Nemtabrutinib, Bortezomib, and Rituximab for WM

Inclusion Criteria: * Participants are eligible to be included in the study only if all of the following criteria apply: 1. Confirmed diagnosis of WM in accordance with the consensus panel of the IWWM (per local evaluation), and treatment naïve 2. Symptomatic disease meeting at least 1 of the recommendations from the IWWM for requiring treatment. 3. Measurable disease defined as serum monoclonal IgM \> 0.5g/dL. 4. Is an individual of any sex/gender, who are at least 19 years of age on the day of signing informed consent (ICF). 5. Participants Assigned Male Sex at Birth If capable of producing sperm, the participant agrees to the following during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention. The length of time required to continue contraception for each study intervention is: * Nemtabrutinib: 12 days * Abstains from penile-vaginal intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agrees to remain abstinent OR * Uses contraception as detailed below unless confirmed to be azoospermic (vasectomized or secondary to medical cause, documented from the site personnel's review of the participant's medical records, medical examination, or medical history interview) as detailed below: * Uses a penile/external condom plus nonparticipant of childbearing potential who is not currently pregnant and should also be advised of the benefit for that partner to use an additional method of contraception, as a condom may break or leak. Note: Participants capable of producing ejaculate whose partner is pregnant or breastfeeding must agree to use penile/external condom during each episode of sexual activity in which the partner is at risk of drug exposure via ejaculate. \-- Contraceptive use by participants capable of producing sperm should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions are more stringent than the requirements above, the local label requirements are to be followed. Participants Assigned Female Sex at Birth A participant assigned female sex at birth is eligible to participate if not pregnant or breastfeeding, and at least one of the following conditions applies: * Is not a person of childbearing potential (POCBP) OR * Is a POCBP and: * Uses a contraceptive method that is highly effective (with a failure rate of \<1% per year), with low user dependency, or is abstinent from penile-vaginal intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis), as described in Appendix 3 during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention. The length of time required to continue contraception for each study intervention is: * Nemtabrutinib: 1 month * The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention. Contraceptive use by POCBPs should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions are more stringent than the requirements above, the local label requirements are to be followed. * Has a negative highly sensitive pregnancy test (urine or serum) as required by local regulations within 24 hours (for urine test) or 72 hours (for serum test) before the first dose of study intervention. If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. Additional requirements for pregnancy testing during and after study intervention are in Section X. * Abstains from breastfeeding during the study intervention period and for at least 30 days after study intervention with nemtabrutinib. * Medical history, menstrual history, and recent sexual activity has been reviewed by the investigator to decrease the risk for inclusion of a POCBP with an early undetected pregnancy. 6. The participant (or legally acceptable representative if applicable) has provided documented informed consent/assent for the trial. 7. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. Evaluation of ECOG is to be performed within 7 days prior to the first dose of study intervention. 8. The ability to swallow and retain oral medication. 9. Participants who are HBsAg positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to randomization. Note: Participants should remain on anti-viral therapy throughout study intervention and follow local guidelines for HBV anti-viral therapy post completion of study intervention. Hepatitis B screening tests should include HBsAg and anti-HBV. Hepatitis B screening tests are not required unless: * Known history of HBV infection * As mandated by local health authority 10. Participants with history of HCV infection are eligible if HCV viral load is undetectable at screening. • Participants must have completed curative anti-viral therapy at least 4 weeks prior to randomization. Hepatitis C screening tests are not required unless: * Known history of HCV infection * As mandated by local health authority 11. Adequate organ function as defined in the following table (Table 5.1.1). Specimens must be collected within 7 days prior to randomization. Table 5.1.1 Adequate organ function System Laboratory Value Hematological Absolute neutrophil count (ANC) ≥500/µL a, b Platelets ≥25 000/µL a, b Hemoglobin ≥8 g/dL a, b Renal Creatinine OR Measured or calculated c creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≤1.5 × ULN OR ≥30 mL/min for participant with creatinine levels \>1.5 × institutional ULN Hepatic Total bilirubin ≤1.5 ×ULN OR direct bilirubin ≤ULN for participants with total bilirubin levels \>1.5 × ULN AST (SGOT) and ALT (SGPT) ≤2.5 × ULN (≤5 × ULN for participants with liver metastases) Coagulation International normalized ratio (INR) OR prothrombin time (PT) Activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper limit of normal. aGrowth factor and/or transfusion support is permissible to stabilize participant prior to study treatment if needed. bNo lower limit if cytopenia is related to bone marrow involvement. cCreatinine clearance (CrCl) should be calculated per institutional standard. Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value requirements should be adapted according to local regulations and guidelines for the administration of specific chemotherapies. Exclusion Criteria: * The participant must be excluded from the study if the participant meets any of the following criteria: 1. Active HBV/HCV infection. 2. Positive for human immunodeficiency virus (HIV). 3. Gastrointestinal dysfunction that may affect drug absorption (e.g., gastric bypass surgery, gastrectomy). 4. Active infection requiring systemic therapy, including IV antibiotics during screening. Participants may be rescreened followed completion of IV antibiotic course. 5. History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator. 6. QTc prolongation (defined as a QTcF \>450 msecs) or other significant ECG abnormalities including second degree AV block type II, third degree AV block, or bradycardia (ventricular rate less than 50 beats/min). 7. A history of anaphylaxis or hypersensitivity to investigational products or components of investigational products (nemtabrutinib, bortezomib, rituximab). 8. History of severe bleeding disorder defined as an ongoing congenital or acquired condition that leads to an increased likelihood of bleeding. 9. History of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years. NOTE: The time requirement does not apply to participants who underwent successful definitive resection of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ, excluding carcinoma in situ of the bladder. 10. A POCBP who has a positive urine pregnancy test within 72 hours prior to allocation (see Appendix 3). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. 11. Prior use of any BTKi. 12. Prior exposure to proteasome inhibitors (bortezomib, ixazomib, carfilzomib). 13. Prior exposure to anti-CD20 antibody. 14. Currently being treated with the following drugs: 1. P-gp substrates with a narrow therapeutic index 2. CYP3A strong inducers 3. CYP3A strong inhibitors NOTE: A washout period of at least 5 times the half-life after the last dose of any of the above treatments is required for a participant to be eligible for study enrollment. A list of example in vivo substrates for specific CYP enzymes and P-gp is provided in Appendix 5. NOTE: Refer to Appendix 5 regarding prohibited concomitant medications and potential drug interactions after participant randomization. 15. Has received prior radiotherapy within 2 weeks of start of study intervention or radiation-related toxicities requiring corticosteroids. Note: Two weeks or fewer of palliative radiotherapy for non-CNS disease, with a 1-week washout, is permitted. 16. Has received a live vaccine or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines are allowed. Note: Refer to Section 5.2.2 for information on COVID-19 vaccines 17. Is currently enrolled on another therapeutic clinical trial. Concurrent enrollment on another therapeutic clinical trial or any trial designed to impact the efficacy of anti-cancer therapy is prohibited. 18. Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration. 19. Has not adequately recovered after 4 weeks from major surgery or has ongoing surgical complications. Note: Biopsy and placement of central venous access devices are not considered major surgery. 20. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.