Abstract Purpose: Given that most patients with multiple myeloma (MM) become refractory to daratumumab (Dara) but retain CD38 expression, we developed a CD38-targeting radioimmunotherapy (RIT) by conjugating the α emitter actinium-225 to Dara using a DOTA chelator (225Ac-Dara). Methods: We conducted a first-in-human trial of 225Ac-Dara co-infused with the imaging agent 111Indium-DOTA-Dara (111In-Dara). Eligible participants had received available therapies with proven clinical benefit and were Dara-refractory (12-week Dara washout). Patients had adequate hematologic and organ function, performance status ECOG ≤2, no prior RIT or radiation ≥25% to marrow, liver, or kidneys. Three radioactivity dose levels (DLs) were 20, 40 and 60 kBq/kg. We used a BOIN design for dose escalation decisions. Patients received an IV dose of unlabeled Dara at 45mg 2-4h prior to RIT. They then received an IV infusion of 111In-Dara for imaging, immediately followed by a single infusion of 225Ac-Dara conjugated to 5mg of Dara. Serial planar (2h, 24h and 144h-168h) and SPECT/CT (24h) imaging were performed. Primary endpoint was toxicity to define MTD/RP2D. Secondary endpoints included ORR and PFS. Exploratory correlatives included tumor uptake, organ dosimetry, and assessment of immune microenvironment. Results: Nine patients were treated. One patient was not evaluable for DLTs and was replaced. One of 6 had a DLT at DL1. Both patients treated at DL2 had DLT. MTD was defined as DL1 (20 kBq/kg). Non-hematologic AEs were grade ≤ 2. All DLTs were hematologic, seen in patients with high disease burden or early progression. One patient with prolonged cytopenias recovered with autologous hematopoietic progenitor cell infusion. All nine patients were evaluable for secondary efficacy endpoints. Eight had best response of stable disease after the single 225Ac-Dara dose; the other had PD. Median PFS was 96d (95% CI: 29-154d). Mass cytometry of marrow plasma cells (CD138⁺CD38⁺) showed high baseline CD38 expression (median MFI ≈ 110), indicating continued target expression despite Dara-refractoriness. PBMC analysis revealed early reductions in CD38⁺ populations, checkpoint modulation, and innate activation with depletion of immunosuppressive subsets. Paired medians at baseline and ∼24 h showed marked declines in CD38⁺ NK cells (−73%), total NK cells (−57. 5%), and CD38⁺ Tregs (−28%). Post-hoc exploratory evaluation revealed an 80% ORR among those receiving bispecific antibody or CAR-T as next line of therapy, with median DOR of 620d (n=5). 111In-Dara imaging showed target specificity, with uptake in marrow and extramedullary disease. Conclusion: 225Ac-Dara in Dara-refractory MM is a novel strategy to circumvent immune exhaustion and repurpose CD38-targeting. Repeated administration of lower doses may improve the therapeutic window and duration. Translational and clinical observations from this trial support possible synergy between 225Ac-Dara and subsequent immunotherapies. We are modeling these hypotheses preclinically to support future study. Citation Format: Scott Ryan Goldsmith, Vikram Adhikarla, Murali Janakiram, Michael Rosenzweig, Savita Dandapani, Sarah Lee, Nitya Nathwani, Azra Borogovac, Myo Htut, Theophilus Tandoh, Alex Pozhitkov, Enrico Caserta, Mariam Murtadha, Ni-Chun Tsai, Arnab Chowdhury, Joycelynne Palmer, Jonathan Keats, James Sanchez, Erasmus Poku, Russell Rockne, Paul Yazaki, Jeffrey Wong, John E. Shively, Flavia Pichiorri, Amrita Krishnan. First-in-human trial of 225Actinium-DOTA-daratumumab, an alpha-emitting radioimmunotherapy, in patients with daratumumab-refractory multiple myeloma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr CT133.
Goldsmith et al. (Fri,) studied this question.