Epcoritamab as Consolidative Therapy for Waldenstr(SqrRoot)(Delta)m Macroglobulinemia (WM) Treated With a Bruton Tyrosine Kinase Inhibitor (BTKi)

Background: Waldenstrom macroglobulinemia (WM) is a type of blood cancer. It causes the blood to get thicker, which slows circulation and makes it harder to carry oxygen and other substances around the body. WM is treated with drugs called Bruton tyrosine kinase inhibitors (BTKi). But WM never goes away completely, and sometimes it gets worse despite treatment. Objective: To test a new drug (epcoritamab) in people with WM. Eligibility: People aged 18 years or older who have WM. They must have been taking a BTKi for a year or more. Design: Participants will be screened. They will have blood and urine tests. They will have imaging scans and a test of their heart function. They may have a bone marrow biopsy: A large needle will be used to remove a sample of the soft tissue and fluids from inside the hip bone. Epcoritamab is injected under the skin, normally on the lower belly or thigh. Participants will be treated in 28-day cycles. They will have 12 treatment cycles. During the first cycle, they will come to the clinic to get an injection once a week for 4 weeks. After that, they will get 1 injection on the first day of each cycle. Blood tests and imaging scans will be repeated at study visits. A saliva sample will be taken for genetic testing. Participants will also continue their normal treatment with BTKi. After their last treatment with the study drug, participants will have 5 follow-up visits in 6 months. Tests, including a bone marrow biopsy, may be repeated. Follow-up visits will continue every 6 months for 3 (Omega) years or more.

* INCLUSION CRITERIA: Patients must meet the following entry criteria to be eligible to participate in the study: 1. Age \>=18 years 2. Ability to comprehend the investigational nature of the study and provide informed consent 3. Diagnosis of WM according to 11th International Workshop on WM (IWWM-11) (19) 1. Presence of an IgM monoclonal protein 2. Bone marrow involvement by lymphoplasmacytic lymphoma 4. Presence of MYD88 L265P mutation 5. Currently receiving a BTKi, zanubrutinib or ibrutinib, for \>=12 months 6. Able to obtain a commercial supply of BTKi 7. Achieved partial response, minor response, or stable disease on a BTKi per IWWM-11 response criteria (19) 8. A female participant is eligible to participate if not pregnant or breastfeeding, and \>=1 of the following conditions applies: Is not a woman of childbearing potential (WOCBP) OR Is a WOCBP and * Uses a contraceptive method * Has a negative highly sensitive serum pregnancy test within 7 days before the first dose of study intervention. 9. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 within 7 days prior to the first dose of study intervention. 10. The ability to swallow and retain oral medication. 11. Participants who are HBsAg positive are eligible if they have received HBV antiviral therapy for \>=4 weeks and have undetectable HBV viral load prior to study entry. Note: Participants should remain on anti-viral therapy throughout study intervention and for at least 12 months following discontinuation of epcoritamab. Hepatitis B screening tests should include HBsAg and anti-HBV. 12. Participants who received treatment for HCV that was intended to eradicate the virus are eligible if hepatitis C RNA levels are undetectable. 13. COVID 19 eligibility criteria: Subject has no known active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. If a subject has signs/symptoms suggestive of SARS-CoV-2 infection or have had recent known exposure to someone with SARS-CoV-2 infection, the subject must have a negative molecular (e.g., PCR) test, or 2 negative antigen test results at least 24 hours apart, to rule out SARS-CoV-2 infection. Subjects who do not meet SARS-CoV-2 infection eligibility criteria must be screen failed and may only rescreen after they meet the following SARS-CoV-2 infection viral clearance criteria: * No signs/symptoms suggestive of active SARS-CoV-2 infection * Negative molecular (e.g., PCR) result or 2 negative antigen test results at least 24 hours apart 14. Adequate organ function as defined below. \*\*Adequate Organ Function Laboratory Values\*\* System Laboratory Value Hematological Absolute neutrophil count (ANC) \>=1000/microL (a) Platelets \>=75000/microL or \>=50000/microLin the presence of bone marrow involvement or splenomegaly (a) Hemoglobin \>=8 g/dL (a) Renal Creatinine \=30 mL/min Hepatic Total bilirubin \