Guideline sources The following summarized guidelines for the evaluation and management of Waldenstrom s macroglobulinemia (WM) are prepared by our editorial team based on guidelines from the British Society for Haematology (BSH 2022; 2014), the European Society of Medical Oncology (ESMO 2018), and the International Workshop on Waldenstrom's Macroglobulinemia (IWWM 2006). 1 2 3 4 5 5 5 6 7 8 Definition WM is a type of lymphoplasmacytic lymphoma associated with monoclonal IgM gammopathy. 5 Epidemiology WM is caused by an uncontrolled clonal proliferation of terminally differentiated B lymphocytes, which may be due to sporadic or inherited cytogenetic abnormalities. 5 Pathophysiology The estimated incidence of WM in the United States is 0.57 per 100,000 person-years. 6 https://web.pathway.md/diseases/reccLkObUU8cn2acy 1/9 6/29/23, 3:14 AM Waldenstr m's macroglobulinemia Pathway Disease course Production of IgM paraproteins by WM clones leads to clinical manifestations of peripheral neuropathy, systemic amyloidosis, hyperviscosity syndrome, congestive HF, cryoglobulinemia, and death. 5 Prognosis and risk of recurrence The 5-year survival rates for patients with low risk, intermediate risk, and high-risk patients WM are 87%, 68%, and 36%, respectively. Treatment-related 1-year mortality rates of up to 44% limit the use of allogeneic transplantation. 7 8 Calculator Calculator Calculat Eastern Cooperative Oncology G International prognostic scoring Karnof Guidelines 1. Screening and diagnosis Diagnostic criteria: Diagnose WM in patients who meet both of the following criteria: SPEP showing a monoclonal IgM of any amount, confirmed by immunofixation bone marrow biopsy showing infiltration by monoclonal lymphoplasmacytic cells. Screening of family relatives: avoid systematic screening of family members of patients with WM, given the low absolute level of risk for first-degree relatives and the absence of obvious clinical benefit. D Differential diagnosis: As per BSH 2022 guidelines, suspect and investigate where appropriate for alternative causes of symptoms apart from WM. A As per ESMO 2018 guidelines, the MYD88L265P mutation is present in approximately 90% of patients with WM. The identification of this mutation can be helpful to distinguish WM from other subtypes of lymphoma and IgM multiple myeloma. 2. Classification and risk stratification Risk assessment: As per BSH 2022 guidelines, insufficient evidence to support the use of International Prognostic Scoring System for Waldenstr m's Macroglobulinemia or other prognostic scoring systems in determining treatment approaches for individual patients, whilst potentially useful to guide discussions with patients. I As per ESMO 2018 guidelines, the risk assessment of patients with WM is currently based on the International Prognostic Scoring System for Waldenstr m's Macroglobulinemia. https://web.pathway.md/diseases/reccLkObUU8cn2acy 2/9 6/29/23, 3:14 AM Waldenstr m's macroglobulinemia Pathway 3. Diagnostic investigations Laboratory evaluation: As per BSH 2022 guidelines, obtain sequential monitoring of IgM/monoclonal protein in a single laboratory using a single methodology. A Show 2 more As per ESMO 2018 guidelines: Obtain a CBC, serum chemistry, -2 microglobulin, SPEP and IgM quantification in the initial evaluation for WM. Consider obtaining Coombs testing, cold agglutinins, cryoglobulins and iron studies in patients with anemia. Screening for viral hepatitis and HIV: screen for hepatitis B and C and human immunodeficiency virus before initiation of treatment. A Show 2 more Diagnostic imaging: As per BSH 2022 guidelines: Obtain CT of the neck, chest, abdomen, and pelvis) in all patients before commencement of each line of therapy. B Do not obtain FDG-positron emission tomography outside of a clinical trial. Recognize that it may have a role in detection of high-grade transformation. D As per ESMO 2018 guidelines, obtain imaging studies (preferably CT or MRI) in the initial evaluation for WM. Evaluation for complications: As per BSH 2022 guidelines, set a low threshold for investigating symptoms likely representing complications of WM, as some can occur regardless of the level of the paraprotein and may be an indication for definitive treatment. A As per ESMO 2018 guidelines, perform fundoscopic examination in patients with symptoms of hyperviscosity. 4. Diagnostic procedures Bone marrow biopsy: perform bone marrow aspiration and trephine biopsy for definitive diagnosis of WM as well as in all patients with suspected symptomatic WM or other IgM- disorder. A Tissue biopsy: As per BSH 2022 guidelines: Perform tissue biopsy in all patients with suspected histological transformation. A Consider directing tissue biopsy positron emission tomography-CT. B As per ESMO 2018 guidelines, obtain cardiac and renal biomarkers, and perform a fat pad aspiration biopsy with Congo red staining in patients with Waldenstrom's macroglobulinemia in whom amyloidosis is suspected. https://web.pathway.md/diseases/reccLkObUU8cn2acy 3/9 6/29/23, 3:14 AM Waldenstr m's macroglobulinemia Pathway Cytogenetic analysis: obtain flow cytometry as the preferred method for establishing B-cell immunophenotype. A Show 2 more 5. Medical management Indications for treatment: initiate treatment in patients with WM who develop B symptoms, cytopenias, hyperviscosity, moderate or severe neuropathy, amyloidosis, symptomatic cryoglobulinemia or cold agglutinin disease. Show 3 more Multidisciplinary care: collaborate with other specialists where appropriate, for example, amyloidosis unit, hematologists with an expertise in coagulation, neurologists, and nephrologists. A First-line therapy: As per BSH 2022 guidelines, offer any of the following regimens as front-line therapy in patients with WM: dexamethasone, rituximab and cyclophosphamide bendamustine and rituximab bortezomib, cyclophosphamide and rituximab bortezomib, dexamethasone and rituximab BTK inhibitors. B Show 3 more As per ESMO 2018 guidelines, initiate a rituximab-containing regimen, combined with alkylating agents (such as cyclophosphamide or bendamustine) or proteasome inhibitors, as first-line therapy for patients with WM in whom treatment is indicated. Show 3 more Second-line therapy, frail/unfit patients: As per BSH 2022 guidelines, offer chlorambucil or rituximab monotherapy in selected elderly frail patients with WM. B As per ESMO 2018 guidelines, use single-agent therapy with alkylating agents, nucleoside analogues or rituximab only in patients who are unfit for more effective chemoimmunotherapy regimens. Show 3 more Maintenance therapy: As per BSH 2022 guidelines, insufficient evidence to support the use of rituximab as maintenance therapy in patients with WM. I As per ESMO 2018 guidelines, avoid using rituximab as maintenance therapy for patients with WM. D Management of relapsed disease: As per BSH 2022 guidelines: Offer BTK inhibitors, rituximab- or bortezomib-containing regimens in patients with a relapse. B https://web.pathway.md/diseases/reccLkObUU8cn2acy 4/9 6/29/23, 3:14 AM Waldenstr m's macroglobulinemia Pathway Determine clinical phenotype of the patient for deciding treatment. B As per ESMO 2018 guidelines: Offer single-agent ibrutinib as the treatment of choice in patients relapsed within 12 months from chemoimmunotherapy. B Consider offering an alternate chemoimmunotherapy combination or a prior effective regimen or ibrutinib in patients with late relapses after chemoimmunotherapy. B Management of refractory disease: As per ESMO 2018 guidelines, offer single-agent ibrutinib as the treatment of choice in rituximab-refractory patients. B As per BSH 2014 guidelines: Consider offering alemtuzumab as a potential treatment option in patients with refractory WM. B Implement surveillance for CMV reactivation in patients being treated with alemtuzumab. B 6. Therapeutic procedures Stem cell transplantation: As per BSH 2022 guidelines, consider offering ASCT as a second or later line of therapy in selected chemotherapy-responsive patients with a relapse. C Show 2 more As per ESMO 2018 guidelines, consider ASCT in selected young patients with chemosensitive relapse. C Show 3 more Plasmapheresis: As per BSH 2022 guidelines, perform plasmapheresis in patients with hyperviscosity syndrome. A As per ESMO 2018 guidelines, perform plasmapheresis for the immediate relief of hyperviscosity syndrome, in addition to initiating appropriate systemic therapy. B Show 2 more 7. Specific circumstances Patients with histological transformation: Treat high-grade transformation to diffuse large B-cell lymphoma with similar regimens used to treat de novo diffuse large B-cell lymphoma, but prognosis is less favorable. B Consider offering ASCT as consolidation for high-grade transformation in suitable patients responding to induction chemotherapy. C Patients with neuropathy: As per ESMO 2018 guidelines, consult with a neurologist in case of neuropathy since neuropathy may not always be associated with WM. https://web.pathway.md/diseases/reccLkObUU8cn2acy 5/9 6/29/23, 3:14 AM Waldenstr m's macroglobulinemia Pathway As per BSH 2014 guidelines, perform a neurological exam in all patients with IgM paraproteins. A Show 2 more Patients with cold agglutinin disease: initiate conservative measures in patients with cold agglutinin disease. Consider offering single-agent rituximab or rituximab-bendamustine as first- line therapy if definitive treatment is required. B Patients with cryoglobulinemia: initiate definitive treatment in patients with symptomatic cryoglobulinemia. Guide treatment choice by severity of symptoms. B Patients with hypogammaglobulinemia: Consider administering antimicrobial prophylaxis in patients with hypogammaglobulinemia developing recurrent bacterial infections, according to local antimicrobial protocols. B Consider offering immunoglobulin replacement in patients with secondary hypogammaglobulinemia and recurrent infection despite antimicrobial prophylaxis, in accordance with the current UK Department of Health clinical guidelines. B Patients with anemia: consider administering parenteral iron in selected patients with anemia, low disease burden, and low transferrin saturation (< 10-12%) unrelated to gastrointestinal bleeding. C Patients with amyloidosis: Initiate definitive treatment in patients with organ involvement by AL (IgM-related) amyloid, with the aim to reduce the light chains as quickly and as deeply as possible to minimize end- organ damage. A Consider offering rituximab-bendamustine as first-line therapy in patients considered fit for this regimen. B 8. Preventative measures Routine immunizations: offer pneumococcal vaccination in the form of pneumococcal conjugate vaccine followed by pneumococcal polysaccharide vaccine at least 2 months later in all patients with WM. B Show 2 more Pneumocystis and herpes prophylaxis: Administer prophylaxis against P. jirovecii in patients requiring intensive and/or immunosuppressive treatment including BTK inhibitors. B Administer prophylaxis against HSV and herpes zoster in patients requiring intensive, immunosuppressive or bortezomib-based therapy. B 9. Follow-up and surveillance Assessment of treatment response: As per BSH 2022 guidelines, use uniform criteria for the assessment of treatment response. A Show 2 more https://web.pathway.md/diseases/reccLkObUU8cn2acy 6/9 6/29/23, 3:14 AM Waldenstr m's macroglobulinemia Pathway As per IWWM 2006 guidelines, classify treatment response in patients with WM according to the following categories: Situation Guidance Disappearance of serum and urine monoclonal protein determined by immunofixation, absence of malignant cells in bone marrow determined by histologic evaluation, resolution of adenopathy/organomegaly, and no signs or symptoms of active disease Complete response 50% reduction of serum monoclonal IgM concentration determined by protein electrophoresis, 50% decrease in adenopathy/organomegaly on physical examination or on CT scan, and no new symptoms or signs of active disease Partial response 25% but < 50% reduction of serum monoclonal IgM determined by protein electrophoresis, and no new symptoms or signs of active disease. E Minor response Clinical findings Patient demographics Symptoms Age 65 Blurry vision Male sex Chronic diarrhea White race Confusion Easy bruising Family history Fatigue Fever Lymphoma Generalized pruritus Respiratory exam Headache Infection Dyspnea Limb numbness Nosebleed Lymphatic exam Oronasal bleeding Lymphadenopathy Sweating Swollen lymph nodes Lab findings Weakness Weight loss serum monoclonal light chains serum viscosity Neurological exam urine protein https://web.pathway.md/diseases/reccLkObUU8cn2acy 7/9 6/29/23, 3:14 AM Waldenstr m's macroglobulinemia Pathway Peripheral neuropathy Imaging findings Abdominal exam Lung nodule Pleural effusion Abdominal distension Pulmonary infiltrates Hepatomegaly Splenomegaly Integument exam Petechiae Purpura Raynaud's phenomenon Hematological findings Anemia Cold agglutinins Cryoglobulins Hemolytic anemia blood neutrophil count blood platelet count Studies 2020 TRIST In patients with hematologic malignancies requiring hematopoietic cell transplantation, restrictive strategy was noninferior to liberal strategy with respect to a health-related quality of life measured by Functional Assessment of Cancer Therapy-BMT score at day 100. Jason Tay et al. J Clin Oncol. 2020 May 1. References 1. Kastritis E, Leblond V, Dimopoulos MA et al. Waldenstr m's macroglobulinaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018 Oct 1;29 Supplement_4):iv41-iv50. Open 2. Guy Pratt, Dima El-Sharkawi, Jaimal Kothari et al. Guidelines on the diagnosis and management of Waldenstr m macroglobulinaemia-A British Society for Haematology guideline. Br J Haematol. 2022 Jan 12. Open 3. Kimby E, Treon SP, Anagnostopoulos A et al. Update on recommendations for assessing response from the Third International Workshop on Waldenstrom's Macroglobulinemia. Clin Lymphoma Myeloma. 2006 Mar;6 5 380 3. Open 4. Owen RG, Pratt G, Auer RL et al. Guidelines on the diagnosis and management of Waldenstr m macroglobulinaemia. Br J Haematol. 2014 May;165 3 316 33. Open 5. Yun S, Johnson AC, Okolo ON et al. Waldenstrom Macroglobulinemia: Review of Pathogenesis and Management. 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