Comparative Molecular Insights and Computational Modeling of Multiple Myeloma and Osteosarcoma.

Multiple myeloma (MM) and osteosarcoma (OS) are two biologically distinct osseous malignancies with similar molecular networks that present translational challenges for their computational modeling. This comparative research analyzes MM and OS biology relevant to in silico approaches, focusing on PI3K-AKT-mTOR signaling, the RANK-RANKL-OPG axis, angiogenic factors (VEGF, TGFs), and immune mediators in MM, alongside the transcription factors (SOX9, RUNX2), signaling pathways (PI3K-AKT-mTOR, NOTCH), immune cell state (TAM2), and interleukins in OS. Based on this pathophysiologic foundation, the review outlines five computational paradigms: (i) mechanistic models; (ii) data-driven/machine learning schemes; (iii) hybrid mechanistic approaches; (iv) digital twins/virtual cohorts, and (v) MIDD/PBPK models for real-world applications. A cross-cancer comparison section summarizes common and distinct biological axes and their computational translation as well as the overlapping features from the bone microenvironment. For both MM and OS, the research assesses strengths, limitations, and data needs of current models, outlining the strategic objectives for next-generation multiscale, AI-enabled models providing a roadmap for tissue engineers, oncology scientists, and translational researchers to design clinically relevant preclinical tests and accelerate safer, more effective strategies for tumor-affected bones. The differences between MM and OS impose distinct biological constraints, so their comparisons are rare. Combining all these features with artificial intelligence capabilities will underpin a promising transition in the development of in silico adaptive and learning models.