Targeting Paraprotein Biosynthesis for Non-Invasive Characterization of Myeloma Biology

Abstract

PurposeMultiple 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-[18F]fluoro-D-glucose (18F-FDG-PET), remains to be determined. Although some studies already suggested a prognostic value of 18F-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-[11C]-methionine (11C-MET) and [18F]-fluoroethyl-L-tyrosine (18F-Fet) for their potential to image myeloma and to characterize tumor heterogeneity. Experimental DesignTo study the utility of 11C-MET, 18F-Fet and 18F-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.ResultsUsing myeloma cell lines and patient-derived CD138+ plasma cells, we found that the relative uptake of 11C-MET exceeds that of 18F-FDG 1.5- to 5-fold and that of 18F-Fet 7- to 20-fold. Importantly, 11C-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 11C-MET.ConclusionThese data suggest that 11C-MET might be a versatile biomarker for myeloma superior to routine functional imaging with 18F-FDG regarding diagnosis, risk stratification, prognosis and discrimination of tumor subtypes.

11C-Methionine-PET: A novel and sensitive tool for monitoring of early response to treatment in multiple myeloma

“…48 h after drug addition, the capacity to store MET or FDG, respectively, was assessed in uptake experiments. In agreement with our previously published data ( 14 ), MET uptake in untreated control cells was higher than that of FDG. Comparing untreated with treated cells, a significant reduction in tracer-retention could be observed for all treatments at any time points analyzed with remaining MET-uptake slightly higher than that of FDG (Figure 1 ).…”

“…We previously demonstrated a significantly higher retention of the radiolabeled amino acid L -methyl-[ 11 C]-methionine ( 11 C-MET) and an association of MET-uptake with Ig light chain levels in biologically diverse myeloma cell lines and patient-derived CD138 + -plasma cells ( 14 ). This study aimed at the in vivo validation of MET as radiotracer and biomarker for MM.…”

11C-Methionine PET of Myocardial Inflammation in a Rat Model of Experimental Autoimmune Myocarditis

“…Radiochemistry 14 C-methionine was purchased from PerkinElmer. 11 C-methionine and 18 F-FDG were produced in-house with a 16-MeV Cyclotron (PETtrace 6; GE Healthcare), as described previously (21). Briefly, 18 F-FDG was produced on a FASTlab synthesizer (GE Healthcare), and 11 C-methionine was synthesized on a TRACERlab FX-C Pro module (GE Healthcare) by an online 11 C-methylation of L-homocysteine.…”

New Approaches to Molecular Imaging of Multiple Myeloma

“…11 C-methionine is a potential amino acid PET tracer for MM (26). Luckerath et al demonstrated in myeloma cells a significantly higher uptake of radiolabeled methionine than of 18 F-FDG, and there was differential methionine uptake in myeloma cell lines (with high uptake in cell lines of worse prognosis) (27). L-type amino-acid transporter 1 (LAT-1) mediates sodium-independent cellular transport of amino acids for protein synthesis and other metabolic pathways, and high levels of LAT-1 correlate with proliferating cancers.…”