Monoclonal gammopathy of undetermined significance overview

# 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. There is no established system for the staging of monoclonal gammopathy of undetermined significance (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.

## 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.

## 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