Purpose <p>To evaluate the prognostic utility of a novel quantitative imaging metric, whole-body metabolic burden (WB-MB), derived from [¹¹C]-Methionine PET/CT, in patients with multiple myeloma (MM), and to assess its correlation with clinical biomarkers and survival outcomes.</p> Methods <p>In this prospective, single-center study, 34 patients with biopsy-confirmed MM underwent whole-body [¹¹C]-Methionine PET/CT for staging or restaging. WB-MB was calculated using a semi-quantitative method incorporating both the extent and intensity of methionine uptake across 12 anatomical regions. Liver- and aorta-normalized WB-MB ratios (WB-MB/liver and WB-MB/aorta) were also computed. Correlations with laboratory biomarkers were analyzed using regression models, and prognostic performance was assessed through Kaplan-Meier survival analysis and hazard ratios for progression-free survival (PFS) and overall survival (OS).</p> Results <p>WB-MB showed significant inverse correlation with hemoglobin and positive correlations with LDH, beta-2 microglobulin (B2M), and serum kappa free light chain levels. No significant associations were observed with platelet count, WBC, or lambda light chains. WB-MB, WB-MB/liver, and WB-MB/aorta were all significantly associated with OS and PFS (<i>p</i> &lt; 0.05), while maximum SUVmean was not. A WB-MB threshold of 164.79 was identified as predictive for PFS. Notably, no deaths occurred in patients with WB-MB &lt; 101 during follow-up.</p> Conclusion <p>WB-MB scoring with [¹¹C]-Methionine PET/CT is a promising, reproducible imaging biomarker for evaluating disease burden and prognosis in MM. It correlates with key laboratory markers and outperforms static SUV-based metrics in predicting survival outcomes. Further multicenter studies are needed to validate these findings and explore integration into therapeutic decision-making.</p>