Assessment of uptake of FDG in the whole bone marrow of multiple myeloma and smoldering multiple myeloma patients through a novel method of PET/CT quantification: comparison with a control group

Objectives: The standardization of FDG PET/CT scans interpretation in myeloma patients in clinical practice is still debatable and the recent proposed alternative methods of quantification still suffer from some deficiencies. According to the International Myeloma Working Group (IMWG), the major limitation of FDG PET/CT for using in multiple myeloma (MM) patients is lack of reproducible methods of quantification, which not only hampers the routine assessment of PET images in the patients, but also makes it difficult to harmonize the results across different centers. We aimed to assess a novel method of PET/CT quantification to evaluate the uptake of FDG in the whole bone marrow (WBM) of MM and smoldering multiple myeloma (SMM) patients and to compare the results with a matched control group. We also evaluated the correlations between WBM FDG uptake and prognostic factors and survival data in MM patients. We used delayed PET scans in this study since it was showed previously that FDG uptake increases significantly in malignant lesions from early to delayed scans and due to the diffuse infiltration of the bone marrow in MM, we hypothesized that our global approach assessment may be more practical for the assessment of delayed scans in the myeloma patients.

Methods: Delayed (3 hours) pre-treatment FDG-PET/CT scans of 42 MM patients (median age: 66.5 years, range 50-87), 12 SMM patients (median age: 63, range 51-80) and 27 control subjects (median age: 63 years, range 50-75) were collected. The protocol was approved by the Danish Ethics Committee (S-20120209), the Danish Data Protection Agency (2008-58-0035) and registered at clinicaltrials.gov (NCT02187731 and NCT01724749). The age and gender differences between the three groups were statistically insignificant. After co-registration of the PET and the CT data, a threshold algorithm was applied based on the bone Hounsfield scale in CT (OsiriX software; PIXMEO, Bernex, Switzerland). This method allows us to segment and quantify the FDG uptake in the entire bone marrow of the subjects, which was expressed as global mean standardized uptake value (GSUVmean). The correlations between GSUVmean and prognostic factors and survival data in MM patients were assessed. All data was replicated by two independent observers to determine the inter-observer variability.

Results: MM patients had a higher GSUVmean in comparison to both SMM patients and control subjects (1.7± 0.6, 1.2± 0.2 and 1.1± 0.1, respectively; ANOVA p< 0.001). A statistically significant difference was observed between the GSUVmean in MM and SMM patients (Independent t-test p-value < 0.001) and also between SMM patients and control subjects (Independent t-test p-value= 0.05). GSUVmean showed a significant correlation with β₂-microglobulin in MM patients (r: 0.4, p= 0.003). GSUVmean higher than 1.59 was associated with inferior progression-free survival (PFS) (median: 24.07 vs 47.3; log-rank p= 0.01). In multivariate Cox regression analysis, a higher GSUVmean was a significant prognostic factor for PFS (HR: 4.4, 95%, p= 0.01). High level of agreement between two measurements was observed for all of the subjects, with an estimated mean difference of .01 and Bland-Altman Limits of Agreement of - 0.5 and 0.5.

Conclusions: GSUVmean showed the difference between the WBM uptake of FDG in MM, SMM and control groups with a high level of agreement between the two observers. A higher GSUVmean was a significant prognostic factor for PFS.