Monoclonal gammopathy of undetermined significance (MGUS)

The most common plasma cell disorder associated with monoclonal gammopathy and a premalignant precursor to multiple myeloma.

One of the most common premalignant disorders in the general population.

In large population studies of patients with monoclonal gammopathy half the patients have MGUS and 15-20% have multiple myeloma.

Benign condition that is a precursor to multiple myeloma, macroglobulinemia, amyloidosis in up to 24%.

Estimated that 169 individuals per 100,000 have a clinical diagnosis of MGUS, and approximately 600,000 people in the US have MGUS.

Only about 20% of prevalent MGUS cases are clinically recognized, and it is estimated that another 2.8 million individuals have undiagnosed disease.

It is generally an incidental finding during evaluation for signs and symptoms of lymphoplasmacytic malignancies including multiple myeloma, immunoglobulin light chain amyloidosis, or Waldenström’s macroglobulinemia.
Testing for monoclonal protein is also seen in certain non-malignant diseases associated with MGUS and may potentially respond to plasma cell directEd therapy and is referred to as monoclonal gammopathy of clinical significance.

Affects more than 3% of population older than 50 years,and 5% of individuals over the age of 70(Kyle RA).

The prevalence of individuals younger than 50 years is tenfold less.

Has the potential to progress to multiple myeloma or amyloidosis at a rate of 1% per year (Kyle RA).

Median time to transformation to myeloma 6-10 years.

Approximately 1%/year convert to myeloma (0.6-3% per year).

Most cases do not progress to malignancy.

The serum M protein is less than 3.0 g/dL.

Bone marrow contains fewer than 10% plasma cells.

Such patients have no M protein or only small amounts of light chains in the urine, have no lytic bone lesions, anemia, hypercalcemia, or renal insufficiency related to the elevated protein.

Occurs in about 3-6% of people older than 70 years of age.

Prevalence in individuals 75 years or older is 7.5%.

Slightly higher prevalence in men.

More common in blacks.

Not associated with and organ damage from plasma cell proliferation, and is therefore asymptomatic.

May be be the result of an event cascade following abnormal responses to antigenic stimulation, which may be mediated by overexpression of IL-6 receptors and aberrant Toll-like receptor expression.

MGUS have acquired genetic changes over time establishing multiple subclones giving growth advantages to different clones over time.

Its subclone subsequently gives a sudden burst of tumor growth resulting in symptomatic myeloma.

Prevalence demonstrated in Sweden 0.1%-0.2% in people aged 30-49 years, 1.1-2.0% in those aged 50-79 years, and 5.7% in those aged 80-89 years.

Prevalence in Minnesota 3.2% in people older than 50 years of age, 5.3% in those older than 70 years.

When first recognized MGUS has likely been present in an undetected state for a median duration of more than 10 years (Therneau TM et al).

It is unknown whether MGUS precedes all cases of multiple myeloma or if the latter can arise deaths novo without preceding M

Probability of malignant transformation 17% at 10 years, 34% at 20 years, and 39% at 25 years with an annual rate of 1.5%.

Risk of malignant transformation may occur after more than 30 years of observation.

May rarely evolve into AL amyloidosis.

Patients with high risk MGUS are considered candidates to investigate therapeutic intervention to prevent progression of disease, whereas low and intermediate risk patients with MGUS are left for follow up.

The presence of two adverse risk factors: and abnormal serum free light chain ratio and high serum and protein level of greater than 1.5 g/dL is associated with the risk of progression at 20 years of 55% and 35%, as compared with 41% and 20% among patients who had 1 adverse risk factor and 19% and 7% among patients with no risk factor.

Uninvolved immunoglobulins reduced in about 38% of patients with benign monoclonal gammopathy.

In about 50% of patients plasma cell clonal proliferation is triggered by translocations involving the immunoglobulin heavy chain (IgH) locus on chromosome 14q32.

Median age at diagnosis is 70 years and less than 2% of patients are younger than 40 years of age.

Prevalence is higher in men than women at 4% vs 2.7%, respectively, in people over the age of 50 years.

Rates are higher for blacks than whites in the U.S.

Currently three clinical types are identified: non-Igm,IgA,Ig, IgM and light chain type.

The more advanced premalignant state in non-IgM MGUS is termed smoldering multiple myeloma and is associated with a much higher risk of progression to multiple myeloma: 10% per year risk of progression versus 1% per year risk for all forms of MGUS.

MGUS, a clonal plasma cell dyscrasia present in 3 to 5% of people old and 65 years and in 10% of those older than 80 years.

MG US is this associated with approximately 1 to 2% a year progression to multiple myeloma, with a 20 year risk of progression to multiple myeloma of approximately 18%.

Mechanisms of progression to myeloma not clear, but but certain pathogenetic abnormalities such as p53, and Ras mutations, myc abnormalities secondary translocations, and p16 methylation may be implicated.

The type and size of serum monoclonal proteins, as well as abnormal serum free light chains ratios are key risk factors in progression to myeloma.

IgM Type the MGUS is associated with a predisposition to Waldenstrom’s macroglobulinemia.

Light chain MGUS is that a premalignant precursor of light chain multiple myeloma and accounts for nearly 20% of all new cases of myeloma.

Blacks had 82-3 fold higher incidence of MGUS compared with whites.

The risk of MGUS is lower in Asians from Japan and in Mexicans.

The risk of MGUS increases with age, male gender, family history, exposure to immunosuppression, an explosion to certain pesticides.

Pathogenesis may be related to abnormal response to antigenic stimulation possibly mediated by toll-like receptors and overexpression of IL-6 receptors and IL1beta.

This abnormal antigenic response may lead to hyperdiploidy or immunoglobulin heavy chain translocations.

Multistep genetic and microenvironmental changes occur leaading to the transformation of MGUS into smoldering myeloma, myeloma and to extramedullary myeloma.

Progression of MGUS to multiple myeloma is likely secondary to a random second hit.

Ras and p53 mutations, p16 methylation, myc abnormalities are associated with progressive disease.

In approximately 50% of cases the primary pathogenic event is hyperdiploidy, and then the remaining 50% is translocation events at the IgH locus of chromosome 14 q32 (Bersagel PL).

Abnormal free light chain ratio kappa:lambda, non-IgG MGUS, and the high serum M protein level of 1.5 g per deciliter are three major risk factors for the progression to multiple myeloma.

Bone marrow examination is not required if the serum M protein is less than 1.5 g/dL, is IgG subtype, if there is a normal free light chain ratio and if the blood count, serum calcium and creatinine levels are normal.

Almost 50% of newly diagnosed patients require a bone marrow examination.

Patients with 2-3 abnormal risk factors, as noted above, require a bone marrow aspiration and biopsy.

FISH analysis and cytogenetics should be performed on bone marrow material.

A metastatic bone survey is indicated in all patients with MGUS with an M. protein of at least 1.5 g/dL and are of IgA or IgM subtype, have an abnormal free light chain ratio or hypercalcemia, renal insufficiency, anemia or bone lesions (CRAB).

After diagnosis of MGUS the patient should be reevaluated with the above testing in 4-6 months.

Light chain amyloidosis in a patient with MGUS suspected if the patient develops fatigue, unexplained weight loss, tongue and voice changes easy bruisability, particularly of the periorbital region, hemorrhage, dyspnea, edema, peripheral neuropathy, macroglossia, hepatomegaly, or splenomegaly.

Light chain amyloidosis is suspected bone marrow stains for amyloid and subcutaneous fat analysis can recognize almost 90% of patients with this entity.

In patients with IgM MGUS Waldenström’s macroglobulinemia can be suspected with fatigue, weight loss, fever or night sweats, hepatomegaly, splenomegaly, symptoms of hyperviscosity, peripheral neuropathy, anemia, or thrombocytopenia.

If no evidence of progression occurs at the 4-6 month interval the patient can be reevaluated at annual intervals.

Patients in low-risk groups can be reevaluated every 3-5 years, but the development of any symptoms should prompt earlier reevaluation.

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