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EMN recommendations on MM diagnosis and monitoring
continued from the previous page
N. Reference
#14 Zagmani et al.; Clin Cancer
Res 2015.92
#15 Patriarca et al., Biol Blood Marrow
117 Transplant 2015.
#16 Lapa et al.; Oncotarget 2014.118
Number of patients
76
54
37
Method used for MRD assessment
FGD-PET/CT
FGD-PET/CT
FGD-PET/CT
Study question
Role of FGD-PET/CT on PFS and OS
Prognostic significance of PET/CT
Prognostic
value of FGD-PET/CT
Patients cohort
NDMM
AlloSCT pts
Pretreated, and progression after SCT
Time points of MRD assessment
Baseline, during post-treatment FU, PD
Before and/or within 6 months after alloSCT.
At relapse, after treatment
Results
PET-negativity post-treatment in 70%, CR in only 53%.
PET-negativity influenced PFS and OS favorably.
Persistence of EMD at transplantation → poor PFS. EMD and <CR or VGPR after alloSCT →shorter PFS/OS. PET CR pts prolonged PFS/OS.
Absence of foci positive factor
for PFS/OS. EMD and intense uptake associated with
shorter PFS/OS. 30% of pts' management changed after PET/CT
Lesson learnt
PET-CT more careful evaluation of CR. PET-negativity independent predictor of prolonged PFS/OS PET/CT imaging significantly associated with outcome.
Prognostic value of PET/CT in post-SCT relapse patients important and significant impact on
pt management
AlloSCT: allogenic stem cell transplantation; ASCT: autologous stem cell transplantation; ASO RQ-PCR: allele-specific oligonucleotide real-time quantitative polymerase chain reaction; BM: bone marrow; CR: complete remission; CRD: cyclophosphamide, lenalidomide, dexamethasone; d: day; EMD: extramedullary disease; FGD-PET/CT: fluorodeoxyglucose positron emission tomography- computed tomography; FU: follow-up; HD: high dose; HR: high risk; ID: initial diagnosis; MFC: multiparameter flow cytometry; MM: multiple myeloma; MRD: minimal residual disease; nCR: near- complete remission; NGS: next generation sequencing; NDMM: newly diagnosed multiple myeloma; OS: overall survival; PCR: polymerase chain reaction; PD: progressive disease; PFS: progression freesurvival;PR: partialremission;pts:patients;R: lenalidomide;sCR:stringentcompleteremission;SCT:stemcelltransplantation;SFCL:serumfreelightchain;SMM:smoulderingmultiplemyelo- ma; SR: standard risk; TTP: time to tumor progression; VGPR: very good partial remission; VMP: bortezomib, melphalan, prednisone; VRD: bortezomib, lenalidomide, dexamethasone; vs.: versus; VTCD: bortezomib, thalidomide, cyclophosphamide, dexamethasone;VTD: bortezomib, thalidomide, dexamethasone;VTP: bortezomib, thalidomide, prednisone.
between the two tests was low, progression-free survival was better in patients who were negative according to both techniques compared to those who were positive by PET and/or flow cytometry (3-year progression-free sur- vival, 86.8% versus 52.9%), indicating that both tech- niques are complementary. A major advantage of PET/CT is its capacity to assess MRD outside the BM; its disadvan- tages are high cost and the lack of reimbursement in cer- tain countries, insufficient standardization and reduced tracer uptake in some MM patients. Evaluation via PET/CT has been incorporated into the new IMWG MRD criteria.77 In the future, the increased capabilities of diffu- sion weighted MRI to detect small lesions and diffuse infiltration may offer advantages that merit prospective evaluation in MRD assessment studies.50
In addition, recent studies have demonstrated that cir- culating DNA fragments carrying tumor-specific sequence alterations can be detected and quantified in the blood of patients with solid tumors.93,94 In MM, various studies have provided evidence that - much like in solid tumors - MM-specific alterations (VDJ rearrangements or somatic genomic alterations) can also be identified and tracked in cell-free DNA circulating in blood.95,96
European Myeloma Network recommendations:
Response assessment is an essential part of myeloma manage- ment. Patients under treatment should be evaluated before the initi- ation of each cycle and according to international guidelines. Minimal residual disease testing is not currently recommended in routine follow-up of patients but is likely to be incorporated in stan- dard response/progression evaluation soon. Valid options for the assessment of minimal residual disease are based on bone marrow cells (next-generation flow cytometry) or molecular analysis (next-
generation sequencing), often also combined with an imaging-based evaluation. These methods require appropriate expertise.
Conclusion
While novel agents have certainly improved the out- comes of patients with myeloma, prompt diagnosis and close follow-up of MM patients remain highly relevant and contribute to better survival. In most cases, the diag- nosis of MM is straightforward, being based on biological and radiological evidence when evocative clinical signs are present. During response assessment, the evaluation of MRD will become increasingly important and, within the next few years, will guide treatment choices in clinical trials and possibly also outside trial scenarios. International efforts are needed to standardize the differ- ent techniques that can be used to evaluate MRD. Guidelines on appropriate follow-up and patient-tailored monitoring have been updated in this EMN consensus paper and should help to improve the outcome and prog- nosis of our patients.
Acknowledgments
The authors thank distinguished IMWG, EMN, DSMM and GMMG experts for their advice and recommendations that have helped us to improve this paper. This work was supported by the Deutsche Krebshilfe (grants 1095969 and 111424 to ME), the Foundation against Cancer, the Fonds National de la Recherche Scientifique and the Fonds d'Investissement de Recherche Scientifique (FIRS) du CHU de Liège (grants to JC), the NIHR Imperial Biomedical Research Centre and the Cancer Research UK Imperial Centre (grants to HWA).
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