Loncastuximab Tesirine in WM

Inclusion Criteria:

* Clinicopathological diagnosis of Waldenström Macroglobulinemia
* Symptomatic disease meeting criteria for treatment using consensus panel criteria from the Second International Workshop on Waldenström macroglobulinemia.
* At least 2 prior lines of treatment, including an anti-CD20 monoclonal antibody-containing regimen and a BTK inhibitor.
* Age 18 years or older
* Measurable disease, defined as presence of immunoglobulin M (IgM) paraprotein with a minimum serum IgM level of \> 2 times the upper limit normal.
* ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A)
* Women of childbearing potential: Females of childbearing potential (FCBP) must agree to use two reliable forms of contraception simultaneously or have or will 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 9 months after discontinuation from the study. FCBP must be referred to a qualified provider of contraceptive methods if needed.
* Men must agree to use a latex condom during sexual contact with a female of childbearing potential (FCBP) even if they have had a successful vasectomy 1) while participating in the study; and 2) for at least 6 months after discontinuation from the study.
* Participants must have normal organ and marrow function as defined below:

  * Absolute neutrophil count ≥1000/ uL. Growth factors are not permitted \<14 days prior to C1D1.
  * Platelets ≥50,000/ uL. Platelet transfusions are not permitted \<14 days prior to C1D1.
  * Hemoglobin ≥ 7 g/dL. RBC transfusions are not permitted \<14 days prior to C1D1.
  * Total bilirubin ≤ 1.5 X ULN, or ≤3 x ULN with documented liver metastases and/or Gilbert's Disease
  * AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal, or ≤5 X ULN with documented liver metastases
  * Creatinine clearance ≥ 30 ml/min using Cockcroft/Gault formula
* Able to adhere to the study visit schedule and other protocol requirements.
* Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

* Prior treatment with CD19 targeted therapy.
* Participants who are receiving any other investigational agents.
* Clinically significant third space fluid accumulation (i.e., ascites requiring drainage or pleural effusion that is either requiring drainage or associated with shortness of breath) unless proven by cytology to be malignant due to WM.
* Pregnant or breastfeeding.
* Participants with known CNS lymphoma.
* Participants with known history of Human Immunodeficiency Virus (HIV), chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring active treatment. Note: Participants with serologic evidence of prior vaccination to HBV (i.e., HBs Ag-, and anti-HBs+ and anti-HBC-) and positive anti-HBc from IVIG may participate.
* Significant cardiovascular disease defined as:

  * Unstable angina within the past 6 months, or
  * History of myocardial infarction within the past 6 months
  * Any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or
  * Uncontrolled or symptomatic arrhythmias
* Participants with a history of Stevens-Johnson syndrome (SJS) or Toxic Epidermal Necrolysis (TEN)
* Concurrent systemic immunosuppressant therapy.
* Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.
* Recent infection requiring systemic treatment that was completed ≤ 14 days before the first dose of the study drug.
* Major surgery within 4 weeks of first dose of study drug.
* Participants with ongoing alcohol or drug abuse.
* History of a non-lymphoma malignancy, except adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, localized prostate cancer, other adequately treated stage 1 or 2 cancer currently in complete remission, or any other cancer that is in a complete remission.
* Prior or ongoing clinically significant illness, medical condition, surgical history, physical finding, EKG finding, or laboratory abnormality that, in the investigator's opinion, could affect the safety of the patient; alter the absorption, distribution, metabolism or excretion of the study drug; or impair the assessment of study results.
* Participants with ongoing \>grade 1 toxicities from prior therapy (alopecia any grade and/or grade 2 neuropathy are permitted).
* Participants with clinically significant history of liver disease, including cirrhosis or hepatitis (viral, autoimmune, etc).
* Participants who are unwilling or unable to comply with the protocol.