Assessment of Total Lesion Glycolysis and Metabolic Tumor Volume Improve the Clinical Value of Focal Lesion Assessment By FDG PET/CT in Myeloma
Authors: McDonald James E , Kessler Marcus M , Gardner Michael , Buros Amy , Waheed Sarah , Ntambi James , van Rhee Frits , Zangari Maurizio , Heuck Christoph , Petty Nathan , Schinke Carolina , Thanendrarajan Sharmilan , Mitchell Alan , Hoering Antje , Barlogie Bart , Morgan Gareth J , Davies Faith E 
Published: October 2019

Abstract
Introduction: Focal lesions are important anatomical features seen in the bone marrow of multiple myeloma patients that contribute to drug resistance and disease relapse. Fluroine-18 fluorodexyglucose positron emission tomography with CT attenuation correction (18F-FDG PET/CT) is useful in the detection and enumeration of focal lesions and in semi-quantitative characterization of metabolic activity by calculation of glucose uptake reported as a standardized uptake value (SUV). Lesion count and SUV are predictors of outcome. Two additional variables, total lesion glycolysis (TLG) and metabolic tumor volume (MTV) can also be assessed and have the potential to improve the value of this approach. The purpose of this study was to determine whether TLG and MTV can predict progression free survival (PFS) and overall survival (OS), and to determine whether they are superior to traditional assessment methods.
Materials and Methods: 191 patients underwent whole body PET/CT in the Total Therapy 3A trial and were evaluated using 3 dimensional region of interest analysis with TLG, MTV, and standard measurement parameters derived for all focal lesions with peak SUV above the background red marrow signal. Survival analysis was performed using Kaplan-Meier and log-rank tests. Univariate and multivariate analyses were performed using Cox proportional hazards regression.
Results: Baseline characteristics show that 43/191 patients (23%) had no detectable lesions by PET. 1-3 lesions were present in 55/191 (28%) of patients and over 3 lesions in 93/191 (49%) of patients. A baseline TLG >205g was seen in 18% (34/191) of patients, with a TLG >620g being seen in 7% (14/191). A baseline MTV >210cm3 was seen in 7% (14/191). The distribution of patients with high TLG scores between molecular subgroups was not even with patients in the PR, MF and HY subgroups having higher scores.
The 3 year PFS and OS for patients with no PET focal lesions was 83.1% and 88.3%, for patients with 1-3 lesions was 83.9%, and 85.5%, and for patients with >3 lesions 59.6% and 63.5% (p<0.0001). The 3 year PFS and OS for patients with a baseline TLG of less than 205g was 82.8% and 86.0%, compared to patients with a baseline TLG between 205g and 620g of 75.0% and 80.0%, and to patients with a baseline TLG of greater than 620g of 14.3% and 21.4% (p<0.0001). A similar pattern was seen for complete response (CR) duration. The MTV also had prognostic importance with 3 year PFS and OS for patients with a baseline MTV of less than 210cm3 at 81.4% and 84.7%, compared to patients with a baseline MTV of greater than 210cm3 of 21.4% and 28.6% (p<0.0001). Pearson Correlation Coefficient (r) between MTV and TLG was 0.94232 (p-value <.0001).
On univariate analysis baseline PET/CT with >3 focal lesions (HR 1.92, 95% CI 1.22-3.04, p=0.004), TLG >205g (HR 2.99, 95% CI 1.83-4.88, p<0.0001), baseline TLG > 620g (HR 6.90, 95% CI 3.67-12.97, p<0.0001), and MTV >210cm3 (HR 6.20, 95% CI 3.33-11.54, p<0.0001) were statistically significant in predicting OS and PFS. In multivariate analysis baseline TLG>620g retained prognostic significance for predicting PFS and OS together with high B2M, LDH and GEP based proliferation. Importantly baseline TLG >620g and baseline MTV >210cm3 were statistically more predictive of poor PFS and OS than baseline PET with >3 focal lesions in both univariate and multivariate models.
Conclusion : TLG assessment is superior to counting the number of focal lesions. It is the optimum method for evaluating the extent of focal lesions and to predict clinical outcome. As this measurement can be standardized using FDA approved software, it should be utilized clinically and in trials going forward.

Disclosures
McDonald: University of Arkansas for Medical Sciences: Employment. Waheed:University of Arkansas for Medical Sciences: Employment. Ntambi:University of Arkansas for Medical Sciences: Employment. van Rhee:University of Arkansa for Medical Sciences: Employment. Zangari:University of Arkansas for Medical Sciences: Employment; Novartis: Research Funding; Onyx: Research Funding; Millennium: Research Funding. Heuck:Janssen: Other: Advisory Board; Millenium: Other: Advisory Board; Foundation Medicine: Honoraria; Celgene: Consultancy; University of Arkansas for Medical Sciences: Employment. Petty:University of Arkansas for Medical Sciences: Employment. Schinke:University of Arkansas for Medical Sciences: Employment. Thanendrarajan:University of Arkansas for Medical Sciences: Employment. Mitchell:Cancer Research and Biostatistics: Employment. Hoering:Cancer Research and Biostatistics: Employment. Barlogie:International Workshop on Waldenström's Macroglobulinemia: Other: Travel Stipend; ComtecMed- World Congress on Controversies in Hematology: Other: Travel Stipend; European School of Haematology- International Conference on Multiple Myeloma: Other: Travel Stipend; Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Myeloma Health, LLC: Patents & Royalties: Co-inventor of patents and patent applications related to use of GEP in cancer medicine licensed to Myeloma Health, LLC; Dana Farber Cancer Institute: Other: Travel Stipend; Multiple Myeloma Research Foundation: Other: Travel Stipend. Morgan:Weisman Institute: Honoraria; CancerNet: Honoraria; MMRF: Honoraria; University of Arkansas for Medical Sciences: Employment; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda-Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Davies:Array-Biopharma: Membership on an entity's Board of Directors or advisory committees; Takeda-Millennium: Membership on an entity's Board of Directors or advisory committees; University of Arkansas for Medical Sciences: Employment; Onyx-Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.