Benign monoclonal gammopathy (monoclonal gammopathy of unknown significance)

I. What every physician needs to know.

Benign monoclonal gammopathy is an abnormal clonal disorder of plasma cells. Also known as monoclonal gammopathy of unknown significance (MGUS), benign monoclonal gammopathy is, by definition, an asymptomatic condition. If a patient has symptoms that are thought related to this disorder (see history and exam below), it can no longer be considered a benign finding.

However, benign monoclonal gammopathy (from here forward referred to as MGUS) is also a pre-malignant condition in that patients with this condition will progress to multiple myeloma or another malignancy at a rate of approximately 1% per year. It is called a “benign” disorder or a disorder with “unknown significance” because the vast majority of patients with the diagnosis will not develop a malignancy. Therefore, it is important to identify which patients are at higher risk of progression to a malignancy.

The approach to MGUS is focused on two key points: ruling out another syndrome associated with a monoclonal gammopathy and assessing the risk of progression to a malignant disorder.

First, by ruling out organ involvement or associated symptoms, the clinician can establish the diagnosis (i.e. a symptomatic patient with MGUS either has symptoms from another disorder or does not have MGUS).

Second, once the diagnosis of MGUS is established, the clinician needs to consider the risk of progression to a malignant condition to provide the patient with appropriate prognostic information and formulate an appropriate follow-up plan.

II. Diagnostic Confirmation: Are you sure your patient has benign monoclonal gammopathy?

MGUS is an asymptomatic disorder. To make the diagnosis, the clinician must establish two key findings:

A monoclonal gammopathy seen on serum protein electrophoresis (or serum immunofixation)
Absence of symptoms related to the monoclonal gammopathy

Since MGUS most often progresses to multiple myeloma, the clinician must rule out symptoms/signs that are attributable to myeloma or related disorders (see below).

A. History Part I: Pattern Recognition:

While MGUS is, by definition, an asymptomatic condition, there are often clues that lead to this diagnosis.

Patients typically have abnormalities that are incidentally noted on either routine lab tests or labs ordered for alternate purposes as there is no established role for screening for the disorder.

There are several “footprints” of the disorder that may be found incidentally: low anion gap, elevated globulin gap or rouleaux formation of red cells on a blood smear.

Because some immunoglobulins (Igs) are cationic, a clone of plasma cells that makes excess cationic immunoglobulin (Ig) can cause a low serum anion gap. A low anion gap can also be due to hypoalbuminemia or laboratory error.

Similarly, because Igs are measured as part of the serum total protein, the globulin gap (total protein minus albumin) can be elevated above 4 g/dL in patients with a monoclonal gammopathy. An elevated globulin gap is also seen commonly in polyclonal gammopathy due to an excess on immunoglobulins that are non-clonal.

Peripheral smear can often reveal rouleaux formation, which is a non-specific indicator of excess protein in the serum.

Rarely, depending on the type of lab assay used, high levels of Ig can interfere with measurement of high-density lipoprotein (HDL) or bilirubin (leading to a falsely low HDL or falsely high total bilirubin).

B. History Part 2: Prevalence:

MGUS is a disease of patients of advanced age. Prior studies have found a low incidence of the disease before age 50, but the incidence progressively increases with each decade of life.

As a rough rule, it is seen in 3% of 50 year olds, 5% of 70 year olds and 7% of 90 year olds.

It is slightly more prevalent among African-American patients, as compared to Caucasian patients, and more common in patients with a diagnosis of obesity.

It is more common in men than women and there is a slight increase in incidence with pesticide or prior radiation exposure.

Despite other known risk factors, the most important risk factor for developing MGUS is advanced age.

C. History Part 3: Competing diagnoses that can mimic benign monoclonal gammopathy.

MGUS must be distinguished clinically from other disorders that feature a monoclonal gammopathy.

Multiple myeloma is a related disorder with a monoclonal gammopathy. The symptoms of myeloma can be remembered by the mnemonic CRAB (hyperCalcemia, Renal insufficiency, Anemia, Bone lesions). If any of these features are present, a work-up for myeloma must be undertaken. See “Myeloma” for further details on evaluation.

Amyloid light-chain (AL) amyloidosis is another disorder with a monoclonal gammopathy. It can also cause renal insufficiency, but other clinical features include macroglossia and restrictive cardiomyopathy. Historical features of congestive heart failure (CHF) or nephrotic syndrome would lead to a higher index of suspicion for amyloidosis.

POEMS syndrome is a rare disorder – seen most often in patients with a subtype of multiple myeloma or Castleman’s disease – that is associated with a monocloncal gammopathy.

POEMS is an acronym for the key features of the disease -Polyneuropathy (such as chronic inflammatory demyelinating polyneuropathy), organomegaly (hepatosplenomegaly or less often lymphadenopathy), endocrinopathies (such as hypothyroidism or hypogonadism), monoclonal gammopathy, and non-specific skin changes (such as hyperpigmentation or hypertrichosis).

POEMS is often recognized clinically by this complex set of symptoms, but notably the majority of patients do not have all of the features listed above.

Castleman’s disease is a lymphoproliferative disorder that may be accompanied by a monoclonal gammopathy. This disease is much more common in HIV positive patients and presents typically with regional lymphadenopathy.

Some types of non-Hodgkin lymphoma also may have a monoclonal gammopathy.

Waldenstrom macroglobulinemia (WM) is a disorder characterized by lymphoplasmacytic lymphoma in the bone marrow and a serum monoclonal gammopathy with IgM. WM is an indolent, slow-growing lymphoma, which can share symptoms with other lymphomas such as fever, chills and weight loss. Patients may also have hepatosplenomegaly or excessive bleeding/bruising. A hallmark feature of WM is the hyperviscosity syndrome, often with neurologic complications of the hyperviscosity such as stroke-like symptoms (visual changes, ataxia, vertigo).

Lastly, there are other rare conditions associated with a monoclonal gammopathy, such as chronic inflammatory demyelinating polyneuropathy (CIDP) (without POEMS syndrome), capillary leak syndrome and other types of lymphoma. These conditions are not discussed in detail here.

D. Physical Examination Findings.

By definition, MGUS is an asymptomatic disorder. As such, there are no physical exam findings that typify the disorder.

However, on exam, the clinician should look for features of related disorders that would point to an alternate diagnosis (such as myeloma).

On head, ears, eyes, nose and throat (HEENT) exam, look for macroglossia (seen in AL amyloidosis) or conjunctival pallor (anemia associated with multiple myeloma).
On cardiac exam, look for elevated neck veins or a S3 (symptoms of cardiomyopathy which can be seen with AL amyloidosis).
On abdominal exam, look for organomegaly (sometimes seen in POEMS syndrome or WM).
On skin exam, look for a rash (sometimes seen in POEMS syndrome).
On neurologic exam, look for symmetric peripheral neuropathy (sometimes seen in POEMS or CIDP). Diplopia or ataxia can be features of WM.
On musculoskeletal exam, look for bone pain, often in the vertebral spine (seen in multiple myeloma).
On lymphatic exam, look for lymphadenopathy that may suggest an underlying lymphoma, POEMS syndrome or Castleman’s disease.

E. What diagnostic tests should be performed?

For lab testing, the patient should have a complete blood count (CBC) and basic chemistries checked. A serum protein electrophoresis, serum immunofixation and serum free light chain ratio should then be ordered.

For diagnostic studies, a skeletal survey should be ordered when there is a high suspicion for multiple myeloma (rather than MGUS).

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Basic labs should be done to look for anemia, elevated creatinine or hypercalcemia (all commonly seen with myeloma).

The core work-up for MGUS consists of three tests: serum protein electrophoresis (SPEP), serum immunofixation (SIF) and serum free light chain ratio (SFLC ratio), which is also sometimes called Ig free light chain ratio.

Further lab tests include a urine protein electrophoresis (UPEP), quantitative Igs and sometimes a bone marrow biopsy.

A serum protein electrophoresis is the first step in the work-up when any of the clues (see pattern recognition) are found.

A SPEP will distinguish a monoclonal from a polyclonal disorder. If a polyclonal gammopathy is found (and other tests are negative below), the work-up for MGUS, myeloma, AL amyloidosis and other related disorders is essentially complete. A polyclonal gammopathy may be a normal immune response to an underlying infection or inflammatory condition.

However, once a monoclonal spike (M spike) is identified on SPEP, a SIF helps determine what type of excess protein is being produced. The results of the SIF will show IgG, IgM, IgD, or IgA and in most cases, will show an Ig that either expresses light chain kappa or lambda. In some cases of MGUS and related disorders, a SPEP will be normal but the SIF will show a clonal population. In other words, a SPEP plus SIF is more sensitive than a SPEP alone to detect MGUS or multiple myeloma.

A SFLC ratio is a test that compares the quantity of subtypes of unbound light chains in the serum. Under normal conditions, the body makes a constant ratio of kappa and lambda, which is close to two to one. In most cases of multiple myeloma, the Ig produced by the malignant clone is either restricted to kappa light chain or lambda light chain. Because either kappa or lambda can be produced in excess, a SFLC ratio can be abnormal by either being very high or very low.

A common pitfall in interpreting the SFLC ratio is when the results of total kappa and total lambda are both high or both low. Since the test is a ratio of kappa to lambda, both levels being high do not suggest a monoclonal gammopathy. This could be seen in polyclonal gammopathy, where more of all types of light chain are being produced. Similarly, kappa and lambda can both be low – e.g., in patients with primary or secondary hypogammaglobulinemia – but but as long as the ratio is within the normal range, a monoclonal gammopathy should not be suspected.

UPEP was part of the myeloma work-up in the past, but this test has been largely replaced by the SFLC ratio as a means of increasing the sensitivity of the SPEP/SIF for detection of multiple myeloma.

Quantitative Igs are also part of the lab work-up. Ig levels are useful for distinguishing myeloma from MGUS, in that, for a minority of cases of multiple myeloma, there will not be an abnormal SPEP or immunofixation, but the patient will have lower levels of Ig.

The SPEP, SIF and SFLC ratio are the cornerstones of the diagnostic work-up.

SPEP will detect a monoclonal gammopathy, if present, in most cases. SIF and SFLC increase the sensitivity for detecting an abnormal clonal protein.

Consequently, if the diagnosis of myeloma is suggested by other clinical features all three tests should be ordered rather than just an SPEP.

As noted above, UPEP and quantitative Igs are sometimes useful in the diagnosis, but these tests should be considered as a secondary screen once the first three tests are ordered and interpreted. These tests may also be useful in follow up of a patient with diagnosed multiple myeloma (not MGUS).

A bone marrow biopsy is a final lab test that is sometimes, but not universally, used to help in distinguishing multiple myeloma from MGUS. By definition, the percentage of clonal plasma cells in the bone marrow is less than 10% in MGUS and greater than 10% in multiple myeloma. If a patient has greater than 10% of clonal plasma cells in the bone marrow, but no other symptoms found by history, exam or other lab tests, they are said to have “smoldering” multiple myeloma. These patients will progress to multiple myeloma over months to years and need very close follow up.

Therefore, MGUS is defined by finding a monoclonal gammopathy either on SPEP or SIF, no evidence of end-organ damage from the monoclonal gammopathy (such as anemia or renal failure) and less than 10% of clonal plasma cells in the bone marrow. The specific results of the SPEP, SIF and SFLC ratio have some prognostic information for the diagnosis of MGUS (see below).

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

A skeletal survey is useful to rule out lytic bone lesions. Even if a patient with a monoclonal gammopathy has no focal bony pain, a skeletal survey is still recommended to screen for lytic lesions. If lytic lesions are seen, one must immediately consider the diagnosis of multiple myeloma rather than MGUS.

One pitfall to consider in evaluating the skeletal survey is that not all lytic lesions are due to multiple myeloma. Patients can have lytic lesions from breast cancer or other malignancies. Just as patients with MGUS can have abnormalities such as anemia due to iron deficiency (rather than due to multiple myeloma), patients with MGUS can have lytic lesions due to an unrelated malignancy.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Beta 2 microglobulin is a test that has prognostic significance in multiple myeloma. It is not needed to establish the diagnosis of MGUS, but if myeloma is highly suspected, it is useful for overall prognosis. This lab test need not be ordered to establish the diagnosis of MGUS.

As discussed above, a UPEP has been replaced by the SFLC ratio as part of the work-up for multiple myeloma. If a SFLC ratio is not available, a UPEP can be ordered (preferably a 24 hour urine collection). If a SFLC ratio is available, usually a UPEP is not necessary.

A common area of confusion is ordering a bone scan instead of a skeletal survey. A bone scan is much less sensitive than plain x-rays in the evaluation for lytic lesions and is not a routine part of the work-up.

Magnetic resonance imaging (MRI) or PET CT are useful in selected cases to evaluate for small lytic lesions (for example in a patient with suspected myeloma and low back pain), but often the work-up is adequate without this test.

III. Default Management.

Because MGUS is asymptomatic, the management required is simply to rule out associated disorders and to provide prognostic information.

Because MGUS will progress to multiple myeloma or another malignancy at a rate of 1% per year, most patients require follow up every 6-12 months. For patients with a non-IgG monoclonal protein (such as IgA or IgD) or a very high quantity of M spike on SPEP, the rate of progression is higher such that closer follow up is usually required.

A. Immediate management.

None

B. Physical Examination Tips to Guide Management.

None

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

The lab tests that are helpful in the management of MGUS are the same three tests that are helpful for diagnosis: SPEP, SIF and SFLC ratio. Of note, none of these tests require repeating or following routinely during a hospitalization.

The higher the M spike on SPEP, the higher the risk of progression to myeloma. A basic cut point is if patients have a M spike greater than 1.5 g/dL, they have a higher risk of progression.

The type of Ig seen on immunofixation also dictates the risk of progression to myeloma. IgG MGUS follows a more benign course than IgM, IgD, or IgA MGUS.

Lastly, if the free light chain ratio is abnormal, patients need closer follow-up, as the risk of progression to myeloma is higher.

Patients with MGUS and a M spike greater than 1.5, a SIF showing a M spike due to IgA or IgM, or an abnormal free light chain ratio require clinic follow-up within a couple of months to monitor for disease progression. These patients will also likely require a bone marrow biopsy after consultation with a hematologist.

D. Long-term management.

No long-term management is required beyond repeating the diagnostic work-up as well as screening for symptoms of related disorders with a monoclonal gammopathy.

E. Common Pitfalls and Side-Effects of Management

A common pitfall in management includes immediately considering the diagnosis of myeloma in a patient with monoclonal gammopathy and anemia or renal insufficiency. Patients with a monoclonal gammopathy can, of course, have anemia due to iron deficiency and renal insufficiency due to pre-renal azotemia.

Consequently, in the work-up, the provider should manage acute kidney injury and the approach to anemia as with any other patient and not immediately attribute anemia to bone marrow involvement of myeloma or kidney disease to cast nephropathy.

Similarly, as mentioned above, even seemingly more specific findings such as lytic bone lesions can be seen in diseases other than multiple myeloma.

IV. Management with Co-Morbidities

N/A

A. Renal Insufficiency.

Renal insufficiency does not affect the management of MGUS but may affect the diagnostic workup. Specifically, the free light chain ratio may be slightly altered by reduced renal clearance of light chains. Consequently, the interpretation of an abnormal free light chain ratio may be different if the patient has underlying renal insufficiency. That said, a very abnormal SFLC ratio cannot be attributed to renal insufficiency.