Waldenström macroglobulinaemia
Description
- Lymphoplasmacytic lymphoma + IgM paraprotein - both required
- An indolent B-cell lymphoma that behaves like a plasma cell disorder
- Symptoms come from three separate sources - separate them, they need different treatment
- Tumour infiltration - cytopenias, nodes, spleen, liver
- IgM as a protein - hyperviscosity, cryoglobulinaemia, cold agglutinins, amyloid
- IgM as an autoantibody - anti-MAG neuropathy, Bing-Neel (CNS)
- *No lytic bone lesions, no hypercalcaemia, renal failure uncommon* - the discriminator from myeloma
- Smouldering / asymptomatic WM - marrow disease + IgM, no symptoms. Observe
Epidemiology
- Rare: ~3-5 per million/yr; ~150 new cases/yr Australia
- Median age ~70; M>F ~2:1; more common in white populations
- Familial clustering in ~20% - 1st-degree relatives have inc risk of WM, other B-cell malignancy, MGUS
- Preceded by IgM MGUS in essentially all (~1.5-2%/yr progression)
Aetiopathogenesis
- Clonal lymphoplasmacytic cells - spectrum from small lymphocyte to plasma cell
- MYD88 L265P in >90%
- -> IRAK/BTK -> constitutive NF-kB
- This is why BTK inhibitors work
- CXCR4 mutations ~30-40% (WHIM-like)
- -> higher IgM, more hyperviscosity, slower/lower response to BTKi
- IgM pentamer: large, ~80% intravascular
- -> disproportionate contribution to serum viscosity for its concentration
- -> and why plasmapheresis works so well
Diagnosis
Diagnostic requirements
- IgM monoclonal paraprotein of any concentration, AND
- >=10% marrow lymphoplasmacytic infiltration on trephine, with a compatible immunophenotype
Immunophenotype
- CD19+, CD20+, CD22+, sIgM+, CD5-, CD10-, CD23-
- CD5 negative separates from CLL and mantle cell; CD10 negative from follicular
- Plasmacytic component: CD138+, cytoplasmic IgM
- MYD88 L265P by allele-specific PCR - supports the diagnosis, distinguishes from IgM myeloma and marginal zone lymphoma
- CXCR4 mutation status - prognostic and predictive for BTKi
Hyperviscosity syndrome
- Symptoms, not a number, define it. Serum viscosity correlates poorly between patients.
- Oronasal and gingival bleeding - often the first sign
- Visual: blurred vision, diplopia; retinal vein engorgement ("sausage-link"/box-car veins), haemorrhages, papilloedema
- Neurological: headache, vertigo, dizziness, nystagmus, tinnitus, ataxia, paraesthesias
- Severe: confusion, dementia, stupor, stroke, coma
- Fundoscopy in every patient with IgM >30 g/L - it is the bedside viscometer
- Typically at IgM >40-50 g/L / viscosity >4 cP, but individual thresholds vary
Other tests
- Serum IgM quantitation + EPG/IFE (IgM kappa in ~80%); nephelometric IgM and EPG-derived paraprotein diverge - track one consistently
- Cryoglobulins (draw and transport at 37 degrees), cold agglutinins, DAT
- Anti-MAG antibodies if neuropathy
- Beta-2 microglobulin, albumin, LDH (for IPSSWM)
- CT chest/abdo/pelvis; PET only if transformation suspected
- MRI brain + CSF flow/PCR (MYD88) if Bing-Neel suspected
- Pseudoanaemia - plasma volume expansion by IgM dilutes Hb; and rouleaux/high ESR are near-universal
IPSSWM
- Age, Hb <=115, platelets <=100, beta-2 microglobulin >3 mg/L, IgM >70 g/L
Management
A. Hyperviscosity - a medical emergency
- Plasmapheresis immediately - removes ~75% of IgM per exchange because IgM is largely intravascular
- Triggered by symptoms and fundoscopy, not by a viscosity level
- Temporising only - always follow with disease-directed therapy or it recurs within days to weeks
- *Do not transfuse red cells before plasmapheresis* - raises viscosity further
- Avoid rituximab as the first agent when IgM >40 g/L
- IgM flare - transient IgM rise in ~40-50%, can precipitate hyperviscosity
- Plasmapherese first, or start with a non-rituximab agent and add anti-CD20 once IgM has fallen
B. When to treat
Never treat the paraprotein number alone.
- Hyperviscosity symptoms
- Hb <100 g/L or platelets <100 from marrow infiltration
- Constitutional/B symptoms, bulky symptomatic nodes or spleen
- Symptomatic cryoglobulinaemia, cold agglutinin haemolysis, AL amyloidosis, progressive anti-MAG neuropathy
- Smouldering WM: observe, 3-6 monthly
C. First-line therapy - choose by IgM level, need for rapid response and comorbidity
| Option | Notes |
|---|---|
| Covalent BTK inhibitor (zanubrutinib preferred; ibrutinib) | Continuous, all-oral, no IgM flare, deep durable responses. Zanubrutinib: less AF and hypertension than ibrutinib (ASPEN); better in MYD88 wild-type. CXCR4 mutation -> slower, shallower response |
| Bendamustine-rituximab | Fixed duration ~6 cycles, rapid cytoreduction. Best where bulky disease or rapid response needed; avoid if stem cell harvest planned |
| Dexamethasone-rituximab-cyclophosphamide (DRC) | Gentler, fixed duration, frail patients |
| Bortezomib-based | Rapid IgM reduction, no marrow toxicity; peripheral neuropathy - avoid with anti-MAG neuropathy |
- Avoid chlorambucil/fludarabine and prolonged alkylator exposure - MDS/AML risk
- *Response is assessed by IgM, and IgM falls slowly - do not declare failure early*
D. Relapsed disease
- Switch mechanism: BTKi <-> fixed-duration chemoimmunotherapy
- Pirtobrutinib (non-covalent BTKi) after covalent BTKi failure
- Venetoclax - active, especially post-BTKi
- Autologous SCT in selected young multiply-relapsed patients
- Bing-Neel: ibrutinib or high-dose methotrexate/cytarabine - CNS-penetrant agents
E. Symptom-directed
- Anti-MAG neuropathy: rituximab-based, treat early - axonal loss is irreversible
- Cold agglutinin disease: avoid cold, treat the clone
- Cryoglobulinaemia: plasmapheresis if severe + clone-directed therapy
- Avoid IV contrast if there is renal impairment; caution with transfusion
Associations
- IgM MGUS (the obligate precursor)
- Type I and type II cryoglobulinaemia
- Cold agglutinin disease
- AL amyloidosis (~5%)
- Anti-MAG demyelinating peripheral neuropathy - distal, symmetrical, sensory-predominant, ataxic
- Acquired von Willebrand syndrome (IgM binds VWF)
- Bing-Neel syndrome (CNS infiltration)
- Schnitzler syndrome (IgM + urticaria + fever)
- Familial clustering with other B-cell malignancy
Natural history & complications
- Indolent; median survival now >10-15 years and many die of unrelated causes
- Age and comorbidity dominate outcome more than disease burden
Adverse markers
- High IPSSWM, MYD88 wild-type (worse, and BTKi less effective), CXCR4 mutation (delayed BTKi response)
- TP53 disruption, high beta-2 microglobulin, low albumin
Complications
- Hyperviscosity, cryoglobulinaemic vasculitis, cold agglutinin haemolysis
- Transformation to DLBCL ~2-10% - rising LDH, B symptoms, rapid nodal growth, falling IgM with worsening disease
- Secondary MDS/AML (alkylator- and nucleoside-analogue related)
- Recurrent infection from hypogammaglobulinaemia of the uninvolved classes
Monitoring
- IgM, FBE, symptoms 3-monthly initially
- Fundoscopy whenever IgM is high or rising
- A rising IgM without symptoms is not itself an indication to treat
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