Modeling the Bone Marrow Niche in Multiple Myeloma: From 2D Cultures to 3D Systems

Abstract

Multiple myeloma is a hematologic malignancy characterized by the clonal proliferation of plasma cells within the bone marrow. The tumor microenvironment plays a crucial role in multiple myeloma pathogenesis, progression, and drug resistance. Traditional two-dimensional cell culture models have been instrumental in multiple myeloma research. However, they fail to recapitulate the complex in vivo bone marrow microenvironment, leading to limited predictive value for clinical outcomes. Three-dimensional cell culture models emerged as more physiologically relevant systems, offering enhanced insights into multiple myeloma biology. Scaffold-based systems (e.g., hydrogels, collagen, and Matrigel), scaffold-free spheroids, and bioprinted models have been developed to simulate the bone marrow microenvironment, incorporating key components like mesenchymal stromal cells, osteoblasts, endothelial cells, and immune cells. These models enable the functional assessment of cell adhesion-mediated drug resistance, cytokine signaling networks, and hypoxia-induced adaptations, which are often lost in 2D cultures. Moreover, 3D platforms demonstrated improved predictive value in preclinical drug screening, facilitating the evaluation of novel agents and combination therapies in a setting that better mimics the in vivo tumor context. Hence, 3D cultures represent a pivotal step toward bridging the gap between basic myeloma research and translational applications, supporting the development of more effective and patient-specific therapies.

Keywords: 3D culture models; bone marrow microenvironment; drug resistance; molecular mechanisms; multiple myeloma; organoids; spheroids; tumor–stroma interactions.

Figure 1

This figure illustrates how MM cells contribute to immunoparesis by secreting immunosuppressive factors such as TGF-β, IL-6, and PD-L1, which inhibit T and NK cell functions. Additionally, MM cells promote the expansion of regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs), further suppressing immune responses and facilitating disease progression.

Figure 2

Schematic representation of a 3D cell culture model mimicking the bone marrow microenvironment in multiple myeloma. Myeloma cells are embedded within a 3D hydrogel scaffold that simulates the extracellular matrix.

Figure 3

Three-dimensional models replicate the stromal support and immune suppression observed in MM patients. Moreover, they mimic the tumor microenvironment more accurately. While traditional 2D cultures have been central to preclinical drug testing, they often fail to capture the heterogeneity of MM cell populations.