Waldenstrom macroglobulinemia

Summary

Waldenstrom macroglobulinemia (MONDO:0100280) is a disease with 1 cohort gene (7 GWAS associations across 2 studies) and 288 clinical trials. Top therapeutic interventions include ibrutinib, pirtobrutinib, and yttrium y 90 ibritumomab tiuxetan.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• GWAS associations: 7
• Phenotypes (HPO): 45
• Clinical trials: 288

Clinical features

Epidemiology

Prevalence records

6 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 1 000 000	0.81	Europe	Validated
Point prevalence	1-9 / 100 000		Europe	Validated
Annual incidence	1-9 / 100 000	2.05	France	Validated
Annual incidence	1-9 / 1 000 000	0.38	United States	Validated
Annual incidence	1-9 / 1 000 000	0.55	United Kingdom	Validated
Annual incidence	1-9 / 1 000 000	0.31	Spain	Validated

Signs & symptoms

Clinical features (HPO)

45 HPO clinical features (Orphanet curated; top 45 by frequency):

HPO ID	Term	Frequency
HP:0001909	Leukemia	Very frequent (80-99%)
HP:0002665	Lymphoma	Very frequent (80-99%)
HP:0005508	Monoclonal immunoglobulin M proteinemia	Very frequent (80-99%)
HP:0000225	Gingival bleeding	Frequent (30-79%)
HP:0000980	Pallor	Frequent (30-79%)
HP:0001874	Abnormality of neutrophils	Frequent (30-79%)
HP:0001897	Normocytic anemia	Frequent (30-79%)
HP:0002093	Respiratory insufficiency	Frequent (30-79%)
HP:0002321	Vertigo	Frequent (30-79%)
HP:0100724	Hypercoagulability	Frequent (30-79%)
HP:0000083	Renal insufficiency	Occasional (5-29%)
HP:0000365	Hearing impairment	Occasional (5-29%)
HP:0000421	Epistaxis	Occasional (5-29%)
HP:0000520	Proptosis	Occasional (5-29%)
HP:0000573	Retinal hemorrhage	Occasional (5-29%)
HP:0000965	Cutis marmorata	Occasional (5-29%)
HP:0000979	Purpura	Occasional (5-29%)
HP:0001025	Urticaria	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001297	Stroke	Occasional (5-29%)
HP:0001635	Congestive heart failure	Occasional (5-29%)
HP:0001744	Splenomegaly	Occasional (5-29%)
HP:0001945	Fever	Occasional (5-29%)
HP:0002014	Diarrhea	Occasional (5-29%)
HP:0002024	Malabsorption	Occasional (5-29%)
HP:0002039	Anorexia	Occasional (5-29%)
HP:0002076	Migraine	Occasional (5-29%)
HP:0002113	Pulmonary infiltrates	Occasional (5-29%)
HP:0002202	Pleural effusion	Occasional (5-29%)
HP:0002239	Gastrointestinal hemorrhage	Occasional (5-29%)
HP:0002240	Hepatomegaly	Occasional (5-29%)
HP:0002354	Memory impairment	Occasional (5-29%)
HP:0002633	Vasculitis	Occasional (5-29%)
HP:0002716	Lymphadenopathy	Occasional (5-29%)
HP:0002719	Recurrent infections	Occasional (5-29%)
HP:0003565	Elevated erythrocyte sedimentation rate	Occasional (5-29%)
HP:0004372	Reduced consciousness/confusion	Occasional (5-29%)
HP:0006824	Cranial nerve paralysis	Occasional (5-29%)
HP:0008046	Abnormal retinal vascular morphology	Occasional (5-29%)
HP:0009830	Peripheral neuropathy	Occasional (5-29%)
HP:0010741	Pedal edema	Occasional (5-29%)
HP:0010841	Multifocal epileptiform discharges	Occasional (5-29%)
HP:0012378	Fatigue	Occasional (5-29%)
HP:0100539	Periorbital edema	Occasional (5-29%)
HP:0100778	Cryoglobulinemia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Waldenstrom macroglobulinemia
Mondo ID	MONDO:0100280
EFO	EFO:0009441
MeSH	D008258
OMIM	153600
Orphanet	33226
DOID	DOID:0060901
ICD-10-CM	C88.0
NCIT	C80307
UMLS	C0024419
MedGen	6174
GARD	0007872
MedDRA	10047801
NORD	1834
Is cancer (heuristic)	no

Also known as: macroglobulinemia of Waldenstrom · Waldenstrom macroglobulinemia · Waldenstrom’s macroglobulinaemia · Waldenstrom’s macroglobulinemia · Waldenstrom’s syndrome · Waldenström Macroglobulinemia · Waldenström macroglobulinemia

Data availability: 7 GWAS associations (2 studies) · 15 cell lines.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › immune system disorder › leukocyte disorder › B-cell neoplasm › lymphoplasmacytic lymphoma › Waldenstrom macroglobulinemia

Subtypes (2): macroglobulinemia, Waldenstrom, 2, macroglobulinemia, Waldenstrom, 1

Genetics & variants

GWAS landscape

7 GWAS associations across 2 studies. Top hits map to 4 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs116446171	1e-54	IRF4 - EXOC2	G	21.14
rs117972357	2e-28	LINC02318	?	20.81
rs117410836	9e-19	LINC02318 - TCL6	C	4.9
rs550571596	1e-08	FAM184B	A	11.88
rs114087367	1e-07	PKHD1 - MIR206	?	6.27
rs75402334	1e-07	EXOC2	?	26.21
rs179159	5e-07	SYNE3	A	1.54

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90624744	Guler M	2025	361	656,254	Clustering of lymphoid neoplasms by cell of origin, somatic mutation and drug usage profiles: a multi-trait genome-wide association study.
GCST006982	McMaster ML	2018	217	3,798	Two high-risk susceptibility loci at 6p25.3 and 14q32.13 for Waldenström macroglobulinemia.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	7

MAF distribution

Bucket	Variants
common (>=0.05)	2
low_freq (0.01-0.05)	2
rare (<0.01)	1
unknown	2

Functional consequences

Consequence	Count
intron_variant	4
intergenic_variant	3

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs116446171	6	484453	C>G	0.019	intergenic_variant	IRF4 - EXOC2	1e-54	Tier 4: intronic/intergenic
rs117972357	14	95577209	G>A		intron_variant	LINC02318	2e-28	Tier 4: intronic/intergenic
rs117410836	14	95585637	T>C	0.027	intergenic_variant	LINC02318 - TCL6	9e-19	Tier 4: intronic/intergenic
rs550571596	4	17674036	T>A	0.003	intron_variant	FAM184B	1e-08	Tier 4: intronic/intergenic
rs114087367	6	52127513	A>C,G		intergenic_variant	PKHD1 - MIR206	1e-07	Tier 4: intronic/intergenic
rs75402334	6	575613	C>T	0.05	intron_variant	EXOC2	1e-07	Tier 4: intronic/intergenic
rs179159	14	95506111	A>G,T	0.247	intron_variant	SYNE3	5e-07	Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 0 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
EXOC2	HGNC:24968	ENSG00000112685	Q96KP1	Exocyst complex component 2	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
EXOC2	Exocyst complex component 2	Component of the exocyst complex involved in the docking of exocytic vesicles with fusion sites on the plasma membrane.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Antibody/Immunoglobulin	1	29.2×	0.034

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
EXOC2	Antibody/Immunoglobulin	yes		IPT_dom, Ig-like_fold, Ig_E-set

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cortical plate	1
male germ line stem cell (sensu Vertebrata) in testis	1
middle temporal gyrus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
EXOC2	255	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, middle temporal gyrus, cortical plate

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EXOC2	2,587

Structural data

PDB: 0 · AlphaFold-only: 1 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
EXOC2	Q96KP1	80.82

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
VxPx cargo-targeting to cilium	1	519.1×	0.003	EXOC2
Insulin processing	1	456.8×	0.003	EXOC2
Translocation of SLC2A4 (GLUT4) to the plasma membrane	1	154.3×	0.006	EXOC2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of entry of bacterium into host cell	1	3370.4×	0.002	EXOC2
obsolete vesicle tethering involved in exocytosis	1	1872.4×	0.002	EXOC2
obsolete vesicle docking involved in exocytosis	1	674.1×	0.004	EXOC2
Golgi to plasma membrane transport	1	561.7×	0.004	EXOC2
membrane fission	1	411.0×	0.004	EXOC2
mitotic cytokinesis	1	259.3×	0.005	EXOC2
exocytosis	1	151.8×	0.008	EXOC2
protein transport	1	43.9×	0.023	EXOC2

Therapeutics

Drugs indicated for this disease

2 approved, 9 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Ibrutinib	Approved (phase 4)
Zanubrutinib	Approved (phase 4)
Bortezomib	Phase 3 (in late-stage trials)
Cyclosporine	Phase 3 (in late-stage trials)
Dexamethasone	Phase 3 (in late-stage trials)
Doxorubicin	Phase 3 (in late-stage trials)
Fludarabine Phosphate	Phase 3 (in late-stage trials)
Mycophenolate Mofetil	Phase 3 (in late-stage trials)
Prednisone	Phase 3 (in late-stage trials)
Rituximab	Phase 3 (in late-stage trials)
Vincristine	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): ANTINEOPLASTON A10, Acalabrutinib, Alemtuzumab, Bendamustine, Carfilzomib, Daratumumab, Enzastaurin, Epratuzumab, Etoposide, Everolimus, Fludarabine, Idelalisib, Ixazomib, Ixazomib Citrate, Lenalidomide, Loncastuximab Tesirine, Melphalan, Methotrexate, Obinutuzumab, Ofatumumab, Orelabrutinib, Panobinostat, Pembrolizumab, Perifosine, Pirtobrutinib, Simvastatin, Sonrotoclax, TOSITUMOMAB 131I, Tacrolimus Anhydrous, Thalidomide, Umbralisib, Valacyclovir, Venetoclax, YTTRIUM Y 90 IBRITUMOMAB TIUXETAN.

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
EXOC2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	EXOC2
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
EXOC2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 288.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	112
PHASE1	84
PHASE1/PHASE2	42
Not specified	37
PHASE3	5
PHASE4	4
EARLY_PHASE1	3
PHASE2/PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02844309	PHASE4	COMPLETED	The Efficacy of TCD Following by TP Maintenance Therapy in Newly Diagnosed WM
NCT02844322	PHASE4	COMPLETED	The Comparison of RCD Versus BCD in Newly Diagnosed Waldenström Macroglobulinemia
NCT02844361	PHASE4	COMPLETED	Comparison of ASCT and Conventional Chemotherapy in High Risk Waldenström Macroglobulinemia
NCT04042376	PHASE4	COMPLETED	A Study of Ibrutinib (PCI-32765) in Chinese Participants With Relapse or Refractory Waldenstrom’s Macroglobulinemia (WM)
NCT01804686	PHASE3	RECRUITING	A Long-term Extension Study of PCI-32765 (Ibrutinib)
NCT04061512	PHASE2/PHASE3	RECRUITING	Rituximab and Ibrutinib (RI) Versus Dexamethasone, Rituximab and Cyclophosphamide (DRC) as Initial Therapy for Waldenström’s Macroglobulinaemia
NCT00075478	PHASE3	COMPLETED	Total-Body Irradiation With or Without Fludarabine Phosphate Followed By Donor Stem Cell Transplant in Treating Patients With Hematologic Cancer
NCT00566332	PHASE3	COMPLETED	Trial Comparing Chlorambucil to Fludarabine in Patients With Advanced Waldenström Macroglobulinemia
NCT01231412	PHASE3	COMPLETED	Graft-Versus-Host Disease Prophylaxis in Treating Patients With Hematologic Malignancies Undergoing Unrelated Donor Peripheral Blood Stem Cell Transplant
NCT02991638	PHASE3	UNKNOWN	Efficacy and Safety of Ibrutinib in Patients With CLL and Other Indolent B-cell Lymphomas Who Are Chronic Hepatitis B Virus Carriers or Occult Hepatitis B Virus Carriers
NCT00492050	PHASE2	ACTIVE_NOT_RECRUITING	Bortezomib and Rituximab for Patients With Waldenstrom’s Macroglobulinemia
NCT02180724	PHASE2	ACTIVE_NOT_RECRUITING	An Open-label, Phase 2 Study of ACP-196 in Subjects With Waldenström Macroglobulinemia
NCT02339922	PHASE2	ACTIVE_NOT_RECRUITING	Ixazomib Citrate and Rituximab in Treating Patients With Indolent B-cell Non-Hodgkin Lymphoma
NCT02952508	PHASE2	ACTIVE_NOT_RECRUITING	Study of Iopofosine I-131 (CLR 131) in Select B-Cell Malignancies (CLOVER-1) With Expansion in Waldenstrom
NCT03015896	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Nivolumab and Lenalidomide in Treating Patients With Relapsed or Refractory Non-Hodgkin or Hodgkin Lymphoma
NCT03147885	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Selinexor Plus Combination Chemotherapy in Treating Patients With Advanced B Cell Non-Hodgkin Lymphoma
NCT03162536	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Study of Nemtabrutinib (MK-1026) in Participants With Relapsed or Refractory Hematologic Malignancies (ARQ 531-101/MK-1026-001)
NCT03192397	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Chemotherapy, Total Body Irradiation, and Post-Transplant Cyclophosphamide in Reducing Rates of Graft Versus Host Disease in Patients With Hematologic Malignancies Undergoing Donor Stem Cell Transplant
NCT03620903	PHASE2	ACTIVE_NOT_RECRUITING	Efficacy of First Line B-RI for Treatment Naive Waldenström’s Macroglobulinemia
NCT04263480	PHASE2	ACTIVE_NOT_RECRUITING	Efficacy and Safety of Carfilzomib in Combination With Ibrutinib vs Ibrutinib in Waldenström’s Macroglobulinemia
NCT04273139	PHASE2	ACTIVE_NOT_RECRUITING	Ibrutinib + Venetoclax in Untreated WM
NCT04624906	PHASE2	ACTIVE_NOT_RECRUITING	Bendamustine, Rituximab and Acalabrutinib in Waldenstrom’s Macroglobulinemia
NCT04840602	PHASE2	RECRUITING	Testing the Combination of Venetoclax and Rituximab, in Comparison to the Usual Treatment (Ibrutinib Plus Rituximab or Zanubrutinib Alone) for Waldenstrom’s Macroglobulinemia/Lymphoplasmacytic Lymphoma
NCT05006716	PHASE1/PHASE2	RECRUITING	A Dose-Escalation and Expansion Study of BGB-16673 in Participants With B-Cell Malignancies
NCT05065554	PHASE2	ACTIVE_NOT_RECRUITING	ACALA-R In Predominantly Demyelinating IgM Mediated Neuropathy
NCT05099471	PHASE2	RECRUITING	Efficacy of Venetoclax in Combination With Rituximab in Waldenström’s Macroglobulinemia
NCT05190705	PHASE2	ACTIVE_NOT_RECRUITING	Loncastuximab Tesirine in WM
NCT05294731	PHASE1/PHASE2	RECRUITING	Treatment of Chinese Participants With B-Cell Malignancies With BGB-16673, a Bruton Tyrosine Kinase-Targeted Protein-Degrader
NCT05734495	PHASE2	ACTIVE_NOT_RECRUITING	Pirtobrutinib and Venetoclax in Waldenström Macroglobulinemia
NCT05914662	PHASE2	RECRUITING	Zanubrutinib Plus BR in Newly Diagnosed Symptomatic WM
NCT05952037	PHASE2	ACTIVE_NOT_RECRUITING	A Study to Investigate Efficacy and Safety of BCL2 Inhibitor Sonrotoclax as Monotherapy and in Combination With Zanubrutinib in Adults With Waldenström Macroglobulinemia
NCT06510491	PHASE2	RECRUITING	Epcoritamab in Previously Treated WM
NCT06547866	PHASE2	NOT_YET_RECRUITING	Study Evaluating the Efficacy and Tolerance of a Zanubrutinib and BGB-11417 Combination in Patients Previously Treated for Waldenström Macroglobulinemia
NCT06561347	PHASE2	RECRUITING	Zanubrutinib, Bendamustine, Rituximab Prev. Untreated WM
NCT06986174	PHASE2	RECRUITING	A Phase 2 Study to Evaluate the Safety and Efficacy of Pacritinib in Relapsed or Refractory Waldenström Macroglobulinemia
NCT07231952	PHASE2	RECRUITING	A Study of Pirtobrutinib, Venetoclax, and Rituximab in People With Waldenström’s Macroglobulinemia (WM)/Lymphoplasmacytic Lymphoma (LPL)
NCT07249905	PHASE1/PHASE2	RECRUITING	Dose Escalation and Dose Expansion Study of MDX2003 in Patients With Different Types of Lymphoma
NCT07259122	PHASE2	NOT_YET_RECRUITING	A Phase II Clinical Study of Zanubrutinib Combined With Four Cycles of CD20 Monoclonal Antibody and Reduced-Dose Bendamustine in the Treatment of Untreated Waldenström Macroglobulinemia
NCT07387471	PHASE2	RECRUITING	Study to Assess Change in Disease Activity of Oral Venetoclax in Adult Participants With Recurring Relapsed or Refractory (R/R) Waldenström Macroglobulinemia (WM)/Lymphoplasmacytic Lymphoma (LPL)
NCT07420959	PHASE1/PHASE2	NOT_YET_RECRUITING	ABBV-383 for the Treatment of Relapsed Refractory Waldenström Macroglobulinemia

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
IBRUTINIB	4	7
PIRTOBRUTINIB	4	6
YTTRIUM Y 90 IBRITUMOMAB TIUXETAN	4	5
ZANUBRUTINIB	4	5
ACALABRUTINIB	4	4
BENDAMUSTINE HYDROCHLORIDE	4	4
IDELALISIB	4	4
ALEMTUZUMAB	4	3
FLUDARABINE PHOSPHATE	4	3
PANOBINOSTAT	4	3
TEMSIROLIMUS	4	3
UBLITUXIMAB	4	3
BELINOSTAT	4	2
CARFILZOMIB	4	2
IXAZOMIB CITRATE	4	2
LONCASTUXIMAB TESIRINE	4	2
PACRITINIB	4	2
UMBRALISIB	4	2
ATORVASTATIN CALCIUM	4	1
BORTEZOMIB	4	1
BRENTUXIMAB VEDOTIN	4	1
CHLORAMBUCIL	4	1
CYANOCOBALAMIN	4	1
DARATUMUMAB	4	1
DEFERASIROX	4	1
EPCORITAMAB	4	1
FOSCARNET	4	1
FOSCARNET SODIUM	4	1
GANCICLOVIR	4	1
IPILIMUMAB	4	1