Multiple myeloma (MM) is an incurable lymphoid malignancy characterized by an uncontrolled accumulation of plasma cells in the bone marrow and represents 10% of all hematological cancers. Approximately 800 patients are diagnosed annually with MM in Belgium. Today, newly diagnosed patients are usually treated with combinations consisting of proteasome inhibitors (e.g. bortezomib), immunomodulatory drugs (e.g. thalidomide, lenalidomide) and glucocorticoids (GCs). As high-dose GCs are used in all MM treatment stages, they remain the cornerstone of MM treatment. Unfortunately, prolonged treatment with GCs leads to the onset of GC therapy resistance and provokes detrimental side effects, such as osteoporosis, diabetes and extreme mood swings which are perceived by patients as the factor that limits quality of life and treatment adherence. GCs act through glucocorticoid receptors (GR) and mineralocorticoid receptors (MR), yet, whether MR plays a role in MM and is implicated in GC resistance is unknown. We found that GCs downregulate MR levels in a GR-dependent manner in GC-sensitive, but not in GC-resistant MM cells. Function-wise, we discovered that MR knockdown decreased the viability of GC-sensitive MM cells and that GCs were unable to downregulate MR levels in a GC resistance onset model. Moreover, combining GR agonists with MR antagonists synergistically decreased the MM cell viability, thus representing a novel drug repurposing strategy for MM treatment. This proposal serves to translate these findings to a clinical setting. As a first objective, we will evaluate the potential of MR expression as a marker for GC therapy resistance by performing immunohistochemical staining of MR on bone biopsies from MM patients in a retrospective manner. Such a marker has added value, as it could speed up the decision making of continuing or ceasing GC treatment. Our second objective is to assess the potential of GR agonists in combination with MR antagonists in MM treatment. To this end, we will first optimize the dosage of both GR agonists and MR antagonists to obtain a maximal synergistic effect on MM cell killing using MM cells isolated from newly-diagnosed MM patients and from relapsed and refractory MM patients. Notably, MM patients would benefit from combining MR antagonists with a lower dose of GCs as the same level of GC-induced cell killing would be obtained compared to high-dose GCs, but with the additional benefit of reduced side effects. If this combination treatment synergistically decreases the viability of patient-derived MM cells, a phase I clinical trial will be organized. In this trial, we will compare high-dose GCs with lower dose GCs plus MR antagonists and both therapy efficacy and side effects will be determined. The overarching aim is to find support for a phase ll/lll clinical trial comparing high-dose GC with our novel lower GC dose-based combination treatment after the completion of this project. Taken together, with this proposal we expect to improve the quality of life of MM patients by identifying earlier on when a patient is becoming GC resistant and by reducing the (severity) of the GC-related side effects which would also prolong treatment adherence.