SUMMARY Multiple Myeloma (MM) is almost always preceded by monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM), with a transformation rate of ~1% and ~10% per year, respectively. Large racial disparities exist in MM and its premalignant conditions; compared to Whites, African-Americans have a two-fold increased prevalence of MGUS/MM and are diagnosed with MM at younger ages. What is lacking is the identification of the true transition steps that occur from early precancerous stages to overt MM and identifying the biological precancer stages of the disease. Here, we propose to construct the Myeloma Multidimensional Pre-Cancer Atlas (MMPCA). We believe that the identification of the transition stages along the spectrum of healthy, precursor MM to overt MM in a racially diverse population represents a missed opportunity to fully inform disease characterization, monitoring, and potential needs for patients to receive early intervention therapies. We will leverage our large collection of samples from two cohort studies that are racially diverse with over 30% African or African Americans and with over 10,000 samples collected serially over the last 10 years; and with well-annotated data of disease progression. Our overarching hypothesis is that malignant transformation occurs through the cooperative acquisition of genomic and microenvironment alterations that occur in a susceptible host environment. The MMPCA will create a comprehensive spatial and temporal atlas of precursor MM to understand genomic and microenvironmental alterations across the spectrum of disease evolution from healthy to MM. In specific Aim 1, we will map the spatial interactions among early B cell clonal expansions with the microenvironment using Xenium spatial transcriptomic and imaging mass cytometry (IMC). In specific Aim 2, we will chart the subclonal genomic structure at the single cell level across the spectrum of disease from healthy to MM, and in specific Aim 3, we will characterize at the single cell level the microenvironment (immune and non-immune stromal cells) and its association with progression across the spectrum of disease from healthy to MM. This provides a unique opportunity to study events in a clinically well-defined precancer hematological condition that can be a great model of disease progression and inform other precancer cell atlases. We also have access to serial blood and marrow samples along the spectrum of the disease with long-term follow up of clinical progression for over 10 years. Unlike in solid cancers, we can obtain biopsies from the tissue of origin without altering the natural course of the precancerous lesions (no need for surgical resection) and therefore, we have a unique resource that can be made available for other precancer atlases.

NARRATIVE We propose to construct the Myeloma Multidimensional Pre-Cancer Atlas (MMPCA); as multiple myeloma (MM) is almost always preceded by monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM), with a transformation rate of ~1% and ~10% per year, respectively. Large racial disparities exist in MM and its premalignant conditions; compared to Whites, African-Americans have a two- fold increased prevalence of MGUS/MM and are diagnosed with MM at younger ages. We will leverage our large collection of samples from two cohort studies that are racially diverse to create a comprehensive spatial and temporal atlas of precursor MM to understand genomic and microenvironmental alterations across the spectrum of disease evolution from healthy to MM.