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Monoclonal Gammopathy of Undetermined Significance (MGUS)

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Published: March 2011

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Our speaker for this program is Jerry Katzmann, PhD, from the Division of Clinical Biochemistry and Immunology at Mayo Clinic. Dr. Katzmann will discuss laboratory testing for monoclonal gammopathy of undetermined significance (MGUS) and clinical implications of this diagnosis.

Presenter: Jerry Katzmann, PhD

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Welcome to Mayo Medical Laboratories' Hot Topics. These presentations provide short discussions of current topics and may be helpful to you in your practice.

Our presenter for this program is Dr. Jerry Katzmann, from the Division of Clinical Biochemistry and Immunology at Mayo Clinic. Dr. Katzmann will discuss laboratory testing for monoclonal gammopathy of undetermined significance (MGUS) and clinical implications of this diagnosis.

Today I want to talk about monoclonal gammopathy of undetermined significance — sometimes shortened to "mugus" or "M-gus." Years ago this abnormality was called benign monoclonal gammopathy (or BMG), but as we'll see, this was a misnomer.

MGUS is by far the most common monoclonal gammopathy that is identified in the laboratory. It is therefore important for laboratorians to understand this disorder.

Multiple Myeloma Slides

Multiple myeloma is the monoclonal gammopathy that we most commonly think of. This composite slide illustrates some important features of multiple myeloma.

The micrograph in the upper left is a bone marrow with Wright-Giemsa stain, and you can see that it is densely packed with plasma cells. Multiple myeloma is a malignant plasma cell proliferative disease, and this malignant proliferation suppresses other marrow elements and can cause the anemia often seen in these patients.

The 2 bone scans on the bottom of the slide illustrate multiple areas within the skull and long bones where clusters of plasma cells are growing and causing lytic lesions. The dissolution of bone in these lesions can cause the hypercalcemia and bone fractures often seen in these patients.

The immunofluorescent micrograph in the upper right has been stained with fluorescent antibodies to kappa light chain and illustrates that the plasma cells are not a polyclonal population with both kappa cells and lambda cells, but a monoclonal plasma cell proliferation. In addition, we should recognize that although these cells grow in multiple sites in the bone marrow, the monoclonal immunoglobulin is secreted by these cells and enters the systemic circulation. High concentrations of the secreted monoclonal immunoglobulins — or abnormal forms of the proteins — may cause the renal disease that is often seen in these patients.

Serum Protein Electrophoresis and Immunofixation Electrophoresis

The secreted immunoglobulin becomes a systemic marker of the plasma cells growing in the bone marrow, and monoclonal immunoglobulins are one of the oldest and best tumor markers that we have. In this slide we see the electrophoretic analysis of a normal serum and a serum from a patient with multiple myeloma. Each panel contains an agarose protein electrophoresis gel (or PEL) and an immunofixation electrophoresis gel (or IFE).

The normal serum in the upper panel shows a smooth electrophoretic distribution of the polyclonal immunoglobulins. The lower panel shows a dense band caused by a monoclonal IgG kappa protein. The protein electrophoretic quantitation indicates an M spike of 3.8 g/dL.

When we identify a monoclonal IgG or IgA of at least 3 g/dL, it is consistent with multiple myeloma. But not all myelomas present this way.

Monoclonal Serum Proteins1: Newly Diagnosed Multiple Myeloma

This slide shows the distribution of monoclonal proteins in newly diagnosed multiple myeloma and at least 25% of these myelomas will have small or no M spikes. Although the IgG, IgA, and IgM myelomas often present with large M spikes, IgD myeloma, light chain myeloma, and nonsecretory myeloma rarely present with large serum M spikes. The implication is that we cannot ignore small monoclonal proteins because they may represent very significant disease.

Monoclonal Gammopathies

This next slide illustrates the distribution all the monoclonal gammopathies that we see in the laboratory.

You can see that in 2008, myeloma represents 17% of the cases seen in the Mayo Rochester practice. MGUS was by far the most common diagnosis following by myeloma, primary amyloid, B-cell lymphoproliferative disease, smoldering myeloma, solitary and extramedullary plasmacytoma, macroglobulinemia, and a category labeled "other."

Monoclonal Gammopathies ("Other")

The "other" category includes 12 rarer diseases such as POEMS, plasma cell leukemia, light chain deposition disease, and MGUS-associated cryoglobulinemia. Note that this slide is a compilation of cases over almost 50 years of practice.

Monoclonal Gammopathies

When we look again at this distribution of monoclonal gammopathies, it is important to again realize that significant diseases such as myeloma and macroglobulinemia may present with large easily recognized serum abnormalities and others such as nonsecretory myeloma and primary amyloid are more subtle and require more intense testing for diagnosis. The laboratory approach to diagnosing monoclonal gammopathies has therefore been based on a panel of tests.

Diagnostic Screening Panels: Sensitivity

On this slide I've indicated the diagnostic sensitivity of various screening panels. The traditional panel was based on serum and urine tests, and as you can see from the first row, the sensitivity is good. With the development of the quantitive free light chain assay, it has been recognized that urine testing is no longer needed as part of a screening panel unless primary amyloid is suspected. The second row contains no urine assays. In the last row, a screening panel of serum protein electropheresis and free light chain is evaluated. This is the simplest and least expensive approach to screening, and the sensitivity is still very good except for patients with MGUS where the sensitivity drops to 88.7%. In spite of that, I think this is the panel of choice to screen for plasma cell proliferative diseases.

In order to understand that conclusion, we need to talk about MGUS.

Monoclonal Gammopathies: Plasma Cell Proliferative Diseases

The next slide groups Plasma Cell Proliferative Diseases into 3 categories.

The malignant diseases, such as multiple myeloma, Waldenström's macroglobulinemia, plasmacytoma, and plasma cell leukemia all have large tumor bulk and require intervention to reduce and eradicate the large numbers of malignant cells.

The protein structure diseases such as primary amyloid and light chain deposition disease may or may not have large numbers of clonal cells but they require intervention to eradicate the cells secreting the disease-causing protein. Although these are not malignancies, the survival of amyloid patients is actually shorter than for myeloma.

The third group of patients with "no symptoms," are considered premalignant and MGUS and smoldering myeloma have no clinical symptoms. These patients should not be treated.

Plasma Cell Proliferative Diseases: MGUS, SMM, MM2

The premalignant disorders of MGUS and smoldering myeloma are compared to multiple myeloma on this next slide.

By definition, MGUS must have <10% bone marrow plasma cells and <3 g/dL serum M spike and importantly, must be asymptomatic with no hypercalcemia, renal damage, anemia, or bone lesions.

Smoldering myeloma differs from MGUS in that there are more than 10% bone marrow plasma cells or an M spike <3 g/dL. Again there are no CRAB symptoms.

Patients with MGUS and smoldering myeloma are asymptomatic and there is no advantage to treat them. They should only be observed.

Multiple myeloma differs from MGUS by having <10% bone marrow plasma cells and symptoms due to the plasma cell proliferative disease. They have end-organ damage and need therapy.

If MGUS and smoldering myeloma have no symptoms and no treatment, why are we concerned with them?

Probability of Progression

This slide lists the probability of MGUS progressing to multiple myeloma and related diseases. This is a study of 1384 patients monitored for up to 25 years. As you can see, the progression rate is approximately 1% per year and it does not change over time. That is, the identification of MGUS is not just the identification of early myeloma and the risk of progression may continue over the lifetime of the patient.

It is because of these progressions that MGUS and smoldering myeloma are called premalignant disorders.

Prevalence of MGUS in Olmsted County, MN

It is also important to recognize that MGUS is a very common disorder. In a study of over 21,000 sera from Olmsted County here in southeastern Minnesota, we determined that 3.2% of the population over 50 years of age had MGUS. That is, they had a monoclonal gammopathy and had no clinical symptoms. You can see that this disease prevalence is age dependent: with a 1.7% prevalence in 50 to 60 year olds and a 6.6% prevalence in ages ?80. Monoclonal gammopathies are relatively uncommon in young people and the prevalence increases as we age.

MGUS Precedes Multiple Myeloma

In addition to the high prevalence and the steady progression of MGUS to multiple myeloma, patients with myeloma have been studied to see if they all have a preceding MGUS. A cohort of normal donors had annual serum samples stored in a freezer bank, and in time, 31 patients developed myeloma. By testing the stored sera it was determined that 90% had a premalignant MGUS for 2.2 to 15.3 years. Interestingly, the patients who developed light-chain myeloma had a preceding free light-chain MGUS with no monoclonal heavy chain.

And in addition, of the 3 myeloma patients in whom no preceding MGUS was detected, 2 were IgD myelomas — and as you recall, IgD is not secreted in large amounts.

Summary: Monoclonal Gammopathy Undetermined Significance (MGUS)

So, at this half-way point in the talk, we recognize that:

  • MGUS is a laboratory abnormality
  • MGUS patients have no clinical symptoms due to their monoclonal gammopathy
  • MGUS is very common in older populations
  • And it is premalignant for multiple myeloma

The remaining question is, "can we tell which MGUS cases will progress to clinical disease and which will be stable?"

Prognosis of MGUS: Size of M Spike and Risk of Progression to Malignancy

When we look at MGUS patients who progress or who remain stable, we can see that the larger the M spike, the higher the risk of progression. Patients with M spikes of one-half g/dL have a 20 year risk of 14%. That is, if they are 60 years old, they have a 14% risk of developing myeloma by the time they are 80. If the size of the initial M spike is larger, then the risk of progression is larger. If the initial M spike is 2.5 g/dL, the risk of progression is increased 4.6-fold such that there is almost a 50% chance of developing myeloma in 20 years.

Prognosis of MGUS: Type of M spike and Absolute Risk of Progression to Malignancy

In addition, the isotype of immunoglobulin heavy chain impacts risk of progression. If the MGUS is IgA or IgM, there is a 2 to 3-fold increased risk of progression compared to IgG.

Population-Based Cohort Study: Impact of Free Light Chain on Progression

Thirdly, an abnormal free light chain ratio at initial MGUS diagnosis is associated with increased risk of progression. The risk of progression increases if the ratio is more abnormal and this risk is independent of M spike size.

Multivariate Analysis of Prognostic Factors for Progression of MGUS

These 3 variables — free light chain ratio, serum M spike size and heavy chain isotype — are significant factors for progression when put into a multivariate analysis.

Each variable was tested as a bivariate factor. That is: The free light chain ratio was normal or abnormal The M spike was > or < 1.5 g/dL And the heavy chain was IgG vs IgA or IgM

Each factor is independently significant and each carries a hazard ratio of approximately 2.5.

Risk Stratification Model Incorporating All 3 Predictive Factors

We have used these 3 serum-derived prognostic factors to construct a risk stratification model for the progression of MGUS to multiple myeloma. This model is based on the presence of 0, 1, 2, or 3 adverse factors.

The lowest risk group has zero adverse risk factors: a small M spike <1.5 g/dL, IgG heavy chain, and a normal free light chain ratio. This group represents approximately 40% of all newly diagnosed MGUS patients and you can see that their 20 year risk is 2%. That is, if you are 70 years old, have MGUS, and live to 90 — there is only a 2% chance of progression to myeloma.

The risk of progression increases with 1, 2, or 3 adverse factors, until with all 3 factors abnormal, the relative risk is approximately 20-fold higher than with no adverse prognostic factors.

This model allows us to stratify risk for MGUS patients. In the low-risk group for example, the patient has only a 2% chance that this abnormality will have any impact on their health during their lifetime — and that they need to focus on the wellness issues that we all focus on. The high-risk groups, however, will need to be periodically evaluated for signs of progression.

Diagnostic Screening Panels: Sensitivity

This brings us full circle, back to this earlier slide on screening panels. You will recall that I said I wasn't concerned about missing 11.3 % of MGUS patients by using a screening panel that does not include serum or urine immunofixation. These MGUS patients are missed by the screening panel because they have a normal serum protein electrophoresis with no M spike and a normal free light chain ratio. They therefore have 0 or 1 adverse prognostic factor and are the lowest risk MGUS patients. We may, in reality, be doing a better job by not identifying their monoclonal gammopathy.

MGUS: Summary

In conclusion: We have talked about monoclonal gammopathy of undetermined significance. It is A laboratory abnormality There are no clinical symptoms It is very common in the older population It is premalignant for multiple myeloma And therapy of MGUS has not been shown to prolong survival There is no reason to screen for MGUS If MGUS is diagnosed, we should define the risk for progression

If the patient has a low-risk MGUS, the clinician should Document the abnormality for when symptoms might develop But there is no need to routinely monitor the M spike

Thank you for your attention.