What is WM?

Waldenström’s Macroglobulinemia (WM) is medically defined as a 'malignant monoclonal gammopathy', considered to be a lymphoplasmacytic lymphoma as defined by the Revised European American Lymphoma Classification and World Health Organization. Its is a type of non-Hodgkin lymphoma, but this term is now less used by specialists. Some doctors may not even mention the term WM at time of diagnosis which makes research by patients more difficult.  If they do, their patients usually have some difficulty spelling it!

Symptoms leading to diagnosis are many, but may include night sweats, anaemia, weight loss, tiredness, symptoms of immune system damage such as pleurisy,shingles and sinus infections. In some cases breathlessness on exertion is present.

Most experts consider that many patients may have had symptomless WM precursors for several years before WM fully develops.  The most common is MGUS -Monoclonal Gammopathy of Unknown Significance. In many cases these changes never transform into full WM.   

The features of this rare and indolent (slow moving) disease result from the presence of IgM (Immunoglobulin M) paraprotein and infiltration of the bone marrow with lymphoplasmacytic cells, usually picked up in an extended blood test.  IgM is natural and helps to fight infection, but in WM the defective WM/LPL cells produce large quantities of non-functional IgM called Paraprotein.   These are very large molecules and can thicken the blood, reducing its flow through capillaries. This is called hyperviscosity.  It can cause shortage of breath and sometimes damage to eyes. A paper on hyperviscosity you can download is in the Media Centre. 

Although rare, some 400+ patients may be diagnosed each year in the UK and it affects men of 65+ years disproportionately. More use of extended blood tests means diagnosis is increasingly made at a younger age. 

Clinical features are similar to those of Multiple Myeloma (MM) except that an enlarged spleen or liver is common in WM and uncommon in MM, while bone lesions (growth defects possibly leading to fractures) and kidney disease are common in MM and uncommon in WM.

The mechanism: defective B cells - (B cells are a type of white blood cell - for more information see the Wikipedia article B cell) are produced in the bone marrow and provide a major part of the body's immune system. The disease begins with a malignant change to the B-cell late in its development so that it continues to reproduce more malignant B-cells.

The result is an overproduction by the malignant B-cells of a protein called monoclonal immunoglobulin M antibody (IgM) or Paraprotein. WM is characterized by a highly variable degree of bone marrow involvement with these defective cells. As a result of marrow involvement, normal marrow functions are suppressed which may lead to the reduction of blood cell counts, i.e. red (leading to anaemia) white (increased infection risk) and platelets (leading to bleeding from the nose etc).

Thus one important method of measuring the progress of the disease, apart from blood tests, is bone marrow samples, usually taken from the hip. The result is usually expressed as % infiltration by the defective B cells - from 0% (no sign of disease) to 100% - complete infiltration.

The B cells may accumulate in the lymphatic system and cause swelling of the lymph glands, particularly round the neck.

A very small number of patients may have masses of WM cells (tumours) which can appear anywhere in the body. For this reason alone, scanning is recommended at the time of diagnosis. In the words of one of the UK’s WM experts: "I routinely scan all patients at diagnosis - you just don’t know what you might find" . IgM levels alone should not be relied upon as a measure of the state of disease. Patients exhibiting masses of WM cells outside the bone marrow (extramedullary masses) may need treatment.  Any decision to treat (and when) would be based on disease burden as well as the location, size and rate of growth of any masses. There are huge variations, but death from the disease itself is rare - death is more usually related to long term weakening of the immune system leading to infections.

Another rare complication is produced by abnormally folded immunoglobulin proteins. This is called
Amyloidosis. The proteins are insoluble and may accumulate in the kidney or heart, causing troubling symptoms. Patients diagnosed are usually referred for treatment to the National Amyloidoisis Centre at University College Hospital, London http://www.ucl.ac.uk/amyloidosis/nac

There is no definitive cause for WM. Some research has shown that it might be linked in some way to hepatitis C infection or to other viral infections, but not all researchers have found these links and not everyone with WM has had one of these infections. WM itself is not infectious and cannot be passed onto other people. 

WM can occur in clusters within families and genetic studies are becoming increasingly important. A recent study of people with WM found that nearly 1 in 5 of them had a relative with either WM or a related blood cancer. This suggests that there may be a genetic tendency for developing WM, rather than that it is directly inherited down the family line. Currently, there are no recommendations to check family members for the condition, but genetic screening at diagnosis is becoming more common in the UK.  Recent research in the USA has shown that most patients (90%+) have a genetic mutation called MYD88, but the relationship to the disease is not fully understood, but this mutation may affect the effectiveness of novel chemotherapy treatments which are emerging rapidly, and act at the molecular level.    These may change the management of  WM into a chronic disease, treated with a daily tablet, possibly for life.   There are considerable challenges about funding of these expensive new medications. 

WM is increasingly treatable. It is not yet curable. Many patients have a protracted series of different treatments with remissions over a number of years.

WMUK  produce a very comprehensive new guide to  WM written by Dr Shirley D'Sa from University College Hospital, London.  You can download or read by clicking here. WMUK Guide

There is also very useful shorter leaflet produced by the Lymphoma Action provides an up to date description of the disease and its treatment. It can be found here: Lymphoma Action WM Leaflet

A little bit of Waldenström history

Jan Gösta Waldenström (17 April 1906 -1 December 1996) was a Swedish doctor who first described the disease which bears his name, Waldenström's Macroglobulinemia.

He was born in Stockholm and arose from a medical family: his father, Johann Henning Waldenström (1877-1972) was a professor of orthopedic surgery in Stockholm, and his grandfather, Johan Anton Waldenström (1839-1879), was professor of internal medicine in Uppsala.

Waldenström obtained his M.D. degree at the University of Uppsala, and studied organic chemistry at the Technical University of Munich. He was professor of theoretical medicine at the University of Uppsala in 1941 and became professor of practical medicine at the University of Lund in 1944. He was the head of the Department of Medicine at Malmö General Hospital until his retirement in 1972.

Waldenström first described in 1944, patients suffering from a disease that has subsequently been named after him, Waldenström's Macroglobulinema, a "hyperviscosity syndrome" in which symptoms are caused by abnormal lymphocytes (specialised white cells) which prevent normal bone marrow function, causing anaemia and hepatosplenomegaly (enlarged spleen), and which secrete large immunoglobulins (IgM) causing bleeding difficulties.

Waldenström's other clinical investigations included studies on the various porphyrias. He originated the concept of classification of gammopathies as "monoclonal gammopahies" vs. "polyclonal gammopathies" in 1961.

He was a member of the National Academy of Science in the United States, the French Academy of Sciences, and was an honorary member of the Royal Society of Medicine, London.

Jan Waldenström