Purpose: Both 18F-FDG PET/CT and clonal circulating plasma cell (CPC) quantification are emerging tools for multiple myeloma (MM) prognostication that have been validated in recent studies. This study investigated the value of PET/CT coupled with CPC quantification for MM prognostication that may contribute to future risk-adapted treatment. Methods: We retrospectively analysed the prognostic relevance of a combination of pretreatment PET/CT findings and CPC levels in 163 consecutive patients with newly diagnosed, symptomatic MM receiving novel agents during induction therapies. Results: High-risk PET/CT findings and elevated CPC levels were defined by the presence of >3 focal lesions with or without extramedullary disease and CPCs ≥0.10% of the total mononuclear cells evaluated, respectively. Subsequently, patients were divided into three groups: PET-CPC stage I included patients with no high-risk PET/CT findings and low CPC levels; stage III included patients with high-risk PET/CT findings and high CPC levels; and stage II included the remaining patients. The three groups of patients differed significantly in terms of both progression-free survival (PFS) and overall survival (OS) (median PFS: not reached [NR] and 36.4 and 15.9 months, and median OS: NR, NR, and 40.4 months for stages I, II, and III, respectively; P < 0.001 for both PFS and OS). This system discriminated both PFS and OS even among younger (age < 75 years) or older (≥ 75 years) patients, patients with Revised International Staging System stage II or III, and patients with or without high-risk cytogenetic characteristics. In the multivariate analysis, the PET-CPC staging system remained prognostic for both PFS and OS. Conclusions: The PET-CPC staging system predicted survival outcomes independently of established risk factors in patients with newly diagnosed MM. Pretreatment 18F-FDG PET/CT assessment combined with CPC quantification may improve the prognostication of MM and facilitate the development of novel risk-adapted approaches for MM. [ABSTRACT FROM AUTHOR]