- - Documented informed consent of the participant and/or legally authorized
- - Assent, when appropriate, will be obtained per institutional guidelines.
- - 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
- - 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
- 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
- Alanine aminotransferase (ALT) =< 3 x ULN (within 14 days prior to day 1 of protocol
- 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
- 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
- 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
- - Childbearing potential defined as not being surgically sterilized (men and women) or
have not been free from menses for > 1 year (women only)
- 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
- - Major surgery within 14 days prior to start of study treatment.
- - Subject is receiving concurrent chemotherapy, radiation, or biologic for cancer
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
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
Concurrent treatment with effective antiretroviral therapy (ART)
according to Department of Health and Human Services (DHHS) treatment guidelines
- - 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
- - 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
- Prospective participants who, in the opinion of the investigator, may not be able to
comply with all study procedures (including compliance issues related to