iMMunocell

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.
The hypothesis of this project is the following: 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.
Taking into account this context, IMMunocell's primary aim is to treat disease causation instead of symptomatology, by developing new minimally-invasive methods that identify individual patients at risk of developing active MM. This will be accomplished through longitudinal and periodic single-cell characterization of circulating tumor (CTCs) and immune cells, during patients’ transition from benign into malignant disease stages. The 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.
The consortium, coordinated by Dr. Jesús San Miguel (FIMA), 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. Partners 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, the partnership will compare immune profiles from SMM vs healthy individuals vs MM patients, and 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.
Although great strides have been made in the management of MM in the last decade, the best bet of this project 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, the consortium wants 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.