PET-CT in MM: a new definition of CR

In this issue of Blood, Zamagni et al report that PET/CT involvement after thalidomide-dexamethasone induction and subsequent tandem autologous stem cell transplantation (ASCT), is a reliable predictor of prognosis in patients with de novo symptomatic multiple myeloma (MM).¹ 

Importantly, multivariate analysis revealed that patients with persistence of 18F-fluorodeoxyglucose (FDG) uptake 3 months after ASCT had significantly worse progression-free survival (PFS) and overall survival (OS). The prognostic impact of this parameter was stronger than that of cytogenetic abnormalities. These data strengthen those already reported by the group from Little Rock that showed that complete FDG suppression after induction (before transplantation) conferred superior OS and event-free survival, regardless of gene array–defined risk, in the context of total therapy 3.²  In both studies, the presence of more than 3 FDG-avid focal lesions at baseline was an independent parameter associated with inferior PFS.

The use of novel agents has improved the quality of response, especially in the high-dose therapy setting, and the definition of complete response (CR) has evolved over the past decade. An updated definition of stringent CR in the International Myeloma Working Group (IMWG) criteria requiring negative clonal cells by multiparametric flow cytometry was recently approved by a consensus panel of international experts. In addition, a new definition of molecular CR, which requires the criteria for stringent CR to be met plus negative allele-specific oligonucleotide polymerase chain reaction (ASO-PCR) was added.³  These 2 new categories of CR are associated with improved outcome.^4,5  After extensive discussions, the panel agreed that PET-CT findings should not be formally incorporated into the response criteria for the assessment of the depth of response, but additional single-center studies to further investigate the methodology were encouraged.³ 

The data presented by Zamagni et al suggest that PET negativity after ASCT could in the future be incorporated into the criteria for the definition of CR. Their important findings also raise several questions. First, with the wide availability of this imaging technique, will PET-CT will replace PCR or flow cytometry, which are more cumbersome and difficult, in the evaluation of the depth/quality of response? Second, could PET-CT replace magnetic resonance imaging (MRI), which is currently a routine method of assessment of symptomatic MM, or full-body x-ray, which frequently underestimates the extent of skeletal lesions in disease evaluation?⁶  In contrast to traditional imaging techniques, another advantage of PET-CT is its ability to detect extramedullary disease, which is a sign of spread of the disease outside the medullary cavity of the bone and is an important adverse prognostic factor.⁷  Third, the use of PET-CT in non-Hodgkin lymphoma and Hodgkin disease, in which FDG suppression after treatment is a reliable predictor of prognosis, is well established. Posttherapeutic PET evaluation according to the new International Working Group Guidelines on Lymphoma is now routinely recommended.⁸  Therefore, one could speculate that persistent focal lesions on PET-CT in MM after high-dose therapy may indicate the presence of residual clonal cells, which increases the risk of relapse. This could impact our future therapeutic strategies, leading to the systematic administration of consolidation therapy in this high-risk group of patients, who represent 35% of the cases in Zamagni and colleagues' trial.

Despite numerous potential advantages, PET-CT is not yet the established gold standard for disease evaluation at diagnosis or at completion of therapy. Concerns with the serial use of this technique exist due to the heterogeneity of visual criteria and the lack of consistency inthe interpretation of results. Standardization of disease definitions for PET-CT imaging is needed to improve the specificity and positive predictive value of this tool. Future prospective studies aimed at comparing PET-CT with MRI, flow cytometry, and/or PCR are still needed.