Waldenström macroglobulinemia (WM) is a subtype of lymphoplasmacytic lymphoma (LPL), a rare type of non-Hodgkin lymphoma (NHL).1 WM results from the accumulation of immunoglobulin M (IgM) antibodies in the blood and lymphoplasmacytic cells in the bone marrow.

WM is rare, with an overall age-adjusted incidence in the United States of 3.6 cases per 1,000,000 people.1 The incidence of WM increases with age, and the condition is almost never diagnosed in people younger than 30 years. In the United States, WM occurs twice as frequently in men than in women.1 Overall, the incidence of WM is higher in white populations than in other racial groups.

Photomicrograph demonstrating Waldenström macroglobulinemia, a rare type of cancer that begins in the white blood cells.
Figure. Photomicrograph demonstrating Waldenström macroglobulinemia, a rare type of cancer that begins in the white blood cells. Credit: Getty Images.

Waldenström Macroglobulinemia Management

Unlike numerous other cancers, WM is not always treated at the time of diagnosis.2 Typically, experts advise against treating patients with WM until symptoms develop.3 Patients with asymptomatic WM often undergo surveillance without treatment.

Treatment for WM is recommended by the National Comprehensive Cancer Network (NCCN) in patients with the following complications3:

  • Hyperviscosity syndrome 
  • Neuropathy 
  • Symptomatic adenopathy or organomegaly 
  • Cryoglobulinemia 
  • Cold agglutinin disease 
  • Anemia 
  • Amyloidosis

Hyperviscosity syndrome is caused by the buildup of IgM in the blood.4 Per NCCN, this syndrome requires immediate plasmapheresis when symptomatic or IgM levels exceed 4000 mg/dL.3 Plasmapheresis should be followed by combination systemic therapy.

Importantly, WM is not curable with current modalities, and there is no standard of care treatment for this disease.2 The focus of WM treatment is symptom management and preventing end-organ damage.

In addition to plasmapheresis, nonpharmacologic treatments for WM include radiation therapy and hematopoietic cell transplantation (HCT).5 An in-depth discussion of these modalities is outside the scope of this article, which will focus on pharmacologic treatments for WM. These include immunotherapy, targeted therapy, and chemotherapy.6-8


WM requires staging prior to being treated.9 In 2009, WM data from 7 cooperating institutions were used to create the International Prognostic Scoring System for Waldenstrom’s Macroglobulinemia (ISSWM).10 This system uses the following cutoffs for scoring to determine prognosis9:

  • Age older than 65 years
  • Hemoglobin level 11.5 g/dL or less 
  • Platelet level 100,000 platelets/µL or less
  • β-2 microglobulin level greater than 3 mg/L 
  • Monoclonal IgM antibody level greater than 7 g/L

Each criterion, except for age, is worth a point toward scoring.9 A person’s age and score put them into 1 of 3 risk categories: 

  • Low-risk: patients aged 65 years and younger with no more than 1 point
  • Intermediate-risk: patients older than age 65 with 2 or fewer points and patients younger than 65 who have 2 points
  • High-risk: patients of any age with at least 3 points

Average 5-year survival rates for low, intermediate, and high-risk WM groups are 87%, 68%, and 36%, respectively.10 That said, the prognosis may vary significantly depending on individual factors, and survival rates are only estimates.11

The ISSWM score is used with a patient’s clinical presentation to guide treatment recommendations.10 Because WM is rare, there are limited data and few randomized trials that compare treatment modalities.3 As a result, recommendations are based primarily on phase 2 and retrospective studies.


Immunotherapy is the foundation for the pharmacologic treatment of WM.3,12 The most commonly used immunotherapeutic drug in WM is rituximab.


Rituximab is a monoclonal antibody that is approved by the United States Food & Drug Administration (FDA) to treat NHL and works by binding to CD20 on the surface of lymphoma cells, triggering their death.13

The safety and efficacy of rituximab as monotherapy have been evaluated by several studies in the last 20 years.14-16 However, NCCN and the European Society for Medical Oncology (ESMO) recommend rituximab combined with bendamustine as a preferred primary regimen for WM.3,12 ESMO highlights this regimen as an excellent primary option for patients with a high tumor burden.12 High tumor burden is defined as WM complicated by severe cytopenias, hyperviscosity, or organomegaly.

Rituximab is also combined with other targeted drugs and chemotherapy agents to treat previously untreated and treated WM.3 

Dosing and Administration 

The dosing recommendation for rituximab differs based on the status of the disease.17 For previously untreated WM, the manufacturer recommends rituximab 375 mg/m2 intravenously (IV) on day 1 of each combination therapy treatment cycle for up to 8 doses. 

For WM that has relapsed or is refractory to treatment, the manufacturer recommends rituximab 375 mg/m2 IV once weekly for 4 to 8 doses.17 For disease that relapses after this treatment, rituximab should be given once weekly for 4 doses.

Adverse Reactions

The most common adverse reactions to rituximab during treatment for NHL were17

  • Infusion reactions; 
  • Fever; 
  • Lymphopenia; 
  • Chills;
  • Infection; and
  • Asthenia. 

Patients should be closely monitored for infusion reactions and tumor lysis syndrome, particularly at the time of initial infusion of rituximab.17

Rituximab can also cause IgM flares, which is a significant rise in IgM levels after completion of a course of treatment with rituximab. 18 Rituximab-induced IgM flares may cause hyperviscosity, worsening neuropathy, and cryoglobulinemia.3 

High IgM levels from a flare can last for months and may require plasmapheresis.3 To prevent IgM flares, prophylactic plasmapheresis (in patients who would not otherwise be candidates for plasmapheresis) is an option for patients with IgM levels higher than 4000 mg/dL prior to starting treatment with rituximab. 

Prior to each course of rituximab, complete blood counts (CBCs) should be obtained, and patients should undergo close monitoring throughout treatment.17 

Drug-Drug Interactions 

Drug interaction studies have not been performed with rituximab.17 

Targeted Therapy 

Targeted treatment modalities are used in combination with immunotherapy and other systemic agents to treat WM.3 The 2 targeted drug types used most often to treat WM are Bruton tyrosine kinase (BTK) inhibitors and proteasome inhibitors.7  BTK inhibitors block the BTK protein inside lymphoma cells, slowing cell growth, and proteasome inhibitors block proteasomes from breaking down proteins within cancer cells, thereby interfering with cell division.


Ibrutinib is a BTK inhibitor that has been approved by the FDA to treat WM.19 NCCN recommends ibrutinib with or without rituximab as a preferred regimen for previously untreated or treated WM.3 ESMO also recommends ibrutinib as monotherapy for relapsed WM and as primary therapy for patients who cannot tolerate systemic chemotherapy.12 

Dosing and Administration

The manufacturer’s recommended dosage of ibrutinib is 420 mg administered daily until disease progression or unacceptable toxicity.19 Ibrutinib is taken orally and comes in tablet, capsule, or liquid form. Ibrutinib should be avoided in patients with severe hepatic impairment.

Adverse Reactions

The most common adverse reactions associated with ibrutinib to treat WM are19:

  • Thrombocytopenia; 
  • Diarrhea; 
  • Fatigue; 
  • Musculoskeletal pain; 
  • Neutropenia; 
  • Rash;
  • Anemia; and 
  • Ecchymosis. 

Ibrutinib may cause serious bleeding events.19 As a result, patients should be monitored closely for bleeding when undergoing treatment with ibrutinib coadministered with anticoagulants or antiplatelet therapy. 

Serious infections may also occur in patients receiving ibrutinib, and cases of progressive multifocal leukoencephalopathy (PML) and Pneumocystis jirovecii pneumonia have been reported.19 Clinicians should consider administering standard-of-care prophylaxis for opportunistic infections in high-risk patients. 

Cardiac side effects have been reported in patients a history of hypertension or cardiac abnormalities undergoing treatment with ibrutinib.19 Cardiac history and current cardiac function should be evaluated prior to and during treatment with ibrutinib. These patients should also be closely monitored for new or worsening hypertension. Antihypertensive medications should be initiated or modified, as needed. 

To monitor for thrombocytopenia and neutropenia, CBCs should be obtained monthly during treatment with ibrutinib.19 

Importantly, secondary malignancy may occur with ibrutinib.19 The most common second primary malignancy identified during clinical trials was nonmelanoma skin cancer. Patients should be closely monitored during and after treatment with ibrutinib for signs of secondary malignancy. 

Drug-Drug Interactions

Ibrutinib interacts with CYP3A inhibitors and inducers.19 When combined with CYP3A inhibitors, the ibrutinib plasma concentration increases, along with the risk of toxicity.

The manufacturer recommends ibrutinib dose modification when the agent is used with posaconazole, voriconazole, and moderate CYP3A inhibitors.19 Ibrutinib should not be combined with strong CYP3A inhibitors. Because grapefruit and Seville or bitter oranges are moderate to strong CYP3A inhibitors, these fruits should also be avoided by patients undergoing treatment with ibrutinib. 

Ibrutinib plasma concentration decreases when combined with CYP3A inducers.19 This combination lowers the efficacy of ibrutinib and therefore should be avoided. 


Zanubrutinib is another BTK inhibitor that has been approved by the FDA to treat WM.20 NCCN recommends zanubrutinib as an alternative preferred primary regimen to ibrutinib.3 Per NCCN, zanubrutinib is also a preferred option for previously treated WM. In the ASPEN trial, patients undergoing treatment with zanubrutinib experienced less atrial fibrillation and nonhematologic adverse reactions compared with those undergoing treatment with ibrutinib, and the overall survival benefit of zanubrutinib was similar to that of ibrutinib.21

Dosing and Administration 

The manufacturer recommends 2 dosing schedules for zanubrutinib: 160 mg taken twice daily or 320 mg taken once daily.20 Zanubrutinib is administered as an oral capsule. The dose should be reduced to 80 mg twice daily for patients with severe hepatic impairment.

Adverse Reactions

The most common adverse reactions associated with zanubrutinib treatment are20

  • Neutropenia;
  • Upper respiratory infection; 
  • Thrombocytopenia;
  • Hemorrhage; 
  • Lymphopenia; 
  • Rash; and 
  • Musculoskeletal pain. 

Like ibrutinib, zanubrutinib can cause serious hemorrhagic side effects.20 Clinicians should use caution when administering this drug with anticoagulants or antiplatelet therapy. 

Serious infections may also occur with zanubrutinib treatment.20 Prophylaxis for herpes simplex virus (HSV) and Pneumocystis jirovecii pneumonia should be administered to patients at high risk for opportunistic infection. 

CBCs should be obtained during zanubrutinib treatment due to its association with cytopenias.20 

Cardiac status should be assessed prior to starting treatment with zanubrutinib due to the risk of atrial fibrillation and atrial flutter.20 Clinicians should monitor all patients undergoing treatment with zanubrutinib for signs of cardiac dysfunction.

Drug-Drug Interactions 

Zanubrutinib interacts with moderate and strong CYP3A inhibitors and inducers.20 Administering zanubrutinib with CYP3A inhibitors increases its plasma concentration and the risk for toxicity. The dose of zanubrutinib should be decreased when given with CYP3A inhibitors. 

The plasma concentration of zanubrutinib decreases when the agent is given with a CYP3A inducer.20 The manufacturer recommends that this combination be avoided.


Bortezomib is a proteasome inhibitor used off-label as primary treatment for WM or to treat relapsed/refractory WM.3,12 Per NCCN and ESMO guidelines, bortezomib, dexamethasone, and rituximab (BDR) is a preferred primary regimen for WM. Bortezomib can also be given alone with dexamethasone to patients who cannot tolerate BDR.

Dosing and Administration

The dosing schedules reviewed here are based on the dosing schedules from 2 clinical trials using bortezomib regimens for untreated WM.22-23 One study administered bortezomib 1.3 mg/m2 IV on days 1, 4, 8, and 11 of a 21-day cycle, followed by 1.6 mg/m2 on days 1, 8, 15, and 22 for up to four 35-day cycles.22 

The other study administered bortezomib 1.3 mg/m2 IV on days 1, 4, 8, and 11 for up to 4 cycles.23 After a 12-week treatment pause, 4 additional cycles were planned, each spaced 12 weeks apart as maintenance therapy.

During both trials, dosing was modified in cases of adverse reactions.22-23 In cases of severe adverse events, treatment was discontinued. HSV prophylaxis was mandated in one trial and was strongly recommended in the other.

Importantly, NCCN recommends the use of subcutaneous bortezomib injections as the preferred method of administration.3 This method reduces the risk of peripheral neuropathy. Administering bortezomib weekly compared to twice weekly also reduces neuropathy risk. The manufacturer also recommends a dose reduction in patients with severe hepatic impairment.25

Experts recommend twice-weekly or once-weekly monotherapy with bortezomib for relapsed/refractory WM.24

Adverse Reactions

Peripheral neuropathy was the most common toxicity reported during clinical trials with bortezomib for WM.22-23 Other common adverse reactions associated with bortezomib included: 

  • Neutropenia;
  • Thrombocytopenia; 
  • Pulmonary toxicity;
  • Anemia; and 
  • Infection.

Drug-Drug Interactions 

The manufacturer reports an interaction between bortezomib and strong CYP3A4 inducers and inhibitors.25 Therefore, coadministration of bortezomib and strong CYP3A4 inducers should be avoided. If bortezomib is given with a strong CYP3A4 inhibitor, patients should be monitored closely for toxicity. 


Systemic chemotherapy is used to treat both previously untreated and relapsed/refractory WM.3 Patients must be evaluated for HCT candidacy prior to starting chemotherapy for WM. Two chemotherapeutic drugs used off-label to treat WM — fludarabine and cladribine — should be avoided in patients who are deemed candidates for HCT. 

Chemotherapy agents are often given in combination with targeted drugs, rituximab, and dexamethasone or prednisone to treat WM.3 


Cyclophosphamide is an alkylating drug that is approved by the FDA to treat lymphocytic lymphoma.26  Alkylating agents work by blocking the transcription of DNA into RNA, thereby inhibiting protein synthesis.27 

NCCN recommends rituximab, cyclophosphamide, and a corticosteroid (either dexamethasone or prednisone) as a primary treatment option for WM.3 This regimen is considered an alternative to bortezomib-containing therapy. 

Cyclophosphamide is also used in combination with other targeted or chemotherapy agents — with or without rituximab — to treat previously treated WM.3 

Dosing and Administration 

Cyclophosphamide can be administered orally or via IV.26 Numerous dosing regimens have been reported for both IV and oral options. 

Dosing schedules that have been used in clinical trials to treat WM include: 

  • Cyclophosphamide 100 mg/m2 orally twice daily on days 1 through 5 every 3 weeks for up to 6 cycles, given in combination with dexamethasone and rituximab as primary treatment28 
  • Cyclophosphamide 100 mg/m2 orally once daily on days 1 through 5 every 3 weeks for up to 6 cycles, given together with dexamethasone and rituximab for untreated or previously treated disease29
  • Cyclophosphamide 250 mg/m2 IV on days 2 through 4 every 28 days for up to 6 courses, given together with dexamethasone and rituximab for untreated or previously treated disease30

Adverse Reactions 

The most common adverse reactions associated with cyclophosphamide include26

  • Febrile or nonfebrile neutropenia; 
  • Fever; 
  • Alopecia; 
  • Nausea;
  • Vomiting; and
  • Diarrhea. 

Cyclophosphamide causes myelosuppression, which puts patients at risk for severe infection.26 The manufacturer recommends antimicrobial prophylaxis in appropriate patients to prevent opportunistic infection. CBCs should be obtained and treatment discontinued in cases of serious infection. 

Cyclophosphamide can cause renal, pulmonary, and cardiac toxicity.26 Patients taking cyclophosphamide should be monitored closely for signs of end-organ damage. 

Drug-Drug Interactions

The manufacturer reports several drug-drug interactions with cyclophosphamide.26 Drugs that interact with cyclophosphamide include: 

  • Protease inhibitors (associated with increased cyclophosphamide toxicity and mucositis)
  • Drugs with hematotoxicity profiles similar to that of cyclophosphamide, including angiotensin-converting enzyme (ACE) inhibitors, natalizumab, paclitaxel, thiazide diuretics, and zidovudine
  • Drugs with similar cardiotoxicity profiles, including anthracyclines, cytarabine, pentostatin, radiation therapy of the cardiac region, and trastuzumab 
  • Drugs with similar pulmonary toxicity profiles, including amiodarone, granulocyte colony-stimulating factor (G-CSF), and granulocyte-macrophage colony-stimulating factor (GM-CSF)
  • Drugs with similar nephrotoxicity profiles, including amphotericin B and indomethacin 
  • Azathioprine (associated with increased hepatotoxicity risk) 
  • Busulfan, associated with hepatic veno-occlusive disease and mucositis
  • Metronidazole (associated with acute encephalopathy) 
  • Tamoxifen (associated with increased thromboembolic events) 
  • Warfarin (associated with increased or decreased warfarin effect) 
  • Cyclosporine (associated with low plasma concentrations of cyclosporine and increased incidence of graft-vs-host disease) 
  • Depolarizing muscle relaxants (associated with inhibition of cholinesterase activity)


Bendamustine is another alkylating agent that is approved by the FDA to treat B-cell NHL.31 Bendamustine is indicated to treat NHL that has progressed during or within 6 months of rituximab therapy. NCCN and ESMO recommend bendamustine as a preferred primary regimen for WM in combination with rituximab.3,12 These recommendations are based on the findings of a phase 3 clinical trial comparing bendamustine plus rituximab and R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).32 R-CHOP has historically been a first-line standard of care for patients with indolent NHL and mantle cell lymphoma in elderly patients. 

The results of this study support bendamustine plus rituximab as the preferred first-line indolent lymphoma treatment over R-CHOP, based on improved progression-free survival and lower toxicity.32 

Per NCCN, bendamustine, with or without rituximab, is also recommended to treat previously treated WM.3 

Dosing and Administration 

The manufacturer’s recommended dosage of bendamustine is 120 mg/m2 IV over 60 minutes on days 1 and 2 of a 21-day cycle for up to 8 cycles.31 The dose should be reduced in increments of 30 mg/m2 should hematologic and nonhematologic toxicities occur. 

Adverse Reactions

The most common adverse reactions associated with bendamustine during NHL treatment are31

  • Nausea; 
  • Vomiting; 
  • Diarrhea; 
  • Pyrexia; 
  • Constipation; 
  • Anorexia; 
  • Cough;
  • Headache;
  • Weight loss; 
  • Dyspnea;
  • Rash; 
  • Stomatitis; 
  • Lymphopenia; 
  • Anemia; 
  • Leukopenia; 
  • Thrombocytopenia; and 
  • Neutropenia. 

Myelosuppression caused by bendamustine requires close monitoring of CBCs during treatment.31 Myelosuppression also puts patients at risk for serious infections. Patients should also be closely monitored during drug administration due to the risk of tumor lysis syndrome and infusion reactions. 

Drug-Drug Interactions

Formal studies to assess drug interactions with bendamustine have not been performed.31 However, based on bendamustine metabolism, inhibitors and inducers of CYP1A2 can affect plasma concentrations of bendamustine. CYP1A2 inhibitors, including fluvoxamine and ciprofloxacin, may increase the active metabolites of bendamustine.31 CYP1A2 inducers, including omeprazole and cigarette smoke, may decrease the active metabolite concentration of bendamustine.31 These drug combinations should be avoided, if possible. 


Vincristine is a chemotherapy drug approved by the FDA to treat NHL.33  The exact mechanism of action of this agent remains under investigation. NCCN includes vincristine as a component of R-CHOP as a treatment option for previously treated WM.3 

Dosing and Administration

Vincristine dosing should be done carefully due to the dose-dependent risk for neurotoxicity.33 The usual dosage of vincristine for adults is 1.4 mg/m2 IV administered weekly. For patients with bilirubin greater than 3 mg/100 mL, the manufacturer recommends a 50% dose reduction. 

Adverse Reactions

The most common adverse reactions associated with vincristine are33

  • Hair loss; 
  • Neuropathic pain; 
  • Leukopenia;
  • Constipation; 
  • Abdominal cramps; 
  • Nausea;
  • Vomiting; 
  • Diarrhea;
  • Neurologic toxicity, including sensory loss, paresthesia, difficulty walking, slapping gait, hyporeflexia, and muscle wasting; and 
  • Renal toxicity.

The neurologic toxicity of vincristine may persist after treatment is discontinued.33 Caution should be used when considering vincristine therapy for patients with a history of neuromuscular disease. NCCN notes that vincristine should be avoided, if possible, due to the risk of neuropathy in patients with WM.3 

Drug-Drug Interactions 

Vincristine should not be administered to patients receiving radiation therapy through ports, including the liver.33  

Giving chemotherapy combinations containing vincristine with phenytoin can decrease phenytoin’s plasma concentration and increase seizure activity.33 Dosing modifications should be based on phenytoin blood level monitoring during treatment. 

Clinicians should also be careful when administering vincristine with CYP3A inhibitors, including itraconazole.33 Increased severity and earlier onset of neuromuscular toxicity have been reported when vincristine is combined with itraconazole, likely due to decreased metabolism of vincristine.


Doxorubicin is an anthracycline topoisomerase II inhibitor that is approved by the FDA to treat NHL.34 Drugs in this class work by blocking the activity of the topoisomerase II enzyme, which is normally involved in DNA repair.35 Interrupting this action may inhibit cancer growth. 

NCCN guidelines include doxorubicin-containing R-CHOP therapy as a treatment option for previously treated WM.3 

Dosing and Administration

When doxorubicin is used in combination therapy, the manufacturer recommends a dosage of 40 to 75 mg/m2 IV administered every 21 to 28 days.34 Doxorubicin is typically administered over 3 to 10 minutes. 

Lower doses should be considered for patients with a history of pretreatment, elderly patients, and patients with high body fat percentages.34

The dose of doxorubicin should be decreased for patients with bilirubin levels between 1.2 and 5 mg/dL.34 Doxorubicin is contraindicated in patients with severe hepatic impairment.

Adverse Reactions

The most common adverse reactions associated with doxorubicin treatment include34:

  • Hair loss; 
  • Nausea; and 
  • Vomiting. 

Doxorubicin can also cause life-threatening complications, including34

  • Cardiomyopathy; 
  • Arrhythmias; 
  • Secondary malignancy, including acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS);
  • Local tissue death at the injection site; 
  • Severe myelosuppression; 
  • Tumor lysis syndrome; and 
  • Radiation sensitization. 

Doxorubicin cardiotoxicity is typically proportional to cumulative drug exposure.34 Cardiomyopathy can occur during treatment or years afterward. Patients should be closely monitored for signs of congestive heart failure and arrhythmias. Risk for cardiomyopathy increases in patients with a history of mediastinal radiation therapy. Cardiac function should be assessed prior to starting treatment with doxorubicin.

Patients should also have blood counts checked prior to and during treatment with doxorubicin due to the risk of severe myelosuppression.34 

Drug-Drug Interactions

The manufacturer reports several drug-drug interactions with doxorubicin.34 Drugs that interact with doxorubicin include:

  • CYP3A4 inhibitors (associated with increased doxorubicin toxicity) 
  • CYP3A4 inducers (associated with decreased doxorubicin plasma concentration and effect)
  • Trastuzumab (associated with increased risk of cardiotoxicity) 
  • Paclitaxel (associated with increased doxorubicin plasma concentration)
  • 6-Mercaptopurine (associated with increased risk of hepatotoxicity)

The cardioprotectant dexrazoxane should not be given with doxorubicin due to its association with lower tumor response.34 

Additional Monitoring Considerations for Waldenström Macroglobulinemia Treatment

Treatment precautions for WM vary based on patient characteristics and the specific treatment modality used. Important monitoring considerations exist for all stages of treatment.


Certain WM treatments necessitate disease screening before starting therapy.3 Rituximab is known to cause hepatitis B virus (HBV) reactivation, which may lead to hepatic failure.17 Therefore, patients at high risk should be screened for HBV prior to initiating rituximab. Patients should be closely monitored during treatment for signs of hepatitis, and rituximab should be discontinued if hepatitis develops. NCCN also recommends HBV screening before treatment with carfilzomib and ofatumumab, 2 drugs used off-label to treat WM.3 Patients who are at high risk should also be screened for HIV and hepatitis C virus. 


For patients who are hepatitis B surface antigen-positive and who receive anti-CD20 therapy, NCCN recommends prophylactic antiviral therapy during treatment.3 If the hepatitis B core antibody is positive, prophylactic therapy is recommended. If core and surface antibodies are positive, patients can be followed with serial hepatitis B viral load levels.

P jirovecii pneumonia prophylaxis may also be indicated in certain patient populations.3 As mentioned earlier, the manufacturers of zanubrutinib and ibrutinib recommend prophylaxis for P jirovecii pneumonia during treatment with these agents.19,20 NCCN also recommends that clinicians consider prophylaxis for patients receiving bendamustine/rituximab or fludarabine/cyclophosphamide/rituximab.3 

Considerations in Specific Populations

Pregnancy and lactation can affect cancer treatment. None of the drugs used to treat WM have adequate data to accurately assess the risk of exposure to a human fetus during pregnancy.17,19,20,25,26,31,33-34 Based on drug mechanisms and animal studies, clinicians should counsel patients on the potential fetal risks if they become pregnant during or before treatment. If possible, pregnancy should be avoided during WM treatment. 

Although there are limited data about risks, manufacturers also recommend against breastfeeding during treatment with these drugs.17,19,20,25,26,31,33-34

Geriatric Populations

Since WM is a disease that disproportionately affects older people, drug effects in the geriatric population are particularly relevant.1 Generally, the drugs discussed here have not shown differing effectiveness or safety profiles in geriatric patients.17,20,25,26,31,33-34 However, ibrutinib is an exception.19 Although treatment effectiveness was similar among younger and older patients, side effects — including anemia, pneumonia, thrombocytopenia, hypertension, and atrial fibrillation — occurred more frequently among the geriatric study population.  

Waldenström Macroglobulinemia Treatment Guidelines 

Several treatment guidelines are available to assist clinicians with decision-making when managing patients with WM. The following are the most current guidelines for WM treatment:

  • NCCN Clinical Practice Guidelines for Waldenström Macroglobulinemia/Lymphoplasmacytic Lymphoma, which can be found here.3
  • ESMO Clinical Practice Guidelines for Waldenström Macroglobulinemia, which can be found here.12 


  1. McMaster ML. The epidemiology of Waldenström macroglobulinemia. Semin Hematol. 2023;60(2):65-72. doi:10.1053/j.seminhematol.2023.03.008
  2. When to treat people with Waldenström macroglobulinemia. American Cancer Society website. Updated September 2, 2021. Accessed June 29, 2023. https://www.cancer.org/cancer/types/waldenstrom-macroglobulinemia/treating/people-with-wm.html
  3. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Waldenström Macroglobulinemia/Lymphoplasmacytic Lymphoma. National Comprehensive Cancer Network. Published December 12, 2022. Accessed June 29, 2023. https://www.nccn.org/professionals/physician_gls/pdf/waldenstroms_blocks.pdf 
  4. Gertz MA. Acute hyperviscosity: syndromes and management. Blood. 2018;132(13):1379-1385. doi:10.1182/blood-2018-06-846816
  5. Waldenström macroglobulinemia: diagnosis and treatment. Mayo Clinic. Accessed June 29, 2023. https://www.mayoclinic.org/diseases-conditions/waldenstrom-macroglobulinemia/diagnosis-treatment/drc-20359986
  6. Chemotherapy for Waldenström macroglobulinemia. American Cancer Society. Updated July 19, 2018. Accessed June 29, 2023. https://www.cancer.org/cancer/types/waldenstrom-macroglobulinemia/treating/chemotherapy.html
  7. ‌Targeted drug therapy for Waldenström macroglobulinemia. American Cancer Society. Updated September 2, 2021. Accessed June 29, 2023. https://www.cancer.org/cancer/types/waldenstrom-macroglobulinemia/treating/targeted-therapy.html
  8. Biological therapy or immunotherapy for Waldenström macroglobulinemia. American Cancer Society. Updated November 30, 2018. Accessed June 29, 2023. 
  9. Waldenström macroglobulinemia stages. American Cancer Society. Updated July 19, 2018. Accessed June 29, 2023. https://www.cancer.org/cancer/types/waldenstrom-macroglobulinemia/detection-diagnosis-staging/staging.html
  10. ‌Morel P, Duhamel A, Gobbi P, et al. International prognostic scoring system for Waldenström macroglobulinemia. Blood. 2009;113(18):4163-4170. doi:10.1182/blood-2008-08-174961
  11. ‌Survival rates for Waldenström macroglobulinemia. American Cancer Society. Updated October 17, 2018. Accessed June 29, 2023. https://www.cancer.org/cancer/types/waldenstrom-macroglobulinemia/detection-diagnosis-staging/survival-rates.html
  12. ‌Kastritis E, Leblond V, Dimopoulos MA, et al; ESMO Guidelines Committee. Waldenström’s macroglobulinaemia: ESMO clinical practice guidelines for diagnosis, treatment, and follow-up. Ann Oncol. 2018;29(suppl 4):iv41-iv50. doi:10.1093/annonc/mdy146
  13. ‌Treon SP, Agus DB, Link B, et al. CD20-directed antibody-mediated immunotherapy induces responses and facilitates hematologic recovery in patients with Waldenstrom’s macroglobulinemia. J Immunother. 2001;24(3):272-279.
  14. Gertz MA, Montserrat Rué, Blood EA, Kaminer L, Vesole DH, Greipp PR. Multicenter phase 2 trial of rituximab for Waldenström macroglobulinemia (WM): An eastern cooperative oncology group study (E3A98). Leuk Lymphoma. 2004;45(10):2047-2055. 
  15. Treon SP, Emmanouilides C, Kimby E, et al. Extended rituximab therapy in Waldenström’s macroglobulinemia. Ann Oncol. 2005;16(1):132-138. 
  16. ‌Dimopoulos MA, Zervas C, Zomas A, et al. Treatment of Waldenström’s macroglobulinemia with rituximab. J Clin Oncol. 2002;20(9):2327-2333. doi:10.1200/JCO.2002.09.039
  17. ‌Rituxan. Prescribing Information. Genentech, Inc; 1997. Updated January 2010. Accessed June 29, 2023. 
  18. Noronha V, Fynan TM, Duffy TP. Flare in neuropathy following rituximab therapy for Waldenstrom’s macroglobulinemia. J Clin Oncol. 2006;24(1):e3. doi:10.1200/JCO.2005.04.6474 
  19. Imbruvica®. Prescribing Information. Pharmacyclics LLC; 2013. Updated August 2022. Accessed June 29, 2023.
  20. Brukinsa®. Prescribing Information. BeiGene USA, Inc.; 2019. Updated September 2021. Accessed June 29, 2023.
  21. Tam CS, Opat S, D’Sa S, et al. A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenström macroglobulinemia: the ASPEN study. Blood. 2020;136(18):2038-2050. 
  22. Dimopoulos MA, García-Sanz R, Gavriatopoulou M, et al. Primary therapy of Waldenström macroglobulinemia (WM) with weekly bortezomib, low-dose dexamethasone, and rituximab (BDR): long-term results of a phase 2 study of the European Myeloma Network (EMN). Blood. 2013;122(19):3276-3282. doi:10.1182/blood-2013-05-503862
  23. Treon SP, Ioakimidis L, Soumerai JD, et al. Primary therapy of Waldenström macroglobulinemia with bortezomib, dexamethasone, and rituximab: WMCTG Clinical Trial 05-180. J Clin Oncol. 2009;27(23):3830-3835. doi:10.1200%2FJCO.2008.20.4677
  24. Chen C, Kouroukis CT, White D, et al. Bortezomib in relapsed or refractory Waldenström’s macroglobulinemia. Clin Lymphoma Myeloma. 2009;9(1):74-76. doi:10.3816/CLM.2009.n.019
  25. Bortezomib. Prescribing Information. MAIA Pharmaceuticals, Inc.; 2003. Updated July 2022. Accessed June 29, 2023.
  26. Cyclophosphamide. Prescribing Information. Baxter International Inc; 1959. Updated May 2013. Accessed June 29, 2023.
  27. National Institute of Diabetes and Digestive and Kidney Diseases. Alkylating agents. In: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Updated March 10, 2015. Accessed June 29, 2023. https://www.ncbi.nlm.nih.gov/books/NBK547849/
  28. Dimopoulos MA, Anagnostopoulos A, Marie-Christine Kyrtsonis, et al. Primary treatment of Waldenström macroglobulinemia with dexamethasone, rituximab, and cyclophosphamide. J Clin Oncol. 2007;25(22):3344-3349. doi:10.1200/JCO.2007.10.9926
  29. ‌ Paludo J, Abeykoon JP, Shreders A, et al. Bendamustine and rituximab (BR) versus dexamethasone, rituximab, and cyclophosphamide (DRC) in patients with Waldenström macroglobulinemia. Ann Hematol. 2018;97(8):1417-1425. doi:10.1007/s00277-018-3311-z
  30. ‌Tedeschi A, Benevolo G, Varettoni M, et al. Fludarabine plus cyclophosphamide and rituximab in Waldenström macroglobulinemia: an effective but myelosuppressive regimen to be offered to patients with advanced disease. Cancer. 2012;118(2):434-443. doi:10.1002/cncr.26303
  31. Treanda®. Prescribing Information. Cephalon, Inc; 2008. Accessed June 29, 2023.
  32. Rummel MJ, Niederle N, Maschmeyer G, et al; Study group indolent Lymphomas (StiL). Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomized, phase 3 non-inferiority trial. Lancet. 2013;381(9873):1203-1210. doi:10.1016/S0140-6736(12)61763-2
  33. Vincristine. Prescribing Information. Hospira, Inc; 2012. Updated August 5, 2014. Accessed June 29, 2023.
  34. Doxorubicin. Prescribing Information. Pfizer Inc; 1974. Updated October 2013. Accessed June 29, 2023.
  35. Topoisomerase II inhibitor. National Cancer Institute. Accessed June 29, 2023. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/topoisomerase-ii-inhibitor

Author Bio

Chelsea Alvarado, MD, earned her BS in Biochemistry from Temple University in Philadelphia, Pennsylvania, and her MD from the University of Maryland School of Medicine in Baltimore. She currently works as a freelance medical writer and is passionate about making medical science accessible to all.