Multiple Myeloma is a chronic malignancy characterized by slow progression and recurrences.
Application of omics technologies, and bioinformatics approaches could identify biological pathways and molecules responsible for the onset, progression and resistance to therapy.
An interdisciplinary approach bringing together clinicians and researchers aiming to integrate epidemiological, clinical and experimental datasets in order to create a molecular model of cellular processes associated with the onset of active MM and response to therapy.
Elucidation of risk factors and health determinants associated with Progression of Monoclonal Gammopathies to Multiple Myeloma
In order to achieve the successful complementation of ELMUMY objectives,
the work-plan is wisely organized and split into the following distinct work packages (WPs):
Work package WP1 – Annotation of available samples and datasets. Collection of new samplesObjectives 1. Create a comprehensive database of samples and associated data relevant for onset of active MM from MGUS/sMM. 2. Collect new samples with complementary/missing features to the ones existing in biobanks.
Work package WP2 – Functional studies in biological fluids, cells and animalsObjectives 1. Elucidation of molecular features associated with MGUS/sMM progression to active MM 2. Assessment of drugs in MM cell and animal models Description of work: This WP concerns the application of novel technologies in MM, aiming (a) at producing new scientific knowledge on the molecular and cellular pathways implicated in myelomagenesis, i.e., the transformation process from normal cell to symptomatic MM, and (b) to translate this knowledge into novel, selective and effective tools and strategies for the early diagnosis and prognosis of MM as well as the outcome of MM therapy. For this, the following experimental systems will be used: a) A large collection of human MM cell lines (HMCLs; n=45) developed by CNRS, including HMCLs that are dependent on the addition of external growth factors for their proliferation and survival as well as drug-resistant HMCLs to melphalan (n=6), lenalidomide (n=6), bortezomib (n=7), dexamethasone (n=4) and HDACi (n=4) b) PBMCs and bone marrow plasma cells (BMPCs) representing the different stages of transition from MGUS/ smoldering MM to symptomatic MM, c) Syngeneic and humanized patient-derived mouse models of MM. The integration of clinical and omics datasets will yield putative therapeutic targets for MM that will be validated using flow cytometry and/or super resolution microscopy. Appropriate drugs that are already used in the clinical setting will be examined for repurposing in the context of MM treatment in multicellular BM/MGUS/sMM/symMM spheroids (static and under flow conditions) and immunocompetent syngeneic and humanized mouse models.
Work package WP3 – Omics profilingObjective Production of transcriptomics/epitranscriptomics, proteomics, peptidomics datasets for elucidation of MM onset and progression. Description of work: Representative samples (total n=180) from the following groups will be analysed by omics approaches MGUS n=60, sMM n=60 and active MM n=60. The 60 samples in the MGUS and sMM groups will be composed of the following subgroups: 30 stable and 30 that progressed to active MM based on at least 5-year follow-up. The analysis of bone marrow plasma cell samples by transcriptomics and proteomics will provide insights on molecular features associated with the onset and progression of MM. The urine samples (n=180) analysis will allow creation of peptide biomarker panels for monitoring MM onset and progression. Lists of omics molecular features with quantity ratios will be generated for changes associated with the onset of active MM by comparing: i) MGUS with sMM, MGUS with MM, and sMM with MM, ii) samples from MGUS progressors with samples from MGUS individuals that did not develop active MM, iii) samples from sMM progressors with samples from sMM patients that did not develop active MM
Work package WP4 – Data integration and Trustworthy AI model for MMObjectives 1 To organize the data information flow 2 To integrate omics and other available data generating a comprehensive holistic profile of each biological state. 3 To computationally highlight the underlying molecular mechanisms by using the generated holistic profiles 4 To propose candidate repurposed drugs
Work package WP5 – Dissemination, outreach and exploitation activitiesObjectives The overall Objective of WP5 is the maximization of the project’s outputs through effective communication and dissemination of its concepts and findings. To communicate and disseminate project knowledge, standards and results during and after the project duration.
Work package WP6 – Project Management and legal frameworkObjectives 1. Supervision and control of the scientific progress towards the project's planned objectives 2. Preparation and delivery of progress reports, as required by the contractual framework 3. Transparent and professional day-to-day financial, administrative and legal management 4. Effective communication between the consortium partners and with the European Commission 5. Logistical support and follow-up of consortium meetings and related activities 6. Coordination of gender equality policy
Work package WP7 – Ethics requirementsThe objective is to ensure compliance with the 'ethics requirements' set out in this work package.