This phase I/II trial studies the side effects and best dose of ABBV-383 and to see how well it works in treating patients with Waldenström macroglobulinemia that has come back after a period of improvement (relapsed) or that does not respond to treatment (refractory). ABBV-383 is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. A monoclonal antibody is a type of protein that can bind to certain targets in the body, such as molecules that cause the body to make an immune response (antigens).

Inclusion Criteria:

• PRE-REGISTRATION: Age ≥ 18 years

• PRE-REGISTRATION: Histological confirmation of relapsed and/or refractory Waldenstrom macroglobulinemia, with known prior exposure to a Bruton tyrosine kinase (BTK) inhibitor unless medically contraindicated. Note: although not preferred, archival bone marrow tumor tissue that was collected within 12 weeks prior to screening and without intervening anti- BCMA treatment may be used if the patient is unwilling to provide a fresh pretreatment marrow biopsy

• PRE-REGISTRATION: Measurable disease as defined as serum immunoglobulin M (IgM) levels ≥ 0.5 g/dL (500 mg/dL)

• PRE-REGISTRATION: Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2

• PRE-REGISTRATION: Subject is naïve to treatment with ABBV-383 or anti-BCMA bispecific antibodies

• PRE-REGISTRATION: Hemoglobin ≥ 8.0 g/dL (obtained ≤ 14 days prior to pre-registration)

• PRE-REGISTRATION: Absolute neutrophil count (ANC) ≥ 1000/mm^3 [neutropenia due to marrow infiltration may be supported by granulocyte colony-stimulating factor (GCSF)] (obtained ≤ 14 days prior to pre-registration). Transfusion and/or growth factor support is permitted prior to assessment, but neutrophils, platelets, and hemoglobin must be stable for ≥ 72 hours after transfusion and/or growth factor administration for the subject to be eligible

• PRE-REGISTRATION: Platelet count ≥ 75,000/mm^3 (obtained ≤ 14 days prior to pre-registration) EXCEPTION: If thrombocytopenia deemed to be related to the bone marrow infiltration (disease burden) by WM cells, platelet count threshold of ≥ 50,000 is acceptable. Transfusion and/or growth factor support is permitted prior to assessment, but neutrophils, platelets, and hemoglobin must be stable for ≥ 72 hours after transfusion and/or growth factor administration for the subject to be eligible

• PRE-REGISTRATION: Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (obtained ≤ 14 days prior to pre-registration) (except for subjects with documented Gilbert's syndrome, in which case direct bilirubin must be ≤ 2 x ULN)

• PRE-REGISTRATION: Alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤ 3 x ULN (obtained ≤ 14 days prior to pre-registration)

• PRE-REGISTRATION: Prothrombin time (PT)/international normalized ratio (INR)/activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN OR if patient is receiving anticoagulant therapy and INR or aPTT is within target range of therapy (obtained ≤ 14 days prior to pre-registration)

• PRE-REGISTRATION: Calculated creatinine clearance ≥ 30 ml/min using the Cockcroft-Gault formula (obtained ≤ 14 days prior to pre-registration)

• PRE-REGISTRATION: Negative pregnancy test done ≤ 7 days prior to pre-registration, for persons of childbearing potential only. Note: Subjects must have 2 negative results for pregnancy tests prior to initiating therapy. The first test (serum) should be performed during the screening period prior to first dose of study drug and the second test (urine, minimum sensitivity of 25 IU/L). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required

• PRE-REGISTRATION: Willing to follow strict birth control measures as suggested by the study

• PRE-REGISTRATION: Female participants: Female participant is eligible to participate if she is not pregnant or breast feeding, and at least one of the following conditions applies:

  • Is not a woman of childbearing potential (WOCBP) OR

  • Due to the risk for embryo-fetal toxicity and prescribed under a pregnancy prevention/controlled distribution program, WOCBP participants will be eligible if they commit to either:

    • Abstain continuously from heterosexual sexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent OR

    • To use birth control as follows:

      • Two methods of reliable birth control (one method that is highly effective and one additional effective (barrier) method), beginning 4 weeks prior to initiating treatment with lenalidomide, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of lenalidomide treatment

• PRE-REGISTRATION: Male patients: Male participants are eligible to participate if they agree to the following from the time of first dose of study treatment until 28-days after the last dose of lenalidomide, to allow for clearance of any altered sperm:

  • Refrain from donating sperm PLUS either:

    • Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent. OR

    • Must agree to use contraception/barrier as detailed below:

      • Agree to use a male condom, even if they have undergone a successful vasectomy, and female partner to use an additional highly effective contraceptive method with a failure rate of < 1% per year as when having sexual intercourse with a woman of childbearing potential (including pregnant females)

• Note: Subjects of childbearing potential must practice at least one of the specified method of birth control with partner(s) initiated prior to first dose of study drug administration to 90 days after the last dose of study drug. These methods include the following:

  • A barrier method of contraception (including male and female condoms with or without spermicide) plus one of the following hormonal contraceptives:

    • Combined (estrogen and progestogen containing) hormonal contraception associated with the inhibition of ovulation
    • Oral, intravaginal or transdermal
    • Progestogen-only hormonal contraception associated with the inhibition of ovulation
    • Oral, injectable, implantable
    • An intrauterine device (IUD)
    • Intrauterine hormone-releasing system (IUS)

  • Bilateral tubal occlusion

  • Vasectomized partner

  • Sexual abstinence (defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatment, starting the day prior to first dose of study drug, for the duration of the study, and for 90 days after the last dose of study drug). Total sexual abstinence should only be used as a contraceptive method if it is in line with the subjects' usual and preferred lifestyle. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of exposure to the investigational medicinal product (IMP), and withdrawal are not acceptable methods of contraception.

• PRE-REGISTRATION: Provide written informed consent and is willing to comply with the tests required per the protocol

• PRE-REGISTRATION: Willingness to provide mandatory blood and bone marrow samples specimens for correlative research

• PRE-REGISTRATION: Rochester only: Willingness to enroll in Institutional Review Board (IRB) #521-93

• REGISTRATION: Ability to complete questionnaire(s) by themselves or with assistance

• REGISTRATION: Negative pregnancy test done ≤ 7 days prior to registration, for persons of childbearing potential only. Note: Subjects must have 2 negative results for pregnancy tests prior to initiating therapy. The first test (serum) should be performed during the screening period prior to first dose of study drug and the second test (urine, minimum sensitivity of 25 IU/L). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required

• REGISTRATION: Subject was pre-registered ≤ 14 days prior to registration

Exclusion Criteria:

• PRE-REGISTRATION: Any of the following because this study involves an investigational agent whose genotoxic, mutagenic, and teratogenic effects on the developing fetus and newborn are unknown:

  • Pregnant persons
  • Nursing persons
  • Persons of childbearing potential (and persons able to father a child) who are unwilling to employ adequate contraception

• PRE-REGISTRATION: Subject has known allergic reaction, significant sensitivity, or intolerance to constituents of the study drugs (and excipients) and/or other products in the same class

• PRE-REGISTRATION: Any of the following prior therapies:

  • Major surgery ≤ 4 weeks prior to registration
  • Chemotherapy ≤ 2 weeks prior to registration
  • An investigational therapy, including chemotherapy, radiotherapy, biological, immunotherapy or targeted small molecule agents within 5 half-lives (or 2 weeks, if half-life is unknown) prior to registration
  • Patient has received steroid therapy given with anti-neoplastic intent ≤ 7 days prior registration
  • Autologous stem cell transplant ≤ 12 weeks or allogeneic transplant ≤ 24 weeks prior to registration
  • Organ transplant requiring continued use of immunosuppressants
  • Live, attenuated vaccines ≤ 4 weeks prior to registration
  • Received a monoclonal antibody given with anti-neoplastic intent ≤ 30 days prior to registration

• PRE-REGISTRATION: Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens

• PRE-REGISTRATION: Immunocompromised patients and patients with a known history of human immunodeficiency virus (HIV). Subjects with HIV may be permitted provided that the subject has an undetectable HIV viral load by standard clinical assays on antiretroviral medication [Highly Active Antiretroviral Therapy (HAART)] and is able to tolerate study treatment per investigator's judgement. Subjects with active, hepatitis C virus or active hepatitis B virus infection [subjects with resolved infection (hepatitis B virus surface antigen (HbsAg) negative, but hepatitis B virus core antibody (antiHBc) or hepatitis B virus surface antibody (antiHBs) positive] must be screened using real-time polymerase chain reaction (PCR) of hepatitis B virus (HBV) deoxyribonucleic acid (DNA).

• PRE-REGISTRATION: Uncontrolled intercurrent life threatening illness including, but not limited to:

  • Ongoing or active infection
  • Symptomatic congestive heart failure
  • Unstable angina pectoris
  • Cardiac arrhythmia
  • Psychiatric illness/social situations that would limit compliance with study requirements
  • Any organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety, interfere with the metabolism of ABBV 383 or put the study outcomes at undue risk specifically
  • A subject with history of stroke or intracranial hemorrhage within ≤ 24 weeks prior to registration
  • Concurrent light and/or heavy chain amyloidosis or central nervous system (CNS) involvement with Waldenström Macroglobulinemia (WM) (Bing Neel syndrome)
  • Active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Note: If a subject has signs/symptoms suggestive of 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. Subjects who meet SARS-CoV-2 infection exclusion criteria must be screen failed and may only rescreen after they meet the following SARS-CoV-2 infection viral clearance criteria

• PRE-REGISTRATION: Other active malignancy other than WM ≤ 3 years prior to registration EXCEPTIONS: with the exception of a) adequately treated in situ carcinoma of the cervix uteri, b) adequately treated basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin, c) prostate cancer Gleason grade 6 or lower AND with stable prostate specific antigen levels off treatment; d) previous malignancy confined and surgically resected (or treated with other modalities) with curative intent and unlikely to impact survival during the duration of the study

• REGISTRATION: If any of the following exist at screening, subject will not be eligible for trial because this trial involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:

  • Pregnant women
  • Nursing women
  • Men or women of childbearing potential who are unwilling to employ adequate contraception (per protocol)