Waldenström macroglobulinaemia, often shortened to WM, is a rare type of slow-growing blood cancer, occurring in 4.1 persons per million per year. It belongs to a group of conditions called lymphomas, which affect white blood cells called lymphocytes.
In WM, abnormal lymphoplasmacytic cells build up in the bone marrow and produce too much of a large antibody called IgM. This IgM protein can sometimes cause symptoms by making the blood thicker, affecting nerves, or interfering with normal blood cell production.
Fig 1. Diagram showing abnormal bone marrow cells producing excess IgM protein in Waldenström macroglobulinaemia.
How common is Waldenström macroglobulinaemia?
WM is uncommon. It accounts for about 1% of lymphomas. It is usually diagnosed in older adults, with the median age around the early 70s. Some people are diagnosed after an abnormal blood test, while others present with symptoms such as tiredness, bleeding, nerve symptoms, or infections.
What symptoms can WM cause?
Many people with WM have no symptoms at first. This is sometimes called smouldering WM, and it may only need monitoring.
When symptoms occur, they can be due to either:
- Crowding of the bone marrow by lymphoma cells
- Effects of the IgM protein in the blood
Common problems include:
Fatigue and anaemia
The most common symptom is tiredness due to anaemia, where the body does not have enough healthy red blood cells. This can cause fatigue, shortness of breath, dizziness, or reduced exercise tolerance.
Enlarged lymph nodes, liver, or spleen
Some patients develop swollen lymph nodes, or enlargement of the spleen or liver, although this is not always present.
Thickened blood — hyperviscosity
Because IgM is a large protein, very high levels can make the blood thicker than normal. This is called hyperviscosity syndrome.
Symptoms may include:
- Nosebleeds or gum bleeding
- Blurred vision or visual changes
- Headache, dizziness, or confusion
- Shortness of breath in severe cases
This is an urgent situation and may require a treatment called plasma exchange, which rapidly removes excess IgM from the blood.
Fig 2. Comparison of normal blood flow and thickened blood caused by high IgM levels.
Can WM affect the nerves?
Yes. Some patients develop peripheral neuropathy, usually causing numbness, tingling, imbalance, or difficulty walking. In WM, neuropathy is often related to the IgM protein reacting with nerve components, especially myelin-associated glycoprotein.
This type of neuropathy is usually slow, often painless, and may progress over years. Treatment may help in selected patients, particularly if symptoms are affecting function.
How is WM diagnosed?
The diagnosis usually involves blood tests and a bone marrow biopsy.
Typical tests include:
- Full blood count
- Kidney and liver function tests
- Serum protein electrophoresis
- Immunofixation to identify IgM
- Quantitative immunoglobulins
- Serum free light chains
- Beta-2 microglobulin and LDH
- Bone marrow biopsy
- Genetic testing for mutations such as MYD88 and sometimes CXCR4
- CT or PET/CT imaging in selected cases
A typical diagnosis requires an IgM monoclonal protein in the blood and lymphoplasmacytic lymphoma cells in the bone marrow. The MYD88 mutation is found in more than 90% of patients, but it is not absolutely required for diagnosis.
Fig 3. Flowchart showing the diagnostic pathway for Waldenström macroglobulinaemia.
Does everyone need treatment straight away?
No. This is one of the most important points for patients.
Some people have WM diagnosed on blood tests but feel well and have no organ damage or significant symptoms. These patients may be safely monitored with regular blood tests and clinical review. This is often called watch and wait or active surveillance.
Importantly, there is no single IgM number alone that automatically means treatment must start. The decision is based on symptoms, blood counts, complications, and overall health.
When is treatment usually needed?
Treatment is generally considered when WM is causing problems such as:
- Symptomatic anaemia
- Very low platelets
- Bulky lymph nodes or enlarged spleen causing symptoms
- Hyperviscosity symptoms
- Significant neuropathy
- Cold agglutinin haemolytic anaemia
- Cryoglobulinaemia
- Amyloidosis
- Constitutional symptoms such as weight loss, night sweats, or marked fatigue
The goal of treatment is usually control of the disease, improvement in symptoms, and prevention of complications. At present, WM is usually considered treatable but not curable with standard therapies.
What treatments are used?
Treatment is personalised. Factors include age, symptoms, other medical conditions, need for rapid response, preference for tablet treatment versus time-limited intravenous treatment, and risk of side effects.
Common treatment approaches include:
Bendamustine and rituximab
This is a commonly used combination. It is given for a fixed number of cycles and can produce long remissions. This is usually first line treatment in relatively fit patients in Australia.
BTK inhibitors
BTK inhibitors are targeted treatments that block a signalling pathway used by WM cells. Currently approved drug from this class in Australia is zanubrutinib only. It is taken as tablets twice a day and may be continued long term. Side effects can include bruising, bleeding risk, infections, diarrhoea, blood pressure changes, and heart rhythm problems, depending on the drug.
Rituximab alone
Rituximab by itself is generally less effective than combination treatments for WM requiring systemic therapy. It may still have a role in selected IgM-related conditions, such as some neuropathies or autoimmune complications.
Other treatments
Other options may be used in relapsed disease, including proteasome inhibitors, venetoclax, pirtobrutinib, and clinical trials. The best choice depends on prior treatment, response duration, side effects, and patient preference.
Fig 4. Treatment decision diagram showing observation for asymptomatic WM and treatment options for symptomatic WM.
What is plasma exchange?
Plasma exchange is not chemotherapy. It is a procedure used when IgM is causing dangerous blood thickening. Blood is passed through a machine that removes the plasma containing excess IgM and returns the blood cells with replacement fluid.
It can rapidly improve symptoms of hyperviscosity, but it does not treat the underlying lymphoma cells. Therefore, it is usually followed by WM-directed treatment.
What is the outlook?
WM often behaves slowly. Many patients live for years with the condition, and survival has improved over time. In older patients, other health conditions may be more likely to affect survival than WM itself.
The outlook varies depending on age, haemoglobin, platelet count, beta-2 microglobulin, albumin, LDH, IgM level, and other disease features. However, risk scores are used mainly to understand prognosis — not to decide automatically whether treatment is needed.
Key messages for patients
Waldenström macroglobulinaemia is a rare, usually slow-growing lymphoma associated with excess IgM protein.
Not every patient needs treatment immediately.
Treatment is started when WM causes symptoms or complications.
High IgM can sometimes cause thickened blood, bleeding, or visual symptoms, which may need urgent treatment.
Modern treatments include fixed-duration chemotherapy-immunotherapy and targeted tablet treatments such as BTK inhibitors.
The best treatment choice should be individualised and discussed carefully with your haematologist.
When should patients seek urgent medical attention?
Patients with WM should seek urgent care if they develop:
- New or heavy nosebleeds
- Gum bleeding
- Sudden visual changes
- Severe headache or confusion
- Chest pain or shortness of breath
- New weakness, severe dizziness, or fainting
- Fever during treatment
- Black stools or significant bleeding
This article is for general education only and should not replace medical advice from your treating haematologist.