Macroglobulinemia (Waldenström's macroglobulinemia) is a plasma cell cancer in which a single clone of plasma cells produces excessive amounts of a certain type of large antibody (IgM) called macroglobulins.

• Although many people have no symptoms, some people have abnormal bleeding, recurring bacterial infections, and bone fractures from severe osteoporosis.
• Blood tests are needed to make the diagnosis.
• Macroglobulinemia is not curable, but progression can be slowed with chemotherapy drugs.

Men are affected by macroglobulinemia more often than women, and the average age at which the disorder appears is 65 years. Its cause is unknown.

Symptoms and Complications

Many people who have macroglobulinemia have no symptoms, and the disorder is discovered by chance when an elevated level of blood proteins is found during routine blood tests. Others have symptoms resulting from interference with blood flow to the skin, fingers, toes, nose, and brain that occurs when the large quantity of macroglobulins thickens the blood (hyperviscosity syndrome). These symptoms include bleeding from the skin and mucous membranes (such as the lining of the mouth, nose, and digestive tract), fatigue, weakness, headache, confusion, dizziness, and even coma. The thickened blood also may aggravate heart conditions and cause increased pressure in the brain. Tiny blood vessels in the back of the eyes can become filled with blood and may bleed, resulting in damage to the retina and impaired eyesight.

People who have macroglobulinemia may also have swollen lymph nodes and an enlarged liver and spleen due to infiltration by cancerous plasma cells. Recurring bacterial infections resulting from inadequate production of normal antibodies may cause fever and chills. Anemia, which may result in weakness and fatigue, occurs when cancerous plasma cells prevent normal blood-forming cells in the bone marrow from being produced. Infiltration of bones by cancerous plasma cells may cause loss of bone density (osteoporosis), which can weaken bones and increase the risk of fractures.

Some people develop a condition called cryoglobulinemia. Cryoglobulinemia involves the development of antibodies that clog up the blood vessels in cold temperatures.

What Is Cryoglobulinemia?
Cryoglobulins are abnormal antibodies produced by plasma cells and dissolved in the blood. When cooled below normal body temperature, cryoglobulins form large collections of solid particles (precipitates). When warmed to normal body temperature, they re-dissolve. The formation of cryoglobulins (cryoglobulinemia) is uncommon. In most instances, people who form cryoglobulins have an underlying disorder as the cause. These disorders include cancers such as macroglobulinemia and chronic lymphocytic leukemia, autoimmune disorders such as systemic lupus erythematosus (lupus), and infections by such organisms as hepatitis C virus. Rarely, a cause for the formation of cryoglobulins cannot be found. Precipitates of cryoglobulins can trigger inflammation of blood vessels (vasculitis), which causes various symptoms, such as bruises, joint aches, and weakness. People with cryoglobulinemia may also be very sensitive to cold or develop Raynaud's syndrome, in which the hands and feet become very painful and turn white when chilled. The vasculitis may damage the liver and kidneys. Damage may progress to liver failure and kidney failure in some people and can be fatal. Avoiding cold temperatures helps prevent vasculitis. Treating the underlying disorder may reduce the formation of cryoglobulins. For example, using interferon alpha to treat hepatitis C virus infection helps to reduce formation of cryoglobulins. Plasmapheresis may help, especially when combined with interferon.

Diagnosis

Blood tests are done when macroglobulinemia is suspected. The three most useful tests are serum protein electrophoresis, measurement of immunoglobulins, and immunoelectrophoresis.

Doctors may do other laboratory tests as well. For example, doctors may check a blood sample to determine if the numbers of red and white blood cells and platelets are normal. In addition, serum viscosity, which is a test to check the thickness of the blood, is often done. Blood clotting test results may be abnormal, and other tests may detect cryoglobulins. An examination of a urine sample may show Bence Jones proteins (pieces of abnormal antibodies). A bone marrow biopsy may reveal an increased number of lymphocytes and plasma cells, which helps confirm the diagnosis of macroglobulinemia, and the appearance of these cells helps differentiate this disorder from multiple myeloma.

X-rays may show a loss of bone density (osteoporosis). Computed tomography (CT) may reveal an enlarged spleen, liver, or lymph nodes.

Treatment and Prognosis

Although chemotherapy, usually with chlorambucilSome Trade Names
LEUKERAN
or fludarabineSome Trade Names
FLUDARA
, can slow the growth of abnormal plasma cells, the disorder remains incurable. Other drugs, such as melphalanSome Trade Names
ALKERAN
or cyclophosphamideSome Trade Names
LYOPHILIZED CYTOXAN
, are sometimes used, alone or in combination. Drugs that work differently from the chemotherapy drugs may be helpful. The monoclonal antibody rituximabSome Trade Names
RITUXAN
is effective at slowing the growth of the abnormal plasma cells. ThalidomideSome Trade Names
THALOMID
and the newer drugs lenalidomideSome Trade Names
REVLIMID
and bortezomibSome Trade Names
VELCADE
, are being used with some success, especially when they are used with corticosteroids.

A person whose blood is thickened must be treated promptly with plasmapheresis, a procedure in which blood is withdrawn, the abnormal antibodies are removed from it, and the red blood cells are returned to the person (see Controlling Diseases by Purifying the Blood). However, only a small number of people with macroglobulinemia require this procedure.

The disease remains incurable, but most patients survive more than 5 years.

Last full review/revision July 2008 by James R. Berenson, MD