Targeted therapies for multiple myeloma (MM) include the anti-CD38 antibody daratumumab (Dara), which, in addition to its inherent cytotoxicity, can be radiolabeled with tracers for imaging and with β- and α-emitter radionuclides for radioimmunotherapy (RIT). We have compared the potential therapeutic efficacy of β -vs α-emitter RIT using radiolabeled DOTA-Dara in a preclinical model of disseminated MM. Multiple dose levels were investigated to find the dose with the highest efficacy and lowest toxicity. In a dose-response study with the β -emitter Lu-DOTA-Dara, the lowest tested dose of 1.85 MBq extended survival from 37 to 47d, but had no effect on tumor growth. The doses of 3.7 and 7.4 MBq extended survival to 55 and 58d, respectively, while causing a small equivalent delay of tumor growth, followed by regrowth. The higher dose of 11.1 MBq eradicated the tumor but had no effect on survival compared to untreated controls, because of whole-body toxicity. In contrast, there was a dose-dependent effect of the α-emitter Ac-DOTA-Dara, in which 0.925, 1.85, and 3.7 kBq increased survival, compared to untreated controls (35d), to 47d, 52d, and 73d, respectively, with a significant delay of tumor growth for all three doses. Higher doses of 11.1 and 22.2 kBq resulted in equivalent survival to 82d but with significant whole-body toxicity. Parallel studies with untargeted Ac-DOTA-trastuzumab conferred no improvement over untreated controls and resulted in whole-body toxicity. Mathematical modeling of the two approaches confirmed the maximal biological doses were achieved by α-emitter-based RIT and predicted Ac to be superior to Lu in delaying tumor growth.Copyright © 2020 by the Society of Nuclear Medicine and Molecular Imaging, Inc.