Waldenström's macroglobulinaemia (WM) is a rare indolent B-cell lymphoma that most commonly occurs in older white men.
The pathophysiological hallmark is monoclonal immunoglobulin M (IgM) production by a malignant lymphoplasmacytic clone that resides in the bone marrow.
Diagnosis is most often made following an incidental finding of an IgM paraprotein on a blood test.
Anaemia (due to marrow infiltration), fatigue, and anorexia are the most common clinical features.
Lymphadenopathy, splenomegaly, and hyperviscosity (which can lead to skin and mucosal bleeding, thrombosis, retinopathy with visual disturbances, and neurological symptoms such as headache, dizziness, and vertigo) are uncommon, but they are important clinical manifestations that require urgent treatment.
WM is incurable but median overall survival is long (approximately 8 years based on US data). Goals of treatment are to reduce symptoms, improve quality of life, and prolong survival. Treatment options include observation (for asymptomatic patients), plasmapheresis, chemotherapy, and targeted therapies (e.g., rituximab and ibrutinib).
There is no standard of care, mainly due to a lack of randomised trials in WM. Participation in clinical trials is recommended where possible.
Waldenström's lymphoma can transform to aggressive high-grade lymphomas in around 5% of cases.
Waldenström's macroglobulinaemia (WM) is an indolent lymphoma in which malignant monoclonal plasmacytoid lymphocytes infiltrate bone marrow and visceral organs, and hypersecrete a monoclonal immunoglobulin M (IgM). It is often diagnosed following an incidental finding of an IgM paraprotein on a blood test.
Clinical manifestations are most commonly related to bone marrow infiltration by malignant cells (e.g., anaemia, thrombocytopenia, pancytopenia). Clinical manifestations are less commonly related to organ infiltration (e.g., splenomegaly, hepatomegaly, and lymphadenopathy) and abnormal IgM properties and/or organ deposition (e.g., hyperviscosity syndrome, polyneuropathy, cryoglobulinaemia, cold agglutinin haemolytic anaemia, bleeding from the nose and gums, purpura, thrombosis [e.g., stroke, angina, myocardial infarction, pulmonary embolism, deep vein thrombosis], and kidney disease). The most common presenting symptoms are fatigue and anorexia. In contrast with multiple myeloma, bone lesions are not a feature of WM.
History and exam
Key diagnostic factors
- age >70 years
- male sex
- white ancestry
Other diagnostic factors
- history of IgM monoclonal gammopathy of undetermined significance (MGUS)
- family history of B-cell lymphoma or myeloma
- family history of WM with or without monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma
- peripheral neuropathy
- weight loss
- Raynaud's phenomenon
- IgM component monoclonal gammopathy of undetermined significance (MGUS)
- family history of B-cell lymphoproliferative disease or multiple myeloma
- family history of WM
- hepatitis C virus (HCV)
1st investigations to order
- FBC with differential
- haematinic test (iron, vitamin B12, and folate)
- renal function panel
- high-resolution serum protein electrophoresis (SPEP) with immunofixation
- high-resolution urine protein electrophoresis (UPEP) and immunofixation
- serum free light chains
- cold agglutinins and cryoglobulins
- lactate dehydrogenase
- beta-2 microglobulin
- serum albumin
- relative serum viscosity
- bone marrow biopsy
- CT chest, abdomen, and pelvis
Investigations to consider
- lymph node biopsy
- 18-F-deoxyglucose (18F-FDG) PET/CT chest, abdomen, and pelvis
- quantitative immunoglobulins
- anti-myelin-associated glycoprotein (MAG) antibodies
- anti-sulfatide IgM antibodies
- fat pad biopsy
- prothrombin time (PT) and activated partial thromboplastin time (APTT)
- viral serology (hepatitis B and C, and HIV)
- genetic mutation testing
symptomatic with low tumour burden
symptomatic with high tumour burden
responders to initial rituximab-containing treatment
relapse or refractory disease
Guy Pratt, MD, FRCP, FRCPath
University Hospitals Birmingham NHS Foundation Trust
Institute of Immunology and Immunotherapy
College of Medical and Dental Sciences
University of Birmingham
GP has received honoraria for speaking, advisory board memberships, and travel support from Janssen, Celgene, Takeda, Binding Site Ltd, and Amgen.
Dr Guy Pratt wishes to gratefully acknowledge Dr Boris Kobrinsky and Dr Kenneth Hymes, the previous contributors to this topic.
BK and KH declare that they have no competing interests.
Shaji Kumar, MD
Department of Hematology
SK declares that he has no competing interests.
Madhav Dhodapkar, MD
Professor of Medicine
Chief, Section of Hematology
Department of Internal Medicine
Yale University School of Medicine
MD declares that he has no competing interests.
Xavier Leleu, MD, PhD
Instructor in Hematology
Department of Hematology
Hopital Huriez CHRU
XL has received lecture fees and research funding from Janssen-Cilag, Celgene, Chugai, Amgen, Novartis, Mundipharma, and Roche. XL is an author of a number of references cited in this topic.
- Multiple myeloma (MM)
- Low-grade B-cell lymphomas (e.g., follicular lymphoma)
- Chronic lymphocytic leukaemia (CLL)
- Diagnosis and management of Waldenström macroglobulinaemia - a British Society for Haematology guideline
- NCCN clinical practice guidelines in oncology: Waldenström's macroglobulinemia/lymphoplasmacytic lymphoma
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