PRIMARY OBJECTIVE:~I. To compare the rate of complete response (CR) in previously untreated participants with Waldenstrom's macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) who are treated upfront with ibrutinib, rituximab and venetoclax (IRV) versus (vs.) ibrutinib and rituximab (IR) regimen.~SECONDARY OBJECTIVES:~I. To compare overall response rates (ORR) in WM participants treated upfront with IRV vs. those treated with IR.~II. To compare progression free survival (PFS), time to next treatment, duration of response in WM participants treated upfront with IRV vs. those treated with IR.~III. To compare the rate of very good partial response (VGPR) or better in WM participants treated upfront with IRV vs. those treated with IR.~IV. To evaluate the safety of the IRV regimen as compared to IR regimen in participants with WM.~V. To evaluate the time to CR in WM participants treated upfront with IRV and those treated with IR.~VI. To evaluate the ORR in participants who progress on treatment with IR and are crossed over to treatment with IRV.~VII. To compare overall survival (OS) in WM participants treated upfront with IRV vs. those treated with IR.~BANK 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 1 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 I may receive ibrutinib, rituximab, and venetoclax as in Arm II for up to an additional 24 cycles.~ARM II: Patients receive ibrutinib PO QD on days 1-28 of cycles 1-24, rituximab IV on days 1, 8, 15, and 22 of cycles 1 and 5, and venetoclax PO QD on days 1-28 of cycles 2-24. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.~After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for up to 5 years.
This phase II trial studies the effects of ibrutinib and rituximab with or without venetoclax 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. Giving venetoclax with ibrutinib and rituximab with may work better in treating patients with previously untreated Waldenstrom's macroglobulinemia than ibrutinib and rituximab alone.