Treatment and prognosis of Waldenström macroglobulinemia

INTRODUCTION — The term "macroglobulinemia" refers to the production of excess immunoglobulin M (IgM) monoclonal protein that occurs in certain clonal lymphoproliferative disorders and plasma cell dyscrasias. Waldenström macroglobulinemia (WM) is a distinct clinicopathologic entity demonstrating both:

●Lymphoplasmacytic lymphoma (LPL) in the bone marrow, and

●Elevated levels of IgM in the blood (IgM monoclonal gammopathy, termed "macroglobulinemia")

Patients may be asymptomatic or present with symptoms related to the infiltration of the lymph nodes and spleen or the effects of monoclonal IgM in the blood.

The treatment and prognosis of WM will be reviewed here. The clinical manifestations and diagnosis of this disorder are discussed separately.

●(See "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia".)

●(See "Clinical manifestations, pathologic features, and diagnosis of lymphoplasmacytic lymphoma".)

PRETREATMENT EVALUATION — The initial evaluation of patients with WM must establish the diagnosis, the extent of disease, the presence of associated conditions, and the performance status of the patient.

Particular attention should be paid to the following in the history and physical examination:

●Symptoms of hyperviscosity (eg, epistaxis, bleeding gums, visual changes, headache, dizziness). Funduscopic examination should be performed in all patients with symptoms of hyperviscosity and/or IgM ≥3 g/dL (≥30 g/L). (See "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia", section on 'Hyperviscosity syndrome'.)

●History of infections and systemic symptoms including fever, weight loss, drenching night sweats, and fatigue. Presence of lymphadenopathy, hepatosplenomegaly, and/or pleural effusions.

●Peripheral neuropathy, which may be related to myelin-associated glycoprotein antibody-positive demyelinating peripheral neuropathy. (See "Chronic inflammatory demyelinating polyneuropathy: Etiology, clinical features, and diagnosis".)

●Clinical manifestations of:

•Cryoglobulinemia (eg, purpura, digital ischemia, arthralgia, fever, Raynaud phenomenon). (See "Overview of cryoglobulins and cryoglobulinemia".)

•Cold agglutinin disease (eg, livido reticularis, acrocyanosis, Raynaud phenomenon). (See "Cold agglutinin disease".)

•Immunoglobulin light chain (AL) amyloidosis (eg, nephrotic syndrome, axonal neuropathy, unexplained cardiac failure, intestinal dysmotility, purpura, macroglossia). (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis".)

•Central nervous system (CNS) involvement (ie, Bing Neel syndrome), including headache, seizure, altered mental status, cranial nerve palsy, limb weakness, and/or atypical neuropathy. (See "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia", section on 'Neuropathy'.)

It is our practice to perform the following pretreatment studies in patients with WM:

●Standard laboratory studies include a complete blood count with differential, chemistries with liver and kidney function and electrolytes, lactate dehydrogenase, serum protein electrophoresis, quantitative immunoglobulins and immunofixation, beta-2 microglobulin, and serum free light chain assay.

We also obtain the following tests in a subset of patients:

•Serum viscosity in those with suspected hyperviscosity syndrome.

•Coombs test in those with suspected cold agglutinin disease.

•Prothrombin time (PT), activated partial thromboplastin time (aPTT), and screening for von Willebrand disease (ie, von Willebrand factor [VWF] antigen, VWF activity, and factor VIII activity) in patients with abnormal bruising and/or bleeding, especially mucocutaneous bleeding.

•Hepatitis C serology in patients with cryoglobulinemia and prior to treatment in all patients. (See "Extrahepatic manifestations of hepatitis C virus infection", section on 'Essential mixed cryoglobulinemia'.)

•Hepatitis B and human immunodeficiency virus (HIV) serology prior to treatment in all patients. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy".)

●Unilateral bone marrow aspiration and biopsy for pathologic review, including immunophenotyping and MYD88 mutation analysis plus CXCR4 mutation, if possible. (See 'Bruton tyrosine kinase inhibitors' below.)

●Computed tomography (CT) of the chest, abdomen, and pelvis with intravenous contrast to measure lymphadenopathy and extramedullary involvement. Integrated whole-body positron emission tomography (PET) with CT in cases suspected to have a more aggressive histology. We have a low threshold to biopsy areas with intense fluorodeoxyglucose (FDG) avidity (eg, standardized uptake value [SUV] >10). (See "Pretreatment evaluation and staging of non-Hodgkin lymphomas", section on 'Imaging'.)

●Evaluation of patients with peripheral neuropathy also includes (see "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia", section on 'Neuropathy' and "Immune-mediated neuropathies", section on 'Waldenström macroglobulinemia'):

•Serologic testing for anti-myelin-associated glycoprotein, anti-ganglioside M1, and anti-sulfatide IgM antibodies

•Electromyography (EMG)

•Evaluation for amyloid deposition

•Evaluation to exclude other causes of neuropathy, such as diabetes, vitamin B12 deficiency, thyroid dysfunction, and Lyme disease

●Evaluation of patients with symptoms suggestive of infiltration of the CNS (ie, Bing Neel syndrome) also includes a magnetic resonance imaging (MRI) of the CNS and an assessment of the cerebral spinal fluid (cytology, flow cytometry, and molecular studies) [1].

●Patients with childbearing potential should receive counseling about the potential effect of treatment on their fertility and options for fertility-preserving measures. (See "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery" and "Effects of cytotoxic agents on gonadal function in adult men".)

INDICATIONS FOR TREATMENT

Asymptomatic patients

Observation — Approximately one-quarter of patients with WM have no constitutional symptoms or anemia and no symptoms attributable to the IgM monoclonal protein or tumor infiltration at the time of presentation [2]. These patients are considered to have smoldering WM and should not be treated until symptoms develop [3]. The decision to postpone treatment in this population is based on their good prognosis without therapy and concerns over the short- and long-term complications of treatment.

We follow asymptomatic patients with complete blood counts and monoclonal protein levels every four to six months for the first five years and then annually, if stable. Another reasonable option included in the National Comprehensive Cancer Network (NCCN) guidelines is to adjust monitoring based on the risk of progression as assessed by the asymptomatic WM patient risk calculator with follow-up every 12 months for low risk, every 6 months for intermediate risk, and every 3 months for high risk [4].  

●Those who develop symptomatic disease, anemia, or thrombocytopenia are offered therapy.

●If disease progression is unclear, repeating evaluation three to six months later can help to clarify the disease tempo and whether treatment is indicated.

While the severity of anemia and/or thrombocytopenia that merits treatment is not well-defined, we generally use a threshold of hemoglobin <10 g/dL and platelet count <100,000/microL.

Studies that have used varying hemoglobin values (<10 g/dL to <12 g/dL) to implement treatment have all noted that smoldering WM may remain stable without treatment for long periods of time [3,5-9]. Overall survival approximates that of the normal population, and the 10-year survival rate is 70 to 75 percent [10,11].

WM is not curable, and there is no evidence that the treatment of asymptomatic patients provides a survival benefit when compared with treatment at the time symptoms develop. Treatment is also associated with both short- and long-term complications that can decrease quality of life and potentially affect survival. As an example, rituximab administration can result in a clinically important temporary increase in serum IgM levels (IgM flare), prolonged immunosuppression, and the reactivation of a latent hepatitis B virus infection. As another example, a small percentage of patients treated with nucleoside analogs or alkylating agents develop a more aggressive lymphoma or leukemia [12].

Risk of progression — The risk of progression to symptomatic disease is greater in the first five years after diagnosis with an estimated annual rate of progression in case series ranging from 4 to 15 percent [3,5,7,13].

The asymptomatic WM patient risk calculator can assess risk of progression using IgM level, bone marrow lymphoplasmacytic infiltration, beta-2 microglobulin, and albumin as continuous variables to stratify patients into three risk groups with different median time to progression (TTP):

●High risk (median TTP 1.8 years)

●Intermediate risk (median TTP 4.8 years)

●Low risk (median TTP 9.3 years)

This model was developed based on a retrospective cohort study that identified progression to symptomatic WM in 317 of 439 patients (72 percent) with smoldering WM followed for a median of 7.8 years and validated in two independent cohorts [13]. Symptoms at progression included anemia (67 percent), neuropathy (20 percent), hyperviscosity (15 percent), and organomegaly (10 percent). The following variables were identified as independent predictors for progression:

●IgM ≥4500 mg/dL

●Bone marrow lymphoplasmacytic infiltration ≥70 percent

●Beta-2 microglobulin ≥4 mg/dL

●Albumin ≤3.5 g/dL

Analysis of a combined cohort also identified wild-type MYD88 as an independent risk factor for progression.

Symptomatic patients — Treatment is indicated for patients with symptomatic WM as indicated by any of the following if attributable to the WM (table 1 and algorithm 1):

●Systemic symptoms – Systemic symptoms – Recurrent fever, drenching night sweats, fatigue, and/or unintentional weight loss

●Cytopenias – Hemoglobin ≤10 g/dL or platelet count <100,000/microL; cold agglutinin anemia, immune hemolytic anemia and/or thrombocytopenia

●Physical signs or symptoms of infiltration – Symptomatic or bulky (≥5 cm) lymphadenopathy, symptomatic hepatomegaly, symptomatic splenomegaly, and/or tissue infiltration

●End organ damage – Hyperviscosity, peripheral neuropathy, immunoglobulin light chain (AL) amyloidosis with organ dysfunction, symptomatic cryoglobulinemia, pleural effusions, or nephropathy due to WM

Symptomatic hyperviscosity is a medical emergency that requires prompt plasmapheresis. Signs and symptoms concerning for hyperviscosity include oronasal bleeding, blurred vision, headache, dizziness, paresthesias, retinal vein engorgement and flame-shaped hemorrhages, papilledema, stupor, and coma. (See 'Emergency management of hyperviscosity' below.)

Management of WM-associated peripheral neuropathy requires coordination between clinicians with expertise in hematology and neurology [14]. Treatment of the underlying WM can ameliorate the peripheral neuropathy, but complete resolution is uncommon. Care should be taken to limit exposure to potentially neurotoxic agents and minimize the risk of IgM flare. (See "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia", section on 'Neuropathy'.)

INITIAL TREATMENT — Experts differ in their approach to the treatment of WM. While various drugs and combinations have demonstrated clinical benefit in prospective trials, few have been compared directly in randomized trials. In addition, individual trials have used different response criteria, thereby making it difficult to compare these agents or regimens based on response rates alone.

Our approach is generally consistent with the consensus treatment recommendations proposed by the International Workshops on WM (IWWM-11), Mayo Stratification of Macroglobulinemia and Risk-Adapted Therapy (mSMART), British Society for Haematology, and National Comprehensive Cancer Network (NCCN) (algorithm 1) [15-19]. There are limited data comparing different treatment approaches, and other experts advocate for the earlier incorporation of novel agents (eg, Bruton tyrosine kinase inhibitors) for a larger percentage of patients [20].

General treatment principles — The initial management of patients with symptomatic WM is dependent on age, the severity of symptoms, presence of comorbidities, and patient preferences (algorithm 1).

When choosing a therapy, the following principles apply:

●WM cannot be cured with current therapies. Instead, the goals of treatment are to control symptoms and prevent end-organ damage while maximizing quality of life.

●Therapy is reserved for patients with symptomatic disease since asymptomatic patients may do well without therapy, and treatment has potential short- and long-term complications. (See 'Asymptomatic patients' above.)

●Patients with symptoms of hyperviscosity require emergency plasmapheresis in addition to therapy directed at the malignant clone. (See 'Emergency management of hyperviscosity' below.)

●The intensity of the regimen is dictated by the severity of symptoms; patients with highly symptomatic disease are offered more intense regimens (eg, bendamustine plus rituximab; or bortezomib, dexamethasone, and rituximab) that may have a quicker response time but increased side effects, while patients with minimal symptoms may be offered regimens (eg, dexamethasone, rituximab, and cyclophosphamide) that are better tolerated but slower. (See 'Choice of initial therapy' below.)

●The treatment regimens vary by delivery route and length of therapy. Rituximab-based and bortezomib-based regimens are administered parenterally over a defined period of time. BTK inhibitors are oral medications administered daily until progression.

●Rituximab is frequently associated with a transient increase in serum IgM level (IgM flare) after administration, which can result in symptoms of hyperviscosity or worsen symptoms of neuropathy, cold agglutinin disease, or cryoglobulinemia. Treatment modifications can reduce the risk of IgM flare. (See 'Minimizing risk of IgM flare with rituximab' below.)

Emergency management of hyperviscosity — Symptomatic hyperviscosity is a medical emergency that requires prompt plasmapheresis. Red blood cell transfusions should be avoided, if possible, prior to plasmapheresis since they might further increase serum viscosity. Although the diagnosis is established by measuring serum viscosity, the clinician should make the decision to initiate plasmapheresis based on the patient's symptoms and physical findings (eg, oronasal bleeding, blurred vision, headaches, dizziness, paresthesias, retinal vein engorgement and flame-shaped hemorrhages, papilledema, stupor and coma) rather than on the magnitude of the viscosity measurement. (See "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia", section on 'Hyperviscosity syndrome'.)

The only effective treatment for the hyperviscosity syndrome is the removal of IgM from the circulation via plasmapheresis. The large size of the IgM molecule restricts it mainly to the intravascular space such that it can be rapidly removed with plasmapheresis, resulting in prompt alleviation of symptoms. Details of the plasmapheresis procedure are discussed separately. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology".)

The following general principles regarding plasmapheresis for hyperviscosity syndrome are important:

●Patients presenting with severe neurologic impairment, such as stupor or coma in the absence of subdural or intracranial bleeding, should be treated with plasmapheresis on an emergency basis.

●Symptoms should subside with the lowering of serum viscosity. However, irreversible changes can occur, such as those due to venous thrombosis in the central nervous system and other sites.

●Plasmapheresis does not affect the disease process. In most cases, serum IgM levels will rise, and symptoms of hyperviscosity will recur within a few weeks of stopping plasmapheresis unless therapy directed at the malignant cells is initiated.

●A reasonable initial prescription is a total plasma volume exchange (ie, 3 to 4 liters in an adult) replaced with albumin (rather than plasma), repeated daily until symptoms subside or until serum viscosity is normal.

●Hyperviscosity syndromes are usually associated with an increased plasma volume. Thus, the volume of plasma needed for a "one volume exchange" may be greater than that calculated by commonly used formulae.

●Transfusion with packed red blood cells during this period may further increase whole blood viscosity and precipitate or aggravate heart failure.

Our approach is consistent with the 2023 guidelines published by the American Society for Apheresis [21] and the 2023 consensus treatment recommendations proposed by the IWWM-11 [15,19], which conclude that plasmapheresis is first-line therapy for hyperviscosity syndrome and may be used before rituximab administration to prevent flare in patients with high IgM levels (typically >4000 mg/dL).

This recommendation is supported by low-quality evidence from small observational studies demonstrating efficacy of plasmapheresis in this setting and large observational studies demonstrating the safety of plasmapheresis in general. There have been no randomized trials of plasmapheresis in the management of hyperviscosity syndrome.

The published literature consists of prospective trials with historical controls, case series, and case reports accumulating data on approximately 300 patients [22]. These studies have demonstrated that a single plasmapheresis treatment reduces IgM levels by 30 to 50 percent and is associated with a decrease in serum viscosity, an increase in capillary blood flow, and an improvement in the clinical manifestations of hyperviscosity [21,23-29]. Complications due to plasmapheresis are seen in less than 2 percent of patients replaced with albumin and most commonly consist of citrate-induced paresthesias, muscle cramps, and urticaria. The complications of plasmapheresis are discussed in detail separately. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Complications".)

Minimizing risk of IgM flare with rituximab — The addition of an anti-CD20 monoclonal antibody (eg, rituximab, ofatumumab) to combination chemotherapy improves response rates and prolongs remissions, but it is also associated with a transient, yet clinically important increase in serum IgM levels (IgM flare) and viscosity [30]. Clinical and laboratory monitoring is therefore warranted in patients receiving an anti-CD20 monoclonal antibody for WM during the first one to two cycles.

We agree with the 2023 guidelines published by the American Society for Apheresis [21] and the 2023 consensus treatment recommendations proposed by the IWWM-11 [15,19], which conclude that plasmapheresis is first-line therapy for hyperviscosity syndrome and may be used before anti-CD20 monoclonal antibody administration to prevent flare in patients with high IgM levels (typically >4000 mg/dL). Alternatively, the anti-CD20 monoclonal antibody may be withheld for the first cycle in patients with high IgM levels receiving combination therapy.

CHOICE OF INITIAL THERAPY

Choice of initial therapy — For most patients with treatment-naïve, symptomatic WM, we prefer bendamustine plus rituximab (BR) rather than other chemotherapy regimens or a Bruton tyrosine kinase (BTK) inhibitor, as BR is an effective option that can be given over a short, defined course (four to six months) with an acceptable toxicity profile (algorithm 1). Continuous therapy with a BTK inhibitor is an appropriate alternative for older adults and for others who are not eligible for or do not want systemic chemotherapy.

While they have demonstrated activity in WM, treatment burdens differ, and most of these treatment options have not been directly compared with each other in prospective trials. In addition, it is difficult to compare these agents based on response rates alone since individual trials have used different response criteria.

●Bendamustine plus rituximab – We prefer BR as the initial therapy for most patients [31-34]; the vast majority will have at least a partial response with this approach. BR is a moderately intensive, time-limited therapy administered monthly over a period of four to six months, followed by a treatment-free period. It consists of intravenous bendamustine (dose: 90 mg/m² given over 30 to 60 minutes on days 1 and 2 of each cycle) in combination with rituximab (dose: 375 mg/m² on day 1 of each cycle) [31]. Lower doses of bendamustine are used for older patients and those with kidney impairment. The most common toxicities are myelosuppression, hypogammaglobulinemia, and infection. Other toxicities include an increased risk of secondary myeloid neoplasms. (See 'Bendamustine plus rituximab' below.)

●BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib) – A BTK inhibitor is an appropriate alternative for older patients and for others who are not eligible for or do not want systemic chemotherapy. BTK inhibitors are highly effective oral medications given until disease progression or unacceptable toxicity. While toxicity is greatest in the first six months of treatment, it continues for the duration of therapy. Important toxicities include bleeding, atrial fibrillation, and hypertension. Other toxicities include fatigue, rash, infections, and myalgia/arthralgia. (See 'Bruton tyrosine kinase inhibitors' below.)

●Dexamethasone, rituximab, cyclophosphamide (DRC) – DRC is an acceptable alternative to BR if disease burden is low. This regimen consists of intravenous dexamethasone (dose: 20 mg on day 1) followed by intravenous rituximab (dose: 375 mg/m² on day 1) in addition to oral cyclophosphamide (dose: 100 mg/m² twice daily on days 1 to 5) [35]. This regimen is repeated every 21 days for a total of six courses. (See 'Dexamethasone, rituximab, and cyclophosphamide' below.)

●Bortezomib plus rituximab with or without dexamethasone (BDR) – We usually reserve BDR for relapsed WM. While it has demonstrated efficacy, there is an increased risk of neurotoxicity. This regimen usually consists of weekly bortezomib combined with rituximab at various schedules with or without dexamethasone [36-40]. Subcutaneous administration of bortezomib helps to reduce neuropathy. (See 'Bortezomib, dexamethasone, and rituximab' below.)

Bendamustine plus rituximab — BR is our preferred regimen for most patients with high tumor burden or moderate/severe symptoms (algorithm 1). BR offers effective, time-limited therapy.

BR consists of intravenous bendamustine (dose: 90 mg/m² given over 30 to 60 minutes on days 1 and 2 of each cycle) in combination with rituximab (dose: 375 mg/m² on day 1 of each cycle) [31]. This regimen is repeated every four weeks for four to six cycles. Lower doses of bendamustine are used for older patients and those with kidney impairment.

Rituximab is also associated with a transient, yet clinically important increase in serum IgM levels (IgM flare) and viscosity [30]. All patients should be monitored for IgM flare. Those with IgM >4000 mg/dL also receive interventions to decrease this risk (either prophylactic plasmapheresis or withholding rituximab). (See 'Minimizing risk of IgM flare with rituximab' above.)

Support for the use of BR in WM comes from prospective trials, which have demonstrated overall response rates over 90 percent and relatively good tolerability:

●A phase 2 trial of BR in 63 patients with low-grade lymphoma included 17 patients with lymphoplasmacytic lymphoma [31]. Overall and complete response (CR) rates were 90 and 60 percent, respectively. The most common toxicity was myelosuppression with severe (grade 3 or 4) leukopenia and thrombocytopenia in 16 and 3 percent, respectively.

●The phase 3 Study Group Indolent Lymphomas (StiL) trial compared BR versus R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) in patients with indolent lymphoma [32]. A subset analysis of the 41 patients with WM found that, when compared with R-CHOP, BR was better tolerated (eg, lower rates of infections, cytopenias, neuropathy, stomatitis, and alopecia), resulted in a similar overall response rate (approximately 95 percent), and improved median progression-free survival (PFS; 70 versus 28 months).

Similar response rates and PFS were reported in a larger multicenter retrospective study of BR in WM [41].

The most common toxicities are myelosuppression, hypogammaglobulinemia, and infection. Bendamustine induces dose-dependent deoxyribonucleic acid (DNA) damage and a risk of secondary myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML), although an increased incidence of MDS/AML after bendamustine has not been clearly demonstrated [42]. General side effects of rituximab include infusion reactions, increased risk of infection, and impaired vaccination responses. Rituximab therapy is also associated with the risk of hepatitis B virus (HBV) reactivation among patients positive for HBV surface antigen (HBsAg) or HBV core antibody (anti-HBc). (See "Hepatitis B virus reactivation associated with immunosuppressive therapy" and "Rituximab: Principles of use and adverse effects in rheumatoid arthritis".)

After the completion of four to six cycles of BR, we offer observation with treatment at the time of progression rather than the use of maintenance therapy. While maintenance rituximab has prolonged remission in some other indolent forms of non-Hodgkin lymphoma, a PFS benefit has not been clearly demonstrated in WM, and there is no improvement in overall survival with maintenance [43]. Instead, treatment is given to alleviate the signs or symptoms that prompted treatment initiation. Once there is improvement in these parameters, there is no clear benefit to continued therapy. Maintenance therapy has associated side effects, inconvenience, and cost and has not demonstrated a clinical benefit.

Bruton tyrosine kinase inhibitors — A BTK inhibitor (zanubrutinib, ibrutinib, acalabrutinib) is an appropriate initial therapy for older patients and for others who are not eligible for or do not want systemic chemotherapy. Prospective studies have demonstrated high response rates and sustained remissions with this approach. However, there have been no randomized trials comparing the efficacy and tolerability of BTK inhibitors versus other treatment regimens in WM. While other experts advocate for initial therapy with a BTK inhibitor in most patients [20], we prefer time-limited therapy with BR for eligible patients and reserve BTK inhibitors for the treatment of relapsed or refractory WM.

Ibrutinib and zanubrutinib are both approved by the US Food and Drug Administration (FDA) for the treatment of WM. While we have longer follow-up with ibrutinib, zanubrutinib appears to be more effective and better tolerated [44,45]. Acalabrutinib does not have regulatory approval in this setting.

Zanubrutinib — Zanubrutinib is our preferred option for older patients and for others who are not eligible for or do not want systemic chemotherapy. It is a highly effective, oral therapy for WM. When compared with ibrutinib, zanubrutinib appears to be more effective and better tolerated [44,45]. Zanubrutinib is also effective and well-tolerated in patients intolerant of ibrutinib or acalabrutinib [46].  

Zanubrutinib is administered by mouth at a dose of 160 mg twice daily or 320 mg once daily until disease progression or unacceptable toxicity [47]. Prescribing information highlights the need to monitor for bleeding, infections, cytopenias, and cardiac arrhythmias. Consider holding zanubrutinib for three to seven days before and after surgery to mitigate the risk of perioperative bleeding. Patients have developed second primary malignancies, including skin cancers, and patients are advised to use sun protection.

Support for zanubrutinib comes from a multicenter phase 3 trial (ASPEN), in which 201 patients with MYD88 mutated WM were randomly assigned to zanubrutinib or ibrutinib, each given until disease progression or unacceptable toxicity [44,45]. After a median follow-up of 44.4 months, zanubrutinib resulted in:

●Faster and deeper responses, with the best responses seen in those with MYD88 mutated, CXCR4 wild-type WM.

●Similar PFS and overall survival (OS; 42-month PFS 78 versus 70 percent; hazard ratio [HR] 0.63, 95% CI 0.36 to 1.12; 42-month OS 88 versus 85 percent; HR 0.75, 95% CI 0.36 to 1.59).

●Less toxic, requiring fewer dose reductions and fewer discontinuations due to toxicity (9 versus 20 percent) with lower rates of diarrhea, muscle spasms, hypertension, atrial fibrillation/atrial flutter, and pneumonia; while there was a higher rate of neutropenia, infection rates were similar, and the prevalence of neutropenia and infection decreased over time.

The ASPEN trial also reported outcomes with zanubrutinib in 26 patients with MYD88 wild-type WM [45,48]. There was one CR, and the rate of very good partial response (VGPR) plus CR was 30.8 percent. Estimated PFS and OS at 42 months were 54 and 84 percent, respectively.

In addition, a single-arm trial evaluated two dosing schedules of zanubrutinib in patients with treatment-naïve (24 patients) or relapsed/refractory (53 patients) WM [49]. Rates of CR plus VGPR increased with time and were 44 percent at 24 months. At a median follow-up of 36 months, the estimated rates of PFS and OS at three years were 81 and 85 percent, respectively.

Ibrutinib — Ibrutinib is an option for older patients and for others who are not eligible for or do not want systemic chemotherapy. It is a highly effective, oral therapy for WM, although zanubrutinib may be preferred based on its better tolerability and likely greater efficacy [44,45]. Some but not all data suggest that ibrutinib is less effective in WM with CXCR4 mutations [50-53].

While prospective trials have evaluated the use of ibrutinib as a single agent and in combination with rituximab, none has compared these two approaches. As there is no clear benefit to the addition of rituximab, we usually offer single-agent ibrutinib.

Ibrutinib is administered at a dose of 420 mg by mouth daily until disease progression or unacceptable toxicity [54]. If included, rituximab (dose: 375 mg/m²) is administered once per week on weeks 1 through 4 and 17 through 20 [55]. While generally well-tolerated, uncommon toxicities, including bleeding, infection, atrial fibrillation, ventricular arrhythmias, and hypertension, are seen [54,56-58].

Ibrutinib is generally avoided in patients with a history of arrhythmia, significant hepatic impairment, or severe bleeding and in those on anticoagulation, although some of these (eg, atrial fibrillation, anticoagulation) may become less of a concern as experience with ibrutinib increases. Consider holding ibrutinib for three to seven days before and after surgery to mitigate the risk of perioperative bleeding. Case reports have described withdrawal symptoms and IgM flare in some patients following temporary or permanent discontinuation [58-60]. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia", section on 'Ibrutinib'.)

Data regarding the use of ibrutinib in WM come from randomized trials comparing it with zanubrutinib or placebo and single-arm trials with longer follow-up. It has not been directly compared with time-limited therapy with BR.

As described separately, in the randomized ASPEN trial, zanubrutinib had improved tolerability and similar efficacy when compared with ibrutinib (42-month PFS 78 versus 70 percent; HR 0.63, 95% CI 0.36 to 1.12; 42-month OS 88 versus 85 percent; HR 0.75, 95% CI 0.36 to 1.59) [44,45]. (See 'Zanubrutinib' above.)

The combination of ibrutinib plus rituximab was compared with placebo plus rituximab in a randomized trial (iNNOVATE) that enrolled 150 patients with symptomatic WM, 68 of whom had not received prior therapy [53,55]. The addition of ibrutinib to rituximab resulted in higher rates of major response (72 versus 32 percent) and sustained improvement in hemoglobin (73 versus 41 percent), and improved PFS (54-month PFS 68 versus 25 percent; HR 0.25, 95% CI 0.15-0.42) regardless of CXCR4 mutation status. Ibrutinib plus rituximab resulted in higher rates of atrial fibrillation (12 versus 1 percent) and hypertension (13 versus 4 percent) and lower rates of anemia (11 versus 17 percent), infusion reactions (1 versus 16 percent), and IgM flare (8 versus 47 percent). OS data are immature with >50 percent of patients in both arms alive at 54 months (HR 0.81, 95% CI 0.33 to 1.99). These results demonstrate that the addition of ibrutinib to rituximab improves PFS and decreases the risk of IgM flare and associated complications. It is unknown how this combination compares with ibrutinib as a single agent or with other rituximab-based combination therapies.

Three smaller, single-arm trials evaluated ibrutinib monotherapy in a total of 124 patients with symptomatic WM [50,61-66]. The overall response rate was >90 percent. There were no CRs. Responses appeared to be deeper among those with mutated MYD88 and wild-type CXCR4. In one trial with a median follow-up of 59 months, estimated PFS at five years was 54 percent for the population as a whole and differed by mutation status (MYD88^MutCXCR^WT 70 percent; MYD88^MutCXRC^Mut 38 percent; MYD88^WTCXCR^WT 0 percent) [50].

Similar response rates were reported in a multicenter retrospective study of ibrutinib in 28 patients with infiltration of the central nervous system (Bing-Neel syndrome) [67].

Acalabrutinib — Acalabrutinib does not have regulatory approval for use in WM, although prospective trials have demonstrated efficacy and relatively good tolerability.

In a multicenter phase 2 trial of 106 patients treated with acalabrutinib, the overall response rate was 93 percent (none complete) [68]. After a median follow-up of 27 months, estimated 24-month PFS and OS rates were 90 and 92 percent, respectively. Thirty patients (28 percent) discontinued acalabrutinib during the study period. Adverse events were consistent with those seen in patients taking acalabrutinib for other conditions. The most common were headache, diarrhea, contusion, dizziness, fatigue, nausea, upper respiratory tract infection, and constipation. Serious adverse events occurred in approximately one-half of patients, and there was one treatment-related death secondary to intracranial hematoma.

Dexamethasone, rituximab, and cyclophosphamide — If the disease burden is low, DRC is an acceptable alternative to BR and is associated with fewer toxicities. While the addition of bortezomib to DRC resulted in faster, deeper responses, it increases the risk of peripheral neuropathy [69].

DRC consists of intravenous dexamethasone (dose: 20 mg on day 1) followed by intravenous rituximab (dose: 375 mg/m² on day 1) in addition to oral cyclophosphamide (dose: 100 mg/m² twice daily on days 1 to 5) [35]. This regimen is repeated every 21 days for a total of six courses.

A phase II trial investigated the use of DRC in 72 patients with previously untreated symptomatic WM [35]. Overall response and CR rates were 83 and 7 percent, respectively, with two-year OS and PFS rates of 81 and 67 percent, respectively. Median time to response was 4.1 months. Toxicities were generally mild (grade 1/2) and included nausea, alopecia, and neutropenia. Chills, fever, and headache that occurred during rituximab infusion were readily reversible after reduction of the infusion rate.

Additional data come from a retrospective analysis of outcomes following DRC [70]. Among the 50 patients with previously untreated WM, the overall response rate was 96 percent, and the median PFS was 34 months. Among the 50 patients with relapsed or refractory WM, the overall response rate was 87 percent, and the median PFS was 32 months. The response rate and duration of response were independent of MYD88 mutation status.

The addition of bortezomib to DRC was evaluated in a randomized trial of 204 patients with previously untreated symptomatic WM [69]. After a median follow-up of 27.5 months, the addition of bortezomib resulted in a modest improvement in time to response and depth of response and similar PFS (24-month PFS 81 versus 73 percent). Rates of grade 3 or 4 toxicities were similar (50 versus 49 percent). However, the trial excluded patients with grade 2 or greater neuropathy. Of the 99 patients without symptoms of neuropathy at the start of treatment, 18 developed neuropathy, and 13 required a dose reduction in bortezomib because of neuropathy.

Limited role for single-agent rituximab — Single-agent rituximab should not be used routinely for WM, particularly if the IgM level is >4000 mg/dL. It is less effective than other treatment options and frequently results in a transient increase in serum IgM levels (IgM flare) that may lead to complications of hyperviscosity. Instead, rituximab is combined with chemotherapy, such as bendamustine (which increases efficacy and decreases the risk of IgM flare), or a BTK inhibitor is used instead. A potential exception is that single-agent rituximab may be offered to highly selected patients with manifestations of WM limited to neuropathy alone or hemolysis alone.

Single-agent rituximab can achieve a partial response in approximately one-half of patients; CRs have not been reported [55,71-75]. Median times to partial and best response are approximately 4 and 17 months, respectively. Studies have reported abrupt and clinically important increases in serum IgM levels and viscosity in approximately one-half of patients at a mean of four weeks (range: one to eight) following initiation of treatment with rituximab [75,76]. Clinical and laboratory monitoring for IgM flare is warranted. Symptoms of hyperviscosity must be treated with emergency plasmapheresis. (See 'Emergency management of hyperviscosity' above.)

A small proportion of WM patients can become intolerant to rituximab [77]. Rituximab intolerance was seen in 7 percent of WM patients exposed to rituximab. Rituximab intolerance can develop while getting rituximab alone or in combination. In these patients, ofatumumab has been used with good tolerability.

FOLLOW-UP — Patients should be evaluated periodically to determine the disease response to treatment and should be followed longitudinally for relapse.

Assessing response to therapy — Response to therapy is determined using the International Working Group on Waldenström Macroglobulinemia's simplified uniform response criteria (ie, "IWWM-11 response criteria," previously referred to as "simplified IWWM-6 response criteria") [78].

For patients treated with bendamustine plus rituximab, we evaluate disease response before each treatment cycle. For those treated with a Bruton tyrosine kinase (BTK) inhibitor, we initially assess disease response before each cycle. Once it is confirmed that the disease is responding, these assessments can be done every few cycles.

●This evaluation always includes a history and physical examination to evaluate for signs and symptoms of progressive disease, serum protein electrophoresis (SPEP), and serum quantitative IgM level. The serum free light chain (sFLC) assay is not used for the routine monitoring of patients with WM, except for those with WM-associated immunoglobulin light chain (AL) amyloidosis.

●Evaluation to confirm a suspected complete response (CR) also includes serum immunofixation and bone marrow aspiration and biopsy. CT imaging to confirm the absence of extramedullary disease is included if extramedullary disease was present at baseline. While studies suggest that it may have prognostic value, we do not routinely obtain positron emission tomography/CT [79]. CR no longer requires reconfirmation at six weeks.

●Disease progression should be considered in patients with signs of active disease. These include clinically significant anemia, thrombocytopenia, leukopenia, adenopathy, hepatomegaly, or splenomegaly, or an increase in symptoms attributable to WM, which may include unexplained recurrent fever, drenching night sweats, ≥10 percent body weight loss, hyperviscosity, neuropathy, symptomatic cryoglobulinemia, or amyloidosis. (See 'Pretreatment evaluation' above.)

Data from this evaluation is used to determine disease response, as follows [78]:

●Complete response – Absence of monoclonal IgM protein by SPEP and immunofixation; normal serum IgM level; no histologic evidence of bone marrow involvement; resolution of any extramedullary disease, including complete resolution or decrease in size of lymph nodes (≤1.5 cm), decrease in the size of spleen (≤15 cm), and complete resolution of any other non-lymph node/non-splenic extramedullary masses related to WM consistent with revised response criteria for lymphoma.

●Very good partial response – ≥90 percent reduction in serum IgM level from baseline or level within normal range.

●Partial response – ≥50 percent and <90 percent reduction in serum IgM level from baseline.

●Minor response – ≥25 percent and <50 percent reduction of serum IgM level from baseline.

●Stable disease – <25 percent reduction to <25 percent increase in serum IgM level from baseline.

●Progressive disease – Requires demonstration of progressive disease (PD) using either IgM or imaging criteria. If IgM level and imaging show discordant findings (eg, IgM response with PD on imaging), then assessment is considered PD.

•Demonstration by IgM: ≥25 percent increase in serum IgM level from lowest nadir (minimum increase of 500 mg/dL from nadir) confirmed on a second sequential measurement. If one measurement suggests PD and the subsequent measurement does not, the patient has not met PD criteria. PD requires two sequential measurements consistent with PD. Suspected IgM flare or IgM rebound related to therapy should not be considered PD.

•Demonstration by imaging showing any of the following:

-Any new lesion (>1.5 cm in any axis)

-Previously involved extramedullary disease sites with unequivocal evidence of enlargement by >50 percent in any axis to >1.5 cm from nadir measurements

-Any new lesion consistent with transformed disease

PD by imaging does not require reconfirmation by repeat imaging.

The term "major response" is used to identify patients who qualify for a partial, very good partial, or complete response. Serum monoclonal IgM levels provide an easily accessible measure of disease status but can sometimes fluctuate independent of disease activity. As an example, IgM levels can increase transiently after treatment with rituximab or bortezomib. As such, bone marrow biopsy should be considered in patients with a clinical picture that does not appear concordant with the serum monoclonal IgM level.

Importantly, IgM values are dependent on the method of measurement used (eg, nephelometry, densitometry). As such, sequential response assessments for individual patients should be performed in the same laboratory using the same methodology.

Patients who have stable or progressive disease are treated as refractory disease. Responses to some chemotherapy regimens may not be seen until after several cycles of therapy. As such, we do not usually switch therapies for stable disease unless there is no response after three or more cycles. (See 'Treatment of relapsed or refractory disease' below.)

Monitoring for progressive disease — Patients with WM are monitored for the development of PD. The frequency of these evaluations depends on initial therapy used (time-limited chemotherapy versus continuous BTK inhibitor) and the comfort of both the patient and clinician.

●Following bendamustine plus rituximab – Following the completion of therapy, we repeat a staging evaluation to document the response to therapy. Our approach to patient surveillance is to schedule patient visits every three months for the first year and then every six months. At these visits, we perform a history and physical examination, complete blood count, and measurement of monoclonal protein in serum or urine. There is no role for routine imaging studies in the longitudinal follow-up of asymptomatic patients after response assessment.

●During Bruton tyrosine kinase inhibitor therapy – For those receiving continuous therapy with a BTK inhibitor, we typically schedule visits monthly for the first two to three months to ensure a response and then every three to six months once the disease has stabilized and the patient is clearly benefiting from therapy.

Histologic transformation — Relapsed or refractory disease must be distinguished from histologic transformation, which requires a different treatment approach. Histologic transformation of WM into a rapidly progressive, high-grade malignant lymphoma may occur after a typical low-grade course [80,81]. The transformation is usually associated with a decrease in performance status, rapid development of lymphadenopathy, increase in serum lactate dehydrogenase levels, presence of abnormal metaphase cytogenetics of involved bone marrow or lymph nodes, and often a decrease in the serum IgM level.

Histologic transformation can be suggested by changes on imaging studies but can only be confirmed by biopsy. As such, a biopsy should always be obtained to document histologic transformation before proceeding with therapy. Survival from the time of transformation is usually very short, and response to treatment has been short-lived. The approach is similar to that of histologic transformation of follicular lymphoma, which is discussed separately. (See "Histologic transformation of follicular lymphoma".)

TREATMENT OF RELAPSED OR REFRACTORY DISEASE

First relapse — Treatment options for patients with relapsed or refractory disease depend on the initial therapy given and the timing of progression. In general, it is not necessary to restart therapy based on monoclonal protein elevations alone in patients who have previously achieved a major response to therapy; rather, the criteria for reinitiation of therapy are similar to those used in newly diagnosed patients and include recurrence of symptoms and cytopenias. Similarly, for patients treated with a BTK inhibitor, it is reasonable to continue therapy despite a rise in monoclonal protein levels as long as the patient is demonstrating a clinical benefit and the therapy is well-tolerated. Relapsed or refractory disease must be distinguished from histologic transformation, which requires a different treatment approach. (See 'Histologic transformation' above.)

Experts differ in their approach to the management of relapsed or refractory disease, and there have been no randomized trials to guide therapy. The following approach is based on a review of the existing data, clinical experience, and observations [82]:

●For symptomatic patients relapsing more than three years following initial systemic chemotherapy (eg, bendamustine plus rituximab [BR]), we repeat the original treatment. With such an approach, patients may respond almost equally well as they did the first time. A Bruton tyrosine kinase (BTK) inhibitor is an acceptable alternative for older patients and for others who are no longer eligible for or do not want systemic chemotherapy. (See 'Bendamustine plus rituximab' above.)

●For symptomatic patients relapsing less than three years after systemic chemotherapy, we suggest a BTK inhibitor. BTK inhibitors are highly effective and well-tolerated treatments. (See 'Bruton tyrosine kinase inhibitors' above.)

●For symptomatic patients with WM progression despite initial therapy with a BTK inhibitor, we offer systemic chemotherapy as given for previously untreated disease. If the patient is not able to tolerate systemic chemotherapy, we usually offer off-label treatment with venetoclax or a next generation BTK inhibitor (eg, pirtobrutinib) as used for multiply relapsed WM, although data on this approach are limited.

Multiply relapsed disease — The management of multiply relapsed disease is individualized based on prior therapy received, general health status, and comorbidities. Options include the off-label use of venetoclax, bortezomib-based regimens, nucleoside analog-based regimens, and other investigational therapies. High-dose chemotherapy followed by autologous hematopoietic cell transplantation (HCT) is rarely used for the treatment of WM.

Venetoclax — Limited data suggest activity of venetoclax in WM. While there are not direct comparisons with other regimens, the generally well-tolerated toxicity profile and high response rates favor its use over that of bortezomib-based regimens and nucleoside analog-based regimens.

A phase II study evaluated up to 24 months of venetoclax in 32 patients with relapsed or refractory WM after a median of two prior therapies [83]. The overall response rate was 84 percent with no complete responses (CRs). Median progression-free survival (PFS) was 30 months. There was a rapid decline of PFS following treatment discontinuation at month 24, suggesting that continued therapy is likely required to maintain disease control. Six patients developed grade 4 neutropenia, one had febrile neutropenia, and one had laboratory tumor lysis syndrome.

Bortezomib, dexamethasone, and rituximab — While bortezomib has activity in WM, it is associated with clinically significant rates of peripheral neuropathy. In addition, changes in serum IgM levels may not be reflective of a response in the bone marrow in a small portion of patients treated with bortezomib [84,85].

The following prospective trials have evaluated bortezomib and rituximab with or without dexamethasone in WM:

●A phase II trial of bortezomib plus rituximab with or without dexamethasone in 23 patients with symptomatic, previously untreated WM found overall and major response rates of 96 and 83 percent, respectively [36]. Peripheral neuropathy was the most common toxicity with 69 percent of patients developing neuropathy that impaired function. Mandatory prophylactic antiviral therapy was added to the treatment protocol after four of the first seven patients developed herpes zoster. None of the patients who took antiviral prophylaxis developed herpes zoster.

●A multicenter phase II trial of bortezomib plus rituximab with or without dexamethasone in 59 patients with symptomatic, previously untreated WM reported an overall response rate of 85 percent (3 percent complete) with most patients demonstrating an initial response at three months [40,86]. Median PFS was 43 months. Overall survival (OS) at seven years was 66 percent. Toxicity resulted in treatment discontinuation in 27 percent. The rate of peripheral neuropathy of any grade was 46 percent (7 percent severe). The lower rate of severe neuropathy may reflect the use of subcutaneous rather than intravenous bortezomib in this trial.

●In another phase II study, once weekly bortezomib was combined with rituximab, which was given weekly during cycles 1 and 4 [87]. Among 37 patients treated for relapsed or refractory WM, a minor response or better (ie, 25 percent or greater reduction in monoclonal protein levels) was seen in 81 percent of patients, including two CRs. The median time to progression was 16 months. Using this weekly schedule of bortezomib, grade 3 neurotoxicity was observed in only two cases (5 percent).

Nucleoside analog-based regimens — Purine nucleoside analogs (eg, fludarabine and cladribine) and alkylating agents (eg, chlorambucil) are treatment options for patients with multiply relapsed and refractory WM with a good performance status. These agents are moderately toxic and associated with a risk of stem cell damage, risk of secondary myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), and a higher risk of transformation [12,88,89].

A single-institution retrospective analysis of 439 patients with WM who received nucleoside analog-containing regimens (193 patients), regimens that did not contain nucleoside analogs (136 patients), or observation alone (110 patients) reported a higher combined rate of transformation to an aggressive lymphoma (Richter syndrome), myelodysplasia, or acute leukemia in patients who received nucleoside analog-based therapy (6.2 versus 0.4 percent, respectively) after a median follow-up of five years [12].

Data on regimens using nucleoside analogs are described below:

●Cladribine plus rituximab – A phase II trial of four monthly cycles of combination therapy with rituximab (dose: 375 mg/m² day 1) plus subcutaneous cladribine (dose: 0.1 mg/kg day 1 through 5) in 29 patients with newly diagnosed or previously treated WM reported overall and complete response rates of 90 and 24 percent, respectively [90]. The median time to best response was four months. The most common toxicities were neutropenia and anemia. These were generally mild with 10 episodes and 1 episode of severe (grade 3/4) neutropenia and anemia, respectively.

●Fludarabine plus rituximab – A prospective, multicenter trial evaluated treatment with six cycles of fludarabine (dose: 25 mg/m² per day for five days) plus eight weekly infusions of rituximab (dose: 375 mg/m² per week) in 43 patients with WM who had received less than two prior therapies [91]. The overall response rate was 95 percent (2 percent complete). The median time to best response and time to progression were 19 and 51 months, respectively. Severe toxicities included neutropenia (27 patients), thrombocytopenia (seven patients), and pneumonia (six patients). After a median follow-up of 40.3 months, there were three patients with transformation to aggressive lymphoma and three cases of MDS/AML. After three cases of herpes zoster were noted in the first 21 patients, prophylaxis with acyclovir or famciclovir was given to subsequent patients until one year after treatment cessation.

●Fludarabine plus cyclophosphamide and rituximab – In a prospective, multicenter Italian trial, 43 patients with symptomatic WM were treated with rituximab (dose: 375 mg/m² on day 1) plus fludarabine (dose: 25 mg/m² on days 2 through 4) and cyclophosphamide (dose: 250 mg/m² on days 2 through 4), administered every 28 days for up to six cycles [92]. Prophylaxis with trimethoprim-sulfamethoxazole and acyclovir were mandatory. The overall response rate was 79 percent (12 percent complete) with a median time to 25 and 50 percent reductions in serum monoclonal protein of two and three months, respectively. The median event-free survival was 50 months. Severe (grade 3/4) toxicities included neutropenia, which was seen in 88 percent of patients and was prolonged in 44 percent.

Other investigational agents — Agents under study, both as single agents and in combinations, include next generation BTK inhibitors (eg, pirtobrutinib), ixazomib, ofatumumab, obinutuzumab, CXCR4 antagonists (plerixafor, ulocuplumab), daratumumab, and pembrolizumab. As examples:

●Ixazomib – A phase II study evaluated the oral proteasome inhibitor ixazomib in combination with dexamethasone and rituximab (IRD) in 26 patients with symptomatic, previously untreated WM [93,94]. The overall response rate was 96 percent, and the major response rate was 77 percent with a median time to response of eight weeks. At a median follow-up of 52 months, all patients were alive, and the median PFS was 40 months. There were no grade 4 adverse events. Grade 3 adverse events included infection (2 patients), hyperglycemia (2 patients), infusion reactions (2 patients), and neuropathy (1 patient). In another phase I/II study of IRD in 59 patients with WM, the overall response rate was 71 percent, and the estimated two-year PFS and OS were 56 and 88 percent, respectively [95].

●Daratumumab – A small, multicenter phase II trial of single-agent daratumumab in patients with previously treated WM reported an overall response rate of 23 percent and a median PFS of two months [96].

●Carfilzomib, rituximab, dexamethasone (CaRD) – A phase II trial of CaRD in 31 patients with symptomatic WM who had not received prior rituximab or bortezomib reported an overall response rate of 87 percent (1 complete) [97]. The median times to first and best response were 2 and 13 months, respectively. At a median follow-up of 15 months, 20 patients remained free of progression. The most common severe (grade 3/4) toxicities were hyperglycemia (77 percent), elevated serum lipase (42 percent), and rituximab-related infusion reactions (19 percent). Mild to moderate peripheral neuropathy (all grade 1/2) was seen in 19 percent.

●Immunomodulatory drugs – A prospective phase II trial of thalidomide plus rituximab in 35 patients with symptomatic WM, naïve to either agent, reported overall and major response rates of 72 and 64 percent, respectively [98]. Neuropathy was the dose-limiting toxicity, and 11 patients developed neuropathy that impaired function (≥grade 2). This neuropathy resolved with cessation of therapy in 10 of these patients at a median of 6.7 months. Dose reductions were required in all patients.

Of note, a prospective phase II trial of the thalidomide-analog lenalidomide plus rituximab was halted due to a high rate of rapid-onset severe anemia [99]. As such, the combination of lenalidomide plus rituximab is not recommended for the treatment of WM outside of a clinical trial.

Hematopoietic cell transplantation — High-dose chemotherapy followed by autologous HCT is rarely used for the treatment of WM. Treatment-related mortality appears to be less than 10 percent, and autologous HCT may be able to produce long-term responses even in heavily pretreated patients [100-105]. Different conditioning regimens have been proposed, but none has demonstrated superior efficacy over another. With available treatment options, the role of autologous HCT in WM is limited, and it is reserved for selected patients with good performance status in whom other treatment options have been exhausted. Allogeneic HCT carries a much higher risk of nonrelapse mortality (NRM) and should not be considered outside the context of a clinical trial [82,102,104,106-108].

Data regarding the efficacy of HCT in WM come from a meta-analysis of 15 retrospective studies that included 278 patients who underwent autologous HCT and 311 patients who underwent allogeneic HCT across several decades [109]. All patients undergoing allogeneic HCT and most patients undergoing autologous HCT had relapsed or refractory disease. Most studies reported OS, PFS, and relapse rates (RR) at three to five years and NRM at one year. Pooled estimates were as follows:

●Autologous HCT – OS 76 percent (95% CI 65-86 percent), PFS 55 percent (95% CI 42-68 percent), RR 42 percent (95% CI 30-55 percent), and NRM 4 percent (95% CI 1-7 percent).

●Allogeneic HCT – OS 57 percent (95% CI 50-65 percent), PFS 49 percent (95% CI 42-56 percent), NRM 29 percent (95% CI 23-34 percent), RR 23 percent (95% CI 18-28 percent). Acute graft-versus-host disease (GVHD) was reported in 71 percent and usually grade I to II. Chronic GVHD was reported in 51 percent. Results following allogeneic HCT were heterogeneous, likely reflecting diversity in conditioning regimens, donor type, stem cell source, and GVHD prophylaxis used at different institutions and across time.

PROGNOSIS — For most patients treated with modern therapy, WM is an indolent disease with a median survival over 10 years [110-112]. Many patients will die of causes other than WM, especially those diagnosed in older age [113]. However, this is a heterogeneous group, and outcomes are variable.

A number of multivariate models have been proposed to assess survival in this disorder [114-120]. Many use similar clinical and laboratory variables in different combinations, and it is not clear if any of these models is superior to another. Poor prognostic factors that are common to most of these systems include older age, cytopenias, and an elevated beta-2 microglobulin level (B2M). In addition, initial studies suggest that patients with a high von Willebrand factor antigen level have shorter survival [121].

We calculate the revised International Prognostic Staging System for WM (revised IPSSWM) to assess prognosis at initiation of first therapy as follows [122]:

●Age <65: 0 points; 66 to 75: 1 point; >75: 2 points

●B2M >4 mg/L: 1 point

●Lactate dehydrogenase >250 IU/L: 1 point

●Serum albumin <3.5 g/dL: 1 point

The total points assigned stratifies patients into the following risk groups, which have differing estimated 3-year, WM-associated death rates and 10-year overall survival (OS) rates following treatment with chemoimmunotherapy:

●0 points (very low risk; 3-year deaths 0 percent; 10-year OS 84 percent)

●1 point (low risk; 3-year deaths 10 percent; 10-year OS 59 percent)

●2 points (intermediate risk; 3-year deaths 14 percent; 10-year OS 37 percent)

●3 points (high risk; 3-year deaths 38 percent; 10-year OS 19 percent)

●4 to 5 points (very high risk; 3-year deaths 48 percent; 10-year OS 9 percent)

The current survival rates are likely better than what was observed when this prognostic index was developed, since it predated the incorporation of Bruton tyrosine kinase (BTK) inhibitors. The IPSSWM has not been validated in patients treated with BTK inhibitors.

Other studies have noted the following:

●A prospective multicenter observational study created a staging system for WM utilizing serum B2M level, hemoglobin (Hb) concentration, and serum IgM concentration [8]:

•Stage A (low risk) – B2M <3 mg/L and Hb ≥12 g/dL

•Stage B (medium risk) – B2M <3 mg/L and Hb <12 g/dL

•Stage C (medium risk) – B2M ≥3 mg/L and serum IgM ≥4 g/dL

•Stage D (high risk) – B2M ≥3 mg/L and IgM <4 g/dL

Five-year rates of OS for patients with stage A, B, C, or D disease were 87, 63, 53, and 21 percent, respectively. Rates of five-year progression-free survival were 83, 55, 33, and 12 percent, respectively. Stage D patients had a significantly higher incidence of anemia, hypoalbuminemia, lymphadenopathy, and hepatosplenomegaly than those in other stages.

A 10-year follow-up of this cohort identified elevated serum lactate dehydrogenase levels as a poor prognostic factor with value added to both the original model and the IPSSWM described above [6]. In addition, there appeared to be a subset of patients with "smoldering macroglobulinemia" who had an excellent prognosis without treatment. (See 'Asymptomatic patients' above.)

●In a Swedish population-based study of 1555 patients with WM or lymphoplasmacytic lymphoma diagnosed from 1980 to 2005, relative survival rates (RSR) at five years compared with the general population improved sequentially from 1980 to 1985 (RSR 0.57; 95% CI 0.46-0.68) to 2001 to 2005 (RSR 0.78; 95% CI 0.71-0.85) [123]. Similarly, an analysis of the United States SEER database that included 2696 patients with WM diagnosed from 1988 to 2005 reported a decline in death rates with each five-year calendar period (hazard ratio [HR] 0.90; 95% CI 0.84-0.96) [124]. This improvement in survival appeared to be driven by large improvements in younger patients. The decrease in death rates was greatest in patients <50 years (HR 0.70; 95% CI 0.58-0.84). While the estimated five-year survival for the entire cohort was 52 percent, this varied dramatically by age: 71 percent in patients <70 years and 39 percent in older patients.

●Analyses of the SEER database evaluated over 6000 patients with WM diagnosed between 1980 and 2010 [125,126]. In these studies, the relative as well as the OS of patients with WM improved in the period 2001 to 2010 when compared with previous years. In a multivariate analysis, older age, male sex, and Black ethnicity were independent adverse prognostic factors for survival. The rate of WM-related death at 10 years ranged from 10 to 20 percent, and the median OS was estimated at nine years.

Patients with WM have a different microribonucleic acid (RNA) expression pattern when compared with healthy subjects [127]. MicroRNAs are short, noncoding RNAs that downregulate gene expression in many tumor types and also play a role in regulating normal physiologic processes. MicroRNA expression may be involved in the pathogenesis of WM, and expression levels may differ among patients of different IPSS risk groups. More studies are required to further evaluate the prognostic potential of microRNAs in WM.

CLINICAL TRIALS — Often there is no better therapy to offer a patient than enrollment onto a well-designed, scientifically valid, peer-reviewed clinical trial. Additional information and instructions for referring a patient to an appropriate research center can be obtained from the United States National Institutes of Health (www.clinicaltrials.gov).

WEBSITES FOR ADDITIONAL INFORMATION — Clinicians and/or their patients may search for additional information concerning the treatment of WM on various websites. The following are listed:

●The National Cancer Institute provides information for clinicians and patients. Information concerning WM can be found at its website [128].

●The International Waldenström's Macroglobulinemia Foundation has a website and provides information to patients with WM, friends, caregivers, and members of the medical profession [129].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Waldenström macroglobulinemia".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Waldenström macroglobulinemia (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Indications for treatment – Many patients with Waldenström macroglobulinemia (WM) are asymptomatic (ie, "smoldering" WM) and can be observed for months or years after the diagnosis is established before requiring treatment (algorithm 1). There is no clear advantage to early therapy. (See 'Asymptomatic patients' above.)

Indications for treatment include (table 1) (see 'Indications for treatment' above):

•The presence of systemic symptoms (eg, weakness, fever, night sweats, fatigue, weight loss) along with physical findings (eg, symptomatic lymphadenopathy, hepatomegaly, and/or splenomegaly) and/or cytopenias (eg, anemia, thrombocytopenia, neutropenia).

•Signs and symptoms due to the presence of hyperviscosity (eg, oronasal bleeding, blurred vision, headaches, dizziness, paresthesias, retinal vein engorgement and flame-shaped hemorrhages, papilledema, stupor and coma). Patients presenting with severe neurologic impairment, such as stupor or coma, should be treated with plasmapheresis on an emergency basis. (See 'Symptomatic patients' above.)

•Presence of severe neuropathy.

While the severity of anemia and/or thrombocytopenia that merits treatment is unknown, we generally use cutoff values of hemoglobin ≤10 g/dL and platelet count ≤100,000/microL. Asymptomatic patients are followed periodically with complete blood counts and monoclonal protein levels. (See 'Asymptomatic patients' above.)

●Emergency management of hyperviscosity – For patients who present with symptoms due to hyperviscosity or who develop hyperviscosity during treatment, we recommend the immediate institution of therapeutic plasmapheresis rather than systemic therapy alone (Grade 1C). Plasmapheresis is widely accepted as the standard of care in this setting and is associated with a decrease in serum viscosity, an increase in capillary blood flow, and improvement in the clinical manifestations of hyperviscosity. Chemotherapy alone does not have a rapid enough onset to prevent severe outcomes. Red blood cell transfusions should be avoided, if possible, prior to plasmapheresis since they might further increase serum viscosity. Once plasmapheresis is completed, patients will need to initiate treatment to control the malignant clone. (See 'Emergency management of hyperviscosity' above.)

●Initial therapy – There is no standard therapy for the treatment of WM. While various drugs and combinations have demonstrated clinical benefit in prospective trials, these have not been compared directly in randomized trials. In addition, individual trials have used different response criteria, thereby making it difficult to compare these agents or regimens based on response rates alone.

For most patients with WM requiring treatment, we suggest bendamustine plus rituximab (BR) rather than a Bruton tyrosine kinase (BTK) inhibitor (algorithm 1) (Grade 2C). BR is administered intravenously over a short, defined course (four to six months) with an acceptable toxicity profile. (See 'Bendamustine plus rituximab' above.)

A BTK inhibitor is an appropriate alternative for older patients and for others who are not eligible for or do not want systemic chemotherapy. BTK inhibitors are well-tolerated oral drugs that are administered daily until progression. While we prefer to reserve these agents for the treatment or relapsed or refractory WM, other experts advocate for their more widespread use as initial therapy. (See 'Bruton tyrosine kinase inhibitors' above.)

Single-agent rituximab is no longer used routinely for WM, particularly if the IgM level is >4000 mg/dL. It is less effective than other treatment options and frequently results in a transient increase in serum IgM level (IgM flare) that may lead to complications of hyperviscosity. (See 'Limited role for single-agent rituximab' above.)

●Relapsed disease – The choice of therapy for patients with relapsed disease is dependent upon the duration of remission from their most recent therapy:

•For symptomatic patients relapsing more than three years following BR, we suggest that the original treatment be repeated first (Grade 2C). (See 'Treatment of relapsed or refractory disease' above.)

•For symptomatic patients relapsing less than three years after BR, we suggest zanubrutinib rather than other therapies (Grade 2C). (See 'Treatment of relapsed or refractory disease' above.)

•Although we typically use BR as initial treatment, some patients will receive a BTK inhibitor as initial treatment. For such patients who experience progression, we offer systemic chemotherapy as given for previously untreated disease. If the patient is not able to tolerate systemic chemotherapy, we usually offer off-label treatment with venetoclax or a next generation BTK inhibitor (eg, pirtobrutinib) as used for multiply relapsed WM, although data on this approach are limited. (See 'Multiply relapsed disease' above.)

•The role of high-dose chemotherapy followed by autologous hematopoietic cell transplantation in WM is limited, and it is reserved for selected patients with good performance status in whom other treatment options have been exhausted. (See 'Hematopoietic cell transplantation' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Robert A Kyle, MD, who contributed to an earlier version of this topic review.