Radioimmunotherapy (111Indium/225Actinium-DOTA-daratumumab) for the Treatment of Relapsed/Refractory Multiple Myeloma

Inclusion Criteria:

• Documented informed consent of the participant and/or legally authorizedrepresentative

• Assent, when appropriate, will be obtained per institutional guidelines

• Age >= 18 years

• Karnofsky performance status (KPS) > 60%

• Multiple myeloma according to International Myeloma Working Group (IMWG) criteriawith measurable disease defined as one of the following:

• Serum monoclonal protein >= 1.0 g/dL (or 0.5 g/dL in patients withimmunoglobulin A [IgA] multiple myeloma [MM])

• 24 hour urine monoclonal protein >= 200 mg/24 hour

• Serum free light chain (FLC) of > 10 mg/dL and an abnormal kappa:lambda ratio

• Minimum of two prior lines of therapy

• Previously received treatment with all of the following: a proteasome inhibitor, animmunomodulatory drug, and an anti-CD38 monoclonal antibody. Refractory (defined perIMWG Consensus Criteria) to daratumumab

• CD38 expression on multiple myeloma (MM) cells from bone marrow aspirate or biopsyas demonstrated by flow cytometry or immunohistochemistry

• Refractory (defined per IMWG Consensus Criteria) or intolerant to most recenttherapy

• Fully recovered from the acute toxic effects (except alopecia) to =< grade 1 toprior anti-cancer therapy

• Prior antitumor therapy must have been completed prior to enrollment as follows:

• >= 21 days for investigational agents, cytotoxic chemotherapy

• >= 21 days for radiation therapy. Note: Patients must have measurable diseasethat has been untreated/unaffected by local radiation therapy

• >= 3 months for prior anti-CD38-targeted therapy, adoptive cell therapy

• >=14 days for proteasome inhibitor therapy

• >= 7 days for immunomodulatory agents

• Absolute neutrophil count (ANC) >= 1,000/mm^3 (within 14 days prior to day 1 ofprotocol therapy)

• NOTE: Growth factor is not permitted within 7 days of ANC assessment unlesscytopenia is secondary to disease involvement

• Platelets >= 75,000/mm^3 (>= 50,000/mm^3 if >= 50% marrow involvement) (within 14days prior to day 1 of protocol therapy)

• NOTE: Platelet transfusions are not permitted within 14 days of plateletassessment unless cytopenia is secondary to disease involvement

• Total bilirubin =< 1.5 x upper limit of normal (ULN) (unless has Gilbert's disease) (within 14 days prior to day 1 of protocol therapy)

• Aspartate aminotransferase (AST) =< 3 x ULN (within 14 days prior to day 1 ofprotocol therapy)

• Alanine aminotransferase (ALT) =< 3 x ULN (within 14 days prior to day 1 of protocoltherapy)

• Creatinine =< 1.5 mg/dl AND/OR creatinine clearance of >= 40 mL/min per 24 hoururine test or the Cockcroft-Gault formula (within 14 days prior to day 1 of protocoltherapy)

• Women of childbearing potential (WOCBP): negative urine or serum pregnancy test

• If the urine test is positive or cannot be confirmed as negative, a serumpregnancy test will be required (within 14 days prior to day 1 of protocoltherapy)

• Woman of childbearing potential must be practicing a highly effective method ofbirth control consistent with local regulations regarding the use of birth controlmethods for subjects participating in clinical studies: e.g., established use oforal, injected or implanted hormonal methods of contraception; placement of anintrauterine device or intrauterine system; barrier methods; condom with spermicidalfoam/gel/film/cream/suppository or occlusive cap (diaphragm or cervical/vault caps)with spermicidal foam/gel/film/cream/suppository; male partner sterilization; trueabstinence (when this is in line with the preferred and usual lifestyle of thesubject) during and after the study (6 months after the last dose of 225Ac-DOTA-Daratumumab for women).

A man who is sexually active with a woman of childbearing potential and has not had a vasectomy must agree to use a barrier method of birth control, e.g., either condom with spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository, and all men must also not donate sperm during the study and for 6 months after receiving the last dose of study drug

• Childbearing potential defined as not being surgically sterilized (men and women) orhave not been free from menses for > 1 year (women only)

Exclusion Criteria:

• Daratumumab or other anti CD38 antibody treatment < 3 months prior to studyenrollment

• Prior radiopharmaceutical therapy

• Detectable antibodies directed against daratumumab

• Subject has received previous radiation to > 25% of their bone marrow

• Female patients who are lactating or have a positive pregnancy test during thescreening period

• Major surgery within 14 days prior to start of study treatment

• Subject is receiving concurrent chemotherapy, radiation, or biologic for cancertreatment. Subject is receiving bone marrow stimulatory factors (e.g.,granulocyte-macrophage colony-stimulating factor [GM-CSF]). Note: Hormonal therapyfor someone with a history of cancer treated with curative intent is permitted ifsubject has been on hormonal therapy > 1 year

• Vaccination with live attenuated vaccines within 4 weeks of study agentadministration

• A diagnosis of primary amyloidosis, plasma cell leukemia, Waldenstrommacroglobulinemia, or POEMS

• Severe persistent asthma (forced expiratory volume in 1 second [FEV1] < 60% and/ordaily symptoms) or severe chronic obstructive pulmonary disease (COPD) definedclinically or by historical pulmonary function tests with an FEV1 < 50% predicted

• Subject has known allergies, hypersensitivity, or intolerance to monoclonalantibodies or human proteins, or their excipients (refer to respective packageinserts or investigator's brochure). Patients with a history of infusion reactionsto daratumumab with prior treatment that resolved with supportive measures and inwhom daratumumab therapy was not previously discontinued because of infusionreactions are permitted

• Subject has uncontrolled human immunodeficiency virus (HIV-1), chronic or activehepatitis B, or active hepatitis A or C

• Patients with HIV are eligible unless their CD4+ T-cell counts are < 350cells/mcL or they have a history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infection within the 12 months prior toregistration. Concurrent treatment with effective antiretroviral therapy (ART)according to Department of Health and Human Services (DHHS) treatmentguidelines is recommended

• Subject has any one of the following:

• Clinically significant abnormal electrocardiogram (ECG) finding at screening

• Congestive heart failure (New York Heart Association class III or IV)

• Myocardial infarction within 12 months prior to starting study treatment

• Unstable or poorly controlled angina pectoris, including Prinzmetal variantangina pectoris

• Subject has presence of other active malignancy [see exceptions below] (However,research participants with history of prior malignancy treated with curative intentand in complete remission are eligible). The following malignancies are exceptionsto the active malignancy statement:

• Basal cell carcinoma of the skin

• Squamous cell carcinoma of the skin

• Non-muscle invasive bladder cancer

• Carcinoma in situ of the cervix

• Carcinoma in situ of the breast

• Incidental histologic finding of prostate cancer (T1a or T1b using the TNMclinical staging system) or prostate cancer that is curative

• Any other condition that would, in the investigator's judgment, contraindicate thepatient's participation in the clinical study due to safety concerns with clinicalstudy procedures

• Prospective participants who, in the opinion of the investigator, may not be able tocomply with all study procedures (including compliance issues related tofeasibility/logistics)