This is the second part of our series about the condition based on our patient booklet “Fast Facts for Patients: Waldenström Macroglobulinemia”. This blog post explains what causes Waldenström macroglobulinemia (WM) and how it will affect you.

 

What Causes Waldenström Macroglobulinemia?

Most people develop a condition called IgM monoclonal gammopathy of uncertain significance (IgM MGUS) before WM. At this early stage, there are very few LPL cells in the body, and they are often undetectable. But it is possible to detect an abnormal amount of IgM paraprotein. This may be picked up from a blood sample that has been taken for an unconnected reason. At this stage, people typically feel normal and have no symptoms.

IgM MGUS becomes more common as people get older, but its cause is unknown. About 2 in 100 people aged over 50 and 3 in 100 people aged over 70 have IgM MGUS.

The raised level of IgM paraprotein in IgM MGUS usually causes no symptoms, though people are monitored once or twice a year in case the level rises or symptoms develop. Sometimes an IgM MGUS level may cause inflammation or tissue damage, which will require further tests and treatment.

Over time (usually years), the monoclonal LPL cells may build up to result in WM, which is eventually diagnosed once symptoms develop, such as fatigue, weight loss, sweats, fevers, nerve damage (peripheral neuropathy) or infections (due to an under-functioning immune system).

Not everyone with IgM MGUS progresses to WM. For those who do, it typically takes years.

WM is not infectious and cannot be passed on to other people. But blood relatives in the person’s immediate family are slightly more likely to develop WM or another kind of B-cell lymphoma.

 

This many people will have developed Waldenström macroglobulinemia in the time shown from a group of 100 people with IgM monoclonal gammopathy of uncertain significance (IgM MGUS)

 

Genetic Mutations

Most people with WM (about 90%) have a mutation in the MYD88 gene in the DNA of the LPL cells. This mutation is not inherited from a parent. Instead, it happens inside the LPL cells. Identifying this mutation helps to confirm a diagnosis of WM and may predict how the disease will develop and respond to treatment (called the prognosis).

 

Changes in the MYD88 gene's instructions change the sequence of amino acids in the protein

 

About 40% of patients with WM have a mutation in the CXCR4 gene, which affects production of a different protein. Mutations in the CXCR4 gene are more varied and complicated, and therefore more difficult to analyze.

These gene mutations result in abnormal proteins that do not work properly in the body’s cells.

Everyone who is suspected of having WM ideally should be tested for these gene mutations, as they may affect treatment choices.

How Will Waldenström Macroglobulinemia Affect Me?

Symptoms vary from person to person depending on how the disease develops. Not everyone gets all of the symptoms. Even after diagnosis, you may not get any symptoms for many years.

Symptoms may develop because of:

  • disrupted production of normal blood cells
  • thickening of the blood because of high levels of IgM paraprotein, an abnormal immunoglobulin (antibody)
  • IgM paraproteins mistakenly targeting tissues and organs
  • the IgM becoming sticky or fragmented
  • the IgM coating nerve cells and causing damage (peripheral neuropathy).

Over time, LPL cells fill up the bone marrow or collect in the lymph nodes or the spleen (and, rarely, in other places in the body).

Effects of Having Fewer Healthy Blood Cells

Having fewer red blood cells leads to anemia, which can cause tiredness, weakness and breathlessness. This is linked with fatigue, an extreme form of tiredness that is the most common symptom of WM. A lack of white blood cells weakens the immune system, so you may tend to develop infections. A lack of platelets leads to a tendency to bruise or bleed easily, as platelets are important in blood clotting.

B Symptoms

Fevers, night sweats and weight loss may be a feature of later-stage WM. You might hear them referred to as B symptoms. They happen when the LPL cells build up to the extent that their metabolic activity becomes physically noticeable through these symptoms. Tell your doctor if you start to notice these symptoms – for example, if you need to change nightclothes regularly or you have lost a significant amount of weight. You may need to start treatment.

Swellings and Lumps

In about a quarter of patients with WM, lymph nodes and/or the spleen may enlarge; you might notice swollen glands. Rarely, a swollen spleen can be uncomfortable or painful.

LPL cells may collect in body cavities, causing soft tissue masses (lumps) or a buildup of fluid in the chest (pleural effusion). Rarely, the cells may build-up in the skeleton, causing bone pain. If these symptoms appear, the diagnosis is confirmed by taking scans and analyzing samples of tissue from a biopsy.

 

Information based on Fast Facts for Patients: Waldenström Macroglobulinemia (Karger, 2022).

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