• Participants must meet the following criteria on screening examination to be eligible to participate. Screening evaluations including consent, physical exam, and laboratory assessments will be done within 30 days prior to Cycle 1 Day 1. Bone marrow biopsy \&aspirate, skin (fat) biopsy, EMG, and CT C/A/P will be done within 90 days prior to Cycle1 Day 1.

• Presence of an IgM monoclonal paraprotein on serum immunofixation electrophoresis

• Diagnosis of IgM MGUS or Waldenstrӧm macroglobulinemia using the criteria from Owen RG, Treon SP, Al-Katib A, Fonseca R, Greipp PR, McMaster ML, et al.Clinicopathological definition of Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia. Semin Oncol. 2003. 30(2): 110-5.

‣ WM diagnostic criteria

• IgM monoclonal gammopathy of any concentration

∙ Bone marrow infiltration by small lymphocytes showing plasmacytoid/plasma cell differentiation

∙ Intertrabecular pattern of bone marrow infiltration

⁃ Surface IgM+, CD5 +/-, CD10-, CD19+, CD20+, CD22+, CD23-, CD25+, CD27+, FMC7+, CD103-, CD138- immunophenotype\* --- Variations from this immunophenotypic profile can occur. However, care should be taken to satisfactorily exclude other lymphoproliferative disorders. This is most relevant in CD5+ cases, for which chronic lymphocytic leukemia and mantle cell lymphoma require specific exclusion before a diagnosis of WM can be made.

• IgM MGUS diagnostic criteria

‣ IgM monoclonal gammopathy of any concentration

⁃ No bone marrow infiltration

• Presence of predominantly sensory neuropathy with predominant demyelinating features on nerve conduction studies.

• Modified Rankin Scale score of ≥1 with progressing symptoms or a score ≥2

• ECOG ≤2

• Age \> 18 years

• Participants may not be on any active therapy for other malignancies with the exception of topical therapies for basal cell or squamous cell cancers of the skin

• At the time of screening, participants must have acceptable organ and marrow function as defined below:

‣ Absolute neutrophil count≥1,000/uL (no growth factor permitted within previous 7 days)

⁃ Platelets ≥100,000/uL (no platelet transfusions permitted within previous 7 days); patients may enroll below this threshold if not attributable to IgM MGUS or WM after consultation with Sponsor-Investigator.

⁃ For participants with platelets \<100,000 uL deemed to be attributable to other causes than IgM MGUS or WM, platelets must be ≥50,000 uL (no platelet transfusions permitted)

• Hemoglobin ≥ 10 g/dL (transfusions permitted); patients may enroll below this threshold if not attributable to IgM MGUS or WM after consultation with Sponsor-Investigator.

• \-- For participants with hemoglobin \<10 g/dL deemed to be attributable to other causes than IgM MGUS or WM, hemoglobin must be ≥7 g/dL(transfusions permitted)

• Total bilirubin \< 1.5 x institutional ULN

• AST(SGOT)/ALT(SGPT) ≤2.5 × institutional ULN

• Estimated GFR ≥30 mL/min

• International normalized ratio (INR) ≤ 2 x ULN and activated partial thromboplastin time (aPTT) ≤ 2 x ULN. Patients with INR and/or aPTT \>2 x ULN who have lupus anticoagulant may be enrolled.

• Females of childbearing potential (FCBP) must use highly effective contraception (see Appendix D) or have complete abstinence from heterosexual intercourse during the following time periods related to this study: 1) while participating in the study; and 2) for at least 1 week after last dose of acalabrutinib and 12 months from last dose of rituximab/biosimilar. FCBP must be referred to a qualified provider of contraceptive methods if needed. FCBP must have a negative serum pregnancy test at screening.

• Men must agree to use a latex condom during treatment and for up to 1 week after the last dose of acalabrutinib and 12 months after the last dose of rituximab during sexual contact with a FCBP

• Ability to adhere to the study visit schedule and other protocol requirements

• Ability to understand and the willingness to sign a written informed consent document