In Vivo Quantitative Assessment of Therapeutic Response to Bortezomib Therapy in Disseminated Animal Models of Multiple Myeloma With [18F]FDG and [64Cu]LLP2A PET

Abstract BackgroundMultiple myeloma (MM) is a disease of cancerous plasma cells. Current treatments have improved the survival rate; however, most MM patients relapse. Imaging based timely determination of therapeutic response is critical for improving outcomes in MM patients. Very late antigen-4 (VLA4) is over expressed in MM cells. Here, we evaluated [18F]FDG and VLA4 targeted [64Cu]LLP2A for quantitative PET imaging in MM models of variable VLA4 expression, and following bortezomib therapy.MethodsIn vitro and ex vivo VLA4 expression was evaluated by flow cytometry. Human MM cells, MM.1S-CG and U266-CG (CG: luciferase and green fluorescent protein), were injected intravenously in NOD-SCID gamma mice. Tumor progression was monitored by bioluminescence imaging (BLI). Treatment group received bortezomib (1mg/kg, twice/week) intraperitoneally. All cohorts (treated, untreated and no-tumor) were longitudinally imaged with [64Cu]LLP2A (2-3 MBq; Molar Activity: 44.14±1.40 MBq/nmol) and [18F]FDG (7.4-8.0 MBq) PET respectively.ResultsFlow cytometry confirmed high expression of CD49d in U266 cells (>99%) and moderate expression in MM.1S cells (~52%). BLI showed decrease in total body flux in treated mice. In MM.1S-CG untreated versus treated mice, [64Cu]LLP2A localized with a significantly higher SUVmean in spine (0.58 versus 0.31) and femur (0.72 versus 0.39) at week 4 post tumor inoculation. In U266-CG treated versus untreated mice, there was a 4-time percent [64Cu]LLP2A increase in spine at week 3. Compared to [64Cu]LLP2A, [18F]FDG PET detected treatment related changes at later time points.Conclusion[64Cu]LLP2A is a promising tracer for in vivo assessment of therapeutic response in disseminated models of MM.