MGUS (monoclonal gammopathy of undetermined significance)

Plasma cells are white blood cells in the bone marrow that make antibodies to fight infection. In MGUS, one small group of plasma cells makes copies of the same antibody. This abnormal protein is called M protein (monoclonal protein) or paraprotein. It is often found by chance, on a blood test done for another reason.

The name means the protein is there, but its meaning is not yet clear. The National Cancer Institute (NCI) says MGUS is not cancer but can become cancer. In MGUS, abnormal plasma cells make up less than 10% of the bone marrow. There is no myeloma, related lymphoma, amyloidosis or organ damage. In most people, the amount of M protein stays the same and causes no symptoms or health problems.

There are three main types, named for the kind of protein. Non-IgM MGUS makes an IgG, IgA or, rarely, IgD protein. IgM MGUS is linked with Waldenström macroglobulinemia. Light-chain MGUS makes only one part of an antibody, the light chain. Each type carries a different chance of change over time.

MGUS starts when genes change inside one plasma cell during a person’s life. Many of the chromosome changes found in myeloma can also be found in MGUS, but less often. Studies have not found some changes seen in myeloma, such as TP53 changes, in MGUS. The exact cause is not known. Researchers think both genes and surroundings play a part.

MGUS becomes more common with age. In one large Minnesota study, it was found in about 3 in 100 people aged 50 or older and about 5 in 100 aged 70 or older. It is more common in men than in women, and two to three times as common in Black people as in White people. It is rare before age 40.

MGUS can cluster in families. A Mayo Clinic study tested parents, brothers, sisters and children (aged over 40) of people with myeloma or MGUS. They were about 2.6 times as likely to have MGUS as people in the general population. The authors say this points to shared genes, shared surroundings or both.

By definition, MGUS does not cause symptoms, and for most people it never causes health problems. It is usually found when a doctor tests the blood while looking into something else, such as nerve, kidney, bone or blood count problems.

The main concern is what MGUS can turn into. In large population studies, the NCI says, the yearly chance of MGUS turning into a blood cancer is 0.5% to 1%. It is higher in people with risk factors. It most often becomes multiple myeloma. It can also become AL amyloidosis, Waldenström macroglobulinemia (lymphoplasmacytic lymphoma) or chronic lymphocytic leukemia.

Three findings raise the chance of change. They are an abnormal free light chain ratio in the blood, a type other than IgG, and an M protein level of 1.5 g/dL or more. Rarely, a small clone harms the kidneys, nerves or heart even though it is not a cancer. When it harms the kidneys, doctors call it monoclonal gammopathy of renal significance. That is treated, not just watched.

MGUS is usually found by chance. A blood test done for another reason, often to look into nerve, kidney, bone or blood count problems, shows an M protein. Screening healthy people for MGUS is not recommended, because finding it early has not been shown to help.

Next, blood tests measure the amount and type of M protein (serum protein electrophoresis and immunofixation) and the free light chains. A blood count, calcium and a kidney test check for any harm to the body. Some people also have urine tests.

MGUS is diagnosed when three things are all true. The M protein is under 3 g/dL. Abnormal plasma cells make up less than 10% of the marrow. And the plasma cells have caused no organ damage, such as high calcium, kidney problems, anemia or bone damage. For low-risk MGUS with no warning signs, a bone marrow biopsy and a full set of bone x-rays (skeletal survey) can often be skipped.

MGUS is not treated. The NCI lists watchful waiting as the treatment option. This means regular blood tests to check the M protein level, and check-ups for any sign of change. Treatment starts only if MGUS turns into a condition that needs it.

Starting cancer medicines early does not help. The NCI says people with MGUS or smoldering myeloma do not respond better, stay in remission longer or live longer when chemotherapy starts before symptoms. Newer medicines have not been proven to prevent or delay MGUS from progressing.

How often tests are repeated depends on risk, and guidelines differ. The International Myeloma Working Group suggests a repeat check about 6 months after diagnosis. If results are stable, people at low risk may then be checked every 2 to 3 years, and people at higher risk about once a year. For low-risk MGUS with no warning signs, a bone marrow test and a full set of bone x-rays (skeletal survey) can often be skipped.

Life with MGUS usually means living as before, with blood tests from time to time. Tests often include a blood count, the M protein level (serum protein electrophoresis), free light chains, calcium and a kidney test (creatinine).

Being told about a condition that could, rarely, turn into cancer can be unsettling. Myeloma Australia says people with MGUS are often most anxious when first diagnosed and while waiting for test results. It also notes that most people with MGUS never develop a serious health condition.

Myeloma Australia asks people to report new symptoms right away, not wait for the next test. Warning signs include a broken bone after little or no injury and unexplained pain, especially in the back or ribs. Others are unexplained bruising or bleeding, feeling tired or breathless, and numbness or tingling in the hands or feet. Losing weight without trying and frequent infections are also signs to report.

MGUS itself is not treated with a stem cell transplant, and no donor is involved. European transplant experts (EBMT) do not list it as a reason for a transplant. NMDP names multiple myeloma, AL amyloidosis and POEMS syndrome as the three main plasma-cell disorders for which a transplant may be indicated.

If MGUS turns into multiple myeloma, a transplant may become part of treatment for some people. That transplant most often uses the person’s own stem cells, collected ahead of time (an autologous transplant). NMDP says a donor (allogeneic) transplant for myeloma is generally kept for people with high-risk disease.

Most people with MGUS never develop a condition that needs a transplant or a donor.

Most people with MGUS never develop myeloma or a related disease. Across large population studies, the yearly chance of progression to a blood cancer is about 0.5% to 1%. It is higher for people with an abnormal free light chain ratio, a type other than IgG, or an M protein of 1.5 g/dL or more.

The chance does not go away over time, which is why check-ups continue. A Minnesota study followed people diagnosed in 1960–1994 for a median of 34 years. The risk of progression stayed at about 1% a year. People with MGUS lived less long on average than other Minnesotans of the same age and sex: 8.1 years compared with 12.4 years (median survival, deaths from all causes). The authors say far more people died of other causes than of MGUS turning into myeloma or a related disorder.