Three-dimensional models of the multiple myeloma bone microenvironment: from disease mechanisms to translational applications

Multiple myeloma (MM) is a hematological malignancy strongly dependent on the bone microenvironment (BME), a dynamic niche that supports malignant plasma cell (PC) survival, immune escape, bone disease, and drug resistance. Conventional two-dimensional (2D) cultures and animal models have provided important insights into MM biology, but they only partially reproduce the spatial organization, cellular complexity, extracellular matrix composition, mechanical cues, and soluble gradients of the human bone marrow (BM). Three-dimensional (3D) models have therefore emerged as complementary experimental platforms to investigate microenvironment-dependent mechanisms of disease progression, therapeutic resistance, and patient-specific drug response. In this review, we provide a critical assessment of both bone-specific and BM like 3D models of MM, with a particular focus on their ability to recapitulate key functional aspects of tumor-bone microenvironment interactions and myeloma bone disease. We differentiate systems that mainly mimic the general BM niche from those that incorporate bone-relevant features, and we evaluate the available platforms based on the biological mechanisms they reproduce, the functional readouts they enable, and their suitability for distinct experimental and therapeutic purposes. We also highlight their relevance for therapeutic target validation and drug testing using patient samples. Finally, we discuss how the integration of patient-derived cells, spatial technologies, and artificial intelligence (AI) may enhance the interpretability and translational value of 3D MM models, ultimately supporting the development of more microenvironment-driven therapeutic approaches.