Low Molecular Weight Theranostics for Multiple Myeloma

. Multiple Myeloma (MM) is a disease characterized by the expansion of malignant plasma cells in the bone marrow. MM patients frequently demonstrate clinical responses to treatments consisting of proteasome inhibitors and immune modulatory drugs, hematopoietic bone marrow transplant, and monoclonal antibodies targeting several cell surface antigens, but all MM patients will eventually relapse, and disease eradication remains elusive. Central to this devastating trend is the persistence and evolution of therapy-resistance malignant plasma cells that arise following multiple therapies and the lack of effective non-invasive detection methods to assess disease status in the whole body. One rational approach to overcoming the intrinsic resistance seen with MM is to deliver a drug that is impervious to resistance directly to the tumor cells, such as targeted alpha-emitter therapy (TAT). TAT uses alpha-emitting radionuclides and causes largely irreparable double strand breaks that leads to selective cytotoxicity in cancer cells. However, there are substantial gaps in tools and knowledge in implementing TAT in MM as only few studies have examined the potential of TAT in MM and none with a focus on developing low molecular weight (LMW) theranostics, which show tractable pharmacokinetics than biologicals. Positron emission tomography (PET) is currently used to determine response to treatment and provide prognostic information in MM patients but more molecularly targeted imaging agents are needed to address the needs of MM patients. To address these unmet needs, our hypothesis is to develop a peptide-based first-in- class LMW theranostic pair for MM that targets cluster of differentiation 38 (CD38) protein, which is expressed uniformly and with high density in MM. Accordingly, our objectives are to create an 18F-labled PET imaging agent for improved prognostication of MM, and a potent actinium-225 (225Ac)-TAT to treat MM, in a single hybrid molecule. We will test our hypothesis in the following specific aims: 1) Develop the diagnostic component of a CD38 theranostic pair that fits within the standard clinical workflow; 2) Develop the therapeutic component of a CD38 theranostic pair; and 3) Characterize the therapeutic efficacy of CD38 TAT to control MM tumor growth. The proposal is innovative because it pursues the development of a first-in-class CD38 binding LMW theranostic pair and takes advantage of 18F for improved detection sensitivity and 225Ac for irreparable cell death. The proposed research is significant because it aims to develop imaging agents with potential to reduce unnecessary biopsies and treatments while also enhancing the prognostic value of minimal residual disease negativity and predicting clinical outcomes in MM. Moreover, this research also aims to develop complementary interventions to enhance existing therapeutic combinations by exploring new therapeutic agents that are highly specific, fundamentally different from current therapies, and overcome the resistance seen with current therapies. Project Number: 1R01CA299906-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Sridhar Nimmagadda | Institution: JOHNS HOPKINS UNIVERSITY, BALTIMORE, MD | Award Amount: $591,419 | Activity Code: R01 | Study Section: Radiation Therapeutics and Biology Study Section[RTB] View on NIH RePORTER: https://reporter.nih.gov/project-details/11296021