Treatment to suppression of focal lesions on positron emission tomography-computed tomography is a therapeutic goal in newly diagnosed multiple myeloma

Faith E Davies, Adam Rosenthal, Leo Rasche, Nathan M Petty, James E McDonald, James A Ntambi, Doug M Steward, Susan B Panozzo, Frits van Rhee, Maurizio Zangari, Carolina D Schinke, Sharmilan Thanendrarajan, Brian Walker, Niels Weinhold, Bart Barlogie, Antje Hoering, Gareth J Morgan, Faith E Davies, Adam Rosenthal, Leo Rasche, Nathan M Petty, James E McDonald, James A Ntambi, Doug M Steward, Susan B Panozzo, Frits van Rhee, Maurizio Zangari, Carolina D Schinke, Sharmilan Thanendrarajan, Brian Walker, Niels Weinhold, Bart Barlogie, Antje Hoering, Gareth J Morgan

Abstract

Fluorine-18 fluorodeoxyglucose positron emission tomography with computed tomography attenuation correction (PET-CT) in myeloma can detect and enumerate focal lesions by the quantitative characterization of metabolic activity. The aim of this study was to determine the prognostic significance of the suppression of PET-CT activity at a number of time points post therapy initiation: day 7, post induction, post transplant, and at maintenance therapy. As part of the TT4-6 trial series, 596 patients underwent baseline PET-CT and were evaluated serially during their disease course using peak standardized uptake values above background red marrow signal. We demonstrate that the presence of more than 3 focal lesions at presentation identifies a group of patients with an adverse progression-free survival and overall survival. At day 7 of therapy, patients with complete focal lesion signal suppression revert to the same prognosis as those with no lesions at diagnosis. At later time points, the continued suppression of signal remains prognostically important. We conclude that for newly diagnosed patients with focal lesions, treatment until these lesions are suppressed is an important therapeutic goal as the prognosis of these patients is the same as those without lesions at diagnosis. (clinicaltrials.gov identifiers: 00734877, 02128230, 00869232, 00871013).

Trial registration: ClinicalTrials.gov NCT00734877 NCT02128230 NCT00869232 NCT00871013.

Copyright © 2018 Ferrata Storti Foundation.

Figures

Figure 1.
Figure 1.
Survival data according to number of focal lesions (FLs). Progression-free survival (PFS) (upper panel) and overall survival (OS) (lower panel) for patients entered into TT4-6 trials by the number of FL detected at presentation: (A) all patients, (B) GEP70 low-risk patients, and (C) GEP70 high-risk patients. A significant difference was observed for patients with FLs at baseline compared to patients with no FL at baseline for both PFS (P<0.0001) and OS (P<0.0001). These differences were significant when considering separately GEP70 low-risk patients (P=0.0007 for PFS, P<0.0001 for OS) and GEP70 high-risk patients (P=0.04 for PFS, P=0.05 for OS).
Figure 2.
Figure 2.
Paired day 1, 7, and end of induction positron emission tomography with computed tomography (PET-CT). (A) Progression-free survival (PFS) and (B) overall survival (OS) for patients entered into TT4-6 trials with paired day 1 and day 7 PET-CT studies. An overall difference in PFS and OS was noted. A significant difference was observed for patients with no focal lesion(s) (FL) at baseline and no FL at day 7 compared to those with lesions present at day 7 in PFS (P=0.0002) and OS (P<0.0001). A significant difference was observed for patients with resolution of FL at day 7 compared to those with lesions present at day 7 in PFS (P=0.0001) and OS (P=0.0015). (C) PFS and (D) OS for patients entered into TT4-6 trials with paired day 1 and end of induction PET-CT studies. A significant difference was observed in PFS for patients with no FL at baseline and no FL at the end of induction compared to those with FL (P=0.0069). A significant difference was observed in PFS for patients with resolution of FL at this time point compared to those still with lesions (P=0.0064).

References

    1. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15(12):e538–548.
    1. Kumar S, Paiva B, Anderson KC, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17(8):e328–346.
    1. Usmani SZ, Mitchell A, Waheed S, et al. Prognostic implications of serial 18-fluorodeoxyglucose emission tomography in multiple myeloma treated with total therapy 3. Blood. 2013;121(10):1819–1823.
    1. Moreau P, Attal M, Caillot D, et al. Prospective evaluation of magnetic resonance imaging and [18F]fluorodeoxyglucose positron emission tomography-computed tomography at diagnosis and before maintenance therapy in symptomatic patients with multiple myeloma included in the IFM/DFCI 2009 trial: results of the IMAJEM study. J Clin Oncol. 2017;35(25):2911–2918.
    1. Bartel TB, Haessler J, Brown TL, et al. F18-fluorodeoxyglucose positron emission tomography in the context of other imaging techniques and prognostic factors in multiple myeloma. Blood. 2009; 114(10):2068–2076.
    1. Waheed S, Mitchell A, Usmani S, et al. Standard and novel imaging methods for multiple myeloma: correlates with prognostic laboratory variables including gene expression profiling data. Haematologica. 2013;98(1):71–78.
    1. Rasche L, Angtuaco E, McDonald JE, et al. Low expression of hexokinase-2 is associated with false-negative FDG-positron emission tomography in multiple myeloma. Blood. 2017;130(1):30–34.
    1. Zamagni E, Patriarca F, Nanni C, et al. Prognostic relevance of 18-F FDG PET/CT in newly diagnosed multiple myeloma patients treated with up-front autologous transplantation. Blood. 2011;118(23):5989–5995.
    1. Hillengass J, Fechtner K, Weber MA, et al. Prognostic significance of focal lesions in whole-body magnetic resonance imaging in patients with asymptomatic multiple myeloma. J Clin Oncol. 2010;28(9):1606–1610.
    1. Walker R, Barlogie B, Haessler J, et al. Magnetic resonance imaging in multiple myeloma: diagnostic and clinical implications. J Clin Oncol. 2007;25(9):1121–1128.
    1. McDonald JE, Kessler MM, Gardner MW, et al. Assessment of total lesion glycolysis by 18F FDG PET/CT significantly improves prognostic value of GEP and ISS in myeloma. Clin Cancer Res. 2017;23(8):1981–1987.
    1. Jethava Y, Mitchell A, Epstein J, et al. Adverse metaphase cytogenetics can be overcome by adding bortezomib and thalidomide to fractionated melphalan transplants. Clin Cancer Res. 2017;23(11):2665–2672.
    1. Jethava Y, Mitchell A, Zangari M, et al. Dose-dense and less dose-intense Total Therapy 5 for gene expression profiling-defined high-risk multiple myeloma. Blood Cancer J. 2016;6(7):e453.
    1. Nair B, van Rhee F, Shaughnessy JD, Jr, et al. Superior results of Total Therapy 3 (2003–33) in gene expression profiling-defined low-risk multiple myeloma confirmed in subsequent trial 2006–66 with VRD main tenance. Blood. 2010; 115(21):4168–4173.
    1. Shaughnessy JD, Qu P, Tian E, et al. Outcome with total therapy 3 (TT3) compared to total therapy 2 (TT2): Role of GEP70-defined high-risk disease with trisomy of 1q21 and activation of the proteasome gene PSMD4. J Clin Oncol. 2010;28:15s (suppl; abstr 8027).
    1. Kaplan EL, Meier P. Nonparametric-estimation from incomplete observations. J Am Stat Assoc. 1958;53(282):457–481.
    1. Gooley TA, Leisenring W, Crowley J, Storer BE. Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Stat Med. 1999;18(6):695–706.
    1. Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep. 1966;50(3):163–170.
    1. Zamagni E, Nanni C, Gay F, et al. 18F-FDG PET/CT focal, but not osteolytic, lesions predict the progression of smoldering myeloma to active disease. Leukemia. 2016;30(2):417–422.
    1. Dhodapkar MV, Sexton R, Waheed S, et al. Clinical, genomic, and imaging predictors of myeloma progression from asymptomatic monoclonal gammopathies (SWOG S0120). Blood. 2014;123(1):78–85.
    1. Bhutani M, Turkbey B, Tan E, et al. Bone marrow abnormalities and early bone lesions in multiple myeloma and its precursor disease: a prospective study using functional and morphologic imaging. Leuk Lymphoma. 2016;57(5):1114–1121.
    1. Zamagni E, Nanni C, Mancuso K, et al. PET/CT improves the definition of complete response and allows to detect otherwise unidentifiable skeletal progression in multiple myeloma. Clin Cancer Res. 2015;21(19):4384–4390.

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