Waldenstrom Macroglobulinemia

The specific causes of WM are unknown. However, there is a familial predisposition to WM, with most studies suggesting that approximately 20 to 25% of patients have a history of the disease or related B-cell disorders in a first degree relative (e.g., parent or sibling). At this time, there is no test that will predict which, if any, family members of a WM patient will ultimately develop WM, but those with IgM-MGUS (monoclonal gammopathy of undetermined significance) are at greater risk. Although individuals with a family history of WM and related disorders are at higher risk than the general public, their overall risk is still extremely low due to the rarity of the disease.

Other risk factors include:

• Male sex—for reasons that are unclear, WM is almost twice as common in men as in women.
• Caucasian race—the disorder is more common in Caucasians than in other racial and ethnic groups.
• Ashkenazi Jewish ethnicity
• Increasing incidence with age—this disorder is quite rare under the age of 40 (less than 1% of patients). The median age at diagnosis of WM is 73 years.
• Viral hepatitis infection (e.g., hepatitis C) or HIV/AIDS
• Autoimmune-related conditions
• Exposure to certain solvents, dyes, Agent Orange, and other pesticides

At least 25% of people with WM show no active symptoms (asymptomatic or smoldering WM) but are identified and diagnosed because of abnormal results from blood tests (e.g., complete blood count, comprehensive metabolic panel) that were ordered usually during a routine physical exam. If WM continues to progress, signs and symptoms may develop. Most signs and symptoms are due to a decrease in red blood cells (anemia) caused by the malignant cells of WM multiplying and crowding out normal blood cells, or to the excess production of monoclonal IgM.

The most common early symptoms of WM are due to anemia:

• Weakness
• Fatigue

Example of other common signs and symptoms include:

• Fever
• Night sweats
• Unintended weight loss
• Enlarged lymph nodes
• Enlarged spleen and/or liver
• Peripheral neuropathy—this is common in people with WM and may be the only source of symptoms. Damage to the peripheral nerves causes pain, numbing, tingling (pins and needles sensation), and/or weakness in the hands and feet but can affect other parts of the body. A referral to a neurologist (expert in nervous system disorders) may be made.

As WM progresses, complications may develop. These may include:

• Slow and progressive decrease in kidney function—acute kidney failure is rare.
• Cryoglobulinemia—some people with WM have abnormal antibodies called cryoglobulins in their blood that are cold-sensitive. When WM patients with cryoglobulinemia are exposed to cold temperatures, their blood thickens, slowing or blocking blood flow. This can lead to circulatory problems, tissue damage, and pain in areas exposed directly to the cold, such as fingertips, ears, nose, or toes, which may turn blue or black. Up to 20% of people with WM may develop this condition, although less than 5% experience noticeable symptoms.
• Cold agglutinin disease—this is a rare condition that occurs when the body’s immune system produces abnormal antibodies that attack the red blood cells and destroy them by causing them to clump together (agglutinate) and break apart (lysis). This is a type of hemolytic anemia and is triggered by cold temperatures. Fewer than 10% of WM patients experience this problem.
• Raynaud syndrome—this is seen with both cold agglutinin disease and cryoglobulinemia, again marked by poor circulation, often resulting in discolored fingers and toes when exposed to the cold.
• Hyperviscosity syndrome—in 10 to 30% of WM patients, over time, the accumulation of the abnormal IgM protein builds up in the blood, causing difficulties, particularly with circulation through the smaller blood vessels. This may result in stroke-like symptoms, possible congestive heart failure, and decreasing, poor eyesight due to blocked blood vessels in the eye (retina).
• Amyloidosis—amyloids are insoluble proteins; one form develops from fragments of the abnormal IgM, called light chains. These proteins can buildup and damage organs, such as the heart or kidneys.

A complete medical history and physical examination are essential components of an initial assessment. Several routine tests may be ordered as part of the initial exam and for monitoring the condition. Depending on results of routine tests, specialized testing may be performed in follow-up.

Laboratory Testing

General laboratory tests include:

• Complete blood count (CBC) with differential—this is a common blood test. Blood counts are often low in people with WM. Anemia (low hemoglobin and a low number of red blood cells) is present in most people with WM at diagnosis. Total white blood cell count may be reduced (leukopenia). However, the number of lymphocytes (a type of white blood cell) is usually increased due to the presence of lymphoma cells. The number of platelets may also be decreased (thrombocytopenia).
• Peripheral blood smear—a drop of blood is spread thinly onto a glass slide that is then treated with a special stain. A microscope is used to examine the blood cells. This exam provides information on both the number and shape of red blood cells and is, therefore, part of the initial testing for WM. Red cells may appear to be stacked upon each other (rouleaux). If present, abnormal lymphocytes or plasma cells appear identical.
• Comprehensive metabolic panel—14 different substances are measured, a few of which may be elevated in WM patients. Examples include total protein or, with decreased kidney function, creatinine and BUN.
• 24-hour urine protein test—detects high levels of protein in the urine
• Liver function tests (LFTs or hepatic panel)—these tests primarily assess liver function.

WM may be suspected if results from these blood tests show low blood counts and unusually high protein levels. To establish a diagnosis of WM, the healthcare practitioner will order tests to further evaluate the elevated protein level, specifically looking for the presence and amount of immunoglobulin M (IgM) monoclonal protein and performing a bone marrow biopsy and aspiration to determine the presence of cancer cells that may be in the bone marrow.

Follow-up tests if WM is suspected typically include:

• Serum protein electrophoresis (SPEP), serum quantitative immunoglobulins, and immunotyping (serum immunofixation electrophoresis (SIFE) or capillary electrophoresis)—used to identify and measure the elevated IgM antibody (also known as M-protein or M-spike) that is seen in WM. Other immunoglobulins (typically IgG and IgA) are also measured but generally are not elevated. While detection of a monoclonal IgM protein in the blood is essential for WM diagnosis, monoclonal IgM may be found in WM, IgM monoclonal gammopathy of undetermined significance (IgM-MGUS), or rarely IgM multiple myeloma. There may be a decrease in the level of other immunoglobulins due to fewer normal B-cells and plasma cells producing immunoglobulins.
• Urine protein electrophoresis (UPEP) and immunofixation—this will be performed if the 24-hour urine protein test detects increased protein in the urine. It is performed to look for free monoclonal light chains (Bence Jones protein).
• Beta2-microglobulin (B2M)—a protein that can be measured in the blood. The level may be high in people with WM as well as people who have abnormal kidney function. This test may provide information about the extent of the cancer (cancer burden).
• Bone marrow aspiration and biopsy and/or lymph node biopsy—these examinations are performed to detect clonal WM cancer cells. Specialized lab techniques, such as immunohistochemistry (IHC) and/or flow cytometry, are done to confirm the elevated number of abnormal B-cells.
• Immunophenotyping by flow cytometry is usually performed on bone marrow, peripheral blood, and/or lymph nodes to detect monoclonal B-cells, i.e., the phenotype of the B-cells based on a panel of markers that are highly specific for identifying and classifying the cell types. WM is a B-cell lymphoma that is positive for B-cell markers (e.g., CD19, CD20, CD22, CD79a) and typically negative for T-cell marker CD5 and CD10 (a marker often positive for B-cell acute lymphoblastic leukemia and Burkitt lymphoma).
• Molecular testing—about 90% of WM patients have a MYD88 L265P gene mutation and 30 to 40% of patients have a CXCR4 gene mutation. Identifying these mutations may help to differentiate WM from other B-cell lymphomas and to guide treatment decisions.
• Serum viscosity testing—measures the “thickness” of the blood. High levels of IgM in the blood can cause it to thicken. Symptoms of hyperviscosity (abnormal bleeding, vision problems, or nervous system problems) usually start when the viscosity significantly increases, generally twice that of normal serum levels. Patients with hyperviscosity symptoms need immediate medical treatment. This test is not frequently ordered.

Special tests that may be ordered include:

• Prothrombin time (PT) and partial thromboplastin time (PTT)—blood clotting tests are ordered if there is unexplained bruising or bleeding. Although rare, WM patients with high IgM can develop a blood clotting disorder called acquired von Willebrand disease. If this is suspected, a test for von Willebrand factor may be performed.
• Cryoglobulins—this testing is ordered when there is a suspicion of cryoglobulins in the blood (cryoglobulinemia). These circulating proteins, specifically abnormal immunoglobulins, clump together when they are exposed to the cold and dissolve when warmed.
• Cold agglutinins—a less common type of cold-sensitive antibodies that can be detected in WM patients. They are an IgM type of abnormal antibodies that are sensitive to cold, targeting red blood cells (RBCs) and causing them to clump and eventually destroyed, often resulting in hemolytic anemia.
• Peripheral neuropathy tests if indicated may include:
  • Testing for a build-up of amyloid—this is an abnormal protein in the organs and tissues (amyloidosis). Testing bone marrow or fat pad biopsies using a special stain called Congo red can detect the presence of amyloid when examined under a microscope using polarized light.
  • Anti-MAG testing—looks for autoantibodies against the myelin-associated glycoprotein (MAG), a protein that is necessary for maintaining a healthy nervous system
  • Testing for antibodies against ganglioside M1—this a complex molecule in the nervous system.
• Hepatitis B virus testing—this is done before initiating therapy to make sure a patient does not have underlying hepatitis B. If a patient has hepatitis B infection, measures will be taken to avoid reactivation of hepatitis B during and after treatment of WM.
• Hepatitis C testing—ordered when cryoglobulinemia is suspected. People with WM, especially those with cryoglobulinemia, may have underlying hepatitis C.

Other blood tests that may be ordered on a regular basis to assess how well the liver, kidney, and other organs are working during treatment include:

• Comprehensive metabolic panel
• Uric acid—may be elevated in WM

Non-laboratory Tests

There are several imaging scans and other exams or studies that may be performed:

• If the level of IgM in the blood is significantly high, or if hyperviscosity is suspected, a retinal exam of the eye is ordered to check for any changes (retinal blood vessels that have become enlarged) or bleeding caused by the IgM-induced thickened blood. Hyperviscosity can cause eyesight problems, such as blurred or double vision. Blindness may occur without warning.
• Imaging tests such as computed tomography (CT) or magnetic resonance imaging (MRI) provide additional information about the extent of WM in order to see if there are any enlarged lymph nodes, spleen, or liver.
• X-rays or MRI of the skeleton can help distinguish between WM and a similar plasma cell cancer called multiple myeloma. In contrast to myeloma, WM patients rarely show destructive bone lesions.

Asymptomatic (smoldering) WM

Not everyone diagnosed with WM needs treatment right away. Some people without troublesome or serious symptoms may be monitored closely and only treated when symptoms worsen. This is because treating asymptomatic WM does not save lives, increase the quality of life, cure the disease, or change the long-term outlook. Furthermore, there may be side effects from medications.

Symptomatic WM

Treatment may be considered if serious signs, symptoms, and complications develop. There is currently no treatment that cures WM. The goals of treatment are to reduce or relieve the severity of symptoms, to improve quality of life, and to maintain that state for an extended period of time.

• Blood transfusions may be required if the red cell count and hematocrit become too low.
• Plasmapheresis may be performed to quickly reduce the viscosity (thickness) of the blood, to relieve symptoms and prevent complications, sometimes in preparation for treatment of the WM. Plasmapheresis is a procedure (not a cancer treatment) that separates abnormal plasma (the liquid part of blood that contains IgM) from blood cells, returning the blood cells back to the patient in addition to normal plasma. The effects of plasmapheresis are temporary, lasting 2-6 weeks.

Typically, combinations of drugs are used for treatment, as this often improves overall response to therapy. Examples of these drugs include:

• Chemotherapy
• Corticosteroids
• Therapeutic monoclonal antibody drugs
• Proteasome inhibitors
• Targeted therapies/pathway inhibitors to B-cell signaling

Stem cell transplantation is also an option for relapsed WM in selected patients.

Treatment options and frequently encountered side effects from WM chemotherapeutics are covered in the IWMF Treatment Options booklets and IWMF Fact Sheets of drugs.

Also, see the links provided under Related Content for more resources on treatment.