This study is a prospective phase II clinical trial designed to evaluate the deep response rate of the ZBR regimen (zanubrutinib combined with reduced-dose bendamustine and CD20 Monoclonal Antibody ) in treatment-naïve symptomatic Waldenström macroglobulinemia (WM) patients. Eligible patients will receive four cycles of the ZBR regimen, followed by zanubrutinib monotherapy for an additional eight months. The assessment period spans from the initiation of treatment until 12 months after treatment completion, with efficacy evaluations conducted every three cycles. Patients will be withdrawn from the study if they experience disease progression (PD) or show no response to treatment. Minimal residual disease (MRD) assessments will be performed at the end of the 3rd and 6th treatment cycles, as well as 12 months after treatment completion, involving evaluations of both bone marrow and peripheral blood MRD rates

Inclusion Criteria:

• 1. Male or female patients aged ≥18 years.
• 2. Must meet the diagnostic criteria for Waldenström's Macroglobulinemia (WM).
• 3. Patients must be treatment-naïve or not have received standard prior therapy, as defined by the following conditions: a) No prior combined chemotherapy with regimens such as BR, RCD, BCD, CHOP, or COP. b) No prior therapy with fludarabine-containing regimens. c) Treatment with chlorambucil or cyclophosphamide (alone or in combination with glucocorticoids) for less than 4 weeks. d) Failure to achieve a minimal response (MR) from the above treatments. e) If any of the above treatments were previously administered, a washout period of at least 2 weeks must be completed before study treatment initiation.
• 4. Presence of indications for WM treatment, meeting at least one of the following criteria: a) Symptomatic hyperviscosity. b) Symptomatic peripheral neuropathy. c) Amyloidosis. d) Cold agglutinin disease; cryoglobulinemia. e) Disease-related cytopenia (Hemoglobin <100 g/L or Platelet count <100×10^9/L). f) Massive lymphadenopathy. g) Presence of constitutional symptoms: persistent/recurrent fever (>38°C) for over 2 weeks unrelated to infection, drenching night sweats, and/or unintentional weight loss >10% within 6 months. h) Rapid disease progression, defined as a >50% increase in lymph node size within 2 months, and/or lymphocyte doubling time <6 months, and/or rapid decline in hemoglobin or platelet counts not due to autoimmune causes. i) Evidence of histologic transformation.
• 5. ECOG Performance Status score of ≤2.
• 6. Laboratory values meeting the following criteria within the screening period: Absolute Neutrophil Count (ANC) ≥ 0.75 × 10^9/L; Platelet count ≥ 50 × 10^9/L; Total Bilirubin ≤ 2 × Upper Limit of Normal (ULN); Alanine Aminotransferase (ALT) / Aspartate Aminotransferase (AST) ≤ 3 × ULN; Calculated creatinine clearance ≥ 30 mL/min (using Cockcroft-Gault formula)
• 7. Life expectancy of ≥ 6 months.

Exclusion Criteria:

• 1. Diagnosis or treatment for any malignancy other than B-cell non-Hodgkin lymphoma (B-NHL) within the past year (including active central nervous system lymphoma).
• 2. Clinical evidence of transformation to large cell lymphoma.
• 3.Pre-existing severe hepatic or renal impairment unrelated to lymphoma: ALT > 3 × ULN; AST > 3 × ULN; Total Bilirubin > 2 × ULN; Estimated creatinine clearance < 30 mL/min
• 4.Any other severe concurrent medical condition that would, in the investigator's judgment, compromise the patient's ability to participate in the study (e.g., uncontrolled diabetes, gastric ulcer, significant cardiac or pulmonary disease, etc.). The final determination rests with the investigator.
• 5. Known history of human immunodeficiency virus (HIV) infection, active hepatitis B virus (HBV) infection, or any uncontrolled active systemic infection requiring intravenous antibiotic therapy. Note: Active HBV infection is defined by ALL of the following criteria: a. HBV DNA ≥ 2000 IU/mL; b. ALT ≥ 2 × ULN; c. Hepatitis not attributable to other causes such as the underlying disease or drugs. Patients with initially active HBV who convert to an inactive carrier state after antiviral therapy may be enrolled if they receive adequate concomitant antiviral prophylaxis.
• 6. Symptomatic central nervous system dysfunction or involvement (Bing-Neel syndrome).
• 7. Major surgery within 14 days prior to the first dose of study drug or anticipated requirement for major surgery during the study treatment period (excluding lymph node biopsy).
• 8. Inability to swallow capsules, or conditions significantly affecting gastrointestinal function (e.g., malabsorption syndrome, status post-gastrectomy or small bowel resection, symptomatic inflammatory bowel disease, ulcerative colitis, partial or complete intestinal obstruction).
• 9. Requirement for concurrent strong Cytochrome P450 (CYP) 3A inhibitors.
• 10. Pregnancy or lactation. Women of childbearing potential unwilling to use effective contraception during the study period.
• 11. Known hypersensitivity to any of the study drugs or their excipients.

Withdrawal Criteria

• 1. Disease progression during treatment (after ≥2 cycles of therapy) or failure to achieve at least a minimal response (MR) after 6 cycles of therapy.
• 2. Occurrence of intolerable adverse events or complications.
• 3. Patient's voluntary decision to withdraw consent for continued treatment.
• 4. Pregnancy during the study.
• 5. Investigator's judgment that the patient should discontinue treatment for any other reason.