This phase II trial studies the effects of venetoclax and rituximab in comparison to ibrutinib and rituximab or zanubrutinib in treating patients with previously untreated Waldenstrom's macroglobulinemia/lymphoplasmacytic lymphoma. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Rituximab is a monoclonal antibody. It binds to a protein called CD20, which is found on B cells (a type of white blood cell) and some types of cancer cells. This may help the immune system kill cancer cells. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Zanubrutinib, a type of tyrosine kinase inhibitor, blocks a protein called BTK, which may help keep cancer cells from growing. Giving venetoclax and rituximab may work better in treating patients with previously untreated Waldenstrom's macroglobulinemia than ibrutinib with rituximab or zanubrutinib alone.

PRIMARY OBJECTIVE:

I. To compare the rate of very good partial response or better (VGPR or better) in previously untreated participants with Waldenström's macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) who are treated upfront with ibrutinib + rituximab (IR) or zanubrutinib alone (Z) versus (vs.) venetoclax +/- rituximab (VR) regimen.

SECONDARY OBJECTIVES:

I. To compare overall response rates (ORR) in WM participants treated upfront with ibrutinib + rituximab or zanubrutinib alone vs. venetoclax + rituximab.

II. To compare progression-free survival (PFS), time to next treatment, duration of response in WM participants treated upfront with ibrutinib + rituximab or zanubrutinib alone vs. venetoclax + rituximab.

III. To compare the rate of complete response (CR) in WM participants treated upfront with ibrutinib + rituximab or zanubrutinib alone vs. venetoclax + rituximab.

IV. To evaluate the safety of ibrutinib + rituximab or zanubrutinib alone vs. venetoclax + rituximab in participants with WM.

V. To evaluate the time to VGPR in WM participants treated upfront with ibrutinib + rituximab or zanubrutinib alone vs. venetoclax + rituximab.

VI. To evaluate the ORR in participants who progress on treatment with ibrutinib + rituximab or zanubrutinib alone and venetoclax + rituximab are crossed over to the other respective arm.

VII. To compare overall survival (OS) in WM participants treated upfront with ibrutinib + rituximab or zanubrutinib alone vs. venetoclax + rituximab.

VIII. To evaluate the rate of VGPR or better and the ORR in WM participants treated upfront with ibrutinib plus rituximab vs. those treated with zanubrutinib alone.

BANKING OBJECTIVE:

I. To bank specimens for future correlative studies.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive ibrutinib orally (PO) once daily (QD) on days 1-28 of cycles 1-24 and rituximab intravenously (IV) on days 1, 8, 15, and 22 of cycles 2 and 5, or zanubrutinib PO QD or twice daily (BID) on days 1-28 of cycles 1-24. Cycles repeat every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. Patients with progressive disease during Arm I may receive rituximab and venetoclax as in Arm II for up to an additional 24 cycles. Patients undergo computed tomography (CT) or positron emission tomography (PET)/CT and bone marrow biopsy and aspiration as well as blood sample collection throughout the trial.

ARM II: Patients receive venetoclax PO QD on days 1-28 of each cycle and rituximab IV on days 1, 8, 15, and 22 of cycles 2 and 5. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. Patients with progressive disease during Arm II may receive ibrutinib and rituximab as in Arm I for up to an additional 24 cycles. Patients undergo CT or PET/CT and bone marrow biopsy and aspiration as well as blood sample collection throughout the trial.

After completion of study treatment, patients removed from protocol prior to progression are followed every 3 months until progression, death or 5 years after initial registration, whichever occurs first. Patients followed after progression of disease are followed every 6 months until death or 5 years after initial registration.

Inclusion Criteria:

• Participants must have had a confirmed diagnosis of Waldenstrom's macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL). Participants must have measurable disease as determined by IgM protein quantification.

  • IgM Spike: ≥ 500 mg/dL (≥ 5 g/L)
  • Extramedullary disease: The manifestation of a lymphoid mass outside of the bone marrow, resulting in enlargement in extramedullary organs such as the lymph nodes or spleen. Note: all participants must have measurable IgM spike, but are not required to have extramedullary disease

• Testing to establish baseline disease status must be performed within 28 days prior to registration

• Participants must have at least one of the criteria to require therapy for WM including:

  • Anemia

  • Thrombocytopenia

  • Neuropathy related to WM

  • Symptomatic hyperviscosity or serum viscosity levels ≥ 4.0 centipoises

  • WM associated glomerulonephritis or renal disease, bulky disease, or constitutional symptoms

    • Constitutional symptoms can be described as:

      • Unintentional weight loss >= 10% within the previous 6 months prior to screening
      • Fevers higher than 100.5 degrees Fahrenheit (F) or 38.0 degrees Celsius (C) for 2 or more weeks prior to screening without evidence of infection
      • Night sweats for more than 1 month prior to screening without evidence of infection
      • Clinically relevant fatigue which is not relieved by rest due to WM

• Participants who require ongoing use or received a moderate or strong CYP3A inducer, moderate or strong CYP3A inhibitor, P-gp inhibitor within 7 days prior to the first dose of study drug will be excluded from the study. If such participants can be safely switched to an alternative agent, then the participants will be eligible to enroll

• Participants must not have had prior systemic therapy. Prior therapy with rituximab will be allowed as long as the last rituximab dose was at least 6 months prior to registration

• Participants must be >= 18 years of age

• Participants must have history and physical exam within 28 days prior to registration

• Participants must have Zubrod performance status =< 2

• Participants must have evidence of adequate renal function, as defined by creatinine clearance (CrCl) >= 30 mL/min. Values must be obtained within 14 days prior to registration

• Total bilirubin =< 1.5 x IULN (institutional upper limit of the norm) (within 14 days prior to registration)

• Aspartate aminotransferase (AST), alanine aminotransferase (ALT) =< 3 x IULN (within 14 days prior to registration)

• Alkaline phosphatase =< 3 x IULN (within 14 days prior to registration)

• Platelet count >= 50,000 cells/mm^3 (within 14 days prior to registration)

  • NOTE: Transfusion and/or growth factor support is allowed up to 7 days prior to registration

• Hemoglobin >= 7.0 g/dL (within 14 days prior to registration)

  • NOTE: Transfusion and/or growth factor support is allowed up to 7 days prior to registration

• Absolute neutrophil count (ANC) >= 1,000 cells/mm^3 (within 14 days prior to registration)

  • NOTE: Transfusion and/or growth factor support is allowed up to 7 days prior to registration

• Participants with known human immunodeficiency virus (HIV)-infection are eligible providing they are on effective anti-retroviral therapy and have undetectable viral load at their most recent viral load test and within 6 months prior to registration

• Participants must be able to take and swallow oral medication (capsules) whole. Participants may not have any known impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of the study drug (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)

• Participants must not be intolerant to rituximab

• Participants must not have known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding localized skin and nail bed fungal infections) at study enrollment, or any major episode of infection requiring treatment with IV antibiotics or hospitalization (relating to the completion of the course of antibiotics) 4 weeks prior to registration

• Participants must not be seropositive for hepatitis C (except in the setting of sustained virologic response, defined as undetectable viral load at least 12 weeks after completion of antiviral therapy). Hepatitis C virus (HCV) testing is only required if clinically indicated or if the participant has a history of HCV

• Participants must not consume grapefruit, Seville oranges or starfruit within 3 days prior to the first dose of venetoclax

• Participants must not be pregnant or nursing because venetoclax has not been studied in pregnant or nursing women and the mechanism of action is expected to cause fetal harm. A woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months. In addition to routine contraceptive methods, "effective contraception" e.g., implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], complete abstinence, or sterilized partner) and a barrier method (e.g., condom, cervical ring, sponge, etc.). This also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation. However, if at any point a previously celibate participant chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures throughout the study and for at least 30 days after competition of therapy

• No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the participant is currently in complete remission, or any other cancer from which the participant has been disease free for two years or watchful waiting is appropriate in the opinion of the treating physician. Also, malignancy that in the opinion of the investigator, is considered cured with minimal risk of recurrence within 5 years, is permissible consideration of eligibility for this trial

• Participants must be offered the opportunity to participate in specimen banking

• Participants must be informed of the investigational nature of this study and must sign and give informed consent in accordance with institutional and federal guidelines. For participants with impaired decision-making capabilities, legally authorized representatives may sign and give informed consent on behalf of study participants in accordance with applicable federal, local, and Central Institutional Review Board (CIRB) regulations

• As a part of the Oncology Participant Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system

• CROSSOVER CRITERIA: Participants must have been registered and received treatment in the IR/Z or VR arm and must show progression of disease at any time during cycles 3-24

• CROSSOVER CRITERIA: In case of transformation to intermediate or high-grade lymphoma or development of Bing-Neel syndrome the participants will not undergo registration step 2 crossover and will be taken off the study

• CROSSOVER CRITERIA: Participants must have Zubrod performance status =< 2

• CROSSOVER CRITERIA: Participants must have evidence of adequate renal function, as defined by creatinine clearance (CrCl) >= 30 mL/min. Values must be obtained within 14 days prior to registration

• CROSSOVER CRITERIA: Participants must have no evidence of marked hepatic dysfunction on any recent liver function tests within 14 days prior to registration

• CROSSOVER CRITERIA: Platelet count >= 50,000 cells/mm^3 (without within 14 days prior to registration)

  • NOTE: Transfusion and/or growth factor support is allowed up to 7 days prior to registration

• CROSSOVER CRITERIA: Hemoglobin >= 7.0 g/dL (without within 14 days prior to registration)

  • NOTE: Transfusion and/or growth factor support is allowed up to 7 days prior to registration

• CROSSOVER CRITERIA: Absolute neutrophil count (ANC) >= 1,000 cells/mm^3 (without within 14 days prior to registration)

  • NOTE: Transfusion and/or growth factor support is allowed up to 7 days prior to registration

NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.