3D-Tissue Engineered Bone Marrow (3DTEBM) Culture Predicts Clinical Efficacy of Drugs Better Than Regular Culture Systems in Multiple Myeloma

Purpose: The second most common hematological malignancy, Multiple Myeloma (MM), continues to be a fatal disease even with the development of novel therapies. Despite promising preclinical data in standard two-dimensional (2D) models, most phase 3 clinical oncology trials fail. This highlights the potential discrepancy between the current in vitro models, the pathophysiology of the disease in the patients, and the urgent need for better in vitro models for drug development and improved prediction of efficacy in patients. We have previously developed a 3D-Tissue Engineered Bone Marrow culture (3DTEBM), which showed superior properties for proliferation of primary MM cells over weeks in culture, derived from the BM of MM patients, including MM cells, other cells in the BM microenvironment, and BM supernatant. In this study, we found that the 3DTEBM model provides better prediction of clinical efficacy as compared to regular tissue cultures.

Methods: We performed a literature search that examined the efficacious concentrations of drugs used for the treatment of MM, in vitro and in patients. We defended the efficacious clinical as the steady state plasma drug concentration (Css), and the efficacious in vitro concentration as the half maximal inhibitory concentration (IC50) of 11 drugs used in MM (Carfilzomib, Bortezomib, Ixazomib, Panobinostat, Lenalidomide, Pomalidomide, Dexamethasone, Etoposide, Doxorubicin, Cytoxan, and Melphalan). The Css and IC50 of each drug were calculated from the average of multiple papers (at least 3 values for each), and the correlation between the IC50 and the Css (both obtained from the literature) was tested.

Moreover, we tested the efficacy of the drugs in the 3DTEBM by treating MM cells with increasing concentrations of the different drugs (unique range for each drug); thus, the IC50 for each drug in the 3DTEBM was established. Correlation between the IC50 (obtained experimentally in the 3DTEBM) and the Css (obtained from the literature) was then tested.

Results: There was no correlation between the in vitro IC50 values from the classic 2D culture systems (based on literature) and the efficacious clinical concentrations (Css), with a correlation coefficient of R2=0.007. In contrast, the in vitro IC50 values obtained experimentally in the 3DTEBM directly correlated with the efficacious clinical concentrations (Css), with a correlation coefficient of R2=0.979.

Conclusions: The 3DTEBM model predicts clinical efficacy of drugs better than regular culture systems in multiple myeloma, and can provide a more pathophysiologically relevant model for preclinical drug development and development of clinical personalized medicine treatment plans in multiple myeloma.