*2.4. The Value of 18F-FDG PET*/*CT in Minimal Residual Disease (MRD) Diagnostics*

A field that is constantly drawing more attention in MM therapy assessment is that of standardization and optimization of minimal residual disease (MRD) detection, which is becoming standard diagnostic care. This is driven by the need to improve the definition of disease remission due to the unprecedented rates of CR brought in recent years by the incorporation of novel agents in the treatment of MM patients. It is clear that in MM there is a direct correlation between the depth of response and prolonged survival rates [28]. At present, MRD is detected within the bone marrow, either by multicolor flow cytometry (MFC) or by next generation sequencing technologies [29].

Data on the potential role of 18F-FDG PET/CT in evaluation of the depth of response—beyond the level of conventionally defined CR- are limited but growing. Zamagni et al. retrospectively analyzed 282 MM patients who were evaluated at baseline and during posttreatment follow-up with serial PET/CT scans. They found that the modality could provide a more accurate definition of CR, allowing to stratify patients in conventional CR after up-front therapy into different prognostic subgroups, according to the persistence or absence of 18F-FDG metabolic activity. In particular, the achievement of PET-negativity after treatment was an independent predictor of prolonged PFS and OS for patients with conventionally defined CR [21]. Furthermore, the complementary role of PET/CT and MRD diagnostics with MFC in predicting patient outcome has been supported by some studies. A subanalysis of the IMAJEM trial in 86 patients before maintenance evaluated for both PET/CT and MRD, assessed by MFC, revealed a higher PFS for the group of patients with both a normalized PET/CT and a negative MRD versus patients with either PET positivity and/or MRD positivity before maintenance [12]. In line with these results, the Little Rock group showed in 83 MM patients in CR with available MRD and functional imaging data (in this case PET/CT and/or diffusion weighted MRI) that double-positive and double-negative features defined groups with dismal and excellent PFS, respectively [30]. Most recently, a retrospective study analyzed the prediction of outcome with the combination of 18F-FDG

PET/CT and MRD, assessed by MFC, in 103 patients with newly diagnosed MM. Apart from confirming the benefit—in terms of PFS—linked to the achievement of negativity by MFC and 18F-FDG PET/CT individually, the authors showed that the combination of negativity by both techniques conferred significantly higher PFS than each technique alone, also supporting the potential complementarity between PET/CT and MFC in MRD detection [31].
