PROJECT SUMMARY / ABSTRACT – Project 3 The majority of patients with multiple myeloma (MM) ultimately die of progressive disease despite high rates of initial response to novel agents. Recent advances allow patients with standard-risk MM to anticipate a median survival of over 7 years from diagnosis, however those with high-risk disease features continue to experience early relapse and death. Although autologous hematopoietic cell transplant (HCT) remains a standard of care, this intervention does not ameliorate the differences in outcome predicted by pre-HCT risk features. In contrast, responses observed after allogeneic HCT cannot be predetermined by high-risk features. Myeloablative conditioning regimens, in concert with a graft-versus-myeloma effect, have cured some patients with MM, but the accompanying toxicity and high rates of non-relapse mortality (NRM) have limited wide adoption. To minimize the risk of NRM associated with high-intensity preparative regimens, reduced-intensity conditioning (RIC) regimens have been introduced. Relapse after RIC however, remains the leading cause of death, and measures that can safely improve the efficacy of the conditioning regimen should be explored. The radio-sensitivity of malignant plasma cells has been well documented, and the poor prognosis associated with high-risk marrow cytogenetics is not predictive of response to radiation therapy. CD38 antigen-targeting with α-emitter radioimmunotherapy (RIT) can eliminate disease in pre-clinical MM models. Based on the physical characteristics of α-emitting radionuclides and new opportunities to harness their potential, there is a compelling rationale for employing α-emitter RIT to treat MM. The α-emitter astatine-211 ( 211At) deposits a very large amount of energy (~100 keV/μm) within a few cell diameters (50-90 μm) resulting in irreparable double strand DNA breaks that overwhelm cellular repair mechanisms. The purpose of this application is to integrate α-emitter RIT targeting CD38 (211At-OKT10-B10) into allogeneic HCT conditioning to improve outcomes without increasing toxicity and NRM. The project will address three hypotheses: 1). 211At-OKT10-B10 will be safe and well tolerated when integrated into an allogeneic HCT conditioning regimen 2). 211At-OKT10-B10 will selectively target all malignant plasma cells irrespective of mutational status, 3). B cell maturation antigen (BCMA) targeting with 211At-BCMA-B10 will represent a further refinement to targeting that will demonstrate efficacy in preclinical mouse models.