radioimmunotherapy (111indium/225actinium-dota-daratumumab) for the treatment of relapsed/refractory multiple myeloma

Conditions: Recurrent Plasma Cell Myeloma; Refractory Plasma Cell Myeloma

Summary: 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.

Eligibility criteria:
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 =\ = 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)