Waldenstrom Macroglobulinaemia

Prepared and reviewed by the PrepElephant Academic Review Team

First published 8 Oct 2026 · Spot an error?

Reference basis: Williams Hematology; Harrison's Principles of Internal Medicine

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Direct answer
What you must remember
A worked case: fatigue, bleeding and blurred vision
Where the examiner sets the trap
Frequently asked questions
Related topics

Direct answer

Waldenstrom macroglobulinaemia is a lymphoplasmacytic lymphoma producing a monoclonal IgM paraprotein, most often carrying the MYD88 L265P mutation, and its main clinical problem is hyperviscosity from the raised IgM. Patients present with fatigue, anaemia, mucosal bleeding, visual disturbance, neuropathy and headache. Urgent plasmapheresis relieves severe hyperviscosity before systemic therapy, which then includes rituximab-based regimens or bortezomib-based combinations that lower the IgM level.

What you must remember

Diagnosis: lymphoplasmacytic marrow infiltration with an IgM paraprotein; treatment depends on IgM level, symptoms and marrow burden rather than the paraprotein alone.
MYD88 L265P: present in over 90 percent of cases, supporting the diagnosis and relevant to choice of BTK inhibitor therapy.
Hyperviscosity signs: headache, visual blurring, retinal haemorrhage, dilated and sausage-like retinal veins, epistaxis and confusion.
Plasmapheresis: rapid symptom relief for severe hyperviscosity, given before chemotherapy because IgM can flare with initial rituximab.
Anti-MAG neuropathy: distal sensory demyelinating neuropathy from IgM antibody to myelin-associated glycoprotein, often responding to rituximab.
Myeloma contrast: myeloma usually has IgG or IgA, plasma cell infiltration and lytic bone lesions, whereas Waldenstrom usually lacks lytic lesions.
Cold agglutinin link: IgM with cold agglutinin activity can cause acrocyanosis, another reason to check cold reactivity.

A worked case: fatigue, bleeding and blurred vision

A 68-year-old man has fatigue, gum bleeding, epistaxis and blurred vision.

Establish the picture: Haemoglobin is 8 g/dL, serum IgM is markedly raised, and fundoscopy shows retinal haemorrhages with dilated veins.
Treat the emergency: Severe hyperviscosity is the immediate concern, so urgent plasmapheresis is performed before systemic therapy. The team checks for cryoglobulins and cold agglutinins.
Start systemic therapy: Once viscosity is reduced, a rituximab-based regimen or a bortezomib-based combination is started, with the IgM flare anticipated and monitored.
Monitor the response: Serial IgM measurements guide the response to treatment. Recurrent viscosity symptoms are the practical trigger for escalating therapy or repeating plasmapheresis.
Contrast with myeloma: A 66-year-old with bone pain, renal impairment, a plasma cell marrow and a lytic skull lesion, with IgG paraprotein, has multiple myeloma instead. Lytic lesions and renal failure from light chain cast nephropathy direct a different workup.
Name the diagnosis: Waldenstrom is the diagnosis that the clinical picture of IgM, lymphoplasmacytic infiltration and hyperviscosity points to.

Where the examiner sets the trap

Examiners set the same few traps around this diagnosis.

Trap: labelling every IgM paraprotein as Waldenstrom Correct: monoclonal IgM gammopathy of undetermined significance, cold agglutinin disease and IgM myeloma also exist, so the marrow and clinical context decide.
Trap: starting rituximab without plasmapheresis cover in severe hyperviscosity Correct: the initial IgM flare can worsen symptoms, so plasmapheresis comes first.
Trap: missing the myeloma distinction Correct: lytic lesions and light chain cast nephropathy are the myeloma features that Waldenstrom lacks.
Trap: not knowing which symptom makes plasmapheresis urgent Correct: visual disturbance or neurological compromise from hyperviscosity makes it urgent.

Frequently asked questions

What is the characteristic paraprotein in Waldenstrom macroglobulinaemia?

A monoclonal IgM paraprotein secreted by lymphoplasmacytic cells defines Waldenstrom macroglobulinaemia, and its large pentameric structure drives hyperviscosity. The MYD88 L265P mutation is present in most cases and supports the diagnosis.

Which hyperviscosity symptoms require urgent plasmapheresis in Waldenstrom macroglobulinaemia?

Severe hyperviscosity with visual disturbance, retinal haemorrhage, confusion, neurological compromise or heart failure needs urgent plasmapheresis. Systemic therapy is started once viscosity is reduced, because chemotherapy and rituximab can transiently raise IgM.

How does Waldenstrom macroglobulinaemia differ from multiple myeloma?

Waldenstrom macroglobulinaemia has an IgM paraprotein with lymphoplasmacytic marrow infiltration and usually no lytic bone lesions, while multiple myeloma has IgG or IgA paraprotein with plasma cell infiltration and lytic lesions. Renal failure in myeloma often arises from light chain cast nephropathy.

Which drug is commonly used for IgM anti-MAG neuropathy in Waldenstrom macroglobulinaemia?

Rituximab is commonly used for IgM anti-MAG neuropathy, because it depletes the B-cell clone producing the antibody. Plasmapheresis may give faster but temporary benefit, and the neuropathy response is usually slow.