Synthetic glucocorticoids (GCs) are part of the treatment regime for many blood cancers, such as multiple myeloma, a plasma cell cancer residing in the bone marrow. GCs activate the glucocorticoid receptor (GR) to induce programmed cell death (apoptosis) of malignant myeloma cells. Unfortunately, prolonged GC treatment at higher doses is severely hampered by GC-associated side effects and a gradual emergence of GC therapy resistance. Using in cellulo models mimicking GC-resistance longitudinally, we characterize molecular tipping points and markers that signal resistance over time by using OMICs analyses and dedicated assays that reflect the GR signal transduction pathway. This molecular knowledge enables identifying small molecule drugs or antibodies that may overcome resistance. We plan to develop and evaluate various molecular cell-based tools to follow myeloma progression in vivo, hereby enabling validation of targets that can prevent/delay GC resistance or restore GC sensitivity.