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Project Topic
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Background: Despite the large number of drugs approved during the last decade for the treatment of active multiple myeloma (MM), most patients relapse, become refractory to virtually all available drugs, and MM remains mostly incurable. However, there is recent evidence suggesting a benefit in survival by treating patients with smoldering MM (SMM) at higher risk of transformation to malignant disease. Hypothesis: The simultaneous availability of novel, effective, well-tolerated (immuno)therapies together with next-generation phenotypic and sequencing technologies, creates momentum for new, minimally-invasive methods to detect SMM patients at risk of transformation, offer precision medicine to prevent disease progression, and increase curability rates. Aims: Our primary aim is to develop new minimally-invasive methods that identify individual patients at risk of developing active MM, towards treating disease causation instead of symptomatology. This will be accomplished through longitudinal and periodic single-cell characterization of circulating tumor cells (CTCs) and immune subsets, during patients’ transition from benign into malignant disease stages. Our secondary aims are to i) evaluate clonal heterogeneity over time with unprecedented single-cell resolution, ii) generate in-depth knowledge on the pathogenesis and dissemination of smoldering into active MM, iii) generate large datasets on single-CTC-RNAseq, ATACseq and immunoscores from SMM patients, and iv) develop minimally-invasive algorithms to tailor pre-emptive (immuno)therapies. Methods: We will determine with single-cell resolution, how the epigenome, transcriptome and proteome of tumor and immune cells from 300 SMM patients evolve every 6 months in peripheral blood (PB), from stable to progressive disease. We will also evaluate the role of CTC numbers, mutation load in circulating free DNA (cfDNA), and content of circulating exosomal-microRNAs (exo-miRNAs) over time as critical biomarkers to predict risk of transformation in SMM. In parallel, we will compare immune profiles from SMM vs healthy individuals and MM patients, to define immune signatures in SMM related to disease stability vs progression. Data will be compared with current stratification models that are based on serological and bone marrow (BM) assessments. Expected results and potential impact: Although we have made great strides in the management of MM in the last decade, our best chances to eradicate this malignancy may lie in preventing progression in the first place. Through the integration of next-generation single-cell immunophenotypic and molecular profiling, we aim to develop new methods based on minimally-invasive characterization of single-CTCs and patients’ immune profiles, towards precise and real-time detection of SMM patients that should be treated to prevent cancer progression.
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