*3.3. 11C-Methionine*

11C-Methionine is an aminoacidic PET tracer mainly employed in the diagnosis of central nervous system tumors. The uptake of the tracer primarily reflects its transmembrane transport by the sodium-independent L-transporter into cells. This transport is driven by concentration gradient and is thus influenced by the intracellular metabolism of the amino acid, which in turn reflects proliferation activity [44]. The concept of applying 11C-methionine in MM is mainly based on the knowledge that radiolabeled amino acids show a rapid uptake and metabolic incorporation into newly synthesized immunoglobulins [45]. Moreover, the uptake of 35S-methionine into myeloma

cells is higher as compared with other hematopoietic cells [46]. Despite the limited literature on the topic, 11C-methionine PET/CT concordantly appears to perform better than 18F-FDG in detection of myeloma lesions.

Dankerl et al. were the first to apply this PET tracer for imaging of MM in a group of 19 patients with active disease. The authors detected disseminated multifocal 11C-methionine–positive bone marrow lesions in all patients, except two, a finding suggesting widespread dissemination of MM in the hematopoietic bone marrow. The two patients without extensive disease on 11C-methionine PET showed exclusive EMD and monofocal medullary MM, respectively [46]. The first comparative study was published in 2013 by Nakamoto et al. in 20 patients with MM (n = 15) and plasmacytoma (n = 5) who underwent 18F-FDG PET/CT and 11C-methionine PET/CT scans. On a patient basis, two patients were accurately diagnosed only by 11C-methionine PET/CT, while in the remaining 18 patients consistent results were obtained. However, the potential upgrade of staging or restaging was necessary in 6 of 11 positive patients because more abnormal lesions were demonstrated by 11C-methionine PET/CT. The patient-based sensitivity, specificity and accuracy of 11C-methionine PET/CT for restaging were 89%, 100% and 93%, respectively, while those of 18F-FDG PET/CT were 78%, 100% and 86%, respectively [47]. Two years later, Okasaki et al. studied 64 patients with MM or MGUS (21 previously untreated, 43 restaged after treatment) undergoing PET/CT with the tracers 11C-4 -thiothymidine (11C-4DST), 11C-methionine, and 18F-FDG. The main findings of the study were the following: firstly, the number of equivocal lesions observed using 18F-FDG was larger compared to using 11C- methionine or 11C-4DST both before and after therapy. Secondly, 11C- methionine and 11C-4DST were superior to 18F-FDG in clearly detecting skull lesions because of their low physiological accumulation in the brain [48].

The Würzburg group has also highlighted the superiority of 11C-methionine over 18F-FDG for staging and re-staging of both intra- and extramedullary MM lesions [49,50]. These results were further confirmed in both patient- and lesion-based analyses in the largest so far, dual-center study of 78 patients (4 solitary plasmacytoma, 5 SMM, 69 symptomatic MM) published in 2017 [51]. Moreover, the same group has recently performed the first head-to-head comparison of 11C-methionine and 11C-choline for metabolic imaging of MM in 19 patients with a history of MM (n = 18) or solitary bone plasmacytoma (n = 1). 11C-methionine provided advantages over 11C-choline in terms of higher sensitivity by detecting a higher number of intramedullary lesions in approximately 40% of patients, as well as by achieving higher lesion-to-background contrast [52].

Drawbacks of 11C-Methionine PET are considered to be its increased physiological biodistribution in the liver parenchyma and the bone marrow, potentially reducing the detection rate of MM lesions. Moreover, the 11C labeling of the tracer prevents a relatively massive production and distribution of 11C-Methionine [53].
