What is Waldenstrom macroglobulinemia?

Waldenstrom macroglobulinemia (WM) is an uncommon form of non-Hodgkin lymphoma (NHL). It is a very rare lymphoma, accounting for about 1 to 2% of all blood cancers. Doctors diagnose about 1,000 to 1,500 cases each year in the United States.

Waldenstrom macroglobulinemia and other forms of non-Hodgkin lymphoma (NHL) affect a type of white blood cell called a lymphocyte. One way doctors classify NHL is by the type of lymphocyte involved—either T-cells or B-cells. WM is a B-cell cancer, which makes it a B-cell lymphoproliferative disease.

B-cells are important immune system cells. Normally, B-cells mature into cells called plasma cells when they encounter a foreign invader, such as bacteria or viruses. Plasma cells then produce antibodies that attach to these germs. WM cells are similar to both B-cells and the mature plasma cells they become. Because of this, another name for WM is lymphoplasmacytic lymphoma.

WM cells produce abnormal amounts of a specific antibody, called IgM (immunoglobulin M) or macroglobulin. Since antibodies are proteins, doctors call the abnormal antibody in WM “M protein.” As WM cells grow out of control, they make more and more M protein. When M protein accumulates in the body, it causes the blood to thicken and can damage organs, such as the eyes and kidneys. WM cells can also crowd out normal cells in the bone marrow. This can result in low levels of red blood cells, normal white blood cells, and platelets.

Waldenstrom macroglobulinemia is a slow-growing—or indolent—lymphoma. About 25% of people have no symptoms when doctors diagnose the disease. Instead, routine blood tests for a physical exam or other reason reveal abnormal results. You may hear doctors call this asymptomatic or smoldering WM.

When symptoms occur, they are usually vague and nonspecific, and can include:

• Enlarged lymph nodes

• Fatigue or weakness

• Fever

• Frequent infections

• Night sweats

• Unintended weight loss

As M protein builds up in the body and blood, it can cause other problems and symptoms including:

• Amyloidosis: this occurs when M protein affects organs, such as the kidneys or heart, causing damage.

• Anemia: this condition is characterized by a low red blood cell count leading to fatigue and other symptoms.

• Clotting or bleeding problems: these are due to abnormal levels of clotting factors or platelets.

• Cold agglutinin disease: this affects about 10% of patients. It’s a form of hemolytic anemia where the M protein destroys red blood cells.

• Cryoglobulinemia: this affects up to 20% of patients. It causes circulatory problems in cooler body areas, such as the fingertips, toes, nose and ears. It can also cause skin lesions and discoloration.

• Hyperviscosity syndrome: This syndrome is characterized by thickening of the blood that impairs circulation, especially to the brain. Symptoms can mimic a stroke, including headache, dizziness, confusion, slurred speech, and one-sided weakness or paralysis.

• Neuropathy due to nerve damage: this causes numbness, pain, tingling, and “pins and needles” sensations in the feet or hands.

• Vision problems: this occurs as a result of M protein deposition leading to poor circulation or bleeding from tiny blood vessels.

Waldenstrom macroglobulinemia occurs when lymphocytes grow uncontrollably. This happens when genes that regulate cell growth and death undergo changes or mutations. Inherited genetic mutations from your parents can make you more vulnerable to certain cancers. However, the mutations in WM are usually acquired, meaning they develop during your lifetime.

There are two types of genes that manage the lifecycle of cells: oncogenes and tumor suppressor genes. Oncogenes control cell growth and division. Tumor suppressor genes slow growth and make sure cells die at the right time. Researchers have found 90% of WM patients have a mutation in a specific gene, MYD88. Normally, it helps immune system cells signal to each other and stay alive. Scientists think the MYD88 mutation in WM results in the gene staying turned on all the time, so certain immune system cells don’t die when they should.

The genetic mutations that lead to Waldenstrom macroglobulinemia mostly occur for no apparent reason scientists can understand. However, certain factors may increase the risk of WM. Because people most often acquire the mutations over time, aging is a major risk factor. It’s most common in people older than 60 years and is rare in people younger than 50 years. Other risk factors include:

• Heredity: about 1 in 5 people with WM has a family member with the disease or with a similar B-cell lymphoproliferative disease.

• Male sex: men are almost twice as likely as women to develop WM.

• MGUS (monoclonal gammopathy of undetermined significance): this condition causes people to create M protein.

• Caucasian race: WM is significantly more common in white people than in African-Americans, although little data is available regarding other races.

Like other forms of slow-growing blood cancers, treatment for WM is not always necessary right away. Of the 25% of people without symptoms at diagnosis, about half will require treatment within three years. So, for asymptomatic WM, watchful waiting is often an option. In watchful waiting, doctors regularly monitor your blood counts and symptoms. Doctors may recommend treatment when symptoms become bothersome, blood counts begin to fall, or M protein builds up enough to cause complications. In general, M protein levels alone aren’t a useful guide for treatment.

Treatment options for WM include:

• Chemotherapy: These drugs kill cancer cells or stop them from growing. Unfortunately, chemo drugs also affect healthy cells and can cause significant side effects.

• Immunotherapy: These drugs modulate the immune system and use it to help find and kill cancer cells.

• Plasmapheresis, or plasma exchange: This process uses a machine to separate plasma—the liquid part of the blood—from blood cells. It returns the blood cells to your body and discards the plasma, which contains the M protein. This reduces the thickness, or viscosity, of the blood. Doctors may recommend this when M protein buildup causes problems.

• Targeted therapy: These drugs use specific molecular targets to precisely identify and fight cancer cells. Targeted therapy drugs tend to spare healthy cells better than standard chemotherapy drugs. While side effects are still possible, people usually tolerate these drugs better.

Doctors may also recommend a stem cell transplant in certain situations. This may include younger patients who have relapsed or have refractory disease.

Current treatments don’t offer a cure for WM. However, these therapies are usually effective at treating the disease. Many people with WM have a long-term response to treatment and live with the disease for years. In addition, researchers continue to explore new drugs and treatment approaches for this rare form of lymphoma.