PROJECT SUMMARY AND ABSTRACT The primary goal of this proposal is to develop novel theranostic agents targeting CD46 for imaging and treatment of multiple myeloma (MM). CD46 is a novel therapeutic target, with a cognate antibody-drug conjugate, FOR46, now in phase 1 clinical trials. Our preliminary data demonstrate high expression of CD46 in MM. In this proposal, we develop and implement [89Zr]DFO-YS5 and [225Ac]DOTA-YS5 as imaging and therapeutic agents targeting MM. The central hypothesis of this proposal is that CD46 is an effective target for molecular imaging and therapy of MM. In this proposal we test this hypothesis in preclinical models, and in a pilot study of patients with MM. In order to test this hypothesis, we have assembled an experienced team of chemists, biologists, imaging scientists, physicists, and physicians to evaluate this method in preclinical models and in patients. In specific aim 1, we will develop [89Zr]DFO-YS5 and [225Ac]DOTA-YS5 as PET imaging and therapeutic agents for MM. In specific aim 2, we will develop new co-treatment approaches to maximize CD46 expression, and use these to augment [89Zr]DFO-YS5 PET and [225Ac]DOTA-YS5 treatment. In aim 3, we perform a pilot [89Zr]DFO-YS5 PET imaging study in patients with MM, and analyze the data to determine its sensitivity for detecting sites of disease. The methods developed in this proposal will ultimately be used to develop novel diagnostic and therapeutic approaches in MM, to help reduce morbidity and mortality for this disease.