Preclinical studies for the immunoprevention of multiple myeloma - PROJECT SUMMARY Smoldering multiple myeloma (SMM) is a premalignant condition present in 1 in 200 people of northern European ancestry and is even more prevalent in those of African ancestry. It progresses with a variable frequency to symptomatic multiple myeloma (MM) associated with anemia, bone lesions and renal failure. Patients with SMM at high risk of progression (>20% per year) are currently being enrolled in diverse clinical trials using therapies that have been approved for the treatment of symptomatic MM. For the vast majority of patients with SMM, that have a lower risk of progression (e.g., 2-10% per year), there are no recommended interventions and a scarcity of clinical trials. In order to develop safe, low-risk clinical trials for these patients, there is the need for faithful, orthotopic, immunocompetent pre-clinical models that recapitulate the life-history of SMM to MM transition in a reasonable time frame and that can be used to assay different interventions. We have developed the clinically predictive, fully immunocompetent Vk*MYC and Vk*MYChCRBN mouse model of MM that can be used to study the slow progression from SMM to MM, as well as the effects of interventions, including treatments that incorporate immunomodulatory thalidomide analogs (IMiDs) that requires human cereblon (CRBN). By analyzing cohorts of Vk*MYC mice maintained in the USA or Italy we identified a key role for the gut microbiome in the progression of MM in both mice and humans. Mechanistically certain microbiota can stimulate TH17 cells in the gut to migrate to the bone marrow and stimulate eosinophils to secrete IL6, stimulating SMM progression. Based on exciting preliminary data we will examine how various factors can lead to an inflamed bone marrow microenvironment (e.g., diet, microbiome, systemic inflammation, clonal hematopoiesis) that can accelerate SMM and the ability of anti-inflammatory immunoprevention approaches including NSAIDs, NLRP3 inhibitors, IMiDs, IL18 antibody to delay or prevent this progression. Overall, these data will provide strong pre-clinical rationale to support clinical trials of immunoprevention approaches for patients with SMM.
