@article {Minnix795, author = {Megan Minnix and Vikram Adhikarla and Enrico Caserta and Erasmus Poku and Russell Rockne and John E. Shively and Flavia Pichiorri}, title = {Comparison of CD38-Targeted α- Versus β-Radionuclide Therapy of Disseminated Multiple Myeloma in an Animal Model}, volume = {62}, number = {6}, pages = {795--801}, year = {2021}, doi = {10.2967/jnumed.120.251983}, publisher = {Society of Nuclear Medicine}, abstract = {Targeted therapies for multiple myeloma (MM) include the anti-CD38 antibody daratumumab, which, in addition to its inherent cytotoxicity, can be radiolabeled with tracers for imaging and with β- and α-emitter radionuclides for radioimmunotherapy. Methods: We have compared the potential therapeutic efficacy of β- versus α-emitter radioimmunotherapy using radiolabeled DOTA-daratumumab in a preclinical model of disseminated multiple myeloma. Multiple dose levels were investigated to find the dose with the highest efficacy and lowest toxicity. Results: In a dose{\textendash}response study with the β-emitter 177Lu-DOTA-daratumumab, the lowest tested dose, 1.85 MBq, extended survival from 37 to 47 d but did not delay tumor growth. Doses of 3.7 and 7.4 MBq extended survival to 55 and 58 d, respectively, causing a small equivalent delay in tumor growth, followed by regrowth. The higher dose, 11.1 MBq, eradicated the tumor but had no effect on survival compared with untreated controls, because of whole-body toxicity. In contrast, the α-emitter 225Ac-DOTA-daratumumab had a dose-dependent effect, in which 0.925, 1.85, and 3.7 kBq increased survival, compared with untreated controls (35 d), to 47, 52, and 73 d, respectively, with a significant delay in tumor growth for all 3 doses. Higher doses of 11.1 and 22.2 kBq resulted in equivalent survival to 82 d but with significant whole-body toxicity. Parallel studies with untargeted 225Ac-DOTA-trastuzumab conferred no improvement over untreated controls and resulted in whole-body toxicity. Conclusion: We conclude, and mathematic modeling confirms, that maximal biologic doses were achieved by targeted α-therapy and demonstrated 225Ac to be superior to 177Lu in delaying tumor growth and decreasing whole-body toxicity.}, issn = {0161-5505}, URL = {https://jnm.snmjournals.org/content/62/6/795}, eprint = {https://jnm.snmjournals.org/content/62/6/795.full.pdf}, journal = {Journal of Nuclear Medicine} }