Monoclonal gammopathy of undetermined significance

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Omer Kamal, M.D. [2] Muhammad Saad, M.B.B.S.[3]

Synonyms and keywords: Benign monoclonal gammopathy; MGUS; monoclonal gammopathy

Overview

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Omer Kamal, M.D.[2] Muhammad Saad, M.B.B.S.[3]

Overview

Monoclonal gammopathy of undetermined significance was first discivered by Jan G. Waldenstrom in 1960 “essential hyperglobulinemia” or “benign monoclonal gammopathy” and then as monoclonal gammopathy of undetermined significance by Robert A. Kyle in 1978. Introduced more than 35 years ago, the term monoclonal gammopathy of undetermined signficance was used because of the increased risk of patients for the development of symptomatic MM, WM, Light-chain (AL) amyloidosis, or a related disorder during long-term follow-up. Monoclonal gammopathy of undetermined significance is a condition in which a low or non-quantifiable level of a monoclonal paraprotein is detected in the blood by means of protein electrophoresis. In addition, some patients develop a polyneuropathy (damage to peripheral nerves) or other problems related to the secreted antibody. MGUS is distinct from multiple myeloma. Pathologically, the lesion in Monoclonal gammopathy of undetermined significance is in fact very similar to that in multiple myeloma. What causes Monoclonal gammopathy of undetermined significance to transform into multiple myeloma is as yet unknown. The most common causes of monoclonal gammopathy of undetermined significance classification are genetic mutations in genes like cyclin D1, FGFR-3, MMSET, C-MAF, and MAFB. Several other illnesses can present with a monoclonal gammopathy, and the monoclonal protein may be the first discovery before a formal diagnosis is made like multiple myeloma, AIDS, chronic lymphocytic leukemia, non-Hodgkin Lymphoma, particularly splenic marginal zone lymphoma and lymphoplasmocytic lymphoma. Several other illnesses can present with a monoclonal gammopathy, and the monoclonal protein may be the first discovery before a formal diagnosis is made like multiple myeloma, AIDS, chronic lymphocytic leukemia, non-Hodgkin Lymphoma, particularly splenic marginal zone lymphoma and lymphoplasmocytic lymphoma. The incidence of monoclonal gammopathy of undetermined significance is approximately 120 per 100,000 in men at age 50, and goes to 530 per 1000 by the age 90. Women however have 60 cases per 1000 at age 50 which goes upto 370 per 1000 at age 90. The prevalence of monoclonal gammopathy of undetermined significance is different in different populations. Frequent complications of Monoclonal gammopathy of undetermined significance include fractures specially in lumbar vertebrae and thromboembolic phenomena. MGUS, is considered as a pre-malignant condition, and its transformation to multiple myeloma. However, as it mostly occurs in elderly, and its slow rate of progression, only a small proportion of people go on to develop a haematological malignancy. In patients with MGUS, although the actuarial risk of myeloma at 25 years of follow-up is 30%, the actual risk (when competing causes of death are taken into account) is only 11%. There is no single gold standard test for the diagnosis of monoclonal gammopathy of undetermined significance. Bone marrow aspiration and biopsy is donein all patients having M-protein level ≥1.5 g/dL. Diagnostic criteria depends on the type of monoclonal gammopathy like Non-IgM, IgM, or light chain gammopathy. The criteria includes serum monoclonal proteins, plasma cells in the marrow and absence of systemic signs.

Historical Perspective

Monoclonal gammopathy of undetermined significance was first discivered by Jan G. Waldenstrom in 1960 “essential hyperglobulinemia” or “benign monoclonal gammopathy” and then as monoclonal gammopathy of undetermined significance by Robert A. Kyle in 1978. Introduced more than 35 years ago, the term monoclonal gammopathy of undetermined signficance was used because of the increased risk of patients for the development of symptomatic MM, WM, Light-chain (AL) amyloidosis, or a related disorder during long-term follow-up.

Classification

Monoclonal gammopathy of undetermined significance (MGUS) may be classified according to cytogenetic differences into subtypes/groups based on translocations. MGUS is typically divided into non-IgM MGUS, IgM MGUS, and light chain MGUS.

Pathophysiology

Pathologically, the lesion in Monoclonal gammopathy of undetermined significance is in fact very similar to that in multiple myeloma. What causes Monoclonal gammopathy of undetermined significance to transform into multiple myeloma is as yet unknown.

Causes

The most common causes of monoclonal gammopathy of undetermined significance classification are genetic mutations in genes like cyclin D1, FGFR-3, MMSET, C-MAF, and MAFB.

Differentiating monoclonal gammopathy of undetermined significance from Other Diseases

Several other illnesses can present with a monoclonal gammopathy, and the monoclonal protein may be the first discovery before a formal diagnosis is made like multiple myeloma, AIDS, chronic lymphocytic leukemia, non-Hodgkin Lymphoma, particularly splenic marginal zone lymphoma and lymphoplasmocytic lymphoma.

Epidemiology and Demographics

The incidence of monoclonal gammopathy of undetermined significance is approximately 120 per 100,000 in men at age 50, and goes to 530 per 1000 by the age 90. Women however have 60 cases per 1000 at age 50 which goes upto 370 per 1000 at age 90. The prevalence of monoclonal gammopathy of undetermined significance is different in different populations.

Risk Factors

Common risk factors in the development of monoclonal gammopathy of undetermined significance include African american race, age, male sex, family history, history of immunosuppression and exposure to pesticides.

Screening

There is no role of screening in patients for monoclonal gammopathy of undetermined significance

Natural History, Complications, and Prognosis

Frequent complications of Monoclonal gammopathy of undetermined significance include fractures specially in lumbar vertebrae and thromboembolic phenomena. MGUS, is considered as a pre-malignant condition, and its transformation to multiple myeloma. However, as it mostly occurs in elderly, and its slow rate of progression, only a small proportion of people go on to develop a haematological malignancy. In patients with MGUS, although the actuarial risk of myeloma at 25 years of follow-up is 30%, the actual risk (when competing causes of death are taken into account) is only 11%.

Diagnosis

Diagnostic Study of Choice

There is no single gold standard test for the diagnosis of monoclonal gammopathy of undetermined significance. Bone marrow aspiration and biopsy is donein all patients having M-protein level ≥1.5 g/dL. Diagnostic criteria depends on the type of monoclonal gammopathy like Non-IgM, IgM, or light chain gammopathy. The criteria includes serum monoclonal proteins, plasma cells in the marrow and absence of systemic signs.Evaluation for MGUS involves a trio of complementary tests which includes SPEP, IF, and Serum FLC.

History and Symptoms

The majority of patients with monoclonal gammopathy of undetermined significance are asymptomatic. Patients with MGUS have no symptoms of myeloma or related malignancy that can be attributable to their monoclonal protein. During evaluation for one of a variety of clinical symptoms and disorders that include peripheral neuropathy, vasculitis, hemolytic anemia, skin rashes, hypercalcemia, and elevated erythrocyte sedimentation rate. It is often an incidental finding on protein electrophoresis.Following symptoms warrant testing of M protein for MGUS; unexplained anemia, bone pain, fractures, kidney dysfunction, recurrent infections.

Physical Examination

Patients with MGUS usually appear normal. Physical examination of patients with MGUS is usually unremarkable except for neuropathies at times. Extremities examination of patients with MGUS is usually normal. However, feet might show numbness, paresthesias, imbalance, gait ataxia, dysesthesia, and lancinating pain.

Laboratory Findings

Patients may be diagnosed with MGUS if they fulfill the three component criteria which includes a monoclonal paraprotein band less than 3 g/dl, plasma cells less than 10% on bone marrow examination, and no evidence of bone lesions, anemia, hypercalcemia, or renal insufficiency related to the paraprotein. Check the blood for hypercalcemia and deterioration in renal function, check the urine for Bence-Jones protein.

Electrocardiogram

There are no specific ECG findings associated with monoclonal gammopathy of undetermined significance. However, it may show intermittent atrial premature beats, poor R wave progression, and Q wave in precordial leads.

X-ray

When first evaluating a case of MGUS, a hematologist will usually perform a skeletal survey (X-rays of the proximal skeleton) and may show bone lesions and myeloma findings which may be further followed up by various blood test in the proceeding months.

Echocardiography and Ultrasound

Echocardiography may show increased thickness of the left ventricle (LV) wall, enlargement of the atria, grade 3 diastolic dysfunction in mitral inflow and sometimes elevated left ventricular filling pressure as a cardiac dysfunction related to MGUS.

CT scan

There are no CT scan findings associated with MGUS. However, a CT scan may be helpful in the diagnosis of complications of multiple myeloma, which include small lytic lesions and focal bonedestruction.

MRI

There are no specific MRI scan findings associated with MGUS. However, MRI may be helpful in the diagnosis of complications and differentiate between various patterns of multiple myeloma, which include normal focal lesions, variegated/salt-and-pepper pattern and diffuse disease in the absence of bone destruction.

Other Imaging Findings

99mTc-Sestamibi and PET/CT may be helpful in the diagnosis of MGUS. 99mTc-Sestamibi show increased mitochondrial activity and findings on PET/CT may show early involvement of bone marrow.

Other Diagnostic Studies

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 haematologist is required. A bone marrow biopsy should be performed.

Treatment

Medical Therapy

There is no specific treatment for monoclonal gammopathy of undetermined significance ; the mainstay of therapy is supportive care, keep an eye and delay the progression to other plasma dyscrasias. Trials using lenalidomide and bisphosphonates are been conducted to determine whether they decrease they progression of the disease both for MGUS and multiple myeloma.

Surgery

Surgery is not the first-line treatment option for patients with MGUS. Surgery is usually reserved for patients with skeletal fractures. Procedures like kyphoplasty and vertebroplasty are usually performed for vertebral fractures.

Primary Prevention

There are no established measures for the primary prevention of MGUS

Secondary Prevention

There are no established measures for the secondary prevention of MGUS

References

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Historical Perspective

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Omer Kamal, M.D.[2]

Overview

Monoclonal gammopathy of undetermined significance was first discivered by Jan G. Waldenstrom in 1960 “essential hyperglobulinemia” or “benign monoclonal gammopathy” and then as monoclonal gammopathy of undetermined significance by Robert A. Kyle in 1978. Introduced more than 35 years ago, the term monoclonal gammopathy of undetermined signficance was used because of the increased risk of patients for the development of symptomatic MM, WM, Light-chain (AL) amyloidosis, or a related disorder during long-term follow-up.

Historical Perspective

Discovery

Monoclonal gammopathy of undetermined significance was first discivered by Jan G. Waldenstrom in 1960 “essential hyperglobulinemia” or “benign monoclonal gammopathy” and then as monoclonal gammopathy of undetermined significance by Robert A. Kyle in 1978. ^[1] Introduced more than 35 years ago, the term monoclonal gammopathy of undetermined signficance was used because of the increased risk of patients for the development of symptomatic MM, WM, light-chain (AL) amyloidosis, or a related disorder during long-term follow-up.^[2]^[3]

References

↑ WALDENSTROM J (1960). “Studies on conditions associated with disturbed gamma globulin formation (gammopathies)”. Harvey Lect. 56: 211–31. PMID 14004528.
↑ Kyle RA, Therneau TM, Rajkumar SV, Larson DR, Plevak MF, Melton LJ (July 2004). “Long-term follow-up of 241 patients with monoclonal gammopathy of undetermined significance: the original Mayo Clinic series 25 years later”. Mayo Clin. Proc. 79 (7): 859–66. doi:10.1016/S0025-6196(11)62151-4. PMID 15244381.
↑ Kyle RA (May 1978). “Monoclonal gammopathy of undetermined significance. Natural history in 241 cases”. Am. J. Med. 64 (5): 814–26. PMID 645746.

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Classification

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Omer Kamal, M.D.[2] Muhammad Saad, M.B.B.S.[3]

Overview

Monoclonal gammopathy of undetermined significance (MGUS) may be classified according to cytogenetic differences into subtypes/groups based on translocations. There is no established system for the staging of monoclonal gammopathy of undetermined significance (MGUS).

Classification

MGUS is typically divided into non-IgM MGUS, IgM MGUS, and light chain MGUS as described in the following flowchart:^[1]^[2]^[3]^[4]

Non IgM MGUS:

1. <10%BM plasma cells
2. Monoclonal protein <3.0g/dL
3. No symptoms

Smoldering MM:

1. No symptoms
2. >10%BM plasma cells

MM:

1. Symptoms
2. >10%BM plasma cells
AL Amyloidosis

IgM MGUS:

1. <10%BM lymphoplasmacytic cells
2. Monoclonal protein <3.0g/dL
3. No symptoms

Smoldering WM:

1. No symptoms
2. >10%BM lymphoplasmacytic cells

WM:

1. Symptoms
2. >10%BM lymphoplasmacytic cells
AL Amyloidosis
IgM MM

Clonal plasma cell or B lymphocyte

Light chain MGUS:

1. <10%BM plasma cells
2. Abnormal FLC ratio
3. No monoclonal protein
4. No symptoms

Light chain MM:

1. Symptoms
2. >10%BM plasma cells
AL Amyloidosis

Monoclonal gammopathy of clinical significance :

1. Presence of monoclonal protein or FLC
2. Symptoms attributable to presence of monoclonal protein
3. Diagnostic criteria of MM not met

Monoclonal gammopathy of undetermined significance (MGUS) may be classified according to cytogenetic differences into the following subtypes/groups:^[5]

Abnormalities in cytogenes	Affected genes
IgH translocation:
t(11;14), q(13;32)	cyclin D1
t(4;14)(p16;q32)	FGFR-3, and MMSET
t(14;16)(q32;q23)	C-MAF
t(6;14)(q32;q11)	MAFB
IgH non-translocated :
Hyper diploid	Numerous

References

↑ Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos MV, Kumar S, Hillengass J, Kastritis E, Richardson P, Landgren O, Paiva B, Dispenzieri A, Weiss B, LeLeu X, Zweegman S, Lonial S, Rosinol L, Zamagni E, Jagannath S, Sezer O, Kristinsson SY, Caers J, Usmani SZ, Lahuerta JJ, Johnsen HE, Beksac M, Cavo M, Goldschmidt H, Terpos E, Kyle RA, Anderson KC, Durie BG, Miguel JF (November 2014). “International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma”. Lancet Oncol. 15 (12): e538–48. doi:10.1016/S1470-2045(14)70442-5. PMID 25439696.
↑ Gertz MA (February 2023). “Waldenström macroglobulinemia: 2023 update on diagnosis, risk stratification, and management”. Am J Hematol. 98 (2): 348–358. doi:10.1002/ajh.26796. PMID 36588395 Check |pmid= value (help).
↑ Kyle RA, Durie BG, Rajkumar SV, Landgren O, Blade J, Merlini G, Kröger N, Einsele H, Vesole DH, Dimopoulos M, San Miguel J, Avet-Loiseau H, Hajek R, Chen WM, Anderson KC, Ludwig H, Sonneveld P, Pavlovsky S, Palumbo A, Richardson PG, Barlogie B, Greipp P, Vescio R, Turesson I, Westin J, Boccadoro M (June 2010). “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. 24 (6): 1121–7. doi:10.1038/leu.2010.60. PMC 7020664 Check |pmc= value (help). PMID 20410922.
↑ Gertz MA, Dispenzieri A (July 2020). “Systemic Amyloidosis Recognition, Prognosis, and Therapy: A Systematic Review”. JAMA. 324 (1): 79–89. doi:10.1001/jama.2020.5493. PMID 32633805 Check |pmid= value (help).
↑ Rajkumar SV, Kyle RA, Buadi FK (October 2010). “Advances in the diagnosis, classification, risk stratification, and management of monoclonal gammopathy of undetermined significance: implications for recategorizing disease entities in the presence of evolving scientific evidence”. Mayo Clin. Proc. 85 (10): 945–8. doi:10.4065/mcp.2010.0520. PMC 2947967. PMID 20884827.

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Pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Omer Kamal, M.D.[2]

Overview

Pathologically, the lesion in Monoclonal gammopathy of undetermined significance is in fact very similar to that in multiple myeloma. What causes Monoclonal gammopathy of undetermined significance to transform into multiple myeloma is as yet unknown.

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+).^[1]^[2]
In MGUS, 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.^[3] What causes MGUS to transform into multiple myeloma is as yet unknown.
The transformation of normal plasma cells to MGUS to multiple myeloma involves several steps of gene mutations.^[4]
After the stimulation by the antigens due to toll-like cell receptors expression, overexpression of interleukin receptors for example IL-6 and loss of regulation of cyclin D gene.^[5]^[6]^[7]
Patients with MGUS may have a “gamma-spike” on serum electrophoresis, as shown below:

References

↑ 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): 1745–57. PMID 11861292.
↑ 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. PMID 12623842.
↑ 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. PMID 9626070.
↑ Chng WJ, Glebov O, Bergsagel PL, Kuehl WM (December 2007). “Genetic events in the pathogenesis of multiple myeloma”. Best Pract Res Clin Haematol. 20 (4): 571–96. doi:10.1016/j.beha.2007.08.004. PMC 2198931. PMID 18070707.
↑ Jego G, Bataille R, Geffroy-Luseau A, Descamps G, Pellat-Deceunynck C (June 2006). “Pathogen-associated molecular patterns are growth and survival factors for human myeloma cells through Toll-like receptors”. Leukemia. 20 (6): 1130–7. doi:10.1038/sj.leu.2404226. PMID 16628189.
↑ Dinarello CA (February 2009). “Targeting the pathogenic role of interleukin 1{beta} in the progression of smoldering/indolent myeloma to active disease”. Mayo Clin. Proc. 84 (2): 105–7. doi:10.4065/84.2.105. PMC 2664579. PMID 19181642.
↑ Merlini G, Palladini G (2012). “Differential diagnosis of monoclonal gammopathy of undetermined significance”. Hematology Am Soc Hematol Educ Program. 2012: 595–603. doi:10.1182/asheducation-2012.1.595. PMID 23233640.

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Causes

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Omer Kamal, M.D.[2]

Overview

The most common causes of monoclonal gammopathy of undetermined significance classification are genetic mutations in genes like cyclin D1, FGFR-3, MMSET, C-MAF, and MAFB.

Causes

The most common causes of monoclonal gammopathy of undetermined significance classification are genetic mutations. However, there is no established cause of progression of multiple myeloma to monoclonal gammopathy of undetermined significance classification.

Genetic causes^[1]

Abnormalities in cytogenes	Affected genes
IgH translocation:
t(11;14), q(13;32)	cyclin D1
t(4;14)(p16;q32)	FGFR-3, and MMSET
t(14;16)(q32;q23)	C-MAF
t(6;14)(q32;q11)	MAFB
IgH non-translocated :
Hyper diploid	Numerous

References

↑ Mikulasova A, Wardell CP, Murison A, Boyle EM, Jackson GH, Smetana J, Kufova Z, Pour L, Sandecka V, Almasi M, Vsianska P, Gregora E, Kuglik P, Hajek R, Davies FE, Morgan GJ, Walker BA (September 2017). “The spectrum of somatic mutations in monoclonal gammopathy of undetermined significance indicates a less complex genomic landscape than that in multiple myeloma”. Haematologica. 102 (9): 1617–1625. doi:10.3324/haematol.2017.163766. PMC 5685224. PMID 28550183.

Differentiating Monoclonal gammopathy of undetermined significance from other Diseases

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Overview

Several other illnesses can present with a monoclonal gammopathy, and the monoclonal protein may be the first discovery before a formal diagnosis is made like multiple myeloma, AIDS, chronic lymphocytic leukemia, non-Hodgkin Lymphoma, particularly splenic marginal zone lymphoma and lymphoplasmocytic lymphoma.

Differentiating Monoclonal gammopathy of undetermined significance form other Diseases

Monoclonal gammopathy of undetermined significance] must be differentiated from following other B cell lymphoid neoplasms and plasma cell disorders:

Disease		Etiology (Genetic or other)	Clinical manifestations						Paraclinical findings		Associated findings
			Clinical manifestations						Lab findings
			Symptoms				Signs		Immunochemistry	Histopathology
			Constitutional symptoms	Rash	Abdominal pain	Diarrhea	Mass	Other	Immunochemistry	Histopathology
Waldenström’s macroglobulinemia ^[1]^[2]^[3]^[4]^[5]		Mature B-cell Lymphoma Mutation of the MYD88 gene (L265P) Nonsense or frameshift mutations in the CXR4 gene	Weakness Anorexia Weight loss Fever	–	–	+	Generalized and local lymphadenopathy	Retinal hemorrhage with blurring of vision Vertigo Dizziness Headache Nystagmus Tinnitus Ataxia Bleeding	Expresses pan B-cell antigens: CD19 CD20 CD22 CD79a CD5 Variable expression of: CD11c CD43 CD25 Majority express: IgM surface immunoglobulin Fewer express: IgG or IgA Lack IgD Lack expression of: CD10 Cyclin D1	≥10 percent infiltration by small lymphocytes, plasmacytoid lymphocytes, and plasma cells Variable numbers of admixed immunoblasts Hyperplasia of mast cells in marrow (characteristic but not pathognomonic) Diffusely effaced lymph nodes Absence of proliferation centers and marginal zone type differentiation Russell bodies (intracytoplasmic inclusions) Dutcher bodies (intranuclear inclusions) Prominent epithelioid histiocytes	Diffuse large B-cell lymphoma Myelodysplastic syndrome/Acute myeloid leukemia Brain tumor Renal MALT lymphoma
B cell chronic lymphocytic leukemia/small lymphocytic lymphoma ^[6]		Mature B-cell Lymphoma Chromosome 13 abnormalities Del13q Del11q Del17p Trisomy 12	33% of patients present with: Fever Weight loss Night sweats	–	–	–	Painless lymphadenopathy	May be asymptomatic Fatigue Recurrent infections Hepatosplenomegaly	Always expresses: CD5 CD38 Usually expresses: CD23 Dim expression of: CD20 Surface Ig	Monoclonal small well differentiated lymphocytes with a dense nucleus, partially aggregated chromatin, no discernible nucleoli, and a narrow border of clear to slightly basophilic cytoplasm Significant number of smudge cells or basket cells	Autoimmune hemolytic anemia Red cell aplasia Autoimmune thrombocytopenia
Follicular lymphoma ^[7]^[8]^[9]^[10]^[11]		Mature B-cell Lymphoma Reciprocal translocation t(14;18) Overexpression of BCL2	20% of patients present with: Fever Weight loss Night sweats	+	+	±	Painless peripheral adenopathy in the cervical, axillary, inguinal, and/or femoral regions Asymptomatic large abdominal mass	Seizures Chest pain Bone pain Cough Dyspnea	Expresses: CD21 CD23 CD10 HLA-DR CD19 CD20 CD79a Expresses Surface: IgM IgG IgA	Nodular growth pattern	Most common clinically indolent NHL Peripheral nerve compression
Mantle cell lymphoma ^[12]^[13]^[14]^[15]^[16]		Mature B-cell Lymphoma CD5 positive antigen in pre germinal center of B-cell Monomorphous small to medium sized B lymphocytes with irregular nuclei Chromosomal translocation at t(11:14)	Fatigue Night sweats Weight Loss	–	Abdominal distention	+	Palpable masses in skin, breast, and salivary glands Generalized lymphadenopathy	Extranodal involvement of GI tract, lungs, and CNS Mental Retardation	Positive for: CD5 B-cell antigen Cyclin D (overexpression) Co-express surface: IgM IgD Negative for: CD23–	Germinal centers filled by small-to-medium atypical lymphocytes Nodular appearance	_
Marginal zone lymphoma	Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type ^[17]^[18]^[19]^[20]^[21]^[22]^[23]^[24]^[25]^[26]	Mature B-cell Lymphoma Recurrent translocations such as: t(1;14)(p22;q32) t(11;18)(q21;q21) t(14;18)(q32;q21) t(3;14)(p14.1;q32)	B symptoms may or may not be present	±	+	+	Painless or painful lymphadenopathy which can be gastric or non-gastric Lump in the superior lateral quadrant of the orbit, breast, neck, or salivary gland	Symptoms depend on the location of the tumor and may include: Fatigue Heartburn Fever Cough with blood in sputum Shortness of breath	B-cell associated antigens that co-express: BCL-2 CD19 CD20 CD22 CD79a Negative for: CD5 CD10 CD43 Cyclin D1	Presence of dense diffuse lymphoid infiltrate of marginal‐zone cells in lamina propria Prominent lymphoepithelial lesions and consisting of small atypical cells with monocytoid features	H. pylori infection Hashimoto’s thyroiditis Sjogren’s syndrome Celiac disease
	Splenic marginal zone lymphoma ^[27]^[28]^[29]^[30]^[31]^[32]^[33]	Mature B-cell Lymphoma Clonal rearrangements of the immunoglobulin genes (heavy and light chains) Deletion 7q21-32 Translocations of the CDK6 gene located on 7q21	Fever Weight loss Night sweats	+	+	–	Painless swelling in the neck, axilla, groin, thorax, and abdomen.	Chest pain Bone pain	CD20 CD79a	Small lymphocytes Transformed blasts Epithelial histocytes Plasmacytic differentiation of neoplastic cells	Hepatitis C infection
	Nodal marginal zone B-cell lymphoma ^[34]^[35]	Mature B-cell Lymphoma Stimulation of antigen receptor by autoantigen and co-stimulatory molecule CD40 Mutations in KMT2D, PTTPRD, NOTCH2, KLF2	Fever Weight loss Night sweats	+	–	–	Painless swelling in the neck, axilla, groin, thorax, and abdomen Generalized and local lymphadenopathy	Hemorrhage Dyspepsia	_	Follicular cells in reactive zone Centrocyte like cells in marginal zone lymphoma Centroblasts Plasma cells Immunoblasts	Hepatitis C infection Chronic infectious conditions or autoimmune processes, such as: H pylori gastritis Hashimoto thyroiditis Sjögren syndrome
Multiple Myeloma^[36]^[37]^[38]^[39]^[40]^[41]		Chromosomal aberrations or other genetic insults Malignant transformation of plasma cells Clonal plasma cell proliferation	Constitutional symptoms may or may not be present Diffuse bone pain and tenderness with osteolytic lesions Worsens with activity Usually involves spine and ribs (axial skeleton) Hypercalcemia symptoms: Polyuria Polydipsia Constipation Loss of appetite Nausea and vomiting Lethary due to anemia Neurological symptoms: Numbness due to plasma cell infiltration of nerves or anti-neuronal glycoprotein antibodies Muscle weakness Confusion Dizziness Headache Paralysis Visual changes	–	Abdominal pain due to mesenteric venous thrombosis	No diarrhea Constipation due to hypercalcemia	Lymphadenopathy Hepatomegaly Splenomegaly Abdominal tenderness (if hypercalcemia is present)	Bone marrow failure–related symptoms, due to crowding out of normal bone marrow precursors by malignant plasma cells: Easy bruising, nosebleeds, bleeding gums due to thrombocytopenia Fatigue, weakness, shortness of breath, dizziness and paleness due to anemia Recurrent infections due to leukopenia Thrombotic symptoms, due to cancer–associated thrombosis and due to lenalidomide, which increases thrombotic risk: Shortness of breath due to pulmonary embolism Lower extremity edema due to deep vein thrombosis and renal involvement Abdominal pain due to mesenteric venous thrombosis Transient ischemic attack Retinal hemorrhage Pallor Ecchymoses Purpura Conjuctival pallor Visual defects Exudative retinal detachment Increased adipose deposition around the neck (if dexamethasone is used for therapy) Cotton-wool spots may be present Bony tenderness along cervical, thoracic, lumbar spine and in long bones Tinel’s sign may be present Phalen sign may be present Dermatomal sensory loss Altered sensation Neuropathy Mood alterations (if hypercalcemia is present)	Expresses: CD138 CD38 CD79a VS38c Infrequently expresses CD19 CD56 (expressed by 70% of myeloma cells) Absent surface Ig	Infiltration of plasma cells in the bone marrow	Relevant history includes: Review of past medical history for other plasma cell diseases, hematologic malignancies, underlying renal disease, and underlying bone disease Review of family history for members with positive history of hematologic malignancies Review of occupational history related to farming, oil industry, or Agent Orange exposure
B-cell prolymphocytic leukemia^[42]^[43]^[44]^[45]^[46]^[47]		Deletion of chromosome 11 Chromosome 13	Anemia Weight loss Loss of appetite Fever	–	–	–	Massive splenomegaly Peripheral lymphadenopathy Hepatomegaly	Rapidly rising lymphocyte count Thrombocytopenia Pallor Petechiae Bruising Tachycardia Tachypnea	Expresses: Bright surface IgM IgD +/- CD20 CD19 CD22 CD79a FMC7 CD5 CD45 HLA-DR CD23+/- CD38 FMC7^[45] Doesn’t express: CD10	Prolymphocytes comprise >55% of the neoplastic cells Bone marrow has interstitial pattern of infiltration Lymph nodes may show vague nodularity, but proliferation centers are absent	t(11;14) must be excluded No associated paraproteinemia More common in white race and Ashkenazi jewish male

References

↑ Steven P. Treon, Lian Xu, Guang Yang, Yangsheng Zhou, Xia Liu, Yang Cao, Patricia Sheehy, Robert J. Manning, Christopher J. Patterson, Christina Tripsas, Luca Arcaini, Geraldine S. Pinkus, Scott J. Rodig, Aliyah R. Sohani, Nancy Lee Harris, Jason M. Laramie, Donald A. Skifter, Stephen E. Lincoln & Zachary R. Hunter (2012). “MYD88 L265P somatic mutation in Waldenstrom’s macroglobulinemia”. The New England journal of medicine. 367 (9): 826–833. doi:10.1056/NEJMoa1200710. PMID 22931316. Unknown parameter |month= ignored (help)
↑ Chi PJ, Pei SN, Huang TL, Huang SC, Ng HY, Lee CT (2014). “Renal MALT lymphoma associated with Waldenström macroglobulinemia”. J. Formos. Med. Assoc. 113 (4): 255–7. doi:10.1016/j.jfma.2011.02.007. PMID 24685302.
↑ Chi PJ, Pei SN, Huang TL, Huang SC, Ng HY, Lee CT (2014). “Renal MALT lymphoma associated with Waldenström macroglobulinemia”. J. Formos. Med. Assoc. 113 (4): 255–7. doi:10.1016/j.jfma.2011.02.007. PMID 24685302.
↑ García-Sanz R, Montoto S, Torrequebrada A, de Coca AG, Petit J, Sureda A; et al. (2001). “Waldenström macroglobulinaemia: presenting features and outcome in a series with 217 cases”. Br J Haematol. 115 (3): 575–82. PMID 11736938.
↑ Merlini G, Baldini L, Broglia C, Comelli M, Goldaniga M, Palladini G; et al. (2003). “Prognostic factors in symptomatic Waldenstrom’s macroglobulinemia”. Semin Oncol. 30 (2): 211–5. doi:10.1053/sonc.2003.50064. PMID 12720138.
↑ Klein, Ulf; Tu, Yuhai; Stolovitzky, Gustavo A.; Mattioli, Michela; Cattoretti, Giorgio; Husson, Hervé; Freedman, Arnold; Inghirami, Giorgio; Cro, Lilla; Baldini, Luca; Neri, Antonino; Califano, Andrea; Dalla-Favera, Riccardo (2001). “Gene Expression Profiling of B Cell Chronic Lymphocytic Leukemia Reveals a Homogeneous Phenotype Related to Memory B Cells”. The Journal of Experimental Medicine. 194 (11): 1625–1638. doi:10.1084/jem.194.11.1625. ISSN 0022-1007.
↑ Ganapathi KA, Pittaluga S, Odejide OO, Freedman AS, Jaffe ES (2014). “Early lymphoid lesions: conceptual, diagnostic and clinical challenges”. Haematologica. 99 (9): 1421–32. doi:10.3324/haematol.2014.107938. PMC 4562530. PMID 25176983.
↑ Lorsbach RB, Shay-Seymore D, Moore J, Banks PM, Hasserjian RP, Sandlund JT; et al. (2002). “Clinicopathologic analysis of follicular lymphoma occurring in children”. Blood. 99 (6): 1959–64. PMID 11877266.
↑ Overview at UMDNJ
↑ Bosga-Bouwer AG, Haralambieva E, Booman M; et al. (November 2005). “BCL6 alternative translocation breakpoint cluster region associated with follicular lymphoma grade 3B”. Genes Chromosomes Cancer. 44 (3): 301–4. doi:10.1002/gcc.20246. PMID 16075463.
↑ Winberg CD, Nathwani BN, Bearman RM, Rappaport H (1981). “Follicular (nodular) lymphoma during the first two decades of life: a clinicopathologic study of 12 patients”. Cancer. 48 (10): 2223–35. PMID 7028244.
↑ Itziar Salaverria, Cristina Royo, Alejandra Carvajal-Cuenca, Guillem Clot, Alba Navarro, Alejandra Valera, Joo Y. Song, Renata Woroniecka, Grzegorz Rymkiewicz, Wolfram Klapper, Elena M. Hartmann, Pierre Sujobert, Iwona Wlodarska, Judith A. Ferry, Philippe Gaulard, German Ott, Andreas Rosenwald, Armando Lopez-Guillermo, Leticia Quintanilla-Martinez, Nancy L. Harris, Elaine S. Jaffe, Reiner Siebert, Elias Campo & Silvia Bea (2013). “CCND2 rearrangements are the most frequent genetic events in cyclin D1(-) mantle cell lymphoma”. Blood. 121 (8): 1394–1402. doi:10.1182/blood-2012-08-452284. PMID 23255553. Unknown parameter |month= ignored (help)
↑ Markus Tiemann, Carsten Schrader, Wolfram Klapper, Martin H. Dreyling, Elias Campo, Andrew Norton, Francoise Berger, Philip Kluin, German Ott, Stephano Pileri, Ennio Pedrinis, Alfred C. Feller, Hartmut Merz, Dirk Janssen, Martin L. Hansmann, Han Krieken, Peter Moller, Harald Stein, Michael Unterhalt, Wolfgang Hiddemann & Reza Parwaresch (2005). “Histopathology, cell proliferation indices and clinical outcome in 304 patients with mantle cell lymphoma (MCL): a clinicopathological study from the European MCL Network”. British journal of haematology. 131 (1): 29–38. doi:10.1111/j.1365-2141.2005.05716.x. PMID 16173960. Unknown parameter |month= ignored (help)
↑ L. H. Argatoff, J. M. Connors, R. J. Klasa, D. E. Horsman & R. D. Gascoyne (1997). “Mantle cell lymphoma: a clinicopathologic study of 80 cases”. Blood. 89 (6): 2067–2078. PMID 9058729. Unknown parameter |month= ignored (help)
↑ Markus Tiemann, Carsten Schrader, Wolfram Klapper, Martin H. Dreyling, Elias Campo, Andrew Norton, Francoise Berger, Philip Kluin, German Ott, Stephano Pileri, Ennio Pedrinis, Alfred C. Feller, Hartmut Merz, Dirk Janssen, Martin L. Hansmann, Han Krieken, Peter Moller, Harald Stein, Michael Unterhalt, Wolfgang Hiddemann & Reza Parwaresch (2005). “Histopathology, cell proliferation indices and clinical outcome in 304 patients with mantle cell lymphoma (MCL): a clinicopathological study from the European MCL Network”. British journal of haematology. 131 (1): 29–38. doi:10.1111/j.1365-2141.2005.05716.x. PMID 16173960. Unknown parameter |month= ignored (help)
↑ Julie M. Vose (2017). “Mantle cell lymphoma: 2017 update on diagnosis, risk-stratification, and clinical management”. American journal of hematology. 92 (8): 806–813. doi:10.1002/ajh.24797. PMID 28699667. Unknown parameter |month= ignored (help)
↑ Non-gastric lymphomas – causes, symptoms and treatments. Lymphoma association 2016. https://www.lymphomas.org.uk/sites/default/files/pdfs/Non-Gastric-malt-lymphoma.pdf. Accessed on January 28, 2016
↑ Risks of Extranodal marginal zone of mucosa-associated lymphoid tissue (MALT lymphoma). Canadian Cancer Society 2016. http://www.cancer.ca/en/cancer-information/cancer-type/non-hodgkin-lymphoma/non-hodgkin-lymphoma/types-of-nhl/malt-lymphoma/?region=on. Accessed on January 25, 2016
↑ Kinkade, Zoe; Esan, Olukemi A.; Rosado, Flavia G.; Craig, Michael; Vos, Jeffrey A. (2015). “Ileal mucosa-associated lymphoid tissue lymphoma presenting with small bowel obstruction: a case report”. Diagnostic Pathology. 10 (1). doi:10.1186/s13000-015-0353-6. ISSN 1746-1596.
↑ Symptoms of MALT lymphoma. Cancer research UK 2016. http://www.cancerresearchuk.org/about-cancer/type/non-hodgkins-lymphoma/about/types/mucosaassociated-lymphoid-tissue-lymphoma. Accessed on January 28, 2016
↑ Symptoms of MALT lymphoma. Cancer research UK 2016. http://www.cancerresearchuk.org/about-cancer/type/non-hodgkins-lymphoma/about/types/mucosaassociated-lymphoid-tissue-lymphoma. Accessed on January 28, 2016
↑ Signs and symptoms of gastric lymphoma. Wikipedia 2016. https://en.wikipedia.org/wiki/Gastric_lymphoma. Accessed on January 28, 2016
↑ Clinical presentation of orbital lymphoma. Dr Craig Hacking and A.Prof Frank Gaillard et al. Radiopaedia 2016. http://radiopaedia.org/articles/orbital-lymphoma. Accessed on January 28, 2016
↑ Non-gastric lymphomas – causes, symptoms and treatments. Lymphoma association 2016. https://www.lymphomas.org.uk/sites/default/files/pdfs/Non-Gastric-malt-lymphoma.pdf. Accessed on January 28, 2016
↑ Taal, B G; Boot, H; van Heerde, P; de Jong, D; Hart, A A; Burgers, J M (1 October 1996). “Primary non-Hodgkin lymphoma of the stomach: endoscopic pattern and prognosis in low versus high grade malignancy in relation to the MALT concept”. Gut. 39 (4): 556–561. doi:10.1136/gut.39.4.556.
↑ Bacon CM, Du MQ, Dogan A (2007). “Mucosa-associated lymphoid tissue (MALT) lymphoma: a practical guide for pathologists”. J Clin Pathol. 60 (4): 361–72. doi:10.1136/jcp.2005.031146. PMC 2001121. PMID 16950858.
↑ Hernández JM, García JL, Gutiérrez NC, Mollejo M, Martínez-Climent JA, Flores T, González MB, Piris MA, San Miguel JF (May 2001). “Novel genomic imbalances in B-cell splenic marginal zone lymphomas revealed by comparative genomic hybridization and cytogenetics”. Am. J. Pathol. 158 (5): 1843–50. doi:10.1016/S0002-9440(10)64140-5. PMC 1891967. PMID 11337382.
↑ Andersen CL, Gruszka-Westwood A, Atkinson S, Matutes E, Catovsky D, Pedersen RK, Pedersen BB, Pulczynski S, Hokland P, Jacobsen E, Koch J (January 2005). “Recurrent genomic imbalances in B-cell splenic marginal-zone lymphoma revealed by comparative genomic hybridization”. Cancer Genet. Cytogenet. 156 (2): 122–8. doi:10.1016/j.cancergencyto.2004.04.026. PMID 15642391.
↑ Salido M, Baró C, Oscier D, Stamatopoulos K, Dierlamm J, Matutes E, Traverse-Glehen A, Berger F, Felman P, Thieblemont C, Gesk S, Athanasiadou A, Davis Z, Gardiner A, Milla F, Ferrer A, Mollejo M, Calasanz MJ, Florensa L, Espinet B, Luño E, Wlodarska I, Verhoef G, García-Granero M, Salar A, Papadaki T, Serrano S, Piris MA, Solé F (September 2010). “Cytogenetic aberrations and their prognostic value in a series of 330 splenic marginal zone B-cell lymphomas: a multicenter study of the Splenic B-Cell Lymphoma Group”. Blood. 116 (9): 1479–88. doi:10.1182/blood-2010-02-267476. PMID 20479288.
↑ Splenic marginal zone lymphoma. Surveillance, Epidemiology, and End Results Program. http://seer.cancer.gov/seertools/hemelymph/51f6cf57e3e27c3994bd5327/. Accessed on December 22, 2015
↑ Weng WK, Levy S (July 2003). “Hepatitis C virus (HCV) and lymphomagenesis”. Leuk. Lymphoma. 44 (7): 1113–20. doi:10.1080/1042819031000076972. PMID 12916862.
↑ Quinn ER, Chan CH, Hadlock KG, Foung SK, Flint M, Levy S (December 2001). “The B-cell receptor of a hepatitis C virus (HCV)-associated non-Hodgkin lymphoma binds the viral E2 envelope protein, implicating HCV in lymphomagenesis”. Blood. 98 (13): 3745–9. PMID 11739181.
↑ Chuang SS, Liao YL, Chang ST, Hsieh YC, Kuo SY, Lu CL, Hwang WS, Lin IH, Tsao CJ, Huang WT (July 2010). “Hepatitis C virus infection is significantly associated with malignant lymphoma in Taiwan, particularly with nodal and splenic marginal zone lymphomas”. J. Clin. Pathol. 63 (7): 595–8. doi:10.1136/jcp.2010.076810. PMID 20530156.
↑ Spina, V.; Khiabanian, H.; Messina, M.; Monti, S.; Cascione, L.; Bruscaggin, A.; Spaccarotella, E.; Holmes, A. B.; Arcaini, L.; Lucioni, M.; Tabbo, F.; Zairis, S.; Diop, F.; Cerri, M.; Chiaretti, S.; Marasca, R.; Ponzoni, M.; Deaglio, S.; Ramponi, A.; Tiacci, E.; Pasqualucci, L.; Paulli, M.; Falini, B.; Inghirami, G.; Bertoni, F.; Foa, R.; Rabadan, R.; Gaidano, G.; Rossi, D. (2016). “The genetics of nodal marginal zone lymphoma”. Blood. 128 (10): 1362–1373. doi:10.1182/blood-2016-02-696757. ISSN 0006-4971.
↑ Nodal marginal zone lymphoma . Canadian Cancer Society. http://www.cancer.ca/en/cancer-information/cancer-type/non-hodgkin-lymphoma/non-hodgkin-lymphoma/types-of-nhl/nodal-marginal-zone-lymphoma/?region=nb Accessed on March 4, 2016
↑ Multiple myeloma. Wikipedia (2015) https://en.wikipedia.org/wiki/Multiple_myeloma#Signs_and_symptoms Accessed on September, 20th 2015
↑ Multiple myeloma. Canadian Cancer Society (2015) http://www.cancer.ca/en/cancer-information/cancer-type/multiple-myeloma/signs-and-symptoms/?region=mb Accessed on September 20th 2015
↑ Multiple myeloma. Cancer. gov(2015) http://www.cancer.gov/types/myeloma Accessed on September, 20th 2015
↑ Reisenbuckler C (2014). “Multiple myeloma and diagnostic imaging”. Radiol Technol. 85 (4): 391–410, quiz 411–3. PMID 24614435.
↑ Sergentanis TN, Zagouri F, Tsilimidos G, Tsagianni A, Tseliou M, Dimopoulos MA, Psaltopoulou T (October 2015). “Risk Factors for Multiple Myeloma: A Systematic Review of Meta-Analyses”. Clin Lymphoma Myeloma Leuk. 15 (10): 563–77.e1–3. doi:10.1016/j.clml.2015.06.003. PMID 26294217.
↑ Eslick R, Talaulikar D (October 2013). “Multiple myeloma: from diagnosis to treatment”. Aust Fam Physician. 42 (10): 684–8. PMID 24130968.
↑ Lens D, Matutes E, Catovsky D, Coignet LJ (2000). “Frequent deletions at 11q23 and 13q14 in B cell prolymphocytic leukemia (B-PLL)”. Leukemia. 14 (3): 427–30. PMID 10720137.
↑ Yamamoto K, Hamaguchi H, Nagata K, Shibuya H, Takeuchi H (April 1998). “Splenic irradiation for prolymphocytic leukemia: is it preferable as an initial treatment or not?”. Jpn. J. Clin. Oncol. 28 (4): 267–9. doi:10.1093/jjco/28.4.267. PMID 9657013.
↑ “Pathology”. Archived from the original on 7 February 2009. Retrieved 2009-01-31.
↑ ^45.0 ^45.1 Crisostomo RH, Fernandez JA, Caceres W (May 2007). “Complex karyotype including chromosomal translocation (8;14) (q24;q32) in one case with B-cell prolymphocytic leukemia”. Leuk. Res. 31 (5): 699–701. doi:10.1016/j.leukres.2006.06.010. PMID 16997373.
↑ “National cancer institute”.
↑ “National cancer institute”.

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Epidemiology and Demographics

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: – Omer Kamal, M.D.[2]

Overview

The incidence of Monoclonal gammopathy of undetermined significance is approximately 120 per 100,000 in men at age 50, and goes to 530 per 1000 by the age 90. Women however have 60 cases per 1000 at age 50 which goes upto 370 per 1000 at age 90. The prevalence of Monoclonal gammopathy of undetermined significance is different in different populations.

Epidemiology and Demographics

Incidence

The incidence of Monoclonal gammopathy of undetermined significance is approximately 120 per 100,000 in men at age 50, and goes to 530 per 1000 by the age 90. Women however have 60 cases per 1000 at age 50 which goes upto 370 pwe 1000 at age 90.^[1]
The incidence of Monoclonal gammopathy of undetermined significance was estimated to be higher per 100,000 in men than women worldwide.^[2]

Prevalence

The prevalence of Monoclonal gammopathy of undetermined significance is different in different populations^[2]

Age	Prevalence
≥50	3.2
≥70	5.3
≥85	7.5

Age

Monoclonal gammopathy of undetermined significance commonly affects individuals older than 50 years of age. ^[1]

Race

Monoclonal gammopathy of undetermined significance usually affects individuals of the african americans and africans^[3]. Caucasian individuals are less likely to develop Monoclonal gammopathy of undetermined significance.^[3]^[4]

Gender

Men are more commonly affected by Monoclonal gammopathy of undetermined significance than women. The men to women ratio is approximately 2 to 1.^[1]

References

↑ ^1.0 ^1.1 ^1.2 Therneau TM, Kyle RA, Melton LJ, Larson DR, Benson JT, Colby CL, Dispenzieri A, Kumar S, Katzmann JA, Cerhan JR, Rajkumar SV (November 2012). “Incidence of monoclonal gammopathy of undetermined significance and estimation of duration before first clinical recognition”. Mayo Clin. Proc. 87 (11): 1071–9. doi:10.1016/j.mayocp.2012.06.014. PMC 3541934. PMID 22883742.
↑ ^2.0 ^2.1 Kyle RA, Therneau TM, Rajkumar SV, Larson DR, Plevak MF, Offord JR, Dispenzieri A, Katzmann JA, Melton LJ (March 2006). “Prevalence of monoclonal gammopathy of undetermined significance”. N. Engl. J. Med. 354 (13): 1362–9. doi:10.1056/NEJMoa054494. PMID 16571879.
↑ ^3.0 ^3.1 ^3.2 ^3.3 Singh J, Dudley AW, Kulig KA (December 1990). “Increased incidence of monoclonal gammopathy of undetermined significance in blacks and its age-related differences with whites on the basis of a study of 397 men and one woman in a hospital setting”. J. Lab. Clin. Med. 116 (6): 785–9. PMID 2246554.
↑ ^4.0 ^4.1 Landgren O, Gridley G, Turesson I, Caporaso NE, Goldin LR, Baris D, Fears TR, Hoover RN, Linet MS (February 2006). “Risk of monoclonal gammopathy of undetermined significance (MGUS) and subsequent multiple myeloma among African American and white veterans in the United States”. Blood. 107 (3): 904–6. doi:10.1182/blood-2005-08-3449. PMC 1895893. PMID 16210333.
↑ Landgren O, Katzmann JA, Hsing AW, Pfeiffer RM, Kyle RA, Yeboah ED, Biritwum RB, Tettey Y, Adjei AA, Larson DR, Dispenzieri A, Melton LJ, Goldin LR, McMaster ML, Caporaso NE, Rajkumar SV (December 2007). “Prevalence of monoclonal gammopathy of undetermined significance among men in Ghana”. Mayo Clin. Proc. 82 (12): 1468–73. doi:10.1016/S0025-6196(11)61089-6. PMID 18053453.
↑ ^6.0 ^6.1 Cohen HJ, Crawford J, Rao MK, Pieper CF, Currie MS (May 1998). “Racial differences in the prevalence of monoclonal gammopathy in a community-based sample of the elderly”. Am. J. Med. 104 (5): 439–44. PMID 9626026.

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Risk Factors

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Omer Kamal, M.D.[2]

Overview

Common risk factors in the development of monoclonal gammopathy of undetermined significance include African american race, age, male sex, family history, history of immunosuppression and exposure to pesticides.

Risk Factors

Common risk factors in the development of monoclonal gammopathy of undetermined significance include African American race, age, male sex. family history, history of immunosuppression and exposure to pesticides.

Common Risk Factors

Common risk factors in the development of monoclonal gammopathy of undetermined significance include:

African Americans^[1] ^[2]
Age^[3]
Male sex
Family History^[4]
History of immunosuppression^[5]
Exposure to pesticides^[6]

Other Risk Factors

Other risk factors in the development of monoclonal gammopathy of undetermined significance include:^[7]^[8]^[9]

Levels of serum monoclonal protein ≥1.5 g/dL ^[10]
Non-IgG MGUS (ie, IgA, IgM, IgD MGUS)
Abnormal serum free light chain ratio (ie, ratio of kappa to lambda free light chains <0.26 or >1.65) ^[11]^[12]

References

↑ Landgren O, Gridley G, Turesson I, Caporaso NE, Goldin LR, Baris D, Fears TR, Hoover RN, Linet MS (February 2006). “Risk of monoclonal gammopathy of undetermined significance (MGUS) and subsequent multiple myeloma among African American and white veterans in the United States”. Blood. 107 (3): 904–6. doi:10.1182/blood-2005-08-3449. PMC 1895893. PMID 16210333.
↑ Landgren O, Katzmann JA, Hsing AW, Pfeiffer RM, Kyle RA, Yeboah ED, Biritwum RB, Tettey Y, Adjei AA, Larson DR, Dispenzieri A, Melton LJ, Goldin LR, McMaster ML, Caporaso NE, Rajkumar SV (December 2007). “Prevalence of monoclonal gammopathy of undetermined significance among men in Ghana”. Mayo Clin. Proc. 82 (12): 1468–73. doi:10.1016/S0025-6196(11)61089-6. PMID 18053453.
↑ Kyle RA, Therneau TM, Rajkumar SV, Larson DR, Plevak MF, Offord JR, Dispenzieri A, Katzmann JA, Melton LJ (March 2006). “Prevalence of monoclonal gammopathy of undetermined significance”. N. Engl. J. Med. 354 (13): 1362–9. doi:10.1056/NEJMoa054494. PMID 16571879.
↑ Vachon CM, Kyle RA, Therneau TM, Foreman BJ, Larson DR, Colby CL, Phelps TK, Dispenzieri A, Kumar SK, Katzmann JA, Rajkumar SV (July 2009). “Increased risk of monoclonal gammopathy in first-degree relatives of patients with multiple myeloma or monoclonal gammopathy of undetermined significance”. Blood. 114 (4): 785–90. doi:10.1182/blood-2008-12-192575. PMC 2716020. PMID 19179466.
↑ Kristinsson SY, Goldin LR, Björkholm M, Koshiol J, Turesson I, Landgren O (November 2009). “Genetic and immune-related factors in the pathogenesis of lymphoproliferative and plasma cell malignancies”. Haematologica. 94 (11): 1581–9. doi:10.3324/haematol.2009.008979. PMC 2770969. PMID 19586941.
↑ Landgren O, Kyle RA, Hoppin JA, Beane Freeman LE, Cerhan JR, Katzmann JA, Rajkumar SV, Alavanja MC (June 2009). “Pesticide exposure and risk of monoclonal gammopathy of undetermined significance in the Agricultural Health Study”. Blood. 113 (25): 6386–91. doi:10.1182/blood-2009-02-203471. PMC 2710931. PMID 19387005.
↑ Kyle RA, Therneau TM, Rajkumar SV, Offord JR, Larson DR, Plevak MF, Melton LJ (February 2002). “A long-term study of prognosis in monoclonal gammopathy of undetermined significance”. N. Engl. J. Med. 346 (8): 564–9. doi:10.1056/NEJMoa01133202. PMID 11856795.
↑ Baldini L, Guffanti A, Cesana BM, Colombi M, Chiorboli O, Damilano I, Maiolo AT (February 1996). “Role of different hematologic variables in defining the risk of malignant transformation in monoclonal gammopathy”. Blood. 87 (3): 912–8. PMID 8562962.
↑ Rosiñol L, Cibeira MT, Montoto S, Rozman M, Esteve J, Filella X, Bladé J (April 2007). “Monoclonal gammopathy of undetermined significance: predictors of malignant transformation and recognition of an evolving type characterized by a progressive increase in M protein size”. Mayo Clin. Proc. 82 (4): 428–34. doi:10.4065/82.4.428. PMID 17418070.
↑ Cesana C, Klersy C, Barbarano L, Nosari AM, Crugnola M, Pungolino E, Gargantini L, Granata S, Valentini M, Morra E (March 2002). “Prognostic factors for malignant transformation in monoclonal gammopathy of undetermined significance and smoldering multiple myeloma”. J. Clin. Oncol. 20 (6): 1625–34. doi:10.1200/JCO.2002.20.6.1625. PMID 11896113.
↑ Rajkumar SV, Kyle RA, Therneau TM, Melton LJ, Bradwell AR, Clark RJ, Larson DR, Plevak MF, Dispenzieri A, Katzmann JA (August 2005). “Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance”. Blood. 106 (3): 812–7. doi:10.1182/blood-2005-03-1038. PMC 1895159. PMID 15855274.
↑ Rajkumar SV, Kyle RA, Therneau TM, Clark RJ, Bradwell AR, Melton LJ, Larson DR, Plevak MF, Katzmann JA (November 2004). “Presence of monoclonal free light chains in the serum predicts risk of progression in monoclonal gammopathy of undetermined significance”. Br. J. Haematol. 127 (3): 308–10. doi:10.1111/j.1365-2141.2004.05169.x. PMID 15491291.

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Screening

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

There is no role of screening in patients for monoclonal gammopathy of undetermined significance.

Screening

There is no role of screening in patients for monoclonal gammopathy of undetermined significance.^[1]

References

↑ Berenson JR, Anderson KC, Audell RA, Boccia RV, Coleman M, Dimopoulos MA, Drake MT, Fonseca R, Harousseau JL, Joshua D, Lonial S, Niesvizky R, Palumbo A, Roodman GD, San-Miguel JF, Singhal S, Weber DM, Zangari M, Wirtschafter E, Yellin O, Kyle RA (July 2010). “Monoclonal gammopathy of undetermined significance: a consensus statement”. Br. J. Haematol. 150 (1): 28–38. doi:10.1111/j.1365-2141.2010.08207.x. PMID 20507313.

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Natural History, Complications and Prognosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Omer Kamal, M.D.[2] Muhammad Saad, M.B.B.S.[3]

Overview

Frequent complications of Monoclonal gammopathy of undetermined significance include fractures specially in lumbar vertebrae and thromboembolic phenomena. MGUS, is considered as a pre-malignant condition, and its transformation to multiple myeloma. However, as it mostly occurs in elderly, and its slow rate of progression, only a small proportion of people go on to develop a haematological malignancy. In patients with MGUS, although the actuarial risk of myeloma at 25 years of follow-up is 30%, the actual risk (when competing causes of death are taken into account) is only 11%.

Natural History

Each patient with MGUS should be followed up for progression to multiple myeloma, it can be considered as a pre-malignant condition. The probability for malignant transformation was 6.1, 15.4 and 31.3% at 5, 10 and 20 years, respectively. 157 patients (59.7%), 119 (45.3%) of whom with no increase and 38 (14.4%) with an increase in serum M-component, died of causes unrelated to MGUS and without development of any plasma cell proliferative disease; 47 patients (17.9%) were still alive without increase in M-component; 11 patients (4.1%) were still alive and at follow-up presented values of serum M-component > 30 g/l without any evidence of plasma cell proliferative or lymphoproliferative disease; 48 patients (18.3%) developed multiple myeloma (35 cases, 13.1%), solitary plasmacytoma of the bone (2 cases, 0.8%), macroglobulinaemia (4 cases, 1.6%), malignant lymphoma (3 cases, 1.2%), amyloidosis (2 cases, 0.8%), chronic lymphocytic leukaemia (1 case, 0.4%), and plasma cell leukaemia (1 case, 0.4%).^[1]

Complications

The following are frequent complications of Monoclonal gammopathy of undetermined significance

Fractures specially in lumbar vertebrae^[2]^[3]^[4]^[5]
Thromboembolic phenomena^[6]^[7]
Hypercoaguable state^[8]^[7]
Development of secondary cancers eg. acute myeloid leukemia and myelodysplastic syndromes^[9]^[10]
Autoimmune diseases^[11]
Increased mortality^[12]

Prognosis

MGUS, is considered as a pre-malignant condition, and its transformation to multiple myeloma. However, as it mostly occurs in elderly, and its slow rate of progression, only a small proportion of people go on to develop a hematological malignancy. In patients with MGUS, although the actuarial risk of myeloma at 25 years of follow-up is 30%, the actual risk (when competing causes of death are taken into account) is only 11%.^[13]

The annual risk of progressing to multiple myeloma is around 1–2% a year. The prevalence of MGUS was 3.2% in people above 50, with a slight male predominance (4.0% vs. 2.7%). Prevalence increases with age. In 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 reported as <1 g/dl, while only a very small group reported levels over 2 g/dl.^[14]

In addition to multiple myeloma, MGUS may also progress to Waldenström’s macroglobulinemia, primary amyloidosis, B-cell lymphoma, orchronic lymphocytic leukemia. ‘

References

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↑ Pepe J, Petrucci MT, Nofroni I, Fassino V, Diacinti D, Romagnoli E, Minisola S (September 2006). “Lumbar bone mineral density as the major factor determining increased prevalence of vertebral fractures in monoclonal gammopathy of undetermined significance”. Br. J. Haematol. 134 (5): 485–90. doi:10.1111/j.1365-2141.2006.06217.x. PMID 16848794.
↑ Melton LJ, Rajkumar SV, Khosla S, Achenbach SJ, Oberg AL, Kyle RA (January 2004). “Fracture risk in monoclonal gammopathy of undetermined significance”. J. Bone Miner. Res. 19 (1): 25–30. doi:10.1359/JBMR.0301212. PMID 14753733.
↑ Gregersen H, Jensen P, Gislum M, Jørgensen B, Sørensen HT, Nørgaard M (October 2006). “Fracture risk in patients with monoclonal gammopathy of undetermined significance”. Br. J. Haematol. 135 (1): 62–7. doi:10.1111/j.1365-2141.2006.06269.x. PMID 16925792.
↑ Kristinsson SY, Tang M, Pfeiffer RM, Björkholm M, Blimark C, Mellqvist UH, Wahlin A, Turesson I, Landgren O (October 2010). “Monoclonal gammopathy of undetermined significance and risk of skeletal fractures: a population-based study”. Blood. 116 (15): 2651–5. doi:10.1182/blood-2010-04-282848. PMC 3324256. PMID 20610813.
↑ Sallah S, Husain A, Wan J, Vos P, Nguyen NP (October 2004). “The risk of venous thromboembolic disease in patients with monoclonal gammopathy of undetermined significance”. Ann. Oncol. 15 (10): 1490–4. doi:10.1093/annonc/mdh385. PMID 15367409.
↑ ^7.0 ^7.1 Auwerda JJ, Sonneveld P, de Maat MP, Leebeek FW (July 2007). “Prothrombotic coagulation abnormalities in patients with paraprotein-producing B-cell disorders”. Clin Lymphoma Myeloma. 7 (7): 462–6. PMID 17875234.
↑ Kristinsson SY, Pfeiffer RM, Björkholm M, Goldin LR, Schulman S, Blimark C, Mellqvist UH, Wahlin A, Turesson I, Landgren O (June 2010). “Arterial and venous thrombosis in monoclonal gammopathy of undetermined significance and multiple myeloma: a population-based study”. Blood. 115 (24): 4991–8. doi:10.1182/blood-2009-11-252072. PMC 2890150. PMID 20299513.
↑ Thomas A, Mailankody S, Korde N, Kristinsson SY, Turesson I, Landgren O (March 2012). “Second malignancies after multiple myeloma: from 1960s to 2010s”. Blood. 119 (12): 2731–7. doi:10.1182/blood-2011-12-381426. PMC 3327452. PMID 22310913.
↑ Mailankody S, Pfeiffer RM, Kristinsson SY, Korde N, Bjorkholm M, Goldin LR, Turesson I, Landgren O (October 2011). “Risk of acute myeloid leukemia and myelodysplastic syndromes after multiple myeloma and its precursor disease (MGUS)”. Blood. 118 (15): 4086–92. doi:10.1182/blood-2011-05-355743. PMC 3204729. PMID 21795746.
↑ Sverrisdottir I, Thorsteinsdottir S, Rognvaldsson S, Aspelund T, Vidarsson B, Onundarson PT, Agnarsson BA, Sigurdardottir M, Thorsteinsdóttir I, Sveinsdottir SV, Palmason R, Olafsson I, Sigurdsson F, Thordardóttir AR, Eythorsson E, Jonsson A, Palsson R, Indridason OS, Gislason GK, Olafsson A, Sigurdsson J, Steingrímsdóttir H, Einarsson Long T, Hultcrantz M, Durie BG, Harding S, Landgren O, Kristinsson SY, Love TJ (June 2024). “Association Between Autoimmune Diseases and Monoclonal Gammopathy of Undetermined Significance : An Analysis From a Population-Based Screening Study”. Ann Intern Med. 177 (6): 711–718. doi:10.7326/M23-2867. PMID 38768457 Check |pmid= value (help).
↑ Ji M, Huber JH, Schoen MW, Sanfilippo KM, Colditz GA, Wang SY, Chang SH (September 2023). “Mortality in the US Populations With Monoclonal Gammopathy of Undetermined Significance”. JAMA Oncol. 9 (9): 1293–1295. doi:10.1001/jamaoncol.2023.2278. PMID 37498610 Check |pmid= value (help).
↑ Bladé J (2006). “Clinical practice. Monoclonal gammopathy of undetermined significance”. N Engl J Med. 355 (26): 2765–70. PMID 17192542 Abstract.
↑ Kyle RA, Therneau TM, Rajkumar SV, Larson DR, Plevak MF, Offord JR, Dispenzieri A, Katzmann JA, Melton LJ 3rd. (2006). “Prevalence of monoclonal gammopathy of undetermined significance”. N Engl J Med. 354: 1362–9. PMID 16571879. Unknown parameter |month= ignored (help)

Template:WH Template:WS

Diagnosis

Treatment

Case Studies

Case #1

Template:WikiDoc Sources

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[B-PLL-46] “National cancer institute”.

[B-PLL2-47] “National cancer institute”.

[pmid22883742-1] 1.0 ^1.1 ^1.2 Therneau TM, Kyle RA, Melton LJ, Larson DR, Benson JT, Colby CL, Dispenzieri A, Kumar S, Katzmann JA, Cerhan JR, Rajkumar SV (November 2012). “Incidence of monoclonal gammopathy of undetermined significance and estimation of duration before first clinical recognition”. Mayo Clin. Proc. 87 (11): 1071–9. doi:10.1016/j.mayocp.2012.06.014. PMC 3541934. PMID 22883742.

[pmid16571879-2] 2.0 ^2.1 Kyle RA, Therneau TM, Rajkumar SV, Larson DR, Plevak MF, Offord JR, Dispenzieri A, Katzmann JA, Melton LJ (March 2006). “Prevalence of monoclonal gammopathy of undetermined significance”. N. Engl. J. Med. 354 (13): 1362–9. doi:10.1056/NEJMoa054494. PMID 16571879.

[pmid2246554-3] 3.0 ^3.1 ^3.2 ^3.3 Singh J, Dudley AW, Kulig KA (December 1990). “Increased incidence of monoclonal gammopathy of undetermined significance in blacks and its age-related differences with whites on the basis of a study of 397 men and one woman in a hospital setting”. J. Lab. Clin. Med. 116 (6): 785–9. PMID 2246554.

[pmid16210333-4] 4.0 ^4.1 Landgren O, Gridley G, Turesson I, Caporaso NE, Goldin LR, Baris D, Fears TR, Hoover RN, Linet MS (February 2006). “Risk of monoclonal gammopathy of undetermined significance (MGUS) and subsequent multiple myeloma among African American and white veterans in the United States”. Blood. 107 (3): 904–6. doi:10.1182/blood-2005-08-3449. PMC 1895893. PMID 16210333.

[pmid18053453-5] Landgren O, Katzmann JA, Hsing AW, Pfeiffer RM, Kyle RA, Yeboah ED, Biritwum RB, Tettey Y, Adjei AA, Larson DR, Dispenzieri A, Melton LJ, Goldin LR, McMaster ML, Caporaso NE, Rajkumar SV (December 2007). “Prevalence of monoclonal gammopathy of undetermined significance among men in Ghana”. Mayo Clin. Proc. 82 (12): 1468–73. doi:10.1016/S0025-6196(11)61089-6. PMID 18053453.

[pmid9626026-6] 6.0 ^6.1 Cohen HJ, Crawford J, Rao MK, Pieper CF, Currie MS (May 1998). “Racial differences in the prevalence of monoclonal gammopathy in a community-based sample of the elderly”. Am. J. Med. 104 (5): 439–44. PMID 9626026.

[pmid16210333-1] Landgren O, Gridley G, Turesson I, Caporaso NE, Goldin LR, Baris D, Fears TR, Hoover RN, Linet MS (February 2006). “Risk of monoclonal gammopathy of undetermined significance (MGUS) and subsequent multiple myeloma among African American and white veterans in the United States”. Blood. 107 (3): 904–6. doi:10.1182/blood-2005-08-3449. PMC 1895893. PMID 16210333.

[pmid18053453-2] Landgren O, Katzmann JA, Hsing AW, Pfeiffer RM, Kyle RA, Yeboah ED, Biritwum RB, Tettey Y, Adjei AA, Larson DR, Dispenzieri A, Melton LJ, Goldin LR, McMaster ML, Caporaso NE, Rajkumar SV (December 2007). “Prevalence of monoclonal gammopathy of undetermined significance among men in Ghana”. Mayo Clin. Proc. 82 (12): 1468–73. doi:10.1016/S0025-6196(11)61089-6. PMID 18053453.

[pmid16571879-3] Kyle RA, Therneau TM, Rajkumar SV, Larson DR, Plevak MF, Offord JR, Dispenzieri A, Katzmann JA, Melton LJ (March 2006). “Prevalence of monoclonal gammopathy of undetermined significance”. N. Engl. J. Med. 354 (13): 1362–9. doi:10.1056/NEJMoa054494. PMID 16571879.

[pmid19179466-4] Vachon CM, Kyle RA, Therneau TM, Foreman BJ, Larson DR, Colby CL, Phelps TK, Dispenzieri A, Kumar SK, Katzmann JA, Rajkumar SV (July 2009). “Increased risk of monoclonal gammopathy in first-degree relatives of patients with multiple myeloma or monoclonal gammopathy of undetermined significance”. Blood. 114 (4): 785–90. doi:10.1182/blood-2008-12-192575. PMC 2716020. PMID 19179466.

[pmid19586941-5] Kristinsson SY, Goldin LR, Björkholm M, Koshiol J, Turesson I, Landgren O (November 2009). “Genetic and immune-related factors in the pathogenesis of lymphoproliferative and plasma cell malignancies”. Haematologica. 94 (11): 1581–9. doi:10.3324/haematol.2009.008979. PMC 2770969. PMID 19586941.

[pmid19387005-6] Landgren O, Kyle RA, Hoppin JA, Beane Freeman LE, Cerhan JR, Katzmann JA, Rajkumar SV, Alavanja MC (June 2009). “Pesticide exposure and risk of monoclonal gammopathy of undetermined significance in the Agricultural Health Study”. Blood. 113 (25): 6386–91. doi:10.1182/blood-2009-02-203471. PMC 2710931. PMID 19387005.

[pmid11856795-7] Kyle RA, Therneau TM, Rajkumar SV, Offord JR, Larson DR, Plevak MF, Melton LJ (February 2002). “A long-term study of prognosis in monoclonal gammopathy of undetermined significance”. N. Engl. J. Med. 346 (8): 564–9. doi:10.1056/NEJMoa01133202. PMID 11856795.

[pmid8562962-8] Baldini L, Guffanti A, Cesana BM, Colombi M, Chiorboli O, Damilano I, Maiolo AT (February 1996). “Role of different hematologic variables in defining the risk of malignant transformation in monoclonal gammopathy”. Blood. 87 (3): 912–8. PMID 8562962.

[pmid17418070-9] Rosiñol L, Cibeira MT, Montoto S, Rozman M, Esteve J, Filella X, Bladé J (April 2007). “Monoclonal gammopathy of undetermined significance: predictors of malignant transformation and recognition of an evolving type characterized by a progressive increase in M protein size”. Mayo Clin. Proc. 82 (4): 428–34. doi:10.4065/82.4.428. PMID 17418070.

[pmid11896113-10] Cesana C, Klersy C, Barbarano L, Nosari AM, Crugnola M, Pungolino E, Gargantini L, Granata S, Valentini M, Morra E (March 2002). “Prognostic factors for malignant transformation in monoclonal gammopathy of undetermined significance and smoldering multiple myeloma”. J. Clin. Oncol. 20 (6): 1625–34. doi:10.1200/JCO.2002.20.6.1625. PMID 11896113.

[pmid15855274-11] Rajkumar SV, Kyle RA, Therneau TM, Melton LJ, Bradwell AR, Clark RJ, Larson DR, Plevak MF, Dispenzieri A, Katzmann JA (August 2005). “Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance”. Blood. 106 (3): 812–7. doi:10.1182/blood-2005-03-1038. PMC 1895159. PMID 15855274.

[pmid15491291-12] Rajkumar SV, Kyle RA, Therneau TM, Clark RJ, Bradwell AR, Melton LJ, Larson DR, Plevak MF, Katzmann JA (November 2004). “Presence of monoclonal free light chains in the serum predicts risk of progression in monoclonal gammopathy of undetermined significance”. Br. J. Haematol. 127 (3): 308–10. doi:10.1111/j.1365-2141.2004.05169.x. PMID 15491291.

[pmid20507313-1] Berenson JR, Anderson KC, Audell RA, Boccia RV, Coleman M, Dimopoulos MA, Drake MT, Fonseca R, Harousseau JL, Joshua D, Lonial S, Niesvizky R, Palumbo A, Roodman GD, San-Miguel JF, Singhal S, Weber DM, Zangari M, Wirtschafter E, Yellin O, Kyle RA (July 2010). “Monoclonal gammopathy of undetermined significance: a consensus statement”. Br. J. Haematol. 150 (1): 28–38. doi:10.1111/j.1365-2141.2010.08207.x. PMID 20507313.

[pmid9066713-1] Pasqualetti P, Festuccia V, Collacciani A, Casale R (1997). “The natural history of monoclonal gammopathy of undetermined significance. A 5- to 20-year follow-up of 263 cases”. Acta Haematol. 97 (3): 174–9. doi:10.1159/000203676. PMID 9066713.

[pmid16848794-2] Pepe J, Petrucci MT, Nofroni I, Fassino V, Diacinti D, Romagnoli E, Minisola S (September 2006). “Lumbar bone mineral density as the major factor determining increased prevalence of vertebral fractures in monoclonal gammopathy of undetermined significance”. Br. J. Haematol. 134 (5): 485–90. doi:10.1111/j.1365-2141.2006.06217.x. PMID 16848794.

[pmid14753733-3] Melton LJ, Rajkumar SV, Khosla S, Achenbach SJ, Oberg AL, Kyle RA (January 2004). “Fracture risk in monoclonal gammopathy of undetermined significance”. J. Bone Miner. Res. 19 (1): 25–30. doi:10.1359/JBMR.0301212. PMID 14753733.

[pmid16925792-4] Gregersen H, Jensen P, Gislum M, Jørgensen B, Sørensen HT, Nørgaard M (October 2006). “Fracture risk in patients with monoclonal gammopathy of undetermined significance”. Br. J. Haematol. 135 (1): 62–7. doi:10.1111/j.1365-2141.2006.06269.x. PMID 16925792.

[pmid20610813-5] Kristinsson SY, Tang M, Pfeiffer RM, Björkholm M, Blimark C, Mellqvist UH, Wahlin A, Turesson I, Landgren O (October 2010). “Monoclonal gammopathy of undetermined significance and risk of skeletal fractures: a population-based study”. Blood. 116 (15): 2651–5. doi:10.1182/blood-2010-04-282848. PMC 3324256. PMID 20610813.

[pmid15367409-6] Sallah S, Husain A, Wan J, Vos P, Nguyen NP (October 2004). “The risk of venous thromboembolic disease in patients with monoclonal gammopathy of undetermined significance”. Ann. Oncol. 15 (10): 1490–4. doi:10.1093/annonc/mdh385. PMID 15367409.

[pmid17875234-7] 7.0 ^7.1 Auwerda JJ, Sonneveld P, de Maat MP, Leebeek FW (July 2007). “Prothrombotic coagulation abnormalities in patients with paraprotein-producing B-cell disorders”. Clin Lymphoma Myeloma. 7 (7): 462–6. PMID 17875234.

[pmid20299513-8] Kristinsson SY, Pfeiffer RM, Björkholm M, Goldin LR, Schulman S, Blimark C, Mellqvist UH, Wahlin A, Turesson I, Landgren O (June 2010). “Arterial and venous thrombosis in monoclonal gammopathy of undetermined significance and multiple myeloma: a population-based study”. Blood. 115 (24): 4991–8. doi:10.1182/blood-2009-11-252072. PMC 2890150. PMID 20299513.

[pmid22310913-9] Thomas A, Mailankody S, Korde N, Kristinsson SY, Turesson I, Landgren O (March 2012). “Second malignancies after multiple myeloma: from 1960s to 2010s”. Blood. 119 (12): 2731–7. doi:10.1182/blood-2011-12-381426. PMC 3327452. PMID 22310913.

[pmid21795746-10] Mailankody S, Pfeiffer RM, Kristinsson SY, Korde N, Bjorkholm M, Goldin LR, Turesson I, Landgren O (October 2011). “Risk of acute myeloid leukemia and myelodysplastic syndromes after multiple myeloma and its precursor disease (MGUS)”. Blood. 118 (15): 4086–92. doi:10.1182/blood-2011-05-355743. PMC 3204729. PMID 21795746.

[pmid38768457-11] Sverrisdottir I, Thorsteinsdottir S, Rognvaldsson S, Aspelund T, Vidarsson B, Onundarson PT, Agnarsson BA, Sigurdardottir M, Thorsteinsdóttir I, Sveinsdottir SV, Palmason R, Olafsson I, Sigurdsson F, Thordardóttir AR, Eythorsson E, Jonsson A, Palsson R, Indridason OS, Gislason GK, Olafsson A, Sigurdsson J, Steingrímsdóttir H, Einarsson Long T, Hultcrantz M, Durie BG, Harding S, Landgren O, Kristinsson SY, Love TJ (June 2024). “Association Between Autoimmune Diseases and Monoclonal Gammopathy of Undetermined Significance : An Analysis From a Population-Based Screening Study”. Ann Intern Med. 177 (6): 711–718. doi:10.7326/M23-2867. PMID 38768457 Check |pmid= value (help).

[pmid37498610-12] Ji M, Huber JH, Schoen MW, Sanfilippo KM, Colditz GA, Wang SY, Chang SH (September 2023). “Mortality in the US Populations With Monoclonal Gammopathy of Undetermined Significance”. JAMA Oncol. 9 (9): 1293–1295. doi:10.1001/jamaoncol.2023.2278. PMID 37498610 Check |pmid= value (help).

[13] Bladé J (2006). “Clinical practice. Monoclonal gammopathy of undetermined significance”. N Engl J Med. 355 (26): 2765–70. PMID 17192542 Abstract.

[Kyle-14] Kyle RA, Therneau TM, Rajkumar SV, Larson DR, Plevak MF, Offord JR, Dispenzieri A, Katzmann JA, Melton LJ 3rd. (2006). “Prevalence of monoclonal gammopathy of undetermined significance”. N Engl J Med. 354: 1362–9. PMID 16571879. Unknown parameter |month= ignored (help)

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Monoclonal gammopathy of undetermined significance

Overview

Historical Perspective

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Genetic causes^[1]