Monoclonal Gammopathy of Undetermined Significance (MGUS) [Hot Topic]

Willrich
Maria Willrich, Ph.D.

Monoclonal gammopathy of undetermined significance (MGUS) is a laboratory finding. This diagnosis is very common in older patients, but can cause significant concern about which patients require close monitoring and which do not. In this presentation, Maria Willrich, Ph.D., provides an overview of the testing involved in both the diagnosis and monitoring of patients with MGUS.

Presenters and Credentials:
Maria Willrich, Ph.D., Assistant Professor of Laboratory Medicine and Pathology and Consultant in the Protein Immunology Laboratory at Mayo Clinic in Rochester, Minnesota

 

Transcript

Our speaker for this program is Dr. Maria Willrich, an Assistant Professor of Laboratory Medicine and Pathology at Mayo Clinic, as well as a consultant in the Protein Immunology Laboratory at Mayo Clinic in Rochester, Minnesota. Dr. Willrich provides an overview of advances in the testing available to diagnose and monitor multiple myeloma and monoclonal gammopathy of undetermined significance. Thank you Dr. Willrich for presenting with us today.Welcome to Mayo Medical Laboratories Hot Topics. These presentations provide short discussion of current topics and may be helpful to you in your practice.

Thank you for that introduction.

We will talk about monoclonal gammopathies of undetermined significance – sometimes referred to as “mugus.” 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.

I would like to thank  Dr. Jerry Katzmann who had an earlier version of this for Hot Topic for his contributions.

Disclosure

I have no conflicts of interest to disclose.

Utilization Message

As you view this presentation, consider the following important points regarding testing:

  • What is the definition of MGUS?
  • How is the finding of MGUS dealt with in your practice?
  • How will results impact patient management?

Multiple Myeloma

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 immunofluorescent micrograph in the center of the slide has been stained with fluorescent antibodies to kappa light chain and illustrates that the plasma cells are not a polyclonal population with both kappa 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 usually enters the systemic circulation. High concentrations of the secreted monoclonal immunoglobulins may cause the renal disease that is often seen in these patients.

The bone scan on the bottom of the slide illustrates areas within the skull 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.

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 1 of the oldest 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 Proteins: 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.

In a retrospective analysis of the cases in the laboratory done in 2008, myeloma represents 17% of the cases seen in the Mayo Rochester practice. MGUS was by far the most common diagnosis with 56% of all cases. MGUS is followed by myeloma, then amyloidosis, B-cell lymphoproliferative disease, smoldering myeloma, solitary and extramedullary plasmacytoma, and macroglobulinemia. The “other” category includes 12 rarer diseases such as POEMS, plasma cell leukemia, light chain deposition disease, and MGUS-associated cryoglobulinemia.

When we look 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

This slide shows the diagnostic sensitivity of various screening panels. The traditional panel was based on serum and urine tests and, as you can see on the first row of this table, 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 amyloidosis is suspected. So the second row contains no urine assays. In the last row, a screening panel of serum protein electrophoresis and free light chains 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 89%, but that is not too concerning at this point, and we will discuss why during this presentation. In order to better understand the sensitivities for each monoclonal gammopathy, we will discuss the 3 main categories, including MGUS.

Monoclonal Gammopahies: Plasma Cell Proliferative Diseases

This slide groups Plasma Cell Proliferative Diseases into 3 categories.

The malignant diseases, such as multiple myeloma, Waldenström 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, for instance.

The third group of patients with “no symptoms” are considered premalignant and both MGUS and smoldering myeloma are in this category. MGUS does not require treatment.

Plasma Cell Proliferative Diseases: MGUS, SMM, MM

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

By definition, MGUS must have less than10% bone marrow plasma cells and less than 3 g/dL serum M spike and, importantly, must be asymptomatic with no hypercalcemia, renal damage, anemia, or bone lesions, defined as the acronym CRAB.

Smoldering myeloma differs from MGUS in that there are more than 10% bone marrow plasma cells or an M spike less than 3 g/dL. Again, there are no CRAB symptoms. Patients with MGUS and smoldering myeloma are asymptomatic. MGUS patients are observed and followed-up every 6 to 12 months, and do not require treatment. Patients with smoldering mulitple meyeloma are also traditionally not treated; however, that concept has recently changed and will be discussed later in this presentation.

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

Prevalence of MGUS in Olmsted County, MN

First of all, 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 subjects greater than ages greater than 80 years of age. Monoclonal gammopathies are relatively uncommon in young people and the prevalence increases as we age.

So one may wonder however: if MGUS and smoldering myeloma have no symptoms why are we concerned with them?

Probability of Progression: MGUS

This slide lists the probability of MGUS progressing to multiple myeloma and related diseases. This is a study of 1,384 patients monitored for up to 25 years. The progression rate is approximately 1% per year and it does not change over time.

Probability of Progression: SMM

For smoldering multiple myeloma, on the other hand, is considered an intermediate stage between MGUS and symptomatic multiple myeloma. Patients diagnosed with smoldering myeloma have higher risk of progression to multiple myeloma at:

    • about 10% per year in the first 5 years of diagnosis (10),
    • 3% in the next 5 years and
    • 1% per year for the next 15 years.

It may represent almost 14% of all patients with myeloma.(11)

Smoldering myeloma is considered a heterogeneous condition composed of patients with multiple myeloma who have not yet manifested clinical symptoms, as well as patients with MGUS-like stable disease.

It is because of these progression risk estimates that MGUS and smoldering myeloma are called premalignant disorders.

Updated Myeloma Definition Criteria

Because smoldering multiple myeloma high-risk patients progress very quickly to myeloma, and differently than a decade ago, there may be therapeutic options available today that can prolong survival of these patients. The international myeloma working group developed an updated criteria to define multiple myeloma requiring treatment, published in November of 2014. International Myeloma Working Group aimed for a biomarker-based definition that can identify the subset of patients who are at imminent risk of disease progression. If a patient has biomarkers associated with 80% probability of progression within 2 years, even in the absence of symptoms, the diagnosis should be multiple myeloma. Waiting for end-organ damage to occur before initiating treatment seemed unreasonable as therapies may now increase survival.

Plasma Cell Proliferative Diseases: MGUS, SMM, MM

On this slide what is in italics is the updated criteria for multiple myeloma, therefore, the definition of “symptomatic multiple myeloma” no longer applies. Myeloma is now a biomarker-defined condition to reflect a disease that requires treatment. The presence of 1 of these biomarkers is enough to define myeloma:

  • Greater than 60% bone marrow plasma cells
  • Involved free light chain ratio greater than 100
  • Or the presence of CRAB symptoms: hypercalcemia, renal damage, anemia, and bone lesions

Myeloma Defining Events by CRAB

End-organ damage has been defined by the acronym CRAB. The definition of hypercalcemia, renal damage, anemia, and bone lesions is shown here. CRAB has been defined as, C for Hypercalcemia and Serum calcium greater than1 mg/dL higher than the upper limit of the reference interval using photometric method established. And R stands for Renal Damage and it is defined as measured or estimated glomerular filtration rate (GFR) calculated with MDRD or CKD-EPI equations less than 40 mL/min. A stands for Anemia and that’s defined as hemoglobin greater than 2 g/dL below the lower limit of the age/gender reference interval, or an absolute hemoglobin value below 10 g/dL. B stands for Bone lesions, defined as osteoporosis with compression fractures attributable to a clonal plasma cell disorder or clear evidence of 1 or more osteolytic bone lesions (greater than or equal to 5mm in size).

New Biomarkers of Malignancy

The new biomarkers of malignancy published on the recent myeloma definition update are shown on this slide. One of more of the following biomarkers is sufficient to place an individual in the myeloma requiring treatment category. One of the criteria is greater than 60% plasma cells on bone marrow, measured by conventional bone marrow aspirate or biopsy. Second having an involved free light chain ratio greater than 100 and that is using nephelometry measurement of kappa and lambda light chains. Minimum concentration of involved light chain (kappa or lambda) should be greater than or equal to 10 mg/dL. It is the first time the nephelometric measurement of free light chains is included in the diagnostic criteria. Three having more than 1 skeletal focal lesion measured by magnetic resonance imaging is preferred.

Summary: Monoclonal Gammpathy Undetermined Significance (MGUS)

While the myeloma definition has changed, the definition of MGUS has not changed and is summarized as:

  • MGUS is a laboratory abnormality
  • MGUS patients have no clinical symptoms due to their monoclonal gammopathy
  • MGUS is very common in older populations
  • 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?”

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 light-chain MGUS with no monoclonal heavy chain. So virtually, all myelomas come from a preceding MGUS.

In addition, of the 3 myeloma patients in whom no preceding MGUS was detected, 2 of them were IgD myelomas  and IgD is not secreted in large amounts.

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 0.5 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.

Furthermore, 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 greater than or less than 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 less than1.5 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% 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, and
  • If MGUS is diagnosed, we should define the risk of 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.

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