This phase I trial tests the safety, side effects, and best dose of actinium Ac 225-DOTA-daratumumab (225Ac-DOTA-daratumumab) in combination with daratumumab and indium In 111-DOTA-daratumumab (111In-DOTA-daratumumab) in treating patients with multiple myeloma that does not respond to treatment (refractory) or that has come back (recurrent). Daratumumab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. 111In-DOTA-daratumumab and 225Ac-DOTA-daratumumab are forms of radioimmunotherapy in which a monoclonal antibody, daratumumab, has been linked to a radiotracer to allow for targeted delivery of the treatment to cancer cells. Giving all three together may kill more cancer cells.

PRIMARY OBJECTIVE:

I. To assess the safety and tolerability of 111In/225Ac-DOTA-daratumumab, at each dose level in order to establish the maximum tolerated dose (MTD), which will inform the recommended phase 2 dose (RP2D).

SECONDARY OBJECTIVES:

I. To describe the anti-myeloma activity of 225Ac-DOTA-daratumumab as assessed by overall response rate (ORR).

II. To evaluate the organ biodistribution, pharmacokinetics and organ dose estimates of 111In/225Ac-DOTA-daratumumab.

EXPLORATORY OBJECTIVE:

I. To assess the activity of 225Ac-DOTA-daratumumab against non-cancer immune cells using the peripheral blood and bone marrow (BM) samples.

OUTLINE: This is a dose-escalation trial of 225Ac-DOTA-daratumumab.

Patients receive daratumumab intravenously (IV) over 45 minutes. Two hours later, patients receive 111In-DOTA-daratumumab and 225Ac-DOTA-daratumumab IV over 20-30 minutes.

After completion of study treatment, patients are followed up weekly for 8 weeks, every 2 weeks for 4 weeks, every 4 weeks for 16 weeks, and then periodically up to 12 months.

Inclusion Criteria:

• Documented informed consent of the participant and/or legally authorized representative

  • 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) criteria with measurable disease defined as one of the following:

  • Serum monoclonal protein >= 1.0 g/dL (or 0.5 g/dL in patients with immunoglobulin 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, an immunomodulatory drug, and an anti-CD38 monoclonal antibody. Refractory (defined per IMWG Consensus Criteria) to daratumumab

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

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

• Fully recovered from the acute toxic effects (except alopecia) to =< grade 1 to prior 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 disease that 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 of protocol therapy)

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

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

  • NOTE: Platelet transfusions are not permitted within 14 days of platelet assessment 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 of protocol therapy)

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

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

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

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

• Woman of childbearing potential must be practicing a highly effective method of birth control consistent with local regulations regarding the use of birth control methods for subjects participating in clinical studies: e.g., established use of oral, injected or implanted hormonal methods of contraception; placement of an intrauterine device or intrauterine system; barrier methods; condom with spermicidal foam/gel/film/cream/suppository or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository; male partner sterilization; true abstinence (when this is in line with the preferred and usual lifestyle of the subject) 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) or have not been free from menses for > 1 year (women only)

Exclusion Criteria:

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

• 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 the screening period

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

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

• Vaccination with live attenuated vaccines within 4 weeks of study agent administration

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

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

• Subject has known allergies, hypersensitivity, or intolerance to monoclonal antibodies or human proteins, or their excipients (refer to respective package inserts or investigator's brochure). Patients with a history of infusion reactions to daratumumab with prior treatment that resolved with supportive measures and in whom daratumumab therapy was not previously discontinued because of infusion reactions are permitted

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

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

• Subject has presence of other active malignancy [see exceptions below] (However, research participants with history of prior malignancy treated with curative intent and in complete remission are eligible). The following malignancies are exceptions to 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 TNM clinical staging system) or prostate cancer that is curative

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

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