*2.3. The Value of 18F-FDG PET*/*CT in Therapy Assessment*

Due to its ability in distinguishing between active and inactive lesions, 18F-FDG PET/CT is the best imaging tool for therapy response assessment and is considered the gold standard for treatment monitoring in MM [7] (Figure 2). Several studies have highlighted the role of the modality in the evaluation of the metabolic response to therapy in different stages of the treatment protocol, for example during induction treatment as well as after ASCT [9,12,15,19–23].

**Figure 2.** A 39-years old symptomatic MM patient scheduled for HDT and ASCT, undergoing 18F-FDG PET/CT before and after therapy. Maximum intensity projection (MIP) 18F-FDG PET/CT before therapy (**A**) revealed a mixed pattern of 18F-FDG uptake with intense, diffuse uptake in the axial skeleton and multiple, focal bone marrow lesions for example in the sternum, ribs, humerus, scapula and femur (arrows). Follow-up 18F-FDG PET/CT MIP after high-dose chemotherapy and ASCT (**B**) demonstrated a complete remission of both diffuse bone marrow uptake as well as focal MM lesions.

In a study published by the Little Rock group in 2009 involving 239 previously untreated MM patients, it was shown that complete 18F-FDG suppression in focal lesions and EMD after induction treatment and before ASCT conferred superior OS and PFS, and was identified as an independent favorable prognostic variable [9]. A few years later, the same group published a study on a larger cohort involving 302 MM patients studied with PET/CT on day 7 of induction treatment. The authors showed that the persistence of more than three 18F-FDG-avid lesions imparted inferior OS and PFS, suggesting a therapy change in patients with persistent findings on PET/CT early after induction therapy [19]. Most recently, this team published the findings of a trial in 596 patients examined with PET/CT at different time points (day 7 of induction, end of induction, post transplantation, and at maintenance treatment). They demonstrated that patients achieving complete suppression of 18F-FDG activity in focal lesions following treatment at each studied time point had nonsignificant differences in their PFS and OS values than the patients with no lesions at baseline. Importantly, at each time point, patients with no detectable lesions had a significantly superior outcome compared to patients with at least one detectable lesion at that time point, irrespective of whether they had lesions at baseline [22].

The Bologna group has also highlighted the importance of 18F-FDG PET/CT in assessment of response to therapy in MM in different time points. In particular, they have shown that the persistence of severe 18F-FDG uptake—as reflected by the number of focal lesions, SUVmax and presence of EMD—after thalidomide/dexamethasone induction therapy is an early predictor of the worst long-term clinical outcomes. Moreover, a complete response (CR) on PET/CT after ASCT conferred superior PFS and OS in comparison with persistence of 18F-FDG uptake, while the prognostic value of PET/CT was retained also at the time of relapse, with patients positive on PET/CT having a significantly shorter survival compared to those with a negative PET/CT scan [15]. A few years later, they showed in a group of 282 patients that attainment of PET/CT negativity by 3 months after the last cycle of first-line treatment (chemotherapy, novel agents with or without ASCT) significantly influenced both PFS and OS [21]. PET/CT has also been shown effective in response evaluation of patients undergoing allogeneic stem cell transplantation with persistence of EMD being an independent predictor of poor outcome and, on the other hand, achievement of CR on PET/CT after transplantation being associated with a significantly longer OS [23].

The French group (IMAJEM trial) recently evaluated the role of PET/CT after induction treatment (lenalidomide, bortezomib, and dexamethasone) as well as before lenalidomide maintenance in a group of 134 MM patients. The authors showed that normalization of PET/CT after three cycles of induction therapy was associated with improved PFS, and that normalization before maintenance resulted in longer PFS and OS, in comparison to patients without normalization of their PET findings [12]. They could, moreover, show that change in SUV after three cycles of induction therapy was an independent prognostic factor for PFS, rendering SUV a potentially powerful tool for the prediction of long-term outcome in MM [24].

Other groups have also studied 18F-FDG PET/CT in the treatment response evaluation of MM, using different therapeutic agents and protocols. Most of them have confirmed the benefit of applying the modality in the workup of MM patients [25–27].
