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PET with ¹⁸F-FDG is the standard modality in nuclear medicine for imaging multiple myeloma (MM). However, viable MM as detected by MRI or PET with other metabolic tracers, including ¹¹C-methionine, may be missed—for example, because of low hexokinase 2 (HK2) expression of tumor cells. The aim of this study was to further investigate potential reasons for PET false negativity. A cohort of 15 mainly pretreated patients with relapsed or refractory biopsy-proven, serologically active MM who underwent both ¹⁸F-FDG and ¹¹C-methionine PET/CT was retrospectively analyzed. In 9 of the 15 patients, ¹⁸F-FDG PET was negative in the presence of viable disease. In the remaining 6 patients, both ¹⁸F-FDG and ¹¹C-methionine PET/CT revealed the same number of MM lesions. At immunohistochemistry, ¹⁸F-FDG–negative myeloma did not exhibit significant differences in HK2 or glucose-6 …