* 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
\<=1.5 x ULN or eGFR \>=30 mL/min
Hepatic
Total bilirubin
\<=1.5 x ULN unless due to Gilbert's syndrome or controlled autoimmune hemolytic anemia (not requiring immunosuppressive other than \<=20 mg of prednisolone daily)
AST and ALT
\<=3 ULN
Coagulation
PT
aPTT
\<=1.5 x ULN unless participant is receiving anticoagulant therapy
eGFR=estimated glomerular filtration rate; ALT =alanine aminotransferase; AST =aspartate aminotransferase; ULN=upper limit of normal; INR=international normalized ratio; PT=prothrombin time; aPTT=activated partial thromboplastin time
1. Growth factor and/or transfusion support is allowed to meet this requirement at Screening only if directly attributable to WM infiltration of the bone marrow, proven by bone marrow biopsy
EXCLUSION CRITERIA:
An individual who meets any of the following criteria will be excluded from participation in this study:
1. Active CNS involvement, including Bing-Neel syndrome
2. Active HBV/HCV infection.
3. Infection with HIV-1 or HIV-2. Exception: patients with well-controlled HIV (e.g., CD4 \>350/mm\^3 and undetectable viral load) are eligible.
4. Gastrointestinal dysfunction that may affect drug absorption (e.g., gastric bypass surgery, gastrectomy).
5. Ongoing active bacterial, viral, fungal, mycobacterial, parasitic, or other infection requiring systemic treatment (excluding prophylactic treatment) at the time of enrollment or within the previous 2 weeks prior to the first dose of epcoritamab, including COVID-19 infection. Note that a past COVID-19 infection may be a risk factor, but if resolved and the subject is vaccinated, it may be allowable to enroll the Subject.
6. Stroke or intracranial hemorrhage within 6 months of screening
7. Hypertensive urgency or emergency
8. Active, clinically significant cardiovascular disease including:
9. Uncontrolled or symptomatic arrhythmias
10. Class 3 or 4 congestive heart failure as defined by New York Heart Association Functional Classification
* Association and/or known decreased ejection fraction \<45%
11. Myocardial infarction, unstable angina or acute coronary syndrome within 6 months of screening.
12. History of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place.
13. QTcF \>450 msecs based on Fridericia's formula
Note: QTcF value may be calculated as the numerical average of up to 3 separate readings for eligibility).
14. Known allergy/sensitivity to epcoritamab
15. History of severe bleeding disorder defined as an ongoing congenital or acquired condition that leads to an increased likelihood of bleeding (i.e., von Willebrand's disease or hemophilia).
16. 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.
17. Currently being treated with the following drugs:
* CYP3A strong inducers
* 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.
18. Has received prior systemic anti-WM therapy besides a BTKi within 3 half-lives or 4 weeks (if prior therapy was a monoclonal antibody) of start of epcoritamab.
19. Has received prior radiotherapy within 2 weeks of start of epcoritamab 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.
20. Has received a live vaccine or live-attenuated vaccine within 28 days before the first dose of epcoritamab. Administration of killed vaccines are allowed.
21. Patients requiring ongoing treatment with warfarin within 7 days of start of epcoritamab
22. Patients who have received \> 140 mg of prednisone for 14 days prior to first dose of epcoritamab or those requiring \> 10 mg prednisone (or equivalent) daily, unless needed for disease control.
23. Confirmed history or current autoimmune disease or other diseases resulting in permanent immunosuppression or requiring permanent immunosuppressive therapy. Low-dose (\<=10 mg/day) prednisolone (or equivalent) for rheumatoid arthritis or similar conditions is allowed.
24. Enrolled on another therapeutic clinical trial for WM at the start of epcoritamab. Concurrent enrollment on another therapeutic clinical trial or any trial designed to impact the efficacy of anti-cancer therapy is prohibited.
25. 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.
26. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
