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# MGUS and Waldenström macroglobulinaemia

Abnormal antibody-making cells release one repeated protein into the blood: harmless at first (MGUS) or, in Waldenström disease, enough to thicken the blood.

Updated 2026-11-01

## Structures involved

Tap one to see what it is and open it in 3D.

- [Retina](https://durgical.com/en/anatomy/retina/)
- [Hip bone](https://durgical.com/en/anatomy/hip-bone/)
- [Central retinal artery](https://durgical.com/en/anatomy/central-retinal-artery/)
- [Optic disc](https://durgical.com/en/anatomy/optic-disc/)
- [Neck lymph nodes](https://durgical.com/en/anatomy/lymph-nodes-of-neck/)
- [Sacrum](https://durgical.com/en/anatomy/sacrum/)

## Why it happens

- [Precancerous conditions: when chronic inflammation, metaplasia or hyperplasia raise the risk](https://durgical.com/en/general-pathology/precancerous-conditions-when-chronic-inflammation-metaplasia-or-hyperplasia-rais/)
- [Flow, pressure and resistance: Poiseuille and turbulent flow](https://durgical.com/en/physiology/flow-pressure-and-resistance-poiseuille-and-turbulent-flow/)
- [Immunoglobulins (antibodies)](https://durgical.com/en/biochemistry/enzymes/immunoglobulins/)
- [Plasma proteins and electrophoresis](https://durgical.com/en/biochemistry/topics/plasma-proteins-and-electrophoresis/)

## What it is

Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant state in which a small clone of plasma cells or B cells makes a monoclonal protein (M-protein) without organ damage. Waldenström macroglobulinaemia (WM) is a slow-growing lymphoplasmacytic lymphoma in the bone marrow that secretes monoclonal IgM, which can make the blood thick (hyperviscosity syndrome).

## Who gets it

MGUS is common and increases with age: it is found in about 3% of people over 50 and more often in men and in people of African descent; most never progress. WM is rare, affecting mainly older white men in their 60s and 70s. In Latin America and Colombia these conditions are usually found incidentally on serum protein electrophoresis done for anaemia, [kidney](https://durgical.com/en/anatomy/kidney/) disease, neuropathy or a raised total protein.

## Causes

- Clonal expansion of plasma cells (non-IgM MGUS) or lymphoplasmacytic B cells (IgM MGUS, WM)
- MYD88 L265P mutation in most cases of WM and many cases of IgM MGUS; CXCR4 mutations in a subset
- IgM MGUS can progress to WM or other lymphomas; non-IgM MGUS can progress to multiple myeloma or AL amyloidosis

## Risk factors

- Older age
- Male sex
- African ancestry (MGUS)
- Family history of MGUS, WM or other B-cell cancers
- Chronic immune stimulation and autoimmune disease

## Pathophysiology

The clone makes one identical immunoglobulin. In MGUS the amount is small and the clone does not damage organs. In WM, large pentameric IgM molecules stay inside the vessels and raise serum viscosity: blood flows sluggishly through small vessels of the [retina](https://durgical.com/en/anatomy/retina/), brain and mucosae, causing visual loss, headache and bleeding. The IgM can also act as an antibody against nerve myelin (anti-MAG neuropathy), behave as a cold agglutinin (haemolysis) or a cryoglobulin (vasculitis), or deposit as amyloid. Marrow infiltration causes anaemia and lymphoma cells can enlarge lymph nodes, spleen and liver.

## Classification

- MGUS: non-IgM (IgG or IgA, risk of myeloma), IgM (risk of WM or lymphoma) and light-chain MGUS
- Risk of progression of MGUS by M-protein size, type and free light chain ratio
- Smouldering (asymptomatic) WM versus symptomatic WM requiring treatment

## Symptoms and signs

- MGUS: no symptoms; found by chance on blood tests
- WM: fatigue and weakness from anaemia
- WM: weight loss, fever and night sweats
- Hyperviscosity: blurred or lost vision, headache, dizziness, confusion and nosebleeds or gum bleeding
- Numbness and tingling of the feet (peripheral neuropathy)
- Enlarged lymph nodes, spleen or liver; acrocyanosis or Raynaud phenomenon with cold

## Red flags

- Sudden visual loss, confusion, drowsiness or seizures (symptomatic hyperviscosity)
- Mucosal bleeding with very high IgM
- Breathlessness or heart failure from volume overload
- In MGUS: new bone pain, anaemia, kidney impairment or high calcium (progression to myeloma)

## Diagnosis

**Clinical**
MGUS is diagnosed when an M-protein is found without CRAB features (hypercalcaemia, renal failure, anaemia, bone lesions) or lymphoma symptoms. WM is suspected in an older patient with anaemia, neuropathy or hyperviscosity signs and a high IgM. Fundoscopy showing dilated, segmented 'sausage-link' retinal veins and haemorrhages supports hyperviscosity.

**Tests**
Serum protein electrophoresis and immunofixation identify and type the M-protein; serum free light chains. MGUS: M-protein below 3 g/dL and fewer than 10% clonal plasma cells in the marrow. WM: IgM M-protein with at least 10% lymphoplasmacytic infiltration on bone marrow biopsy and MYD88 L265P testing. Serum viscosity, full blood count, creatinine, calcium, Coombs and cold agglutinin tests, cryoglobulins, and anti-MAG antibodies in neuropathy.

**Imaging**
CT of [chest](https://durgical.com/en/anatomy/region/chest/), [abdomen](https://durgical.com/en/anatomy/region/abdomen/) and [pelvis](https://durgical.com/en/anatomy/region/pelvis/) to stage lymph nodes, [spleen](https://durgical.com/en/anatomy/spleen/) and [liver](https://durgical.com/en/anatomy/liver/) in WM; skeletal imaging when myeloma is suspected from a non-IgM MGUS (WM itself rarely causes lytic bone lesions).

## Differential diagnosis

- Multiple myeloma and smouldering myeloma
- AL amyloidosis
- Chronic lymphocytic leukaemia and marginal zone lymphoma
- Polyclonal hypergammaglobulinaemia from chronic infection, liver disease or autoimmune disease
- Cryoglobulinaemia from hepatitis C

## Goal of treatment

Watch MGUS for progression without treating it; in WM, treat only when symptoms or complications appear, and urgently lower viscosity in hyperviscosity syndrome.

## Treatment

**Follow-up**
MGUS: no treatment; periodic blood counts, creatinine, calcium and M-protein levels, with follow-up intervals set by risk, and teaching of warning symptoms. Asymptomatic WM is also observed.

**Acute**
Symptomatic hyperviscosity is an emergency treated with plasmapheresis, which quickly removes IgM because it stays in the bloodstream; red cell transfusion is delayed or given slowly because it raises viscosity further.

**Medical**
Symptomatic WM: rituximab-based regimens combined with chemotherapy (such as bendamustine) or with proteasome inhibitors, or Bruton tyrosine kinase (BTK) inhibitors such as ibrutinib or zanubrutinib.

**Medical**
Supportive care: treatment of anaemia, neuropathy, cold agglutinin disease and infections; vaccination against influenza and pneumococcus.

## Complications

- Progression of MGUS to multiple myeloma, WM, lymphoma or amyloidosis (about 1% per year)
- Hyperviscosity syndrome with visual loss, stroke or bleeding
- Peripheral neuropathy
- Cold agglutinin haemolysis and cryoglobulinaemic vasculitis
- Transformation of WM to aggressive lymphoma

## Prognosis

Most people with MGUS never develop cancer, but the lifelong risk justifies follow-up. WM is incurable but slow; with current treatment many patients live for well over a decade, and outcomes depend on age, blood counts, IgM level and β2-microglobulin.

## Test yourself

Think of the answer, then tap the question to see it.

## What features separate MGUS from multiple myeloma?

MGUS has an M-protein below 3 g/dL, fewer than 10% marrow plasma cells and no CRAB organ damage.

## Which immunoglobulin is produced in Waldenström macroglobulinaemia?

Monoclonal IgM.

## Why does IgM cause hyperviscosity more readily than IgG?

IgM is a large pentamer that stays within the vessels, so it raises blood viscosity at lower concentrations.

## What is the emergency treatment for symptomatic hyperviscosity syndrome?

Plasmapheresis to remove the IgM quickly.

## Which mutation is found in most cases of Waldenström macroglobulinaemia?

MYD88 L265P.

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## Related conditions

- [Multiple myeloma](https://durgical.com/en/conditions/multiple-myeloma/)
- [Amyloidosis](https://durgical.com/en/conditions/amyloidosis/)
- [Non-Hodgkin lymphoma](https://durgical.com/en/conditions/non-hodgkin-lymphoma/)
- [Chronic lymphocytic leukaemia](https://durgical.com/en/conditions/chronic-lymphocytic-leukaemia/)
- [Central retinal vein occlusion](https://durgical.com/en/conditions/central-retinal-vein-occlusion/)
- [Peripheral neuropathy (diabetic and other)](https://durgical.com/en/conditions/peripheral-neuropathy/)
- [Cryoglobulinemic vasculitis](https://durgical.com/en/conditions/cryoglobulinemic-vasculitis/)
- [Autoimmune haemolytic anaemia](https://durgical.com/en/conditions/autoimmune-haemolytic-anaemia/)
- [Chronic kidney disease](https://durgical.com/en/conditions/chronic-kidney-disease/)
- [Ischaemic stroke](https://durgical.com/en/conditions/ischaemic-stroke/)

Educational information, not medical advice. For any symptom, see a health professional.

Sources: [Waldenstrom macroglobulinemia](https://medlineplus.gov/ency/article/000588.htm) (MedlinePlus (U.S. National Library of Medicine), 2026); [Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment (PDQ®)–Health Professional Version](https://www.cancer.gov/types/myeloma/hp/myeloma-treatment-pdq) (National Cancer Institute, 2025).

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Source: https://durgical.com/en/conditions/mgus-and-waldenstrom-macroglobulinaemia/
License: CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Cite as: DurgiPedia (durgical.com), https://durgical.com/en/conditions/mgus-and-waldenstrom-macroglobulinaemia/