# Waldenström macroglobulinaemia

Source: https://onco.cc/cancers/waldenstrom/  
OnCo record `waldenstrom` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Summary

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.

## Fields

- Kind: Cancer
- Last checked: 2026-09-08
- Also known as: Lymphoplasmacytic lymphoma; WM
- Tags: gap-fill; haematologic
- Group: haematologic
- Burden: About 3-4 per million per year; median age ~70; median survival now exceeds 10 years.
- Subtypes: 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)
- Biomarkers: MYD88 L265P (AS-PCR/NGS); CXCR4 mutation (S338X and others); Serum IgM and viscosity; IPSSWM / rIPSSWM; Anti-MAG antibodies (neuropathy); Cryoglobulins, cold agglutinins

## Sections of this record

The page is a hub with ten sections in reading order; large sections have their own page. The same plan as JSON: https://onco.cc/api/v1/cancers/waldenstrom/sections.json

- Overview (on the hub): The TL;DR, the family this cancer belongs to, the organ, who gets it and what the state of the art is. https://onco.cc/cancers/waldenstrom/#overview [4 state-of-the-art points]
- What it is (on the hub): Anatomy, the subtypes and how they differ, how it is staged, and where advanced disease spreads. https://onco.cc/cancers/waldenstrom/#what-it-is [5 subtypes]
- Finding it (on the hub): How it shows itself, how it is confirmed, what screening exists, and the biomarkers clinicians test for. https://onco.cc/cancers/waldenstrom/#finding-it [6 biomarkers, 1 prevalence rows]
- Treating it (on the hub): The standard of care by setting, the medicines, surgery and radiotherapy named in it, and the regimens behind them. https://onco.cc/cancers/waldenstrom/#treating-it [3 settings, 1 regimen, 2 decisions with options]
- Evidence (on the hub): Trials recruiting now, the landmark trials, the key papers and what they mean, the latest literature, and the milestones year by year. https://onco.cc/cancers/waldenstrom/#evidence [7 trials, 1 key paper, 7 milestones]
- The science (on the hub): The molecular landscape: the targets and how often each appears, the pathways, the mechanics stages and the preclinical models. https://onco.cc/cancers/waldenstrom/#science [6 targets, 1 pathway]
- Where you are (own page): Cases by country, the UK and NHS pathway and other country lenses, and the expert centres with trials on record. https://onco.cc/cancers/waldenstrom/where-you-are/
- Living with it (on the hub): The decisions you may face, the aids that walk through them, the warnings on record, the first sixty days and the questions to ask. https://onco.cc/cancers/waldenstrom/#living-with-it [14 questions, 6 red cards]
- What is coming (own page): Everything in development, the open problems and what is being done about them, the roadmaps, and what changed on this record. https://onco.cc/cancers/waldenstrom/coming/ [11 medicines, 7 trials, 4 open problems]
- Data (own page): Every connected record, the notes, the JSON, Markdown and RDF twins, and where the record came from and when it was checked. https://onco.cc/cancers/waldenstrom/data/ [57 connected records]

## Standard of care

- Asymptomatic: Observation; treat on symptoms, cytopenias, hyperviscosity or neuropathy, not on IgM level alone. ([Active surveillance](https://onco.cc/technologies/active-surveillance/))
- Symptomatic, first line: Bendamustine-rituximab or dexamethasone-rituximab-cyclophosphamide for fixed duration; or zanubrutinib / ibrutinib (± rituximab) continuously; plasmapheresis first for hyperviscosity. ([Bendamustine](https://onco.cc/drugs/bendamustine/), [Rituximab](https://onco.cc/drugs/rituximab/), [Zanubrutinib](https://onco.cc/drugs/zanubrutinib/), [Ibrutinib](https://onco.cc/drugs/ibrutinib/))
- Relapsed: Switch class (BTKi ↔ chemo-immunotherapy); bortezomib- or carfilzomib-based regimens; venetoclax; pirtobrutinib after covalent BTKi; autologous transplant in selected young patients. ([Bortezomib](https://onco.cc/drugs/bortezomib/), [Carfilzomib](https://onco.cc/drugs/carfilzomib/), [Venetoclax](https://onco.cc/drugs/venetoclax/), [Pirtobrutinib](https://onco.cc/drugs/pirtobrutinib/), [Autologous stem cell transplant (high-dose therapy)](https://onco.cc/technologies/autologous-stem-cell-transplant/))

## State of the art

- 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.
- Median survival now exceeds 10 years; death from WM itself is uncommon in patients under 70.
- Fixed-duration BTKi-venetoclax and CXCR4 antagonists are the next questions.

## 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%) is the hardest event to treat.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Waldenstr%C3%B6m_macroglobulinemia
- NCCN Guidelines: WM/LPL: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1475
- IWMF (patient foundation): https://iwmf.com/
- ASPEN (Blood 2020): https://doi.org/10.1182/blood.2020006844

## Connected records

- cancers: [Follicular lymphoma](https://onco.cc/cancers/follicular-lymphoma/), [Mantle cell lymphoma](https://onco.cc/cancers/mantle-cell-lymphoma/), [Marginal zone lymphoma](https://onco.cc/cancers/marginal-zone-lymphoma/), [Non-Hodgkin lymphoma (all types)](https://onco.cc/cancers/non-hodgkin-lymphoma/)
- technologies: [Active surveillance](https://onco.cc/technologies/active-surveillance/), [Autologous stem cell transplant (high-dose therapy)](https://onco.cc/technologies/autologous-stem-cell-transplant/), [Monoclonal antibodies](https://onco.cc/technologies/monoclonal-antibody/), [Small-molecule kinase inhibitors](https://onco.cc/technologies/kinase-inhibitors/)
- targets: [BCL-2](https://onco.cc/targets/bcl2/), [BTK (Bruton tyrosine kinase)](https://onco.cc/targets/btk/), [CD20](https://onco.cc/targets/cd20/), [CXCR4](https://onco.cc/targets/cxcr4/), [HCK kinase](https://onco.cc/targets/hck/), [MYD88](https://onco.cc/targets/myd88/)
- drugs: [Acalabrutinib](https://onco.cc/drugs/acalabrutinib/), [Bendamustine](https://onco.cc/drugs/bendamustine/), [Bortezomib](https://onco.cc/drugs/bortezomib/), [Carfilzomib](https://onco.cc/drugs/carfilzomib/), [Cladribine](https://onco.cc/drugs/cladribine/), [Ibrutinib](https://onco.cc/drugs/ibrutinib/), [Mavorixafor](https://onco.cc/drugs/mavorixafor/), [Pirtobrutinib](https://onco.cc/drugs/pirtobrutinib/), [Rituximab](https://onco.cc/drugs/rituximab/), [Venetoclax](https://onco.cc/drugs/venetoclax/), [Zanubrutinib](https://onco.cc/drugs/zanubrutinib/)
- companies: [AbbVie (incl. ImmunoGen, Capstan)](https://onco.cc/companies/abbvie/), [AstraZeneca](https://onco.cc/companies/astrazeneca/), [BeOne Medicines (formerly BeiGene)](https://onco.cc/companies/beone/), [Cellectar Biosciences](https://onco.cc/companies/cellectar/), [Johnson & Johnson](https://onco.cc/companies/johnson-johnson/), [ModeX Therapeutics](https://onco.cc/companies/modex-therapeutics/)
- terms: [BTK C481S, PLCG2 and BCL2 G101V resistance mutations](https://onco.cc/terms/btki-bcl2i-resistance-mutations/), [Histologic transformation](https://onco.cc/terms/histologic-transformation/), [IGHV mutational status](https://onco.cc/terms/ighv-status/), [M-protein, immunofixation and serum free light chains](https://onco.cc/terms/m-protein-free-light-chains/), [MYD88 L265P and CXCR4 mutations](https://onco.cc/terms/myd88-l265p/)
- trials: [A Study of Mavorixafor in Combination With Ibrutinib in Participants With Waldenstrom's Macroglobulinemia (WM) Whose Tumors Express Mutations in MYD88 and CXCR4](https://onco.cc/trials/nct04274738/), [A Study to Investigate Efficacy and Safety of BCL2 Inhibitor Sonrotoclax as Monotherapy and in Combination With Zanubrutinib in Adults With Waldenström Macroglobulinemia](https://onco.cc/trials/nct05952037/), [An Open-label, Phase 2 Study of ACP-196 in Subjects With Waldenström Macroglobulinemia](https://onco.cc/trials/nct02180724/), [ASPEN (Waldenström macroglobulinaemia)](https://onco.cc/trials/aspen-wm/), [Dose Escalation and Dose Expansion Study of MDX2003 in Patients With Different Types of Lymphoma](https://onco.cc/trials/nct07249905/), [Study of Iopofosine I-131 (CLR 131) in Select B-Cell Malignancies (CLOVER-1) With Expansion in Waldenstrom](https://onco.cc/trials/nct02952508/), [Study to Assess Change in Disease Activity of Oral Venetoclax in Adult Participants With Recurring Relapsed or Refractory (R/R) Waldenström Macroglobu](https://onco.cc/trials/nct07387471/)
- people: [Meletios A. Dimopoulos](https://onco.cc/people/meletios-dimopoulos/), [Steven P. Treon](https://onco.cc/people/steven-treon/)
- key papers: [A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenström macroglobulinemia: the ASPEN study](https://onco.cc/key-papers/paper-tam-blood/)
- pathways: [B-cell receptor / BTK signalling (to NF-κB)](https://onco.cc/pathways/bcr-signalling/)
- collections: [Lymphoma Research Foundation (LRF)](https://onco.cc/collections/lymphoma-research-foundation/)
- journals: [Clinical lymphoma, myeloma & leukemia](https://onco.cc/journals/clinical-lymphoma-myeloma-and-leukemia/)

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JSON: https://onco.cc/api/v1/entities/waldenstrom.json