Defining immune determinants oftransformation in MGUS/SMM

Multiple Myeloma (MM) almost always progresses from the precursor states of monoclonal gammopathy of undetermined significance (MGUS)/smoldering multiple myeloma (SMM). However, not all patients with MGUS/SMM develop MM, suggesting that further tumor evolution may depend on the surrounding cells in the microenvironment that can create conditions permissive for or against clonal expansion. Indeed, tumors are more than insular masses of proliferating cancer cells. Instead, they are complex ecosystems defined by spatiotemporal interactions between malignant and immune cells. In this project, we aim to define the role of the immune system in being permissive or protective against “malignant transformation”. We hypothesize that the permissive immune microenvironment is a critical regulator of the “malignant switch” in MGUS/SMM and defining these specific alterations is critical for the development of immunotherapeutic approaches that intercept disease progression. This will also allow us to determine the role of immune profiling as a biomarker of disease progression in conjunction with genomic aberrations (in Project 1) and response to immunotherapy (in Project 3). In Aim 1, we characterize immune alterations that define the malignant switch in MGUS/SMM and develop a comprehensive model of disease progression using clinical, genomic, and immune markers. In Aim 2, we characterize spatial transcriptomic and proteomic characteristics of immune cells in MGUS/SMM. We hypothesize that a reactive “hot” immune microenvironment defines the equilibrium state seen in patients who do not progress from MGUS/SMM to MM. With the advent of technologies such as spatial transcriptomics and proteomic imaging techniques, we can assess the state and abundance of multiple cell types at once while preserving the spatial architecture in large cohorts of patients. In Aim 3, we interrogate the functional role of specific immune cells in vivo using murine Multiple Myeloma models. We hypothesize that specific immune cells, specifically T-cells reactive to tumor cells (tumor-specific TCR) and immunosuppressive T regulatory cells (Treg) are critical regulators of MGUS/SMM equilibrium. This approach will allow us to determine the functional impact of immune cells on the regulation of disease progression in MGUS/SMM. Project Number: 1P01CA306849-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Irene Ghobrial | Institution: DANA-FARBER CANCER INST, BOSTON, MA | Award Amount: $959,573 | Activity Code: P01 | Study Section: Special Emphasis Panel[ZRG1 CTH-W (45)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11262548