Conventionally-Defined and PET/CT-Defined Complete Response (CR) to Novel Agent-Based Induction Therapy and Autologous Stem-Cell Transplantation (ASCT) In Multiple Myeloma (MM): A Prospective Study of Clinical and Prognostic Implications
Authors: Zamagni Elena , Nanni Cristina , Patriarca Francesca , Pezzi Annalisa , Zannetti Beatrice Anna , Tacchetti Paola , Englaro Emanuela , Perrone Giulia , Buttignol Silvia , Brioli Annamaria , Pantani Lucia , Carobolante Francesca , Baccarani Michele , Fanti Stefano , Cavo Michele 
Published: October 2019

Abstract
Abstract 826
Incorporation of novel agents into ASCT allowed the achievement of unprecedented high rates of CR in young MM patients, a gain which translated into extended PFS and OS. As a consequence, interest in the evaluation of the depth of CR has progressively grown. More sensitive tools, such as multiparametric flow cytometry or molecular biology, led to the demonstration of a correlation between the depth of CR and prognosis, but failed to identify the persistence of residual disease outside of the bone marrow level. 18 F-FDG PET/CT is a careful technique to detect with high sensitivity and specificity the presence of active bone lesions and/or bone marrow involvement in newly diagnosed and previously treated MM.
We prospectively analysed the prognostic significance of FDG-PET/CT at diagnosis, after induction therapy and ASCT in an homogeneous population of 192 patients with newly diagnosed MM, followed for a median of 43 months. By study design, all patients were studied with FDG-PET/CT at baseline, after induction treatment, after 3 months from ASCT (single or double), once a year during the maintenance/follow-up phase and at time of relapse. Bone marrow involvement was described as negative, diffuse or focal. The number of focal lesions (FLs), as well as size and associated standardized uptake values (SUV) were recorded. Extra-medullary disease (EMD), if present, was described by location, size, number and SUV.
Twenty four percent of the patients had a negative PET/CT scan at diagnosis. Among PET/CT-positive patients, 44% showed ≥3 FLs, 46% had SUV values >4.2 and in 6% EMD could be detected. These 3 variables adversely affected 4-year estimates of PFS and OS. In particular, both EMD and severe FDG uptake were significantly associated with shorter PFS and OS.
Thirty seven percent of the patients were PET/CT-negative after induction. A strong correlation between conventional response and SUV max reduction was evident, the mean SUV value of patients achieving CR being significantly lower in comparison with that of patients reaching very good partial response (VGPR) or partial response (mean: 1.4 vs 3, respectively) (Cuzick's trend test, P= 0.016). Persistence of severe FDG uptake (SUV max still >4.2) after induction predicted for shorter PFS at 4 years (P= 0.004).
PET/CT negativity (PET-CR) was observed in 65% of patients after 3 months from ASCT(s). A close relationship between PET/CT negativity and response to ASCT was evident, since 95% of patients with a negative PET/CT had achieved at least a VGPR (P= 0.003). Moreover, a correlation between conventional response and SUV max reduction was evident after ASCT as well (mean: 0.8 vs 1.8, respectively) (Cuzick's trend test, P= 0.001). PET-CR after ASCT conferred superior PFS and OS in comparison with persistence of FDG uptake. In particular, the 4-year estimates of PFS and OS for PET-CR patients were 66% and 89%, respectively, as compared with 45% and 65% for positive patients (P=0.02 both for PFS and OS). Notably, 23% of patients achieving CR according to conventional criteria still had positive PET/CT scans and their 4-year estimate of PFS was 30%, as compared with 61% for negative patients (P=0.02).
After ASCT, patients were followed with evaluation of M protein every 3 months and of PET/CT once a year. In 44% of those who had a conventionally-defined relapse or progression, the mean time to relapse/progression was 27.6 months for PET-negative patients as compared with 18 months for positive patients (P=0.05). In PET-positive patients, the SUV max was inversely correlated to the time to relapse (correlation coefficient −0.7, P= 0.003).
In multivariate analysis, both severe PET/CT involvement at diagnosis (SUV >4.2 and/or EMD) and persistence of FDG uptake after ASCT were independent predictors of worst PFS (SUV >4.2= HR: 2.0, 95%CI: 1.13–3.72; EMD= HR: 15.0, 4.0–55.8; FDG uptake after ASCT= HR: 2.12, 1.19–3.77) and OS (EMD= HR: 6.99, 2.28–21.46; FDG uptake after ASCT= HR: 3.57, 1.03–12.39).
In conclusion, PET-defined CR was linked to conventionally-defined CR and was an independent prognostic factor in MM patients receiving up-front novel agent-based induction therapy and ASCT. PET/CT contributed to a more careful definition of CR, in particular after ASCT, and could be usefully incorporated into the algorithm to evaluate the depth of response in young MM patients.

Disclosures:
No relevant conflicts of interest to declare.