Patient-derived mesenchymal stromal cells establish an IL-6 axis that marks progression from smouldering to active multiple myeloma.

IL-6 signalling in the bone marrow (BM) is compartmentalised. Different cell populations within the BM niche contribute distinct components of the IL-6 signalling network, yet how their roles change during myeloma progression has remained unclear. We examined how the respective contributions of mesenchymal stromal cells (MSCs) and primary multiple myeloma (MM) cells to the IL-6 signalling machinery change during disease progression. MSCs were identified as the principal source of IL-6, whereas MM cells secreted minimal IL-6 but were the primary source of soluble IL-6 receptor (sIL-6R). This functional interplay, with MSCs supplying the ligand and MM cells providing the soluble receptor, establishes a paracrine IL-6 trans-signalling axis. The contribution of MM cells to this axis increases significantly with disease stage: cells from patients with active MM secreted substantially greater quantities of sIL-6R than those from patients with smouldering disease, identifying sIL-6R as a marker of biologically active disease. This increase is mirrored by higher basal IL-6 secretion from MSCs in advanced disease, demonstrating augmentation of the IL-6 signalling pathway as disease progresses. Using Hyper-IL-6 and sgp130, we demonstrated that trans-signalling through gp130 is the dominant mechanism by which stromal-derived IL-6 protects MM cells from treatment-induced apoptosis, independent of membrane-bound IL-6R expression. Therefore, targeted inhibition of IL-6 trans-signalling with sgp130 could be used to suppress pathogenic effects in MM while preserving beneficial classical IL-6 signalling, offering a more precise and potentially safer alternative to total IL-6/IL-6R blockade. As disease progression increases trans-signalling through higher sIL-6R expression, early intervention in smouldering myeloma, before pathway amplification, may represent a more effective therapeutic strategy.