Multiple myeloma (MM) is a plasma cell malignancy that is localized in the bone marrow. MM represents 10% of all hematological cancers and approximately 800 patients are diagnosed annually with MM in Belgium. Today, newly diagnosed patients are treated with varying combinations of chemotherapy, proteasome inhibitors, immunomodulatory drugs and glucocorticoids (GCs). As high-dose GCs are used in all treatment stages, theyremain the cornerstone of MM treatment. Unfortunately, prolonged GC treatment is severely hampered by detrimental GC-associated side effects (e.g. osteoporosis, diabetes), which are perceived by patients as the factor that limits their quality of life.Long-term GC treatment also leads to the emergence of GC resistance, in which the beneficial, MM-targeting effects are lost, while the GC-related side effects often persist. Of note, all MM patients will develop GC resistance during treatment. Therefore, this thesis aims to explore previously un(der)studied contributors to GC resistance in MM. In part one of this dissertation, we determine the coregulator profile of the glucocorticoid receptor (GR), a nuclear receptor and transcription factor, in different myeloma and leukemia cell lines, as their identity is largely unknown. We further establish that GC resistance in a leukemia cell line is not due to qualitative differences, but (partly) due to quantitative differences in the GR coregulator profile. In a second part, we evaluate whether the selective GR modulator CpdA can modulate the action of GC-bound GR in myeloma and leukemia cell lines. We find that CpdA neither enhances GC-induced apoptosis nor additionally inhibits proliferation in these cell lines. CpdA also does not protect GR protein from GC-induced homologous downregulation, hereby excluding CpdA’ potential to prolong GC responsiveness via sustained GR levels. These results either rule out the potential of compounds that favor GR-mediated gene repression for the treatment of lymphoid malignancies, or may point to a GR-independent action of CpdA in myeloma and leukemia cell lines. In part three, we investigate whether cross-modulation between GR and the closely related mineralocorticoid receptor (MR) can affect therapy responsiveness, as this was shown between GR and other nuclear receptors in solid malignancies. We discover that GC-activated GR can decrease MR levels in GCsensitive, yet, not in GC-resistant MM cells. MR knockdown further reduces the viability of GC-sensitive MM cells and GC-mediated MR downregulation is no longer observed in an in vitro GC resistance onset model. Interestingly, we find that the combination of a GR agonist with an MR antagonist enhances GC-induced apoptosis of GC-sensitive MM cells. Therefore, we envisage combining lower doses of GCs with MR antagonists for the treatment of MM patients, as this may result in less (severe) GC-related side effects and thus better quality of life. In the fourth part, we search for transcriptional markers that are candidates to predict the emergence of GC resistance. Pending validations, these markers enable detecting GC resistance in patients in a timelier manner and at the same time can represent interesting therapeutic targets. Taken together, we gather further mechanistic insights into GC resistance in MM and identify potential therapeutic strategies and targets for the treatment of MM.