Waldenström macroglobulinaemia
A slow lymphoma that makes an abnormal IgM antibody, causing thick blood, anaemia and nerve damage. Nearly all cases share one mutation (MYD88 L265P), and BTK inhibitors control it for years.
Waldenström macroglobulinaemia (WM) is an IgM-secreting lymphoplasmacytic lymphoma with MYD88 L265P in ~95% and CXCR4 WHIM-like mutations in ~30-40%, the latter predicting slower BTK-inhibitor response. Symptoms come from marrow infiltration (cytopenias), IgM (hyperviscosity, neuropathy, cryoglobulinaemia, cold agglutinins) and adenopathy. Asymptomatic WM is observed.
Treatment for symptomatic disease is rituximab-based chemo-immunotherapy (bendamustine-rituximab, DRC) or a covalent BTK inhibitor: ibrutinib (first WM approval 2015, iNNOVATE with rituximab), zanubrutinib (ASPEN 2021, fewer cardiac events than ibrutinib) or acalabrutinib. Plasmapheresis treats hyperviscosity before rituximab, which can transiently raise IgM (flare). Relapse options include the alternative class, proteasome inhibitors (bortezomib, carfilzomib), venetoclax, pirtobrutinib after covalent BTKi, and transplant in young fit patients. Bing-Neel syndrome (CNS involvement) responds to ibrutinib.
Open problems: fixed-duration versus indefinite therapy, CXCR4-mutant disease (mavorixafor trials), and transformation to DLBCL.
State of the art today
- MYD88 L265P (2012) turned WM from a descriptive diagnosis into a genotype and made BTK inhibitors the rational therapy.
- Zanubrutinib is the best-tolerated BTK inhibitor in head-to-head comparison (ASPEN) and is the preferred agent in many guidelines.
- Fixed-duration BTKi-venetoclax and CXCR4 antagonists are the next questions.
Show survival figures (1)
Averages across everyone diagnosed, often years ago. Your stage, subtype, age, fitness and the treatment you receive matter more than the average, and the numbers are improving quickly.
- Median survival now exceeds 10 years; death from WM itself is uncommon in patients under 70.
Show survival figures (1)
Averages across everyone diagnosed, often years ago. Your stage, subtype, age, fitness and the treatment you receive matter more than the average, and the numbers are improving quickly.
- About 3-4 per million per year; median age ~70; median survival now exceeds 10 years.
Where the cases are
No country-level case numbers. This cancer is not mapped to a GLOBOCAN site.
Observation; treat on symptoms, cytopenias, hyperviscosity or neuropathy, not on IgM level alone.
Bendamustine-rituximab or dexamethasone-rituximab-cyclophosphamide for fixed duration; or zanubrutinib / ibrutinib (± rituximab) continuously; plasmapheresis first for hyperviscosity.
Switch class (BTKi ↔ chemo-immunotherapy); bortezomib- or carfilzomib-based regimens; venetoclax; pirtobrutinib after covalent BTKi; autologous transplant in selected young patients.
Subtypes & biomarkers
top- MYD88-mutant, CXCR4-wild-type (~55-60%)
- MYD88-mutant, CXCR4-mutant (~30-40%)
- MYD88-wild-type (~5%, higher transformation risk)
- IgM MGUS and smouldering WM (precursors)
- Bing-Neel syndrome (CNS)
- MYD88 L265P (AS-PCR/NGS)
- CXCR4 mutation (S338X and others)
- Serum IgM and viscosity
- IPSSWM / rIPSSWM
- Anti-MAG antibodies (neuropathy)
- Cryoglobulins, cold agglutinins
Target prevalence in this cancer
| Target / alteration | Prevalence | Measure | Source |
|---|---|---|---|
| CXCR4 | 30-40% | CXCR4 mutation | doi.org |
How common each drug target or alteration is in this cancer. Population-level and approximate; see the target page for detail. Full matrix.
- 1944Waldenström describes the syndrome
Two patients with hyperviscosity, bleeding and a large serum globulin.
- 2002Consensus diagnostic criteria (IWWM-2)
- 2012MYD88 L265P discovered
Treon et al. (NEJM): whole-genome sequencing finds the mutation in over 90% of WM.
- 2014CXCR4 WHIM-like mutations
Present in ~30% and associated with BTKi resistance.
- 2015Ibrutinib: first drug ever approved for WM
- 2018iNNOVATE: ibrutinib-rituximab
- 2021Zanubrutinib approved (ASPEN)
Fewer atrial fibrillation events than ibrutinib.
Open problems
- Indefinite BTKi therapy: cost, toxicity and resistance (BTK C481S).
- CXCR4-mutant disease responds slower and shallower.
- No approved therapy specific to IgM-related neuropathy.
- Transformation to DLBCL (5-10%) carries poor prognosis.
Trials
topRecruiting now (live from ClinicalTrials.gov)
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Expert centres
topCentres linked to this cancer in OnCo
- The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research InstituteColumbus, OH, USNCI comprehensivevia Ibrutinib, BTK (Bruton tyrosine kinase)
- HOVONRotterdam, NLvia Venetoclax
- Walter and Eliza Hall Institute of Medical ResearchMelbourne, AUvia Venetoclax
Questions to ask
topQuestions to ask your oncologist about Waldenström macroglobulinaemia
Newly diagnosed
- What is my exact diagnosis, stage, and grade, and which tests established them?Why: Everything else follows from an accurate stage and subtype.
- Which biomarkers have been tested on my tumour (for example MYD88 L265P, CXCR4 mutation, Serum IgM and viscosity, IPSSWM / rIPSSWM, Anti-MAG antibodies), and what were the results?Why: These results decide eligibility for targeted therapy, immunotherapy, and trials.
- Which subtype is my cancer, and does that change the recommended treatment?Why: Recognised subtypes for this cancer include MYD88-mutant, CXCR4-wild-type, MYD88-mutant, CXCR4-mutant, MYD88-wild-type.
- Is germline (inherited) genetic testing recommended for me or my family?Why: Inherited variants can change treatment and matter for relatives.
Asymptomatic
- For my situation (asymptomatic), which of the standard options do you recommend and why?Why: Guideline options include: Observation; treat on symptoms, cytopenias, hyperviscosity or neuropathy, not on IgM level alone.
Symptomatic, first line
- For my situation (symptomatic, first line), which of the standard options do you recommend and why?Why: Guideline options include: Bendamustine-rituximab or dexamethasone-rituximab-cyclophosphamide for fixed duration; or zanubrutinib / ibrutinib (± rituximab) continuously; plasmapheresis first for hyperviscosity.
- Am I a candidate for Bendamustine, Rituximab, Zanubrutinib or related drugs, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
Relapsed
- For my situation (relapsed), which of the standard options do you recommend and why?Why: Guideline options include: Switch class (BTKi ↔ chemo-immunotherapy); bortezomib- or carfilzomib-based regimens; venetoclax; pirtobrutinib after covalent BTKi; autologous transplant in selected young patients.
- Am I a candidate for Bortezomib, Carfilzomib, Venetoclax or related drugs, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
Any stage
- Are there clinical trials I could join, for example of Pirtobrutinib, Venetoclax, Zanubrutinib?Why: Trials are how the next standard of care is set; asking early keeps options open.
- Would a second opinion at a high-volume centre change anything, and can you help arrange it?Why: Rare or high-stakes decisions benefit from a centre that treats many similar patients.
- What supportive care (symptom control, nutrition, exercise, mental health, financial help) is available from the start?Why: Supportive care improves quality of life and helps patients complete treatment.
- I read that “Indefinite BTKi therapy: cost, toxicity and resistance (BTK C481S)”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
- I read that “CXCR4-mutant disease responds slower and shallower”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
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topQuery for this cancer: (TITLE:"Waldenström macroglobulinaemia" OR ABSTRACT:"Waldenström macroglobulinaemia" OR TITLE:"Lymphoplasmacytic lymphoma" OR ABSTRACT:"Lymphoplasmacytic lymphoma") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about Waldenström macroglobulinaemia, not a curated reading list.