Monoclonal gammopathy of undetermined significance (MGUS) is a condition caused by altered plasma cells. A plasma cell is a type of white blood cell that usually makes disease-fighting antibodies.

In MGUS, plasma cells in bone marrow make monoclonal proteins that circulate in the blood. These proteins also may be called M proteins, myeloma proteins or paraproteins. The amount of monoclonal protein is low in MGUS, and the plasma cell condition doesn't cause myeloma-related organ damage. Most people with MGUS don't get multiple myeloma.

MGUS is not cancer, but having MGUS raises the risk of getting cancer of the plasma cells and related conditions.

MGUS doesn't require treatment. With regular checkups and blood tests, your healthcare team looks for changes in M protein levels and signs of cancer or other diseases. If your healthcare team suspects that MGUS is getting worse, also called progressing, they may test whether the number of altered plasma cells has increased.

Types

Monoclonal gammopathy of undetermined significance (MGUS) has three main types. They differ in the type of monoclonal protein involved and in the conditions to which they are most likely to progress.

• Non-IgM MGUS. This is the most common type of MGUS. The M protein usually is immunoglobulin (Ig) G or IgA. If non-IgM MGUS progresses, it most often becomes multiple myeloma or, less commonly, amyloid light-chain (AL) amyloidosis.
• IgM MGUS. The M protein is IgM. If IgM MGUS progresses, it is more likely to become Waldenstrom macroglobulinemia, a type of lymphoma, than become multiple myeloma.
• Light-chain MGUS. Instead of making a whole antibody, the altered plasma cells make only part of an antibody, called a light chain. The light chain may be kappa or lambda. A blood test called a serum free light chain test helps find this type. If light-chain MGUS progresses, it can develop into light-chain multiple myeloma or amyloid light chain (AL) amyloidosis.

What do terms such as IgG kappa mean?

The name of an M protein may describe both its antibody type and its light chain:

• IgG, IgA and IgM describe the type of antibody.
• Kappa and lambda are the two types of light chains.
• IgG kappa, for example, means the M protein is an IgG antibody with a kappa light chain.

These terms describe the type of monoclonal protein found. They do not, by themselves, mean that you have cancer.

People with MGUS usually don't have symptoms. Most often, the condition is found with blood tests done for regular checkups or for diagnosing another condition.

Experts don't know exactly what causes MGUS. It begins when a group of plasma cells gets genetic changes and starts making copies of the same monoclonal protein. Researchers know that these changes help establish the altered group of plasma cells, but they don't know what triggers the changes in most people.

Factors such as age, family history, obesity and some environmental exposures are linked to MGUS. But having one or more risk factors doesn't mean that they caused MGUS. These factors are discussed in more detail below.

Factors that increase your risk of getting MGUS include:

• Age. MGUS becomes more common with age. About 3% of people older than 50 have MGUS compared with about 5% of people older than 70 and 9% of people older than 85.
• Race. Black people and people of African descent have a higher risk of MGUS than do other people. Some studies suggest that MGUS is less common in Asian American people than in non-Hispanic white people.
• Sex at birth. MGUS is more common in men.
• Family history. A family history of MGUS raises your risk.
• Weakened immune system. Having a weakened immune system is linked to a higher risk of MGUS.
• Chemical exposure. Exposure to toxic chemicals in the workplace or environment — such as pesticides, asbestos and fertilizers — may raise the risk of MGUS.
• Things you can change. Obesity and cigarette smoking have been linked to MGUS.

Each year, about 1% of people with MGUS get cancer of the plasma cells or related conditions. The risk varies from person to person. These conditions include the following:

• Multiple myeloma. This is cancer of the plasma cells in the bone marrow. It results in poor blood cell production, weakened bones and bone pain.
• Lymphomas. These are cancers that begin in the lymphatic system, which is part of the immune system. They develop when lymphocytes, a type of white blood cell, grow and multiply out of control. Some types of MGUS can become certain lymphomas.
• Waldenstrom macroglobulinemia. This is a type of lymphoma that can develop from IgM MGUS. The altered cells make an IgM M protein. This may cause thickened blood, bleeding, frequent infections, and a liver and spleen that are larger than usual.
• AL amyloidosis. This happens when light chains from M proteins build up as amyloid in tissues and organs. These amyloid proteins often build up in the heart, kidneys and nerves.

Monoclonal gammopathies of clinical significance

M proteins may cause disease in tissues and change how organs function. If this type of M protein-related condition develops, it's called monoclonal gammopathy of clinical significance. These conditions may affect the:

• Kidneys.
• Nervous system.
• Eyes.
• Skin.

Other complications

Other complications include:

• Osteoporosis and bone fractures. People with MGUS may have a higher risk of osteoporosis and bone fractures. Osteoporosis causes bones to become weaker and more likely to break.
• Risk of infections. MGUS raises the risk of viral and bacterial infections, especially infections of the nose, throat and lungs.
• Venous thromboembolism. MGUS also raises the risk of blood clots in veins. Clots can block the flow of blood. This condition is called venous thromboembolism.

MGUS is usually found with blood tests done for other conditions or for regular checkups. When M proteins are found, you have more tests so your care team can better understand the condition and see whether there are signs of cancer or other organ damage. These tests include:

• Blood tests. Lab tests of blood samples tell your healthcare team more about the M proteins in your body and can show signs of organ damage.
  • Serum protein electrophoresis (SPEP). SPEP looks for and measures M proteins. If an M protein is present, it may appear as an M spike. An M spike does not by itself mean that you have cancer.
  • Immunofixation. This identifies the type of M protein, such as IgG kappa. It also helps tell the difference between a monoclonal protein and a polyclonal pattern. A polyclonal pattern means several types of antibodies are increased. This can happen with inflammation or infection and is different from the monoclonal protein found in MGUS.
  • A serum free light chain test measures kappa and lambda light chains.
• Urine tests. Urine samples taken over 24 hours can help show M proteins and signs of kidney damage.
• Imaging tests. You may have imaging tests of the whole body to rule out damage to the bones or changes in the bone marrow.
• Bone marrow test. A hollow needle removes a piece of bone marrow from the back of one of the hip bones for study. This test usually is done only for those at risk of more-serious disease.
• Bone density test. You may have an X-ray test to measure the density of bone and look for signs of osteoporosis.

MGUS versus smoldering multiple myeloma

Test results also help your healthcare team confirm that you have MGUS rather than smoldering multiple myeloma (SMM) or active multiple myeloma.

SMM has more altered plasma cells in the bone marrow or more monoclonal protein than MGUS, but it does not cause the organ damage or other features of active multiple myeloma.

MGUS doesn't require treatment. Your care team schedules regular checkups to repeat blood and urine tests to look for any rise in M proteins. You may have more tests if a change in M proteins suggests a higher risk of cancer or other diseases.

Watchful waiting

You'll likely have a first follow-up exam about six months after being diagnosed with MGUS. Your healthcare team decides how often to repeat exams depending on the risk of MGUS leading to cancer or other diseases.

Talk with your healthcare professional if you have new symptoms. Symptoms to watch for include:

• Bone pain.
• Tiredness or weakness.
• Weight loss without trying.
• Fever with no known cause.
• Frequent infections.
• Tingling or numbness in legs or arms.
• Easy bruising or bleeding.
• Trouble breathing.
• Confusion or trouble thinking.

Medicines

If you get osteoporosis, your care team may prescribe a medicine called a bisphosphonate to slow the loss of bone tissue. Examples include alendronate (Binosto, Fosamax), risedronate (Actonel, Atelvia), zoledronic acid (Reclast, Zometa) and ibandronate.

Prognosis

Most people with MGUS do not get a blood cancer.

Your outlook depends in part on the type and amount of M protein and your serum free light chain test results. Studies report different long-term outcomes, so a single life expectancy number does not apply to everyone with MGUS.

Can MGUS go away on its own?

Sometimes the M protein associated with MGUS becomes undetectable, but this is not common. In a long-term study, the M protein became undetectable without a known cause in about 2% of people with MGUS. This was more common when the M protein level was very low at diagnosis.

Your healthcare professional may refer you to a doctor who specializes in blood conditions, called a hematologist.

Here's information to help you get ready for your appointment.

What you can do

Ask a family member or friend to go with you. Someone who's with you can help you remember the information you get.

Make a list of:

• Your symptoms and when they began. Include symptoms that don't seem linked to the reason you made the appointment.
• Key information, including other illnesses you or people in your family have had.
• All medicines, vitamins and supplements you take, including the doses and the reasons for taking them.

Questions to ask your doctor

For MGUS, basic questions to ask your health professional include:

• What tests do I need?
• Do I need to do something to get ready for tests?
• How often do I need to come back?
• Should I start treatment or change my lifestyle?
• I have other health conditions. How can I best manage them together?

Be sure to ask all the questions you have.

What to expect from your doctor

Your healthcare professional is likely to ask you questions, including:

• Do your hands or feet tingle or feel numb?
• Have you had broken bones?
• Have you had a diagnosis of osteoporosis?
• Has someone in your family had MGUS or cancer of the blood?
• Have you ever had a blood clot?