Summary
Monoclonal gammopathies represent a wide spectrum of related diseases.[1][2][3][4] The common denominator is the presence of a monoclonal protein in the serum or urine, which can be in the form of intact immunoglobulin, immunoglobulin fragments, and/or free light chains. This will be accompanied by the presence of monoclonal plasma cells in the bone marrow, in soft tissue (with plasmacytomas), or in the peripheral circulation (in more advanced disease stages).
Plasma cells and monoclonal proteins
Plasma cells are terminally differentiated (specialized cells that typically do not proliferate) effector cells of B-cell lineage.[5][6][7][8] They are the primary mediators of humoral immunity, secreting antigen-specific immunoglobulins. Abnormalities of plasma cells are responsible for a variety of autoimmune diseases and plasma cell neoplasms. Clonal evolution of one or more plasma cells sets the stage for development of the monoclonal gammopathies.[5][6][7][8]
Plasma cells normally secrete an intact immunoglobulin that is made up of 2 identical light chains and 2 identical heavy chains. There are 5 major classes of heavy chains, which correspond to the major classes of immunoglobulins: mu (IgM), delta (IgD), gamma (IgG), alpha (IgA), and IgE (epsilon). In each of the immunoglobulin molecules, the heavy chains are bound to one or the other of the 2 light chains (either kappa or lambda), but not both. The heavy chains, which have 4 or 5 domains, and the light chains, which have 2 domains, are covalently bonded to each other through disulfide bonds.[Figure caption and citation for the preceding image starts]: Immunoglobulin structureFrom the personal collection of Dr Kumar [Citation ends].
Monoclonal proteins are abnormal, immunologically homogeneous immunoglobulins or parts of immunoglobulins, produced by a single clone of plasma cells. They may be the result of an underlying lymphoid malignancy, be part of a clonal expansion of plasma cells causing no symptoms (e.g., monoclonal gammopathy of unknown significance), or lead to life-threatening complications (e.g., primary amyloidosis).[9]
Protein electrophoresis is performed to detect and identify monoclonal proteins in the serum and urine.[10][11] Quantitation of immunoglobulins is achieved by nephelometry. Immunoglobulin free light chains in serum are assessed using antibodies specific for the light chain part of the immunoglobulins.
Clonal expansion of plasma cells
Clonal expansion of plasma cells is the underlying abnormality among the monoclonal gammopathies. These cells may be found in the bone marrow, peripheral circulation, or soft tissue. They are typically demonstrated on bone marrow exams, where presence of clonal plasma cells may or may not be accompanied by an absolute increase in the plasma cell proportion. Whereas plasma cells are identified by their surface staining for CD138 (syndecan) on immunohistochemistry, demonstration of clonality depends on light chain restriction, and an excess of kappa- or lambda-expressing plasma cells resulting in a skewing of the normal kappa to lambda ratio.[12] The skewed ratio can be demonstrated by immunohistochemistry using antibodies against kappa or lambda light chains or by polymerase chain reaction (PCR) performed on marrow biopsy specimens.
Clonal plasma cells numbers are typically small in most monoclonal gammopathies, except for advanced myeloma and plasma cell leukemia.[13][14] Sensitive flow cytometry techniques can be used for routine evaluation of bone marrow aspirates to detect small numbers and for immunophenotypic characterization of abnormal plasma cells.[15][16][17][Figure caption and citation for the preceding image starts]: Monoclonal plasma cellsFrom the personal collection of Dr Kumar [Citation ends].
Epidemiology
Monoclonal gammopathy of undetermined significance (MGUS) is the most common monoclonal gammopathy and is found in about 1% to 2% of adults.[3][18][19][20][21][22] The prevalence increases with age and is generally higher in males compared with females, and in patients over 70 years of age.[3][23] Prevalence rates vary according to geographic and racial factors, with lower rates in Asia compared with those in Europe and North and South America, and higher prevalence rates among black people compared with white people.[24] Increased prevalence has been observed among first-degree relatives of patients with monoclonal gammopathies.[25]
Associated conditions
There are disease conditions other than MGUS where a monoclonal protein may be detected in the serum and/or urine. These include:
Lymphoproliferative diseases where clonal B lineage cells secrete a monoclonal protein (chronic lymphocytic leukemia, non-Hodgkin lymphoma, post-transplant monoclonal gammopathies)[26]
Conditions associated with or predisposing to a higher prevalence of monoclonal gammopathy (hepatitis C virus infection, HIV infection)
Infectious or inflammatory conditions associated with a transient development of several clones of reactive B cell/plasma cell populations (systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, Sjogren syndrome, Schnitzler syndrome).
Differentials
Common
- Monoclonal gammopathy of undetermined significance
- Chronic lymphocytic leukemia
- Non-Hodgkin lymphoma
Uncommon
- Light chain deposition disease
- Post-transplant monoclonal gammopathies
- Multiple myeloma
- Plasma cell leukemia
- Waldenstrom macroglobulinemia
- Solitary plasmacytoma
- POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes)
- Hepatitis C
- HIV infection
- Primary amyloidosis
- Cryoglobulinemia
- Systemic lupus erythematosus (SLE)
- Rheumatoid arthritis
- Psoriatic arthritis
- Sjogren syndrome
- Schnitzler syndrome
Contributors
Authors
Shaji Kumar, MD
Mark and Judy Mullins Professor of Hematological Malignancies
Division of Hematology
Mayo Clinic
Rochester
MN
Disclosures
SK has received research funding for clinical trials for his institution from: Abbvie, Amgen, BMS, Carsgen, Janssen, KITE, Merck, Astra-Zeneca, Novartis, Roche-Genentech, Takeda, and Tenebio. SK has participated in consulting and advisory boards (with no personal payment) for Abbvie, Amgen, BMS, Janssen, Roche-Genentech, Takeda, KITE, Astra-Zeneca, Bluebird Bio, and (with personal payment) Oncopeptides, Beigene, and Antengene.
Peer reviewers
Antonio Palumbo, MD
Associate Professor
University of Turin
Chief
Myeloma Unit
Ospedale Molinette
Turin
Italy
Disclosures
AP declares that he has no competing interests.
John R. Wingard, MD
Price Eminent Scholar and Professor of Medicine Director
Bone Marrow Transplant Program
Division of Hematology and Oncology
University of Florida College of Medicine
Gainesville
FL
Disclosures
JRW declares that he has no competing interests.
John Densmore, MD, PhD
Associate Professor of Clinical Medicine
Department of Medicine
Division of Hematology/Oncology
University of Virginia
Charlottesville
VA
Disclosures
JD declares that he has no competing interests.
References
Key articles
Rajkumar SV, Dispenzieri A, Kyle RA. Monoclonal gammopathy of undetermined significance, Waldenstrom macroglobulinemia, AL amyloidosis, and related plasma cell disorders: diagnosis and treatment. Mayo Clin Proc. 2006 May;81(5):693-703. Abstract
International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol. 2003 Jun;121(5):749-57. Abstract
Katzmann JA, Dispenzieri A. Screening algorithms for monoclonal gammopathies. Clin Chem. 2008 Nov;54(11):1753-5.Full text Abstract
Kyle RA, Therneau TM, Rajkumar SV, et al. A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med. 2002 Feb 21;346(8):564-9.Full text Abstract
Kyle RA, Durie BG, Rajkumar SV, 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. Abstract
Dispenzieri A, Kyle R, Merlini G, 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. Abstract
Reference articles
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