Malignant plasma cells accumulating in the bone marrow trigger the development of lytic bone lesions in 80% of patients suffering from multiple myeloma. These lesions often lead to fractures and are notoriously difficult to treat surgically. Myeloma cells that remain viable after treatment within the protective milieu of these bone defects continue to disrupt normal bone metabolism, thereby preventing proper healing. Such residual activity likely contributes to the frequent disease recurrence observed even in cases where minimal residual disease (MRD) is undetectable. Biomaterials intended for direct application at the site of lesions could provide mechanical reinforcement, facilitate bone repair, and enable the local administration of anticancer drugs at high concentrations that would be intolerable if delivered systemically, helping to overcome acquired resistance. Silica-collagen xerogels (sicXer) together with bortezomib-releasing variants (boXer) were formulated for targeted intervention against osteolytic bone involvement and persistent MRD. Release profiles of bortezomib were determined in vitro as well as directly from tissue sections in vivo by means of ultrahigh-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS). Effects on bone-forming processes were studied in vitro by quantifying changes in osteoclast and osteoblast populations and their respective activities. In vivo evaluation involved applying the materials to drill-hole defects created in rat bones and in the 5T33-myeloma mouse model, with subsequent analysis performed via immunohistochemistry, UPLC-MS/MS, µCT, and ToF-SIMS. The materials’ capacity to eliminate myeloma cells was tested in 10 human myeloma cell lines (HMCLs) and 8 primary patient-derived myeloma samples, 4 of which originated from individuals who had not responded to systemic bortezomib therapy. Both sicXer and boXer provided initial structural stability equivalent to that of trabecular bone. Degradation rates were adjustable by varying granule dimensions and fabrication protocols, as reflected in the liberation patterns of silica, collagen, and bortezomib into the culture environment. In vitro testing demonstrated reduced osteoclast function without compromising osteoblast differentiation or activity. The resulting promotion of net bone deposition while preserving essential remodeling mechanisms was confirmed in a rat bone defect model, in which defects treated with boXer showed markedly superior bone formation compared with untreated controls. In addition, both materials induced apoptosis in myeloma cells from all HMCLs and all primary samples examined. Application in the 5T33-myeloma mouse model confirmed that the materials effectively stabilized the created defects and locally restrained the proliferation of malignant plasma cells. By simultaneously providing mechanical stability to fragile bone lesions, stimulating regenerative healing, and exerting potent anti-tumor effects, sicXer and boXer represent promising candidates for clinical trials within multimodal treatment frameworks combining systemic and localized approaches for multiple myeloma and certain non-malignant bone disorders.
