Daratumumab with indium‑111 and actinium‑225 radioimmunotherapy for relapsed or refractory multiple myeloma

Phase 1 Trial of 111Indium/225Actinium-DOTA-Daratumumab in Patients With Relapsed/Refractory Multiple Myeloma

This trial will see if combining daratumumab with indium‑111 and actinium‑225 labeled daratumumab is safe and may help adults whose multiple myeloma has returned or stopped responding to prior treatments.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 15 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: City of Hope Medical Center (Academic / other)
• Drugs / interventions: daratumumab, chemotherapy, radiation
• Locations: 1 site (Duarte, California)
• Trial ID: NCT05363111 on ClinicalTrials.gov

What this trial studies

This Phase 1 dose‑escalation trial gives standard daratumumab IV followed two hours later by daratumumab labeled with indium‑111 and actinium‑225 to deliver targeted radiation to myeloma cells. The primary goal is to establish safety, tolerability, and the maximum tolerated dose to inform a recommended Phase 2 dose. Secondary objectives include measuring anti‑myeloma activity (overall response rate) and characterizing biodistribution, pharmacokinetics, and organ radiation doses using the indium tracer. Exploratory analyses will examine effects on non‑cancer immune cells using peripheral blood and bone marrow samples, and participants are followed regularly for up to 12 months after treatment.

Who should consider this trial

Good fit: Adults (≥18) with measurable relapsed or refractory multiple myeloma who have had at least two prior lines of therapy, are refractory to daratumumab, have CD38‑positive disease, and meet performance and organ function criteria are ideal candidates.

Not a fit: Patients without CD38 expression on their myeloma cells, with poor performance status or significant organ dysfunction, or those unable to travel to the site are unlikely to benefit or be eligible.

Why it matters

Potential benefit: If successful, this approach could deliver targeted radiation to CD38‑expressing myeloma cells and produce stronger responses in patients who have exhausted standard options.

How similar studies have performed: Radioimmunotherapy and alpha‑emitter approaches have shown promise in preclinical work and limited clinical settings, but using actinium‑225 linked to daratumumab is an early, largely experimental strategy with limited human data.

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 =\< 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)

Where this trial is running

Duarte, California

• City of Hope Medical Center — Duarte, California, United States (Recruiting)

Study contacts

• Principal investigator: Scott R Goldsmith — City of Hope Medical Center

Conditions Recurrent Plasma Cell Myeloma; Refractory Plasma Cell Myeloma