C-11-methionine (C-11-MET) is a new positron emission tomography (PET) tracer for the assessment of disease activity in multiple myeloma (MM) patients, with preliminary data suggesting higher sensitivity and specificity than F-18-fluorodeoxyglucose (F-18-FDG). However, the value of tumor burden biomarkers has yet to be investigated. Our goals were to corroborate the superiority of C-11-MET for MM staging and to compare its suitability for the assessment of metabolic tumor burden biomarkers in comparison to F-18-FDG. Twenty-two patients with newly diagnosed, treatment-naive symptomatic MM who had undergone C-11-MET and F-18-FDG PET/CT were evaluated. Standardized uptake values (SUV) were determined and compared with total metabolic tumor volume (TMTV) for both tracers: total lesion glycolysis (TLG) and total lesion C-11-MET uptake (TLMU). PET-derived values were compared to Revised International Staging System (R-ISS), cytogenetic, and serologic MM markers such as M component, beta 2 microglobulin (B2M), serum free light chains (FLC), albumin, and lactate dehydrogenase (LDH). In 11 patients (50%), C-11-MET detected more focal lesions (FL) than FDG (p < 0.01). SUVmax, SUVmean, SUVpeak, TMTV, and TLMU were also significantly higher in C-11-MET than in F-18-FDG (p < 0.05, respectively). C-11-MET PET biomarkers had a better correlation with tumor burden (bone marrow plasma cell infiltration, M component; p < 0.05 versus p = n.s. respectively). This pilot study suggests that C-11-MET PET/CT is a more sensitive marker for the assessment of myeloma tumor burden than F-18-FDG. Its implications for prognosis evaluation need further investigation.