Waldenström’s macroglobulinaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
Authors: E. Kastritis, V. Leblond, M.A. Dimopoulos, E. Kimby, P. Staber, M.J. Kersten, A. Tedeschi, C. Buske
Journal: Annals of Oncology (2018)

Waldenström’s macroglobulinaemia (WM) is a rare disease that accounts for 1%–2% of non-Hodgkin lymphomas. The reported age-adjusted incidence rate is 3.4 per million among the male population and 1.7 per million among the female population in the United States, and 7.3 and 4.2 per million, respectively, in the European standard population [1.Groves F.D. Travis L.B. Devesa S.S. et al.Waldenstrom's macroglobulinemia: incidence patterns in the United States, 1988–1994.Cancer. 1998; 82: 1078-1081Crossref PubMed Scopus (159) Google Scholar, 2.Phekoo K.J. Jack R.H. Davies E. et al.The incidence and survival of Waldenstrom's macroglobulinaemia in South East England.Leuk Res. 2008; 32: 55-59Crossref PubMed Scopus (36) Google Scholar]. In contrast to multiple myeloma, WM prevalence is higher among Caucasians than among African-Americans (IRR: 1.75) [3.Teras L.R. DeSantis C.E. Cerhan J.R. Morton L.M. Jemal A. Flowers C.R. 2016 US lymphoid malignancy statistics by World Health Organization subtypes.CA Cancer J Clin. 2016; 66: 443-459Crossref PubMed Scopus (605) Google Scholar]. WM is a disease of the elderly, with the median age at the time of diagnosis being 63–75 years in different series [3.Teras L.R. DeSantis C.E. Cerhan J.R. Morton L.M. Jemal A. Flowers C.R. 2016 US lymphoid malignancy statistics by World Health Organization subtypes.CA Cancer J Clin. 2016; 66: 443-459Crossref PubMed Scopus (605) Google Scholar, 4.Kastritis E. Kyrtsonis M.C. Morel P. et al.Competing risk survival analysis in patients with symptomatic Waldenstrom macroglobulinemia: the impact of disease unrelated mortality and of rituximab-based primary therapy.Haematologica. 2015; 100: e446-e449Crossref PubMed Scopus (31) Google Scholar, 5.Treon S.P. How I treat Waldenstrom macroglobulinemia.Blood. 2009; 114: 2375-2385Crossref PubMed Scopus (166) Google Scholar]. A strong familial predisposition has been reported [6.McMaster M.L. Familial Waldenstrom's macroglobulinemia.Semin Oncol. 2003; 30: 146-152Crossref PubMed Scopus (59) Google Scholar, 7.Treon S.P. Hunter Z.R. Aggarwal A. et al.Characterization of familial Waldenstrom's macroglobulinemia.Ann Oncol. 2006; 17: 488-494Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar, 8.Treon S.P. Tripsas C. Hanzis C. et al.Familial disease predisposition impacts treatment outcome in patients with Waldenstrom macroglobulinemia.Clin Lymphoma Myeloma Leuk. 2012; 12: 433-437Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar] and first degree relatives of WM patients have up to 20-fold increased risk for developing WM (and also increased risk but at lower level for other B-cell disorders) [9.Kristinsson S.Y. Bjorkholm M. Goldin L.R. et al.Risk of lymphoproliferative disorders among first-degree relatives of lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia patients: a population-based study in Sweden.Blood. 2008; 112: 3052-3056Crossref PubMed Scopus (119) Google Scholar]. The diagnosis of WM is based on the histopathological confirmation of bone marrow (BM) infiltration by lymphoplasmacytic cells/lymphoplasmacytic lymphoma (LPL) and the detection of any amount of monoclonal immunoglobulin M (IgM) protein [10.Owen R.G. Treon S.P. Al-Katib A. et al.Clinicopathological definition of Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's macroglobulinemia.Semin Oncol. 2003; 30: 110-115Crossref PubMed Scopus (732) Google Scholar, 11.WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 2. WHO Press, Geneva2017Google Scholar], which should always be confirmed by immunofixation. The presence of monoclonal IgM without the histopathological diagnosis of LPL in the BM is not considered as WM, because this situation could correspond to monoclonal gammopathy of undetermined significance (MGUS), or to a nodal LPL without BM infiltration. A diagnosis of LPL without detection of monoclonal IgM does not fulfil the criteria for WM. The clonal lymphoplasmacytic cell population in the BM (which contains a population with lymphocytic differentiation and one with plasmacytic differentiation) should be documented by a trephine biopsy and/or aspiration and confirmed by immunophenotypic studies (immunohistochemistry or flow cytometry) showing expression of CD19, CD20, CD22 and CD79a on the lymphocytic as well as CD38 on the plasmacytic component (small variations can occur) [10.Owen R.G. Treon S.P. Al-Katib A. et al.Clinicopathological definition of Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's macroglobulinemia.Semin Oncol. 2003; 30: 110-115Crossref PubMed Scopus (732) Google Scholar, 11.WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 2. WHO Press, Geneva2017Google Scholar]. Multiparametric flow cytometry may provide additional data on the immunophenotypic characterisation of WM showing accumulation of light-chain-isotype-positive B cells with a characteristic phenotype [CD22(+dim)/CD25+/CD27+/IgM+] that differs from other B-lymphomas by negative expression of CD5, CD10, CD11c or CD103 [12.Paiva B. Montes M.C. Garcia-Sanz R. et al.Multiparameter flow cytometry for the identification of the Waldenstrom's clone in IgM-MGUS and Waldenstrom's macroglobulinemia: new criteria for differential diagnosis and risk stratification.Leukemia. 2014; 28: 166-173Crossref PubMed Scopus (67) Google Scholar]. About 90% of patients with WM harbour the myeloid differentiation primary response MYD88L265P gene mutation in their lymphoplasmacytic cells [13.Treon S.P. Xu L. Yang G. et al.MYD88 L265P somatic mutation in Waldenstrom's macroglobulinemia.N Engl J Med. 2012; 367: 826-833Crossref PubMed Scopus (920) Google Scholar], which can be helpful for the differential diagnosis from other morphologically similar diseases (such as multiple myeloma). The MYD88L265P mutation alone is not diagnostic of WM. This mutation is also found in 50%–80% of patients with IgM MGUS and may also be found in other lymphomas such as marginal zone lymphoma. Furthermore, 5%–10% of patients who fulfil the immunophenotypic and clinical criteria of WM do not have the MYD88L265P mutation (they may either have other MYD88 mutations [14.Treon S.P. Xu L. Hunter Z. MYD88 mutations and response to ibrutinib in Waldenstrom's macroglobulinemia.N Engl J Med. 2015; 373: 584-586Crossref PubMed Scopus (177) Google Scholar] or may have wild type MYD88). Diagnostics for the detection of MYD88L265P have not been standardised but should be based on BM sampling, because peripheral blood detection may give false-negative results [15.Xu L. Hunter Z.R. Yang G. et al.Detection of MYD88 L265P in peripheral blood of patients with Waldenstrom's macroglobulinemia and IgM monoclonal gammopathy of undetermined significance.Leukemia. 2014; 28: 1698-1704Crossref PubMed Scopus (79) Google Scholar]. A sensitive method, such as allele-specific oligonucleotide polymerase chain reaction (ASO-PCR) is recommended and each laboratory should report the method and detection limits. The use of molecular methods for MYD88L265P detection and flow cytometry may also be useful for the diagnosis of cases with extranodal involvement (pleura, central nervous system, etc.) [16.Poulain S. Boyle E.M. Roumier C. et al.MYD88 L265P mutation contributes to the diagnosis of Bing Neel syndrome.Br J Haematol. 2014; 167: 506-513Crossref PubMed Scopus (59) Google Scholar]. Activating C–X–C chemokine receptor type 4 (CXCR4) mutations are found in ∼30% of patients with WM [13.Treon S.P. Xu L. Yang G. et al.MYD88 L265P somatic mutation in Waldenstrom's macroglobulinemia.N Engl J Med. 2012; 367: 826-833Crossref PubMed Scopus (920) Google Scholar]. More than 30 different CXCR4 mutations have been described in WM, complicating diagnostic standardisation. Since there are as yet no therapeutic implications outside clinical trials, diagnostic testing for the presence or the absence of CXCR4 mutations is not routinely recommended. However, in patients considered for treatment with ibrutinib, CXCR4 mutational status may be evaluated given the effects in depth and response kinetics in those with CXCR4 mutations [17.Treon S.P. Tripsas C.K. Meid K. et al.Ibrutinib in previously treated Waldenstrom's macroglobulinemia.N Engl J Med. 2015; 372: 1430-1440Crossref PubMed Scopus (658) Google Scholar, 18.Dimopoulos M.A. Trotman J. Tedeschi A. et al.Ibrutinib for patients with rituximab-refractory Waldenstrom's macroglobulinaemia (iNNOVATE): an open-label substudy of an international, multicentre, phase 3 trial.Lancet Oncol. 2017; 18: 241-250Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar]. Besides patient history and documentation of symptoms, initial evaluation should include a complete blood count (CBC) with differential and serum chemistry, including lactate dehydrogenase (LDH) and serum albumin. Anaemia may be the only indication for therapy, and thus its association with WM and not to other concomitant disorders should be confirmed [e.g. by evaluation of iron status (ferritin) or additional tests]. The β2 microglobulin (B2M) level should be measured: it is a prognostic marker for survival and a component of the International Prognostic Scoring System for WM (IPSSWM) [19.Morel P. Duhamel A. Gobbi P. et al.International prognostic scoring system for Waldenstrom macroglobulinemia.Blood. 2009; 113: 4163-4170Crossref PubMed Scopus (280) Google Scholar]. Serum protein electrophoresis and immunofixation and quantification of Ig levels (IgM, IgG, IgA) are essential at initial assessment. The determination of IgM levels can be based either on densitometry or on total serum IgM quantification by nephelometry, although densitometry may be more accurate [20.Murray D.L. Ryu E. Snyder M.R. Katzmann J.A. Quantitation of serum monoclonal proteins: relationship between agarose gel electrophoresis and immunonephelometry.Clin Chem. 2009; 55: 1523-1529Crossref PubMed Scopus (56) Google Scholar]. For response assessments, the same method should be used for the sequential measurement of IgM for an individual patient, ideally in the same laboratory as intra-laboratory and inter-laboratory variation can occur as well [21.Owen R.G. Kyle R.A. Stone M.J. et al.Response assessment in Waldenstrom macroglobulinaemia: update from the VIth International Workshop.Br J Haematol. 2013; 160: 171-176Crossref PubMed Scopus (190) Google Scholar, 22.Castillo J.J. Garcia-Sanz R. Hatjiharissi E. et al.Recommendations for the diagnosis and initial evaluation of patients with Waldenstrom macroglobulinaemia: a task force from the 8th International Workshop on Waldenstrom Macroglobulinaemia.Br J Haematol. 2016; 175: 77-86Crossref PubMed Scopus (51) Google Scholar]. The usefulness of measurement of serum free light chain (FLC) in patients with WM is still under investigation and is recommended in situations where there is suspicion of light chain (AL) amyloidosis or renal failure, or in the rare occasion of a patient with measurable FLCs levels but very low (and non-quantifiable) IgM levels. However, in patients with renal failure the evaluation of FLCs may be challenging [23.Quantitative assessment of serum and urinary polyclonal free light chains in patients with chronic kidney disease.Clin J Am Soc Nephrol. 2008; 3: 1684-1690Crossref PubMed Scopus (269) Google Scholar]. Urine protein electrophoresis and/or urine immunofixation for exclusion of abnormal renal Ig secretion should be carried out (Table 1).Table 1Diagnostic work-upRecommended•History and physical examination○Include familial history for WM and other B cell lymphoproliferative disorders•Review of systems (B symptomsa, organomegaly, hyperviscosity symptoms, neuropathy, Raynaud’s disease, rash, peripheral oedema, skin abnormalities, dyspnoea)○Include fundoscopic examination if IgM is high and hyperviscosity is suspected•Laboratory studies:○Complete blood count○Complete metabolic panel○Serum Ig levels (IgA, IgG, IgM)○Serum and urine electrophoresis with immunofixation○Serum B2M level○Viral serology (HBV, HCV and HIV)•BM aspiration and biopsy○IHC (required for diagnosis)○Flow cytometry (optional; consider if IHC not available)○Testing for MYD88L265P gene mutation•CT of the chest, abdomen and pelvis (if clinically indicated and in all patients being considered for therapy)Optional (if clinically indicated)•Cryoglobulins•Cold agglutinin titre•Serum viscosity•Screening for acquired von Willebrand disease•24-h urine protein quantification•Serum FLCs•NTproBNP, cardiac troponins•EMG, anti-MAG, anti-GM1 (consultation with neurologist)aFever, night sweats and weight loss. anti-GM1, anti-ganglioside M1; anti-MAG, myelin-associated globulin antibody; B2M, β2 microglobulin; BM, bone marrow; CT, computed tomography; EMG, electromyogram; FLC, free light chain; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; IHC, immunohistochemistry; Ig, immunoglobulin; NTproBNP, N-terminal pro b-type natriuretic peptide; WM, Waldenström’s macroglobulinaemia. Open table in a new tab aFever, night sweats and weight loss. anti-GM1, anti-ganglioside M1; anti-MAG, myelin-associated globulin antibody; B2M, β2 microglobulin; BM, bone marrow; CT, computed tomography; EMG, electromyogram; FLC, free light chain; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; IHC, immunohistochemistry; Ig, immunoglobulin; NTproBNP, N-terminal pro b-type natriuretic peptide; WM, Waldenström’s macroglobulinaemia. Hyperviscosity syndrome related to high IgM levels is common in WM. Serum viscosity measurement may be considered in patients with symptoms of hyperviscosity (headaches, blurry vision or visual loss, confusion, epistaxis) but does not correlate well with the clinical severity of the syndrome. Fundoscopic examination showing venous engorgement (sausaging) of the retinal veins is a more reliable sign of clinically relevant hyperviscosity [24.Menke M.N. Feke G.T. McMeel J.W. Treon S.P. Ophthalmologic techniques to assess the severity of hyperviscosity syndrome and the effect of plasmapheresis in patients with Waldenstrom's macroglobulinemia.Clin Lymphoma Myeloma. 2009; 9: 100-103Abstract Full Text PDF PubMed Scopus (28) Google Scholar]; a baseline photography of the retina may help for future comparisons. However, the interpretation of fundoscopic signs should also take into account associated comorbidities such as arterial hypertension or diabetes that may cause or contribute to the observed abnormalities. Testing for cold agglutinins and cryoglobulins should be carried out at diagnosis in patients with symptoms or laboratory evidence suggestive of their presence; physicians should be aware that the presence of cold agglutinins or cryoglobulins may affect the determination of IgM levels. Coombs testing and cold agglutinin titres are indicated if anaemia with evidence of haemolysis occurs. In patients with Raynaud-like symptoms, acrocyanosis, ulcerations of the extremities or hyperviscosity testing for cryoglobulins should be considered. In case of bleeding, diathesis screening for acquired von Willebrand disease should be carried out (Table 1). Viral serology for hepatitis B and C viruses (HBV and HCV) and human immunodeficiency virus (HIV) is strongly recommended, especially before therapy initiation. Neuropathy is common in patients with WM and often an indication for treatment of otherwise asymptomatic patients; however, other unrelated causes for neuropathy may also exist. The most common clinical presentation is a slowly progressing, demyelinating, symmetrical sensory peripheral neuropathy, usually affecting initially the feet [25.D'Sa S. Kersten M.J. Castillo J.J. et al.Investigation and management of IgM and Waldenstrom-associated peripheral neuropathies: recommendations from the IWWM-8 consensus panel.Br J Haematol. 2017; 176: 728-742Crossref PubMed Scopus (41) Google Scholar]. Myelin-associated globulin antibodies (anti-MAGs) are detectable in the serum of ∼50% of these patients and should be evaluated [26.Levine T. Pestronk A. Florence J. et al.Peripheral neuropathies in Waldenstrom's macroglobulinaemia.J Neurol Neurosurg Psychiatry. 2006; 77: 224-228Crossref PubMed Scopus (74) Google Scholar]. Anti-ganglioside M1 (GM1) antibodies may also be evaluated if motor neuropathy predominates [27.Vlam L. Piepers S. Sutedja N.A. et al.Association of IgM monoclonal gammopathy with progressive muscular atrophy and multifocal motor neuropathy: a case-control study.J Neurol. 2015; 262: 666-673Crossref PubMed Scopus (15) Google Scholar]. Axonal degeneration may be found in patients with longstanding sensorimotor neuropathy or amyloidosis. Small fibre neuropathy can also be seen. In patients with peripheral neuropathy, consultation with a neurologist and specialised neurological evaluation including electromyography/nerve conduction studies should be considered [25.D'Sa S. Kersten M.J. Castillo J.J. et al.Investigation and management of IgM and Waldenstrom-associated peripheral neuropathies: recommendations from the IWWM-8 consensus panel.Br J Haematol. 2017; 176: 728-742Crossref PubMed Scopus (41) Google Scholar]. Nerve biopsies are generally not indicated. Amyloidosis is an infrequent complication of WM mostly affecting kidneys, heart, liver and peripheral nerves [28.Milani P. Merlini G. Monoclonal IgM-related AL amyloidosis.Best Pract Res Clin Haematol. 2016; 29: 241-248Crossref PubMed Scopus (25) Google Scholar, 29.Sachchithanantham S. Roussel M. Palladini G. et al.European collaborative study defining clinical profile outcomes and novel prognostic criteria in monoclonal immunoglobulin M-related light chain amyloidosis.J Clin Oncol. 2016; 34: 2037-2045Crossref PubMed Scopus (47) Google Scholar]. AL amyloidosis is the most common type in WM, but other types such as amyloid A (AA) amyloidosis have been described. If suspected, a fat aspirate and evaluation of the BM biopsy with Congo red can help establish the diagnosis. Organ assessment with cardiac imaging [echocardiography (echo), cardiac magnetic resonance (CMR)] and cardiac biomarkers [N-terminal pro b-type natriuretic peptide (NTproBNP), troponins], renal markers [24-hour proteinuria, estimated glomerular filtration rate (eGFR)] and liver function tests should be carried out. At diagnosis, imaging studies should be included in the evaluation to document organomegaly and/or lymphadenopathy, preferably with computed tomography (CT) or magnetic resonance imaging (MRI). Positron emission tomography (PET) scanning does not seem to offer additional information [30.Banwait R. O'Regan K. Campigotto F. et al.The role of 18F-FDG PET/CT imaging in Waldenstrom macroglobulinemia.Am J Hematol. 2011; 86: 567-572Crossref PubMed Scopus (35) Google Scholar] unless transformation to an aggressive lymphoma or another malignancy is suspected, in which case a biopsy of the most fluorodeoxyglucose (FDG)-avid target lesion is indicated. Risk assessment is currently based on the IPSSWM (Table 2) [19.Morel P. Duhamel A. Gobbi P. et al.International prognostic scoring system for Waldenstrom macroglobulinemia.Blood. 2009; 113: 4163-4170Crossref PubMed Scopus (280) Google Scholar]; however, this prognostic tool was designed only for symptomatic patients.Table 2Prognostification of WM (IPSSWM) (adapted from [19])Risk groupStage 1Stage 2Stage 3(low risk)(intermediate risk)(high risk)Risk factors presentaRisk factors for IPSSWM include: age ≥ 65 years, Hb ≤ 11.5 g/dL, platelets ≤ 100 × 109/L, B2M > 3 mg/L and IgM > 70 g/L. Other risk factors not included in IPSSWM include elevated serum LDH and low serum albumin.0 or 1 (except age)Age or 2≥ 35-year OS (%)876836B2M, β2 microglobulin; Hb, haemoglobin; IgM, immunoglobulin M; IPSSWM, International Prognostic Scoring System for Waldenström’s macroglobulinaemia; LDH, lactate dehydrogenase; OS, overall survival; WM, Waldenström’s macroglobulinaemia.a Risk factors for IPSSWM include: age ≥ 65 years, Hb ≤ 11.5 g/dL, platelets ≤ 100 × 109/L, B2M > 3 mg/L and IgM > 70 g/L. Other risk factors not included in IPSSWM include elevated serum LDH and low serum albumin. Open table in a new tab B2M, β2 microglobulin; Hb, haemoglobin; IgM, immunoglobulin M; IPSSWM, International Prognostic Scoring System for Waldenström’s macroglobulinaemia; LDH, lactate dehydrogenase; OS, overall survival; WM, Waldenström’s macroglobulinaemia. Table 3 depicts indications to start therapy. Patients with asymptomatic disease should be followed without therapy [III, C] [31.Kyle R.A. Treon S.P. Alexanian R. et al.Prognostic markers and criteria to initiate therapy in Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's macroglobulinemia.Semin Oncol. 2003; 30: 116-120Crossref PubMed Scopus (258) Google Scholar, 32.Gobbi P.G. Baldini L. Broglia C. et al.Prognostic validation of the international classification of immunoglobulin M gammopathies: a survival advantage for patients with immunoglobulin M monoclonal gammopathy of undetermined significance?.Clin Cancer Res. 2005; 11: 1786-1790Crossref PubMed Scopus (53) Google Scholar, 33.Leblond V. Kastritis E. Advani R. et al.Treatment recommendations from the Eighth International Workshop on Waldenstrom's macroglobulinemia.Blood. 2016; 128: 1321-1328Crossref PubMed Scopus (138) Google Scholar]. The median time to symptom development for patients with asymptomatic WM exceeds 5–10 years. Patients with low haemoglobin levels, high lymphoplasmacytic cell infiltration and IgM-spike and high B2M level may be at higher risk for development of symptomatic WM [34.Garcia-Sanz R. Montoto S. Torrequebrada A. et al.Waldenstrom macroglobulinaemia: presenting features and outcome in a series with 217 cases.Br J Haematol. 2001; 115: 575-582Crossref PubMed Scopus (193) Google Scholar, 35.Kyle R.A. Benson J.T. Larson D.R. et al.Progression in smoldering Waldenstrom macroglobulinemia: long-term results.Blood. 2012; 119: 4462-4466Crossref PubMed Scopus (84) Google Scholar]. No data exist to support early initiation of therapy over a watch and wait strategy. The level of monoclonal IgM alone is not considered an indication to start treatment [III, C] [31.Kyle R.A. Treon S.P. Alexanian R. et al.Prognostic markers and criteria to initiate therapy in Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's macroglobulinemia.Semin Oncol. 2003; 30: 116-120Crossref PubMed Scopus (258) Google Scholar, 32.Gobbi P.G. Baldini L. Broglia C. et al.Prognostic validation of the international classification of immunoglobulin M gammopathies: a survival advantage for patients with immunoglobulin M monoclonal gammopathy of undetermined significance?.Clin Cancer Res. 2005; 11: 1786-1790Crossref PubMed Scopus (53) Google Scholar, 33.Leblond V. Kastritis E. Advani R. et al.Treatment recommendations from the Eighth International Workshop on Waldenstrom's macroglobulinemia.Blood. 2016; 128: 1321-1328Crossref PubMed Scopus (138) Google Scholar]. However, a recent study indicated that IgM levels > 60 g/L are associated with imminent risk of symptomatic hyperviscosity and are therefore considered to be a treatment indication [36.Gustine J.N. Meid K. Dubeau T. et al.Serum IgM level as predictor of symptomatic hyperviscosity in patients with Waldenstrom macroglobulinaemia.Br J Haematol. 2017; 177: 717-725Crossref PubMed Scopus (50) Google Scholar]. The most common indications for treatment initiation include anaemia, B symptoms and hyperviscosity; other indications such as neuropathy, bulky organomegaly and immune related cytopaenias are less common.Table 3Indications for initiation of therapy in patients with WM [31]Clinical indications for initiation of therapy•Recurrent fever, night sweats, weight loss, fatigue•Hyperviscosity•Lymphadenopathy: either symptomatic or bulky (≥ 5 cm in maximum diameter)•Symptomatic hepatomegaly and/or splenomegaly•Symptomatic organomegaly and/or organ or tissue infiltration•Peripheral neuropathy due to WMLaboratory indications for initiation of therapy•Symptomatic cryoglobulinaemia•Symptomatic cold agglutinin anaemia•Autoimmune haemolytic anaemia and/or thrombocytopaenia•Nephropathy-related to WM•Amyloidosis-related to WM•Hb ≤ 10 g/dL•Platelets < 100×109/L•IgM levels > 60 g/LHb, haemoglobin; IgM, immunoglobulin M; WM, Waldenström’s macroglobulinaemia. Open table in a new tab Hb, haemoglobin; IgM, immunoglobulin M; WM, Waldenström’s macroglobulinaemia. Participation in clinical trials is strongly encouraged for all patients, given the increasing treatment options and promising new approaches. Treatment choice is guided by the clinical presentation of the disease (i.e. mainly cytopaenias versus hyperviscosity) or complications requiring immediate treatment response versus immunological complications without high BM infiltration or presentation with bulky disease (such as massive orgamomegaly/lymphadenopathy, hyperviscosity) (Table 4 and Figure 1). For the immediate relief of symptomatic hyperviscosity, plasmapheresis should be used concomitantly with the appropriate systemic therapy [IV, A] [33.Leblond V. Kastritis E. Advani R. et al.Treatment recommendations from the Eighth International Workshop on Waldenstrom's macroglobulinemia.Blood. 2016; 128: 1321-1328Crossref PubMed Scopus (138) Google Scholar, 37.Kapoor P. Ansell S.M. Fonseca R. et al.Diagnosis and management of Waldenstrom macroglobulinemia: Mayo stratification of macroglobulinemia and risk-adapted therapy (mSMART) guidelines 2016.JAMA Oncol. 2017; 3: 1257-1265Crossref PubMed Scopus (84) Google Scholar].Table 4Treatment options in first line according to disease presentationClinical syndromeTreatment optionsHyperviscosityPI-based therapy (BDR, VR)IbrutinibBRCytopaeniasDRCPI-based therapy (BDR, VR)BRIbrutinibBulky diseaseBRPI-based therapy (BDR, VR)IbrutinibNeed for immediate tumour reduction (due to WM-related complications)PI-based therapy (BDR, VR)BRIbrutinibNeuropathyDRCBRRituximab monotherapyAL amyloidosisPI-based therapy (BDR, VR)BRAL, amyloid light chain; BDR, bortezomib/dexamethasone/rituximab; BR, bendamustine/rituximab; DRC, dexamethasone/rituximab/cyclophosphamide; PI, proteasome inhibitor; VR, bortezomib/rituximab; WM, Waldenström’s macroglobulinaemia. Open table in a new tab AL, amyloid light chain; BDR, bortezomib/dexamethasone/rituximab; BR, bendamustine/rituximab; DRC, dexamethasone/rituximab/cyclophosphamide; PI, proteasome inhibitor; VR, bortezomib/rituximab; WM, Waldenström’s macroglobulinaemia. Anti-CD20-based (rituximab-based) combinations are the mainstay of first-line treatment. A transient increase of serum IgM (IgM flare) occurs in 30%–80% of patients treated with rituximab-based therapies, which may exacerbate IgM-related complications [38.Dimopoulos M.A. Zervas C. Zomas A. et al.Treatment of Waldenstrom's macroglobulinemia with rituximab.J Clin Oncol. 2002; 20: 2327-2333Crossref PubMed Scopus (226) Google Scholar, 39.Ghobrial I.M. Fonseca R. Greipp P.R. et al.Initial immunoglobulin M ′flare′ after rituximab therapy in patients diagnosed with Waldenstrom macroglobulinemia: an Eastern Cooperative Oncology Group study.Cancer. 2004; 101: 2593-2598Crossref PubMed Scopus (165) Google Scholar]. Pre-emptive use of plasmapheresis may be considered in symptomatic patients with very high levels of IgM and at high risk for hyperviscosity or IgM-related complications before starting anti-CD20-based chemoimmunotherapy [V, B]. Combinations of rituximab with oral or intravenous (i.v.) cyclophosphamide and dexamethasone (DRC regimen for six cycles) induce higher response rates than rituximab alone, but complete responses (CRs) are infrequent. DRC is associated with a progression-free survival (PFS) of about 3 years, a treatment-free interval > 4 years and median overall survival (OS) of ∼8 years with favourable short- and long-term safety profiles [40.Kastritis E. Gavriatopoulou M. Kyrtsonis M.C. et al.Dexamethasone, rituximab, and cyclophosphamide as primary treatment of Waldenstrom macroglobulinemia: final analysis of a phase 2 study.Blood. 2015; 126: 1392-1394Crossref PubMed Scopus (81) Google Scholar]. DRC or similar regimens are primary options for patients with low tumour burden and comorbidities [III, B]. Bendamustine with rituximab (BR for four to six cycles) is associated with longer PFS and OS than rituximab with cyclophosphamide/doxorubicin/vincristine/prednisolone (R-CHOP), based on a sub-analysis of a randomised study [41.Rummel M.J. Niederle N. Maschmeyer G. et al.Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial.Lancet. 2013; 381: 1203-1210Abstract Full Text Full Text PDF PubMed Scopus (1056) Google Scholar]. Dose intensity of bendamustine should be adapted to the individual characteristics of the patients by reducing the number of cycles and/or by reducing the dosing per cycle. BR has not been prospectively compared with DRC but is a primary option for patients with high tumour burden [II, B]; no data are available to support the role of BR in patients with hyperviscosity. Bortezomib alone or in combination with rituximab (VR) is very active in WM [42.Gavriatopoulou M. Garcia-Sanz R. Kastritis E. et al.BDR in newly diagnosed patients with WM: final analysis of a phase 2 study after a minimum follow-up of 6 years.Blood. 2017; 129: 456-459Crossref PubMed Scopus (46) Google Scholar, 43.Ghobrial I.M. Xie W. Padmanabhan S. et al.Phase II trial of weekly bo