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

Abstract

Multiple myeloma (MM) remains an essentially incurable hematologic malignancy. However, new treatment modalities and novel drugs have been introduced and thus additional tools for therapy monitoring are increasingly needed. Therefore, we evaluated the radiotracers 11C-Methionine (paraprotein-biosynthesis) and 18F-FDG (glucose-utilization) for monitoring response to anti-myeloma-therapy and outcome prediction. Influence of proteasome-inhibition on radiotracer-uptake of different MM cell-lines and patient-derived CD138+ plasma cells was analyzed and related to tumor-biology. Mice xenotransplanted with MM.1S tumors underwent MET- and FDG-μPET. Tumor-to-background ratios before and after 24 h, 8 and 15 days treatment with bortezomib were correlated to survival. Treatment reduced both MET and FDG uptake; changes in tracer-retention correlated with a switch from high to low CD138-expression. In xenotransplanted mice, MET-uptake significantly decreased by 30–79% as early as 24 h after bortezomib injection. No significant differences were detected thus early with FDG. This finding was confirmed in patient-derived MM cells. Importantly, early reduction of MET- but not FDG-uptake correlated with improved survival and reduced tumor burden in mice. Our results suggest that MET is superior to FDG in very early assessment of response to anti-myeloma-therapy. Early changes in MET-uptake have predictive potential regarding response and survival. MET-PET holds promise to individualize therapies in MM in future.

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

“…L-[methyl-11 C]methionine ( 11 C-methionine) has been widely used for diagnosis of various cancers, such as brain tumors (14) and multiple myeloma (15). Recently, several experimental studies have suggested the potential of 11 C-methionine PET to detect inflammatory lesions (16,17).…”

Harnessing Preclinical Molecular Imaging to Inform Advances in Personalized Cancer Medicine

“…For example, in recent work by Lückerath et al, treatment of multiple-myeloma xenografts with the proteasome inhibitor bortezomib could attenuate tumor L-[methyl-11 C]-methionine accumulation within 24 h of treatment. The reduced uptake occurred before measurable changes in 18 F-FDG accumulation or tumor proliferation and, importantly, was predictive of overall survival (40). Though this and other examples provide evidence that amino acid PET tracers can be used to rapidly monitor treatment response, the underlying biology connecting how specific therapies affect the accumulation of these probes is unknown.…”

“…To measure the consumption of these amino acids, PET imaging probes based on the structures of amino acids have been developed, including 18 F-fluoroethyl-tryosine, 18 F-fluoro-L-dihydroxy-phenylalanine, and L-[methyl-11 C]-methionine (37)(38)(39). Various preclinical studies suggest that these tracers can be used to monitor early responses to therapies (40)(41)(42). For example, in recent work by Lückerath et al, treatment of multiple-myeloma xenografts with the proteasome inhibitor bortezomib could attenuate tumor L-[methyl-11 C]-methionine accumulation within 24 h of treatment.…”

Hexokinase-2 Expression in 11C-Methionine–Positive, 18F-FDG–Negative Multiple Myeloma

“…In addition, we and others have reported on 18 F-FDG-negative, viable myeloma detectable with PET using 11 C-methionine, a radiolabeled amino acid (14)(15)(16)(17)(18)(19). The aim of this study was to further investigate the underlying biology of metabolically active, so-called 18 F-FDG false-negative MM.…”

“…PETwi th 18 F-FDG as the standard nuclear medicine imaging modality is increasingly used in the diagnosis, prognostication, and management of multiple myeloma (MM) (1)(2)(3)(4)(5)(6)(7). Although sensitivity is generally high, particularly in extramedullary disease (8), subsets of viable malignant plasma cells might not be 18 F-FDG-avid and therefore might be missed by standard PET imaging (4,9). Recently, so-called false-negative 18 F-FDG PET results have been reported in 11% of patients with viable disease detectable on diffusion-weighted MRI and were linked to low hexokinase 2 (HK2) gene expression (10).…”