Waldenstrom Macroglobulinaemia
B-cell lymphoproliferative disorder characterised by bone marrow infiltration with lymphoplasmacytic lymphoma and production of monoclonal IgM paraprotein.
Key Facts
Waldenström macroglobulinaemia (WM) is a rare lymphoplasmacytic lymphoma producing monoclonal IgM paraprotein Incidence approximately 3 per million per year in the UK; median age at diagnosis 65-70 years MYD88 L265P mutation found in >90% of cases – key diagnostic marker distinguishing from other IgM-producing lymphomas Hyperviscosity syndrome occurs in 10-30% due to pentameric IgM structure causing increased serum viscosity First-line treatment: rituximab-based chemotherapy (e.g., DRC: dexamethasone, rituximab, cyclophosphamide) Ibrutinib 420mg OD (BTK inhibitor) is effective in relapsed/refractory disease and increasingly used first-line Median overall survival is approximately 5-8 years with treatment
Overview
Key Facts
Waldenström macroglobulinaemia is a lymphoplasmacytic lymphoma characterised by infiltration of the bone marrow by clonal lymphoplasmacytic cells and secretion of monoclonal IgM. The large pentameric IgM molecule predisposes to hyperviscosity syndrome.
Epidemiology
- Rare: approximately 1,500 people living with WM in the UK
- Median age at diagnosis: 65-70 years
- Male predominance (M:F ratio 2:1)
- More common in White European populations
- Accounts for 1-2% of haematological malignancies
Aetiology
- Exact cause unknown; often preceded by IgM MGUS
- IgM MGUS progresses to WM at 1.5% per year
- MYD88 L265P mutation is present in >90% (activates NF-κB signalling)
- CXCR4 mutations in ~30% (associated with resistance to ibrutinib)
- Familial clustering observed; first-degree relatives have 20-fold increased risk
Pathophysiology
- Clonal B-cell lymphoplasmacytic proliferation in bone marrow
- Overproduction of monoclonal IgM (pentameric) → markedly raised serum viscosity
- Hyperviscosity: IgM is the largest immunoglobulin → sludging of blood in microcirculation
- Bone marrow infiltration → cytopenias (anaemia most common)
- IgM may act as autoantibody → cold agglutinin disease, peripheral neuropathy, cryoglobulinaemia
- Unlike myeloma, lytic bone lesions are rare
Clinical Presentation
Constitutional Symptoms
- Fatigue (most common, due to anaemia)
- Weight loss, night sweats
- Hepatosplenomegaly and lymphadenopathy (more common than in myeloma)
Hyperviscosity Syndrome (10-30%)
- Visual disturbance: blurred vision, diplopia
- Headache, confusion, somnolence
- Mucosal bleeding: epistaxis, gingival bleeding
- Fundoscopy: engorged retinal veins ("sausage-link" appearance), papilloedema, retinal haemorrhages
IgM-Related Complications
- Peripheral neuropathy (20-25%): anti-MAG antibodies → sensorimotor neuropathy
- Cold agglutinin disease: Raynaud phenomenon, acrocyanosis, haemolytic anaemia in cold
- Cryoglobulinaemia: purpura, arthralgia, renal involvement
- AL amyloidosis (rare)
Red Flags
- Sudden visual loss or severe headache → hyperviscosity emergency → urgent plasmapheresis
- Rapidly worsening cytopenias → marrow failure
- Unexplained neuropathy with IgM paraprotein → investigate for WM
Differential Diagnosis
| Diagnosis | Key Features | Investigation |
|---|---|---|
| IgM MGUS | IgM <30 g/L, no symptoms, no marrow infiltration | SPEP, bone marrow |
| Multiple myeloma | IgG/IgA paraprotein (rarely IgM), lytic lesions, CRAB | SPEP, imaging, marrow |
| Marginal zone lymphoma | May produce IgM, splenic involvement | CT, bone marrow, flow cytometry |
| CLL | Lymphocytosis, smear cells, rarely IgM paraprotein | Blood film, flow cytometry |
| Primary amyloidosis | Organ deposition, various Ig types | Congo red stain, SAP scan |
| Cryoglobulinaemia (Hep C) | HCV-associated, vasculitis, mixed cryoglobulins | Cryoglobulins, HCV serology |
Diagnosis / Investigation
Bedside
- Fundoscopy: hyperviscosity changes (dilated veins, haemorrhages)
- Peripheral neurological examination: neuropathy assessment
Bloods
- FBC: anaemia (normocytic), may show rouleaux
- SPEP and immunofixation: monoclonal IgM band
- Serum IgM level: typically >30 g/L
- Serum free light chains
- Serum viscosity: >4 cP associated with hyperviscosity symptoms
- Beta-2 microglobulin: prognostic
- LDH: prognostic
- DAT (Coombs test): if cold agglutinin disease suspected
- Cryoglobulins: if cryoglobulinaemia suspected
- Hepatitis B and C serology: exclude HCV-associated cryoglobulinaemia
Imaging
- CT neck/chest/abdomen/pelvis: lymphadenopathy, hepatosplenomegaly
- MRI brain: if CNS involvement suspected (Bing-Neel syndrome)
Special Tests
- Bone marrow aspirate and trephine: lymphoplasmacytic infiltrate, confirm clonality
- MYD88 L265P mutation testing: present in >90% (helps distinguish from marginal zone lymphoma)
- CXCR4 mutation testing: treatment implications
- Nerve conduction studies: if neuropathy present
- Anti-MAG antibodies: if peripheral neuropathy
Management
Non-pharmacological
- Watch and wait if asymptomatic (smouldering WM) – regular monitoring
- Treatment indicated for: symptomatic hyperviscosity, cytopenias, neuropathy, constitutional symptoms, amyloidosis, cryoglobulinaemia
Pharmacological
First-line:
- DRC regimen: dexamethasone 20mg IV day 1 + rituximab 375 mg/m² IV + cyclophosphamide 100 mg/m² BD PO days 1-5, q21 days × 6 cycles
- Alternative: bendamustine-rituximab (BR): bendamustine 90 mg/m² IV days 1-2 + rituximab, q28 days × 6
- Ibrutinib 420mg OD – increasingly used first-line, particularly if MYD88 mutated
- Avoid rituximab monotherapy initially if IgM >40 g/L (risk of IgM flare)
Hyperviscosity emergency:
- Urgent plasmapheresis to rapidly reduce IgM levels
- Followed by systemic chemotherapy
Relapsed disease:
- Ibrutinib, zanubrutinib, venetoclax, bortezomib-based regimens
- Zanubrutinib 160mg BD (ASPEN trial) – second-generation BTK inhibitor
Referral Criteria
- All patients with IgM paraprotein → haematology
- Acute visual loss or neurological symptoms → urgent assessment for plasmapheresis
Prognosis
- Median overall survival: 5-8 years with modern therapy
- International Prognostic Scoring System for WM (IPSSWM): age >65, Hb ≤115 g/L, platelets ≤100, β2M >3, IgM >70 g/L
- Low-risk IPSSWM: 5-year survival 87%
- High-risk IPSSWM: 5-year survival 36%
- Risk of transformation to DLBCL (diffuse large B-cell lymphoma) in 5-10%
- Neuropathy can be debilitating and may not fully resolve with treatment
Other Relevant Information
IPSSWM Prognostic Scoring
| Risk Factor | Criterion |
|---|---|
| Age | >65 years |
| Haemoglobin | ≤115 g/L |
| Platelets | ≤100 × 10⁹/L |
| β2-microglobulin | >3 mg/L |
| IgM level | >70 g/L |
| Risk Group | Factors | 5-year Survival |
|---|---|---|
| Low | 0-1 (except age) | 87% |
| Intermediate | 2 or age only | 68% |
| High | ≥3 | 36% |
Key Differences: WM vs Multiple Myeloma
| Feature | WM | Myeloma |
|---|---|---|
| Paraprotein | IgM | IgG/IgA (rarely IgM) |
| Bone lesions | Rare | Common (lytic) |
| Hyperviscosity | Common (10-30%) | Rare |
| Lymphadenopathy | Common | Rare |
| MYD88 mutation | >90% | Rare |