Inclusion Criteria:
* Histologically and serologically confirmed diagnosis of WM.
* Received at least one prior therapy for WM.
* Received treatment with a BTKi (including covalent BTKi or non-covalent BTKi).
* Symptomatic disease progression requiring therapy. Specifically, participant must meet one of the following:
a. Biochemical progression or progression by imaging: i. ≥ 25% increase in serum IgM levels with a minimum increase of 500 mg/dL from nadir. If serum IgM is used to support progression, 2 sequential measurements are required. ii. Any new lesion (\>1.5 cm in any axis) or unequivocal evidence of an increase by \>50% in any axis to \>1.5 cm in size of previously involved extramedullary disease sites from their nadir measurements. Progression by imaging does not require re-confirmation for eligibility.
b. Clinical signs or symptoms as determined by the investigator (e.g., constitutional symptoms (fatigue, fevers, night sweats, etc.), hyperviscosity syndrome, demyelinating peripheral neuropathy, cytopenias, organomegaly, etc.).
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2.
* Participant is ≥ 18 years of age.
* Life expectancy ≥ 6 months.
* Presence of elevated total serum IgM (2x above institutional upper limit of normal (ULN)). Participants with extramedullary disease only may not be enrolled.
* Participant must meet the following hematological laboratory criteria:
1. Platelets ≥ 75,000/uL.
2. Absolute neutrophil count (ANC) ≥ 1000/uL
3. Hemoglobin ≥ 8 g/dL, that can be maintained by packed red blood cell (PRBC) transfusions
4. Estimated glomerular filtration rate ≥ 30 mL/min/1.73 m2 (as calculated using the CKD-EPI 2021 formula) OR serum creatinine ≤ 1.5 x ULN
5. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × ULN
6. Bilirubin \< 1.5 × ULN, except for patients with Gilbert's syndrome, who may be enrolled if bilirubin is \< 3 x ULN or direct bilirubin is \< 1.5 x ULN.
* Patient who has undergone autologous stem cell transplant must be at least one year from the date of hematopoietic recovery.
* Patient must express willingness and ability to comply with scheduled study visits, treatment plans, laboratory tests, and other study procedures.
* Patient or their legally authorized representative must have the ability to understand and provide signed informed written consent before the initiation of any study-related procedures.
* Female patients of childbearing potential, defined as all women physiologically capable of becoming pregnant, must have a negative serum or urine beta human chorionic gonadotropin (b-hCG) pregnancy test result within one week prior to first dose of study treatment and agree to use a highly effective method of contraception during the study and for 12 months following administration of the last dose of study treatment.
* Sexually active males, including those who have had a vasectomy, must agree to use a condom during intercourse while receiving iopofosine I 131 or R-CD and for three months after the last dose of iopofosine I 131 or R-CD.
Exclusion Criteria:
* Receipt of:
1. Anti CD-20 MoAb \< 6 months prior to study drug administration.
2. Any conventional cytotoxic chemotherapy ≤ four weeks prior to study drug administration.
3. Non-anti CD20 MoAb therapy for the treatment of WM ≤ three months prior to study drug administration. i. The only exception to this is for those patients who have documented evidence of progression while receiving non-anti CD20 MoAb therapy.
4. BTKi therapy ≤ 48 hours prior to study drug administration.
5. Any investigational agents ≤ two weeks or five half-lives, whichever is shorter, prior to study drug administration.
* Evidence of Bing Neel disease or disease transformation at the time of study entry.
* Evidence of or suspected of having Myelodysplastic Syndrome (MDS) based upon laboratory and bone marrow testing at the time of trial entry. Note: this includes suspicion of or presence of MDS or CHIP mutation as per the trial screening bone marrow biopsy.
* Ongoing Grade 2 or greater toxicities due to previous therapies, excluding alopecia, that in the opinion of the investigator might be exacerbated by study treatment.
* Prior external-beam radiation therapy resulting in greater than 20% of total bone marrow receiving greater than 20 Gy. For estimation purposes, the following bone marrow percentages can be used:
1. Vertebral bodies: Cervical 0.5%, thoracic 1%, lumbar 2% per vertebral body
2. Hemipelvis (ilium, acetabulum, ischium): 13% per side
3. Sacrum: 10%
4. Skull: 12%
5. Scapula: 5% per side
6. Ribs: 4% per side
7. Femur: 3% per side
* Prior total body irradiation.
* Patients with presence of second malignancies in addition to WM. However, patients with the following malignancies within the past two years may enroll as long as there is no evidence of disease: non-melanoma skin cancers only requiring topical treatment or surgical excision; melanoma in situ; localized cancer of the prostate with current prostate-specific antigen of \< 0.1 µg/mL; treated cervical carcinoma in situ; or ductal/lobular carcinoma in situ of the breast.
* Ongoing chronic immunosuppressive therapy.
* Any other concomitant serious illness or organ system dysfunction (including cardiac and pulmonary dysfunction) that in the opinion of the Investigator would either compromise patient safety or interfere with the evaluation of the safety of the study drug.
* Major surgery (e.g., intra-abdominal, intra-thoracic, or intra-pelvic) ≤ 4 weeks prior to study drug administration, or lack of recovery from side effects of such surgery. Video-assisted thoracic surgery (VATS) and mediastinoscopy, placement of central venous catheter, endoscopy procedures, and percutaneous tissue biopsies will not be considered major surgery and patients can receive study drug ≥ one week after these procedures.
* History of hypersensitivity to thyroid protection medication (e.g., potassium iodide, Lugol's solution, etc.), murine compounds, or anti CD-20 MoAbs (e.g., rituximab).
* History of severe hypersensitivity reactions to cyclophosphamide, any of its metabolites, or to other components of the product.
* History of hypersensitivity to any components of dexamethasone, including sodium sulfites.
* Ongoing urinary outflow obstruction or systemic fungal infection.
* Known history of human immunodeficiency virus (HIV).
* Known history or active or chronic infection with hepatitis C virus (HCV) or hepatitis B virus (HBV) defined by positive polymerase chain reaction (PCR). Hepatitis patients receiving antiviral therapy (e.g., entecavir) who do not have a positive PCR are eligible.
* Presence of active infection within 72 hours prior to initiation of study treatment. Patients with ongoing use of prophylactic antibiotics, antifungals, or antivirals are eligible as long as there is no evidence of active infection and the antibiotics, antifungals, or antivirals are not included on the list of prohibited medications.
* Pregnancy or breast-feeding.
