The glucocorticoid receptor (GR) is a crucial drug target in multiple myeloma as its activation with glucocorticoids triggers myeloma cell death. However, as high-dose glucocorticoids are also associated with deleterious side effects, novel approaches are urgently needed to improve GR’s action in myeloma.

Here we reveal a functional crosstalk between GR and the closely related mineralocorticoid receptor (MR) that culminates in improved myeloma cell killing. We show that the GR agonist Dexamethasone (Dex) downregulates MR levels in a GR-dependent way in myeloma cells. Co-treatment of Dex with the MR antagonist Spironolactone (Spi) enhances Dex-induced cell killing in (primary, newly diagnosed) GC-sensitive myeloma cells, while in a relapsed, GC-resistant setting Spi alone also induces distinct myeloma cell killing. Spatial fluorescence-based imaging of longitudinal bone biopsies ranging from diagnosis to multiple relapses, confirms the presence of MR, in addition to GR, in these patient samples and confirms the potential of MR as an additional therapeutic target. On a mechanistic level, this GR-MR crosstalk is arising from an endogenous interaction between GR and MR in myeloma cells that is induced by the combination of Dex and Spi, yet, to a lower extent than Dex alone. Unbiased transcriptomics further revealed a distinctive gene expression profile upon Dex and Spi combination, of which a subset of genes can predict prognosis in the CoMMpass patient cohort (N=1143).

Our study demonstrates that GR-MR crosstalk is therapeutically relevant in myeloma and presents a glucocorticoid-based dose-reduction strategy that could diminish glucocorticoid-related side effects in patients.