Targeting Paraprotein Biosynthesis for Non-Invasive Characterization of Myeloma Biology

PURPOSE: Multiple myeloma is a hematologic malignancy originating from clonal plasma cells. Despite effective therapies, outcomes are highly variable suggesting marked disease heterogeneity. The role of functional imaging for therapeutic management of myeloma, such as positron emission tomography with 2-deoxy-2-[(18)F]fluoro-D-glucose ((18)F-FDG-PET), remains to be determined. Although some studies already suggested a prognostic value of (18)F-FDG-PET, more specific tracers addressing hallmarks of myeloma biology, e.g. paraprotein biosynthesis, are needed. This study evaluated the amino acid tracers L-methyl-[(11)C]-methionine ((11)C-MET) and [(18)F]-fluoroethyl-L-tyrosine ((18)F-Fet) for their potential to image myeloma and to characterize tumor heterogeneity. EXPERIMENTAL DESIGN: To study the utility of (11)C-MET, (18)F-Fet and (18)F-FDG for myeloma imaging, time activity curves were compared in various human myeloma cell lines (INA-6, MM1.S, OPM-2) and correlated to cell-biological characteristics, such as marker gene expression and immunoglobulin levels. Likewise, patient-derived CD138(+) plasma cells were characterized regarding uptake and biomedical features. RESULTS: Using myeloma cell lines and patient-derived CD138(+) plasma cells, we found that the relative uptake of (11)C-MET exceeds that of (18)F-FDG 1.5- to 5-fold and that of (18)F-Fet 7- to 20-fold. Importantly, (11)C-MET uptake significantly differed between cell types associated with worse prognosis (e.g. t(4;14) in OPM-2 cells) and indolent ones and correlated with intracellular immunoglobulin light chain and cell surface CD138 and CXCR4 levels. Direct comparison of radiotracer uptake in primary samples further validated the superiority of (11)C-MET. CONCLUSION: These data suggest that (11)C-MET might be a versatile biomarker for myeloma superior to routine functional imaging with (18)F-FDG regarding diagnosis, risk stratification, prognosis and discrimination of tumor subtypes.