title: Targeting paraprotein biosynthesis for non-invasive characterization of myeloma biology.
abstract: OBJECTIVE
  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-[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.
  
  
  METHODS
  To 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.
  
  
  RESULTS
  Using 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.
  
  
  CONCLUSIONS
  These 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.
authors.affiliation: University Wuerzburg, Medical Center, Department of Nuclear Medicine, Wuerzburg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Lückerath
authors.affiliation: University Wuerzburg, Medical Center, Department of Nuclear Medicine, Wuerzburg, Germany.
authors.forename: Constantin
authors.initials: C
authors.lastname: Lapa
authors.affiliation: University Wuerzburg, Medical Center, Department of Nuclear Medicine, Wuerzburg, Germany.
authors.forename: Annika
authors.initials: A
authors.lastname: Spahmann
authors.affiliation: University Wuerzburg, Medical Center, Department of Nuclear Medicine, Wuerzburg, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Jörg
authors.affiliation: University Wuerzburg, Medical Center, Department of Nuclear Medicine, Wuerzburg, Germany.
authors.forename: Samuel
authors.initials: S
authors.lastname: Samnick
authors.affiliation: University Wuerzburg, Institut of Pathology, Wuerzburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Rosenwald
authors.affiliation: University Wuerzburg, Medical Center, Department of Hematology and Oncology, Wuerzburg, Germany.
authors.forename: Herrmann
authors.initials: H
authors.lastname: Einsele
authors.affiliation: University Wuerzburg, Medical Center, Department of Hematology and Oncology, Wuerzburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Knop
authors.affiliation: University Wuerzburg, Medical Center, Department of Nuclear Medicine, Wuerzburg, Germany.
authors.forename: Andreas K
authors.initials: AK
authors.lastname: Buck
mesh_terms: D045744:Cell Line, Tumor; D005434:Flow Cytometry; D019788:Fluorodeoxyglucose F18 / Q000138:chemical synthesis; D006801:Humans; D008715:Methionine / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D009101:Multiple Myeloma / Q000175:diagnosis* / Q000378:metabolism*; D010266:Paraproteins / Q000096:biosynthesis*; D049268:Positron-Emission Tomography / Q000379:methods; D011849:Radioactive Tracers; D018709:Statistics, Nonparametric; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis
chemical_list: D010266:Paraproteins; D011849:Radioactive Tracers; D019788:Fluorodeoxyglucose F18; C545932:(18F)fluoroethyltyrosine; D014443:Tyrosine; D008715:Methionine; C038344:methionine methyl ester