Role of PET/CT As a Measure of Minimal Residual Disease (MRD) Negativity Among Patients with Myeloma Post Autologous Stem Cell Transplant (ASCT)

Background: In the context of improved novel therapeutic anti-myeloma regimens using combinations of antibodies and other small molecules, measuring the efficacy of therapy is an ongoing challenge. Minimal residual disease (MRD) assessment by multiparameter flow cytometry (MFC), polymerase chain reaction (ASO-PCR), next-generation sequencing are sensitive tests that are becoming more significant as improved therapies result in deeper responses, however challenges remain, such as standardizing these testing methods. 18F Fluorodeoxglucose Positron Emission Tomography/Computed Tomography (PET/CT) is a non invasive imaging modality that can provide essential information in diagnosis and management of MM. PET/CT has high sensitivity (80-90%) and specificity (80-100%) to detect MM lesions. PET/CT also has a recently acknowledged role in prognostic information.  Standardized uptake value maximum (SUVmax) is a widely used PET/CT parameter for assessment of therapy response in a variety of cancers. Recent publication by Zamagni et al showed that in addition to the presence of three or more focal lesions, a maximum standardized uptake value (SUVmax) of over 4.2 and presence of extramedullary disease were negative prognostic factors. Our aim in this study was to evaluate the prognostic role of PET/CT in MM patients post ASCT at day 100 restaging.

Methods: We have identified 130 myeloma patients that underwent autologous stem cell transplant (ASCT) from 09/2014 until 04/2015. Along with their hematologic restaging post-ASCT for response assessment per International Myeloma Working Group (IMWG) criteria, patients also underwent PET/CT for MRD assessment. After excluding 3 patients that underwent tandem transplants, and one patient that received stem cell boost, 102 patients were evaluable for the current analysis (24 patients did not undergo PET/CTs). We have done an exploratory analysis with previously described SUVmax cut off of <2.0 (Waheed S) and <4.2 (Zamagni E). 

Results: The median age of the patients that underwent ASCT was 64 years (range: 38-76 years). 77 pts (75%) received melphalan 200 mg/m², 22 pts (22%) received melphalan 140 mg/m², 2 pts received melphalan+bortezomib and 1 pt received BEAM regimen as conditioning regimen. Median time from day 0 to response assessment is 98 days (range: 55-189 days). Hematological restaging shows that 89% of patients achieved ≥VGPR (SCR: 46% and CR: 11%). 13 pts did not have prior lytic lesions while 89% had lytic lesions (one lesion: 4%, two lesions: 2% and multiple (≥3): 82%). PET/CT negativity was achieved among 63% of the patients. At SUV cut off of <2.0 and <4.2, PET/CT negativity was achieved among 64% of the patients and 83% of the patients respectively. Taking the patients that have achieved SCR, for the same cut offs, PET/CT negativity rates were 59% and 76% respectively (Table 1).

Conclusions: Negative PET/CT rates post-ASCT are in accordance with previously published studies. With taking SUVmax as sole criteria for assessing MRD negativity, false positive PET/CT results will continue to remain a challenge. Although SUVmax is the most widely used PET/CT parameter, it has limitations. There are other PET/CT parameters mean or peak standardized uptake values (SUVmean, SUVpeak); metabolic tumor volume (MTV); total lesion glycolysis (TLG); standardized added metabolic activity (SAM); and, normalized standardized added metabolic activity (NSAM) used in clinical practice and research. These PET/CT parameters may have role as prognostic imaging probes in MM patients post ASCT. With longer follow up to assess PFS and OS, we can evaluate the prognostic impact of using PET/CT as MRD measure.

Table 1. PET parameters and hematological responses

Response	Response rates	PET positive	PET negative	PET positive (≥SUV 2.0)	PET negative (<SUV 2.0)	PET positive (≥SUV 4.2)	PET negative (<SUV 4.2)
SCR	46	19	27	19	27	11	35
CR	11	7	4	6	5	3	8
VGPR	34	9	25	9	25	3	31
PR	10	2	8	2	8	0	10
PD	1	1	0	1	0	1	0
≥CR	57	26	31	25	32	14	43
≥VGPR	91	35	56	34	57	17	74