoproliferative conditions such
    as chronic lymphocytic lymphoma.

    Waldenström’s macroglobulinaemia: a type of small cell lymphoma associated with production
    (often large amounts) of monoclonal IgM. The median age at presentation is 63 years, and over 60% of patients are male.
    Clinical features include enlargement of liver and spleen and anaemia, due to increasing concentration of IgM, and hyperviscosity
    syndrome.3

    Amyloidosis: Primary amyloidosis is associated with a monoclonal gammopathy in 85% of cases and is
    characterised by pathological deposits of monoclonal light-chain fragments in various tissues such as heart, liver, bone
    marrow, lymph nodes and bowel.

    Plasmacytoma: refers to a localised solid collection of plasma cells in the body outside the bone marrow.

    Laboratory tests for monoclonal gammopathies

    There are number of laboratory tests which are useful for determining the presence of a monoclonal gammopathy, and then
    eventually characterising it.

    Serum total protein and albumin

    These are relatively crude tests, but will often be abnormal if a monoclonal gammopathy and/or immune paresis is present.
    A large band may show as a high serum total protein with a raised calculated globulin result. If the total serum protein
    is very high, e.g. >90 g/L, protein electrophoresis may be performed on a reflex basis by the laboratory.

    Immunoglobulins

    A person with a monoclonal gammopathy will have an increase in a particular class of immunoglobulin: IgG, IgA, IgM or
    IgD (IgE monoclonal gammopathy is extremely rare). Quantitation of immunoglobulins (routinely IgG, IgA and IgM) is performed
    if a new monoclonal gammopathy is detected. It is also usually performed when following a known monoclonal gammopathy,
    to provide information about progression.

    Serum protein electrophoresis

    Serum protein electrophoresis is a means of separating serum proteins. A small amount of serum is placed on a specific
    medium (such as agarose) and an electrical charge is applied. The proteins then migrate across the medium in a characteristic
    manner, due to the net charge and size and shape of the protein.

    In routine serum protein electrophoresis, the protein will separate into five main components (Figure 1), identified
    as albumin and the globulins (alpha1, alpha2, beta and gamma) . The gamma region contains the largest portion of globulins,
    therefore monoclonal gammopathies are most frequently encountered in this portion of the electrophoresis.

    Immunofixation

    When serum protein electrophoresis identifies a mono-clonal gammopathy, the laboratory will automatically perform immunofixation
    (i.e. reflex test) to further determine the exact type of monoclonal protein. The heavy chain of the immunoglobulin will
    be identified as IgA, IgG or IgM (most commonly) or IgD (or IgE rarely). The light chains will be identified as kappa
    or lambda (κ or λ). In a minority of cases only light chains (without heavy chains) are produced. Light chain-only
    monoclonal gammopathy are often barely visible in serum but may show as large amounts of monoclonal light chains excreted
    in the urine; hence the need to consider urine testing when clearly suspecting a monoclonal gammopathy.

    Urine free light chain testing (Bence-Jones protein)

    Even in disease-free people, light chains are produced in small excess over heavy chains, creating a surplus of (polyclonal)
    free light chains. In a person with a monoclonal gammopathy this is often more marked, due to dysregulation of light versus
    heavy chain production. All of the excess light chains also have an identical class and mobility. Excess free light chains
    are frequently detectable in the urine by electrophoresis and immunofixation. The presence of monoclonal urine light chains,
    often referred to as Bence-Jones protein, is found nearly exclusively in patients with lymphoproliferative processes such
    as multiple myeloma.

    Serum free light chains

    Serum free light chain assays can detect normal levels of light chains in the blood, as well as elevated levels, even
    when those levels are undetectable by serum protein electrophoresis and immunofixation. Both free κ and λ chains
    are measured and the ratio is calculated. Excessive free κ or λ increases the likelihood a of monoclonal
    plasma cell disorder.

    Some evidence suggests that in patients with newly identified MGUS, an abnormal light chain ratio increases the likelihood
    of progression independent of other factors such as band size and type. However, formal guidelines differ as to the use
    of serum free light chains in this setting. Recent British Haematology Society guidelines do not recommend their use,
    other than in patients who are otherwise at higher risk of progression (see “Monitoring monoclonal
    gammopathy” below) and those where a malignant plasma cell disorder is otherwise clearly suspected.

    Serum free light chains are useful in certain specific and uncommon settings, e.g. concern over a possible non-secretory
    myeloma or amyloidosis, after specialist consultation. Light chains are sometimes used in specialist settings to monitor
    the response of mutiple myeloma to treatment.

    Serum free light chains are not recommended as a first line routine test for plasma cell disorders. There is also no
    current evidence to support their use in long-term monitoring,9 except for monitoring response of mutiple myeloma
    to treatment.

    Clinical presentation of monoclonal gammopathy

    Asymptomatic patients with chance findings

    Approximately 30% of patients with monoclonal gammopathy are asymptomatic at diagnosis. In these cases the diagnosis
    is made due to an unusual result being noticed by either the laboratory or the GP. Some of the more suspicious laboratory
    findings include:

    • Unexplained raised ESR (a monoclonal gammopathy does not increase CRP)
    • Increased rouleaux formation on the blood film
    • Increased serum total protein and/or calculated globulin (total protein minus albumin)
    • Elevated immunoglobulin result

    N.B. ESR and immunoglobulins are not recommended screening tests for monoclonal bands, which are only detected by electrophoresis

    Symptomatic patients

    Although the diagnosis of multiple myeloma is often made by chance, a significant number of people will present with
    symptoms.

    Two-thirds of patients complain of bone pain, frequently located in the back, long bones, skull and pelvis. In addition,
    patients often have a range of non-specific (constitutional) symptoms, including fatigue, weight loss, chronic infections,
    paresthesia and symptoms related to hypercalcaemia.





    Table 3: Red flags for potential diagnosis of multiple myeloma in patients with back pain (adapted
    from George, et al 1991)10
    Red Flags

    Age over 50 years

    Pain that is worse in supine position

    Pain that is worse at night or awakens patient from sleep

    Pain with a band-like distribution around the body

    Pain that is not relieved with conventional methods (i.e., rest, nonsteroidal anti-inflammatory drugs)

    Associated constitutional symptoms (fever, weight loss, dehydration)

    Progressive neurologic deficit in lower extremities

    As many patients with multiple myeloma present with lower back pain, a number of “red flags” have been identified
    in the assessment of patients with acute lower back pain. Multiple myeloma should be considered as a diagnosis in patients
    aged over 50 years with back pain persisting more than one month, if one or more red flags are identified (Table 3).

    Testing for monoclonal gammopathy

    In patients with a possible monoclonal gammopathy, the following investigations are required:

    • Serum protein electrophoresis
    • Urine free light chain testing

    If a band is identified by serum electrophoresis or if immune paresis is noted then immunofixation, immunoglobulins
    and band quantification are recommended. A casual urine sample for protein and albumin and free light chains (Bence-Jones
    protein) should be collected. Other tests which should also be requested in this clinical situation are complete blood
    count, corrected calcium, creatinine (eGFR) and electrolyte measurements.

    Monitoring monoclonal gammopathy

    Periodic monitoring and watching for clinical and laboratory features of change is of key importance when managing patients
    with a monoclonal gammopathy. This is because transformation can occur, e.g. a patient may transition from MGUS to asymptomatic
    myeloma to multiple myeloma.

    Approximately 1% of people with MGUS develop multiple myeloma, amyloidosis or Waldenström’s macroglobinaemia
    annually, although most (especially those who are older at diagnosis) die of other diseases.11

    The follow-up for patients with MGUS depends on the risk of progression. Both the British/Nordic Study Group (2009)9 and
    the International Myeloma Working Group (IMWG, 2010)12 have recently published guidelines. These differ in
    detail, but their common thread is that it is important to fully investigate patients at high risk, whereas those with
    low risk can be spared unnecessarily invasive initial investigations and need less frequent long-term monitoring.

    The patient should be informed about the range of possible symptoms and advised to report new symptoms such as bone
    pain, weight loss, fatigue or other symptoms of progression. They should be aware that the risk of progression is life-long
    and does not plateau. The risk of eventual progression is higher for a young fit person with more years of life expectancy,
    than for an older person with other significant co-morbidities.

    Low risk MGUS: The majority of patients with MGUS are at low risk of progression, judged by:

    • Small band size (IgG <15 g/L OR IgA or IgM <10 g/L)
    • They are asymptomatic
    • No other abnormal results (normal adjusted calcium, creatinine and eGFR, blood count).

    These patients should be followed-up several times in the first year, and this interval can be extended to six to 12
    monthly and up to two to three yearly in long-term stable patients.9,12

    High risk MGUS: These patients should be referred to a haematologist and require more active initial
    evaluation and closer long-term monitoring. Risk factors include one or more of the following:

    • Band size IgG > 15 g/L OR IgA or IgM > 10 g/L
    • Any IgD or IgE monoclonal gammopathy regardless of concentration
    • Symptoms or signs of a suspected multiple myeloma or lymphoproliferative disorder, e.g. bone pain or pathological
      fractures, constitutional symptoms such as weight loss, peripheral neuropathy, nephrotic syndrome
    • Other unexplained laboratory or radiology abnormalities regardless of band size, e.g. hypercalcaemia, renal impairment,
      anaemia, lytic lesions or significant osteopaenia
    • The presence of Bence-Jones proteinuria, immune suppression, age and sex are not in themselves prognostic. However,
      significant Bence-Jones proteinuria (>500 mg/L) should prompt haematologist referral because of the risk of development
      or progression of renal impairment.

    Further evaluation usually includes bone marrow aspirate and trephine biopsy. Serum free light chains and beta-2 microglobulin
    may also be helpful in stratifying these patients – a normal light chain ratio and low beta-2 microglobulin level carries
    lower risk.

    Other possible investigations for higher risk patients include; spine/pelvic MRI scan for possible lytic lesions, abdominal
    CT for retroperitoneal lymph nodes (in patients with IgM bands), and renal investigations including; possible renal/tissue
    biopsy for patients with unexplained nephrotic proteinuria or renal impairment (looking for amyloidosis).

    Long-term patients with a high risk MGUS should usually be monitored at least several times in the first year, then
    annually for life. New symptoms or laboratory abnormalities should prompt earlier review. An increase in band size of
    more than 25% over three months (minimal 5 g/L) is regarded as significant.

    Patients with asymptomatic multiple myeloma have significant risk (about 10% annually) of progression
    to symptomatic disease, and should be under haematologist review. A skeletal survey and a bone marrow aspirate and biopsy
    should be carried out at baseline. Laboratory tests and clinical work-up should be done at diagnosis including baseline
    MRI of the spine and pelvis. Tests should be repeated two to three months after the initial recognition of the diagnosis.
    If the results are stable, the studies should be repeated every four to six months for one year and, if stable, evaluation
    intervals can be lengthened to every six to 12 months. A skeletal survey should be performed if there is evidence of progression.

    Understanding immunoglobulins

    Plasma cells produce immunoglobulins which are composed of heavy and light chains. Each plasma cell produces only one
    type of heavy chain (IgA, IgD, IgG, IgM and IgE) and one type of light chain (either kappa or lambda [κ or λ]).
    After the chains are produced they are assembled within the plasma cell to form a whole immunoglobulin.

    Figure 2: Immunoglobulin (showing light and heavy chains).

    A PCP’s Guide to Screening for Monoclonal Gammopathy of Undetermined Significance – Consult QD

    By Jack Khouri, MD, Christy Samaras, DO, Jason Valent, MD, Alex Mejia Garcia, MD, Beth Faiman, PhD, CNP, Saveta Mathur, CNP, Kim Hamilton, CNP, Megan Nakashima, MD, and Matt Kalaycio, MD

    Cleveland Clinic is a non-profit academic medical center. Advertising on our site helps support our mission. We do not endorse non-Cleveland Clinic products or services Policy

    The monoclonal gammopathies encompass a number of disorders characterized by the production of a monoclonal protein (M protein) by an abnormal clone of plasma cells or other lymphoid cells. Monoclonal gammopathy of undetermined significance (MGUS) is the most common of these disorders. The diagnostic criteria for MGUS are listed below.

    Its clinical relevance lies in the inherent risk of progression to hematologic malignancies such as multiple myeloma or other lymphoproliferative disorders, or of organ dysfunction due to the toxic effects of the M protein. An M protein may consist of an intact immunoglobubin (Ig) molecule — i.e., two light chains and two heavy chains (most commonly IgG type followed by IgA and IgM) — or a light chain only (kappa or lambda).

     

    MGUS is present in 3 to 4 percent of the population over age 50 and is more common in older men, African-Americans and Africans.

    The overall risk of progression to myeloma and related disorders is less than or equal to 1 percent per year depending on the subtype of the M protein (higher risk with IgM than non-IgM and light-chain MGUS). While the risk of malignant transformation is low, multiple myeloma is almost always preceded by the presence of an asymptomatic and often unrecognized monoclonal protein.

    When should we look for an M protein?

    An M protein is typically an incidental finding when a patient is being assessed for any of a number of presenting symptoms or conditions. A large retrospective study found that screening for MGUS was mostly performed by internal medicine physicians. The indications for testing were anemia, bone-related issues, elevated creatinine, elevated erythrocyte sedimentation rate and neuropathy.

    Routine screening for an M protein in the absence of clinical suspicion is not recommended, given the low risk of malignant progression, lack of effect on patient outcomes, the accompanying emotional burden and lack of treatment options. Evaluation for monoclonal gammopathy may be considered as part of the workup of associated clinical symptoms and signs and laboratory and imaging findings.

    A low anion gap is not a major indicator of an M protein unless in a high concentration, in which case other manifestations would be present, such as renal failure, which would guide the diagnosis. Polyclonal hypergammaglobulinemia as a cause of low anion gap is far more common than MGUS.

    Serum protein electrophoresis is an initial test used to identify an M protein and has a key role in quantifying it. An M protein appears as a narrow spike on the agarose gel and should be distinguished from the broad band seen in polyclonal gammopathies associated with cirrhosis and chronic infectious and inflammatory conditions, among others. A major disadvantage of serum protein electrophoresis is that it cannot detect an M protein in very low concentrations or determine its identity.

    Serum immunofixation is more sensitive than serum protein electrophoresis and should always be ordered in conjunction with it, mostly to ensure detecting tiny amounts of M protein and to identify the type of its heavy chain and light-chain components.

    The serum free light-chain assay is also considered an essential part of the screening process to detect light-chain MGUS and light-chain myeloma. As many as 16 percent of myeloma patients secrete only light chains, which may not be identified on serum immunofixation. In general, a low kappa-lambda ratio (< 0.26) indicates the overproduction of lambda light chains, and a high ratio (> 1.65) indicates the overproduction of kappa light chains.

    The serum free light-chain assay helps detect abnormal secretion of monoclonal light chains before they appear in the urine once the kidney tubules become saturated and unable to reabsorb them.

    Of note, the free light-chain ratio can be abnormal (< 0.26 or > 1.65) in chronic kidney disease. Thus, it may be challenging to discern whether an abnormal light-chain ratio is related to impaired light-chain clearance by the kidneys or to MGUS. In general, kappa light chains are more elevated than lambda light chains in chronic kidney disease, but the ratio should not be considerably skewed. A kappa-lambda ratio below 0.37 or above 3 is rarely seen in chronic kidney disease and should prompt workup for MGUS.

    Tests in combination. The sensitivity of screening for M proteins ranges from 82 percent with serum protein electrophoresis alone to 93 percent with the addition of serum immunofixation and to 98 percent with the serum free light-chain assay. The latter can replace urine protein electrophoresis and immunofixation when screening for M protein, given its higher sensitivity. An important caveat is that urine dipstick testing does not detect urine light chains.

    Once an M protein is found, immunoglobulin quantification, a complete blood cell count, and serum creatinine and calcium measurements are also recommended to look for anemia, renal failure and hypercalcemia, which can be associated with symptomatic myeloma.

    Future posts will discuss the differential diagnosis of MGUS as well as risk stratification.

    Dr. Khouri is a fellow in the Department of Hematology and Medical Oncology. Drs. Samaras, Valent and Mejia Garcia are staff in the Department of Hematology and Medical Oncology. Dr. Faiman, Ms. Mathur and Ms. Hamilton are clinical nurse practitioners in the Department of Hematologic Oncology and Blood Disorders. Dr. Nakashima is staff in the Department of Clinical Pathology. Dr. Kalaycio is Chairman of the Department of Hematology and Medical Oncology.

    This abridged article was originally published in Cleveland Clinic Journal of Medicine.

    90,000 Free kappa and lambda chains of immunoglobulins in serum, IgG

    Quantitative study of free kappa and lambda chains of immunoglobulins in the blood, used for diagnosis, assessment of prognosis and control of treatment of monoclonal gammopathies and some other lymphoproliferative diseases.

    Russian synonyms

    Free κ and λ chains of immunoglobulins in the blood; free light chains of immunoglobulins in the blood.

    Synonyms English

    Free Light Chains, FLCs; FLCs, κ and λ; Serum FLC, sFLC.

    Research method

    Enzyme-linked immunosorbent assay (ELISA).

    Units

    μg / ml (micrograms per milliliter).

    Which biomaterial can be used for research?

    Venous blood.

    How to properly prepare for the study?

    • Eliminate physical and emotional stress for 30 minutes before the study.
    • Do not smoke for 30 minutes prior to examination.

    General information about the study

    Monoclonal gammopathies are a group of diseases in which monoclonal proliferation of plasma cells is observed (multiple myeloma, Waldenstrom’s macroglobulinemia, monoclonal gammopathy of unclear significance, and others). As a rule, in these diseases, altered plasma cells secrete immunoglobulins or their components (the common name is paraproteins), which determine the clinical picture of the disease and can be measured for diagnostic purposes.

    Different types of plasma cell tumors secrete different paraproteins:

    • Monoclonal immunoglobulin is a complete immunoglobulin molecule composed of light and heavy chains. Hypersecretion of IgG immunoglobulin is most often detected.
    • Light chains. In this case, complete assembly of immunoglobulins does not occur, and tumor cells secrete only (or predominantly) light chains of immunoglobulins. These light chains are called free, in contrast to light chains associated with heavy chains in the immunoglobulin molecule.Immunoglobulin free light chains are also called Bence Jones protein. A myeloma that secretes only light chains is known as Bence Jones myeloma. For a long time, the identification of free light chains was impossible, since there were no methods to differentiate free and bound light chains. Subsequently, with the invention of such methods, it became known that overproduction of free light chains is observed not only in multiple myeloma, but also in some other diseases, including AL-type amyloidosis and diseases of light chain deposition.
    • Non-secreting plasma cell tumors. Despite the proliferation of plasma cells, they do not secrete either immunoglobulins or their individual fragments.

    The following laboratory methods can be used to diagnose monoclonal gammopathies:

    • electrophoresis and immunofixation of serum proteins;
    • electrophoresis and immunofixation of urine proteins, including determination of Bens-Jones protein;
    • Determination of free light chains of immunoglobulins in serum or urine using enzyme-linked immunosorbent assay (ELISA).

    The ELISA method is relatively new (it was developed in 2001), however, due to its advantages, it was included in the standard algorithm for examining patients with suspected monoclonal gammopathy. The method is based on identifying epitopes of light chains that are available in molecules of free light chains and hidden in molecules of immunoglobulins, which makes it specific for free light chains. Both blood and urine can be analyzed for free light chains.

    The main advantage of ELISA determination of FLCs is its higher sensitivity compared to other methods. So, for example, using serum electrophoresis, it is possible to determine monoclonal immunoglobulin at a level of 500-2000 mg / l. The sensitivity of the method of immunofixation of serum proteins is about 10 times higher. Electrophoresis and immunofixation of urine proteins are more sensitive methods with a resolution of 20-50 mg / l. These methods, however, are still not sensitive enough to detect diseases in which the concentration of FLCs is low (Bens-Jones myeloma, AL-type amyloidosis and light chain deposition diseases).Using the ELISA method, it is possible to determine FLCs in the blood serum at a concentration of only 1.5-3 mg / L.

    In 80% of cases, plasma cell tumors secrete enough immunoglobulins that can be easily measured using electrophoretic methods. Although, as a rule, these tumors also secrete FLCs, in this group of patients, the study of FLCs using ELISA does not add significant diagnostic information. This study allows monoclonal gammopathies, secreting low concentrations of light chains, to be avoided by electrophoretic methods.

    It should be noted that an increase in the concentration of free light chains does not always indicate the presence of monoclonal gammopathy. Their concentration also increases with polyclonal gammopathies observed in some infectious diseases or impaired renal function. In polyclonal gammopathies, however, there is a proportional increase in both kappa and lambda chains and the κ / λ ratio remains normal. With monoclonal gammopathies, the concentration of only one of the two types of light chains increases and the κ / λ ratio changes.Therefore, for the differential diagnosis of mono- and polyclonal gammopathies when an increased concentration of free light chains is detected, it is advisable to separately determine the concentration of kappa and lambda chains and calculate their κ / λ ratio.

    The concentration of FLCs and the κ / λ ratio can be used as prognostic factors in assessing the risk of progression of unclear monoclonal gammopathy or asymptomatic myeloma to symptomatic myeloma. In addition to monoclonal gammopathies, FLCs can be used to predict some B-cell lymphomas.

    The determination of FLCs by ELISA can be used to monitor the treatment of monoclonal gammopathies. Due to the short half-life of FLCs (2-6 hours compared to intact immunoglobulin – 21 days), FLCs are a more dynamic clinical and laboratory marker, which can be used to assess the response to treatment faster. This is especially true for monitoring Bence Jones myeloma. Usually, to control the treatment of this disease, multiple studies of the Bence-Jones protein in daily urine are performed, which is inconvenient for both the doctor and the patient.The ELISA test for serum FLCs has been shown to reflect tumor volume even better than Bens-Jones proteinuria and is likely to replace this assay altogether.

    The study result is evaluated taking into account additional clinical, laboratory and instrumental data.

    What is the research used for?

    • For diagnostics, assessment of prognosis and control of treatment of monoclonal gammopathies (multiple myeloma, primary amyloidosis, monoclonal gammopathy of unclear significance) and some other lymphoproliferative diseases.

    When is the study scheduled?

    • If you suspect multiple myeloma or other diseases from the group of monoclonal gammopathies;
    • in assessing the prognosis of some B-cell lymphomas.

    What do the results mean?

    Reference values ​​

    Free kappa chains of immunoglobulins in serum: 3.25 – 15.81 μg / ml

    Free lambda chains of immunoglobulins in serum: 3.23 – 28.05 μg / ml

    Index of kappa / lambda light chains of immunoglobulins: 0.3 – 1.9

    Reasons for the increase:

    • multiple myeloma;
    • primary systemic amyloidosis;
    • solitary plasmacytoma;
    • monoclonal gammopathy of unclear significance;
    • chronic lymphocytic leukemia;
    • B-cell lymphoma;
    • 90,041 kidney disease;

      90,041 infectious diseases;

    • autoimmune diseases.

    Reasons for downgrade:

    • Disease control during treatment.

    What can influence the result?

    • Renal dysfunction;
    • concomitant infectious and inflammatory or autoimmune diseases.

    Download an example of the result

    Important notes

    • An increase in the concentration of free light chains does not always indicate the presence of monoclonal gammopathy;
    • research results should be interpreted taking into account additional clinical, laboratory and instrumental data.

    Also recommended

    [20-018] Free lambda chains of immunoglobulins in serum

    [20-015] Free kappa chains of immunoglobulins in serum

    [06-035] Total whey protein

    [06-038] Total protein in urine

    [08-010] Total immunoglobulins G (IgG) in serum

    [08-011] Total immunoglobulins M (IgM) in serum

    [06-011] Protein fractions in whey

    [13-101] Bens-Jones protein, quantitative (urine immunofixation)

    [13-056] Immunofixation of serum immunoglobulins with antisera IgG, A, M K, L with quantitative determination of paraprotein

    Who orders the study?

    General practitioner, oncologist, hematologist.

    Literature

    • Tosi P, Tomassetti S, Merli A, Polli V. Serum free light-chain assay for the detection and monitoring of multiple myeloma and related conditions. Ther Adv Hematol. 2013 Feb; 4 (1): 37-41. doi: 10.1177 / 2040620712466863.
    • Jenner E. Serum free light chains in clinical laboratory diagnostics. Clin Chim Acta. 2014 Jan 1; 427: 15-20. doi: 10.1016 / j.cca.2013.08.018. Epub 2013 Aug 30.

    Free kappa and lambda chains of immunoglobulins in urine, IgG

    Quantitative study of free κ – kappa and lambda – λ chains of immunoglobulins in urine, used to diagnose monoclonal gammopathies.

    Russian synonyms

    Free κ and λ chains of immunoglobulins in urine

    Free light chains of immunoglobulins in urine

    Synonyms English

    Free Light Chains, FLCs

    FLCs, κ and λ

    Urine FLCs

    Research method

    Enzyme-linked immunosorbent assay (ELISA).

    Units

    μg / ml (micrograms per milliliter).

    Which biomaterial can be used for research?

    Daily urine.

    How to properly prepare for the study?

    • Eliminate alcohol from the diet within 24 hours before the study.
    • Avoid (in consultation with your doctor) taking diuretics within 48 hours before urine collection.

    General information about the study

    Monoclonal gammopathies are a group of diseases in which monoclonal proliferation of plasma cells is observed (multiple myeloma, Waldenstrom’s macroglobulinemia, monoclonal gammopathy of unclear significance, and others).As a rule, in these diseases, altered plasma cells secrete immunoglobulins or their components (the common name is paraproteins), which determine the clinical picture of the disease and can be measured for diagnostic purposes.

    Different types of plasma cell tumors secrete different paraproteins:

    • Monoclonal immunoglobulin is a complete immunoglobulin molecule composed of light and heavy chains. Hypersecretion of IgG immunoglobulin is most often detected.
    • Light chains. In this case, complete assembly of immunoglobulins does not occur, and tumor cells secrete only (or predominantly) light chains of immunoglobulins. These light chains are called “free”, in contrast to light chains associated with heavy chains in the immunoglobulin molecule. Free light chains of immunoglobulins – Bens-Jones protein. A myeloma that secretes only light chains is known as Bence Jones myeloma. For a long time, the identification of free light chains was impossible, since there were no methods to differentiate free and bound light chains.Subsequently, with the invention of such methods, it became known that overproduction of free light chains is observed not only in multiple myeloma, but also in some other diseases, including AL-type amyloidosis and diseases of light chain deposition.
    • Non-secreting plasma cell tumors. Despite the proliferation of plasma cells, they do not secrete either immunoglobulins or their individual fragments.

    The following laboratory methods can be used to diagnose monoclonal gammopathies:

    • electrophoresis and immunofixation of serum proteins;
    • electrophoresis and immunofixation of urine proteins, including determination of Bens-Jones protein;
    • Determination of free light chains of immunoglobulins in serum or urine using enzyme-linked immunosorbent assay (ELISA).

    The ELISA method is based on the identification of epitopes of light chains that are available in molecules of free light chains and hidden in molecules of immunoglobulins, which makes it specific for free light chains.

    Both blood and urine can be tested for free light chains. In urine, free light chains of immunoglobulins polymerize, forming dimers and tetramers, and can also break down into smaller fragments. The process of polymerization / fragmentation of light chains in urine depends on parameters such as their concentration and urine pH, and is poorly predictable, which ultimately has a significant impact on the accuracy of the test result.For this reason, the study of free light chains in urine is considered as an additional analysis.

    In 80% of cases, plasma cell tumors secrete an amount of immunoglobulins that can be easily measured using electrophoretic methods. Although these tumors typically also secrete FLCs, ELISA studies of FLCs in this group of patients do not add any diagnostic information. This study allows electrophoretic methods not to miss monoclonal gammopathies secreting intact immunoglobulins or light chains in low concentration.

    It should be noted that an increase in the concentration of free light chains does not always indicate the presence of monoclonal gammopathy. Their concentration also increases with polyclonal gammopathies observed in some infectious diseases or impaired renal function. In polyclonal gammopathies, however, there is a proportional increase in both kappa and lambda chains and the κ / λ ratio remains normal. With monoclonal gammopathies, the concentration of only one of the two types of light chains increases and the κ / λ ratio changes.Therefore, for the differential diagnosis of mono- and polyclonal gammopathies when an increased concentration of free light chains is detected, it is advisable to separately determine the concentration of kappa and lambda chains and calculate their κ / λ ratio.

    What is the research used for?

    • For the diagnosis of monoclonal gammopathies (multiple myeloma, primary amyloidosis, monoclonal gammopathy of unclear significance).

    When is the study scheduled?

    • If you suspect multiple myeloma or other diseases from the group of monoclonal gammopathies.

    What do the results mean?

    Reference values ​​

    Kappa chains: 0.4 – 20 μg / ml.

    Lambda chains: 0.3 – 5 μg / ml.

    Reasons for the increase:

    • multiple myeloma;
    • primary systemic amyloidosis;
    • solitary plasmacytoma;
    • monoclonal gammopathy of unclear significance;
    • chronic lymphocytic leukemia;
    • B-cell lymphoma;
    • 90,041 infectious diseases;

    • autoimmune diseases.

    Reasons for downgrade:

    • Disease control during treatment.

    What can influence the result?

    • Renal dysfunction;
    • concomitant infectious and inflammatory or autoimmune diseases.

    Download an example of the result

    Important notes

    • The study of free light chains in urine is inferior in accuracy to the study of blood and is currently considered as an additional analysis;
    • research results should be interpreted taking into account additional clinical, laboratory and instrumental data.

    Also recommended

    [20-014] Free kappa chains of immunoglobulins in urine

    [20-017] Free lambda chains of immunoglobulins in urine

    [06-038] Total protein in urine

    [06-011] Protein fractions in whey

    [13-101] Bens-Jones protein, quantitative (urine immunofixation)

    [13-056] Immunofixation of serum immunoglobulins with antisera IgG, A, M K, L with quantitative determination of paraprotein

    Who orders the study?

    General practitioner, oncologist, hematologist.

    Literature

    1. Tosi P, Tomassetti S, Merli A, Polli V. Serum free light-chain assay for the detection and monitoring of multiple myeloma and related conditions. Ther Adv Hematol. 2013 Feb; 4 (1): 37-41. doi: 10.1177 / 2040620712466863.

    2. Jenner E. Serum free light chains in clinical laboratory diagnostics. Clin Chim Acta. 2014 Jan 1; 427: 15-20. doi: 10.1016 / j.cca.2013.08.018. Epub 2013 Aug 30.

    3. Dispenzieri A et al. International Myeloma Working Group.International Myeloma Working Group guidelines for serum-free light chain analysis in multiple myeloma and related disorders. Leukemia. 2009 Feb; 23 (2): 215-24.

    4. Snyder MR, Clark R, Bryant SC, Katzmann JA. Quantification of urinary light chains. Clin Chem. 2008 Oct; 54 (10): 1744-6. doi: 10.1373 / clinchem. 2008.107599.

    90,000 M-gradient, typing. Serum electrophoresis and immunofixation with a panel of antisera (IgG / A / M / kappa / lambda) with a quantitative assessment of the M-gradient

    Method of determination

    Electrophoresis and immunofixation with a panel of antisera (to IgG, IgA, IgM, kappa and lambda chains) with densitometry and assessment of the M-component content.

    Study material
    Blood serum

    Synonyms : Electrophoretic separation of serum proteins; Clinical electrophoresis and immunofixation; Paraproteins (m-gradient) in blood serum.

    Serum protein electrophoresis; Immunofixation electrophoresis (IFE); Detection of kappa and lambda light chain monoclonal proteins in human serum; Immunofixation for characterizing monoclonal proteins (M8proteins) in human serum.

    Brief description of the test “M-gradient, typing. Serum electrophoresis and immunofixation with a panel of antisera (IgG / A / M / kappa / lambda) with a quantitative assessment of the M-gradient “

    Detection and typing of monoclonal immunoglobulins.

    Immunoglobulins – proteins with antibody activity (the ability to specifically bind certain antigens).

    Unlike most serum proteins, which are produced in the liver, immunoglobulins are produced by plasma cells – the descendants of B-lymphocyte precursor stem cells in the bone marrow.According to structural and functional differences, 5 classes of immunoglobulins are distinguished – IgG, IgA, IgM, IgD, IgE and a number of subclasses. Polyclonal increases in immunoglobulins are the normal response to infections.

    Monoclonal gammopathies are conditions when an abnormal amount of immunoglobulin is produced by a clone of plasma cells or B-lymphocytes (a population of cells originating from a single precursor B-cell). These conditions can be benign or a manifestation of a disease.Monoclonal gammopathies are detected by the appearance of an abnormal protein band on serum or urine electrophoresis.

    Immunoglobulin molecules consist of one or more structural units built according to a single principle – two identical heavy chains and two identical light peptide chains – kappa or lambda. Varieties of heavy chains are the basis for dividing immunoglobulins into classes. Immunoglobulin chains have constant and variable regions, the latter being associated with antigenic specificity.

    Immunoglobulin produced by one clone of cells has an identical structure – it represents one class, subclass, characterized by an identical composition of heavy and light chains. Therefore, if an abnormally large amount of monoclonal immunoglobulin is present in the serum, during the electrophoretic separation of serum proteins, it migrates in the form of a compact band, which stands out against the background of the standard distribution pattern of serum protein fractions. When describing the results of electrophoresis of serum proteins, it is also called paraprotein, M-peak, M-component, M-protein or M-gradient.According to its structure, such a monoclonal immunoglobulin can be a polymer, monomer, or a fragment of an immunoglobulin molecule (in the case of fragments, these are more often light chains, less often – heavy ones).

    Light chains are capable of passing through a renal filter and can be detected by urine electrophoresis.

    The detection of monoclonal paraproteins is based on the use of protein electrophoresis. Sometimes fibrinogen and CRP that migrate to beta or gamma fractions can be mistaken for paraproteins.The immunoglobulin nature of the identified monoclonal component is confirmed by immunofixation of the separated proteins with a specific polyvalent precipitating antiserum directed against immunoglobulins (test No. 4050). When confirming the presence of monoclonal immunoglobulin, densitometry is performed and its quantitative content is determined. Full identification (typing) of the monoclonal component requires a detailed study using electrophoresis and immunofixation with an expanded panel of antisera against IgG, IgA, IgM, kappa and lambda chains (test No. 4051).In the diagnosis and prognosis, the class of the identified paraprotein, its concentration at the time of diagnosis, and the rate of increase in its concentration in dynamics are taken into account. The presence of paraprotein is a marker of a number of hemato-oncological diseases.

    What can affect the results of the test “M-gradient, typing. Serum electrophoresis and immunofixation with a panel of antisera (IgG / A / M / kappa / lambda) with a quantitative assessment of the M-gradient “

    When examining patients using drugs based on monoclonal antibodies (can be used as antitumor therapy, immunosuppressants, etc.), it should be borne in mind that at peak concentrations after administration, such drugs can sometimes be the reason for the detection of small abnormal bands of an immunoglobulin protein during electrophoresis.

    For what purpose is the study “M-gradient, typing. Serum electrophoresis and immunofixation with a panel of antisera (IgG / A / M / kappa / lambda) with a quantitative assessment of the M-gradient “

    Multiple myeloma is a classic hematological disease caused by malignant proliferation of plasma cells secreting monoclonal immunoglobulin (paraprotein) or its fragments.Plasma cells more often proliferate diffusely in the bone marrow, the disease leads to osteolytic lesions of the bones, reduction of other bone marrow cells, which leads to anemia, thrombocytopenia, leukopenia, inhibits the development of normal clones of plasma cells. Patients may present with localized symptoms of bone pathology (pain, fractures) or nonspecific symptoms (weight loss, anemia, bleeding, recurrent infections, or kidney failure). In most patients, at the time of diagnosis, the concentration of paraprotein exceeds 25 g / l.In myeloma, serum paraprotein is most often IgG (60%), less often IgA (20%), and about 20% of cases are Bens-Jones myeloma associated with the production of free light chains kappa or lambda (20%), which can be found in urine. Sometimes in myeloma, a biclonal paraprotein, represented by immunoglobulins of different classes or of the same class, but containing light chains of different classes, can be noted. IgD and IgE myeloma is rarely noted. Determination of the concentration of paraprotein is used to monitor the effectiveness of myeloma treatment, such monitoring for myeloma during therapy should be carried out every 3 months.If the content of paraprotein has dropped below the detectable level, it is advisable to re-measure it after 6 or 12 months.

    Waldenstrom’s macroglobulinemia is a lymphoma with overproduction of monoclonal IgM. Lymphoplasmacytic tumor cells with a characteristic immunophenotype are diffusely distributed in the lymph nodes, spleen and bone marrow. A high concentration of monoclonal IgM often exceeds 30 g / L and leads to an increase in blood viscosity and a number of clinical manifestations, including confusion, blindness, bleeding tendencies, heart failure, and hypertension.In macroglobulinemia, paraproteinemic polyneuropathy, cold hemolytic anemia, and cryoglobulins are common. In other types of lymphomas and chronic lymphocytic leukemia, paraproteins of the IgM class are observed in 20% of patients, but the concentration of paraprotein is usually lower than 30 g / l.

    Heavy chain disease (Franklin’s disease) is accompanied by the synthesis of only the heavy chain IgG-gamma, without the accompanying light chain. This extremely rare disease is manifested by edema of the soft palate and lymphoid infiltration.Also rarely noted is the alpha heavy chain disease, in which chronic diarrhea occurs, malabsorption caused by lymphoid infiltration of the intestinal wall.

    Monoclonal paraprotein can be detected in a number of non-neoplastic diseases, in particular, in essential cryoglobulinemia (usually IgM), paraproteinemic chronic polyneuropathy, cold hemolytic anemia, AL-amyloidosis of the kidneys (free lambda chains), and internal organs, diseases of the deposition of light chains.Serum paraprotein is also noted in Castelmann’s disease (IgM / lambda), POEMS syndrome (polyneuropathy with organ megalium) and myxedema lichen (IgG / kappa).

    In screening examinations, the frequency of detection of paraproteinemia increases sharply in the population after reaching 50 years of age and reaches 4-10% in persons over 65 years of age. However, the majority of newly diagnosed paraproteinemias in the general population are asymptomatic monoclonal gammopathies of unexplained significance (MGNZ).The concentration of paraprotein at MGNZ is significantly lower than 30 g / l and usually does not exceed 10–15 g / l. In addition, with MGNZ, paraprotein is detected against the background of polyclonal immunoglobulins, i.e., inhibition of the normal synthesis of other immunoglobulins does not occur. The term “MGNZ” indicates cases of paraproteinemia without other signs of oncohematological disease, which require annual monitoring so as not to miss the moment when the process becomes glorified. When paraproteins are detected in patients under 50 years of age, even more frequent repeated examinations are required, since they have a high risk of developing multiple myeloma.If the concentration of M-protein is more than 15 g / L, regardless of age, it is recommended to conduct an extended examination, including electrophoresis of a 24-hour urine sample and immunofixation every 3-6 months, since the risk of malignant transformation is very high. Benign paraproteinemia is distinguished, which is characterized by the preservation of paraprotein without progression to multiple myeloma or other disease within 5 years of follow-up. In transient paraproteinemia, the paraprotein concentration is usually below 3 g / l.

    Literature

    1. Andreeva N.E., Balakireva T.V. Paraproteinemic hemoblastosis // Guide to hematology / ed. A.I. Vorobyov. 3rd ed., M., 2003. T. 2, p. 151-184.

    2. Berenson J.R. Monoclonal gammopathy of undetermined significance: a consensus statement. Br. J. Haematol. 2010,150 (1): 28-38.

    90,000 M-gradient, immunotyping with a panel of antisera (IgG / A / M / kappa / lambda) with a quantitative assessment of the M-gradient

    Determination of quantitative and qualitative changes in the main fractions of blood protein used for diagnostics and control of treatment of acute and chronic inflammations of infectious and non-infectious genesis, as well as cancer (monoclonal gammopathies) and some other diseases.

    With the proliferation of a clone of plasma cells, the synthesis of immunoglobulin is increased, represented by one class, subclass and isotype, which includes heavy and light protein chains of the same type. During the electrophoretic separation of blood serum proteins, this immunoglobulin migrates in the form of a compact band, which is determined against the background of other protein fractions. This immunoglobulin is called monoclonal immunoglobulin or paraprotein. In serum protein electrophoresis, it is called the M-gradient.Paraprotein is a tumor marker in a number of hemato-oncological diseases.

    Multiple myeloma is a classic hematological disease caused by the proliferation of plasma cells secreting monoclonal immunoglobulin (paraprotein) or its fragments. In most cases, at the time of diagnosis, the concentration of paraprotein exceeds 25 g / l.

    In myeloma, serum paraprotein is most often represented by IgG (60%), less often IgA (20%).The remaining about 20% of cases are Bens-Jones myeloma associated with the production of free light chains of kappa or lambda (20%). In 2–4% of myeloma cases, there may be a biclonal paraprotein, represented by immunoglobulins of different classes or one class, but containing light chains of different classes. Changes in paraprotein concentration serve as an indicator of the effectiveness of myeloma treatment. Monitoring the concentration of PP in myeloma during therapy should be carried out every 3 months. If the PP content has dropped below the detectable value, it is advisable to re-measure it after 6 or 12 months.

    Waldenstrom’s macroglobulinemia is a lymphoma with overproduction of monoclonal IgM. Lymphoplasmacytic tumor cells with a characteristic immunophenotype are diffusely distributed in the lymph nodes, spleen and bone marrow. A high concentration of monoclonal IgM often exceeds 30 g / L and leads to an increase in blood viscosity and a number of clinical manifestations, including confusion, blindness, bleeding tendencies, heart failure, and hypertension.In macroglobulinemia, paraproteinemic polyneuropathy, cold hemolytic anemia, and cryoglobulins are common. In other types of lymphomas and chronic lymphocytic leukemia, paraproteins of the IgM class are observed in 20% of patients, but the concentration of paraprotein is usually lower than 30 g / l.

    Heavy chain disease (Franklin disease) is accompanied by the synthesis of only the heavy chain IgG-gamma, without the accompanying light chain. This extremely rare disease is manifested by edema of the soft palate and lymphoid infiltration.Also rarely noted is the alpha heavy chain disease, in which chronic diarrhea occurs, malabsorption caused by lymphoid infiltration of the intestinal wall.

    In screening examinations, the frequency of detection of paraproteinemia increases sharply in the population after reaching 50 years of age and reaches 4-10% in persons over 65 years of age. However, the majority of newly diagnosed paraproteinemias in the general population are asymptomatic monoclonal gammopathies of unexplained significance (MGNZ).The concentration of paraprotein at MGNZ is significantly lower than 30 g / l and usually does not exceed 10–15 g / l. In addition, with MGNZ, paraprotein is detected against the background of polyclonal immunoglobulins, i.e., inhibition of the normal synthesis of other immunoglobulins does not occur. The term “MGNZ” indicates cases of paraproteinemia without other signs of oncohematological disease, which require annual monitoring in order not to miss the moment of malignancy of the process. When paraproteins are detected in patients under 50 years of age, even more frequent repeated examinations are required, since they have a high risk of developing multiple myeloma.If the concentration of M-protein is more than 15 g / L, regardless of age, it is recommended to conduct an extended examination, including electrophoresis of a 24-hour urine sample and immunofixation every 3-6 months, since the risk of malignant transformation is very high. Benign paraproteinemia is distinguished, which is characterized by the preservation of paraprotein without progression to multiple myeloma or other disease within 5 years of follow-up. In transient paraproteinemia, the paraprotein concentration is usually below 3 g / l.

    Indications for the appointment of the study:

    1. Typing paraprotein.

    2. Differential diagnosis of monoclonal gammopathies.

    3. Evaluation of the effectiveness of the therapy for myeloma and other gammopathies.

    Interpretation of results:

    Positive:

    • Monoclonal gammopathies of unexplained significance, benign paraproteinemia;
    • Multiple myeloma;
    • Waldenstrom’s macroglobulinemia;
    • Lymphoma and chronic lymphocytic leukemia;
    • Heavy chain disease;
    • Paraproteinemic polyneuropathy;
    • AL amyloidosis or light chain deposition disease;

    Negative:

    • Normal M-gradient is not detected in serum.

    LOINC 74868-1 – IgG.kappa / IgG.lambda [Mass Ratio] in Serum or Plasma

    Term Description

    Measuring both the IgGκ and IgGλ, calculating the IgGκ / IgGλ ratio, and then comparing with normal subjects levels may provide a more sensitive indication of clonality. Usage of the IgGκ / IgGλ ratio may also compensate for any fluctuations in plasma volume and adjust for half-life variations. This term was based on, but not limited in use to, the Hevylite Human IgG Kappa and Lambda assays.
    Source: Regenstrief LOINC

    Fully-Specified Name

    Component
    IgG.kappa / IgG.lambda
    Property
    MRto
    Time
    Pt
    System
    Ser / Plas
    Scale
    Qn
    Method

    Additional Names

    Short Name
    IgG Kappa / G lambda SerPl
    Display Name
    IgG.kappa / IgG.lambda [Mass ratio]
    Consumer Name
    Alpha
    IgG.kappa / IgG.lambda, Blood

    Basic Attributes

    Class
    CHEM
    Type
    Laboratory
    First Released
    Version 2.48
    Last Updated
    Version 2.48
    Order vs. Observation
    Both

    Formula (Readable)

    IgG kappa (unit g / L) is divided by IgG lambda (unit: g / L) to calculate the IgG kappa / lambda-ratio.

    Member of these Panels

    LOINC Long Common Name
    74773-3 Immunoglobulin light chains and heavy chains panel – Serum or Plasma

    Language Variants