Recent developments on the application of molecular probes in multiple myeloma: Beyond [18F]FDG.
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ABSTRACT:
SUBMITTER: Zhang S
PROVIDER: S-EPMC9459033 | biostudies-literature | 2022
REPOSITORIES: biostudies-literature
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Recent developments on the application of molecular probes in multiple myeloma: Beyond [<sup>18</sup>F]FDG.
Zhang Shaojuan S Shang Jingjie J Ye Weijian W Zhao Tianming T Xu Hao H Zeng Hui H Wang Lu L
Frontiers in bioengineering and biotechnology 20220826
Multiple myeloma (MM) is a neoplastic plasma cell proliferative disorder characterized by various osteolytic bone destruction as a radiological morphological marker. Functional imaging, particularly nuclear medicine imaging, is a promising method to visualize disease processes before the appearance of structural changes by targeting specific biomarkers related to metabolism ability, tumor microenvironment as well as neoplastic receptors. In addition, by targeting particular antigens with therape ...[more]
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Project description:Purpose[18F]FDG PET/CT in multiple myeloma (MM) is currently the best technology to demonstrate patchy and extramedullary disease. However, [18F]FDG PET has some limitations, and imaging with alternative tracers should be explored. In this study, we aimed to evaluate the performance of [18F]fluciclovine PET compared to [18F]FDG PET in newly diagnosed MM patients.ProceduresThirteen newly diagnosed transplant eligible MM patients were imaged both with [18F]FDG PET/CT and [18F]fluciclovine PET/CT within 1 week in a prospective study. The subjects were visually assessed positive or negative for disease. The number of lesions and the SUVmax of selected lesions were measured for both tracers. Furthermore, tracer uptake ratios were obtained by dividing lesion SUVmax by blood or bone marrow SUVmax. Between-group differences and correlations were assessed with paired t-tests and Pearson tests. Bone marrow SUVs were compared to bone marrow plasma cell percentage in biopsy samples.ResultsNine subjects were assessed positively by [18F]FDG PET (69%) and 12 positives by [18F]fluciclovine PET (92%). All positive subjects had [18F]fluciclovine scans that were qualitatively scored as easier to interpret visually than the [18F]FDG scans. The number of lesions was also higher; seven of nine subjects with distinct hot spots on [18F]fluciclovine PET had fewer or no visible lesions on [18F]FDG PET. The mean lesion SUVmax values were 8.2 and 3.8 for [18F]fluciclovine and [18F]FDG, respectively. The mean tumour to blood values were 6.4 and 2.0 for [18F]fluciclovine and [18F]FDG, and the mean ratios between tumour and bone marrow were 2.1 and 1.5 for [18F]fluciclovine and [18F]FDG. The lesion SUVmax and ratios were significantly higher for [18F]fluciclovine (all p < 0.01). Local [18F]fluciclovine SUVmax or SUVmean values in os ilium and the percentage of plasma cells in bone marrow biopsies were linearly correlated (p = 0.048). There were no significant correlations between [18F]FDG SUVs and plasma cells (p = 0.82).ConclusionsBased on this pilot study, [18F]fluciclovine is a promising tracer for MM. The visual and semi-quantitative evaluations indicate that [18F]fluciclovine PET/CT can out-perform [18F]FDG PET/CT at diagnosis.
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Project description:Multiple myeloma (MM) is a debilitating neoplasm of terminally differentiated plasma B cells that resulted in over 13,000 deaths in 2017 alone. Combination therapies involving melphalan, a small-molecule DNA alkylating agent, are commonly prescribed to patients with relapsed or refractory MM, necessitating the stratification of responding patients to minimize toxicities and improve quality of life. Here, we evaluated the use of 3,4-dihydroxy-6-18F-fluoro-l-phenylalanine (18F-FDOPA), a clinically available PET radiotracer with specificity to the L-type amino acid transporter 1 (LAT1), which also mediates melphalan uptake, for imaging melphalan therapy response in a preclinical immunocompetent model of MM. Methods: C57BL/KaLwRij mice were implanted subcutaneously with unilateral murine green fluorescent protein-expressing 5TGM1 tumors and divided into 3 independent groups: untreated, treated beginning week 2 after tumor implantation, and treated beginning week 3 after tumor implantation. The untreated and week 2 treated groups were imaged with preclinical MRI and dynamic 18F-FDG and 18F-FDOPA PET/CT at week 4 on separate, contiguous days, whereas the week 3 treated group was longitudinally imaged weekly for 3 wk. Metabolic tumor volume, total lesion avidity, SUVmax, and total uptake were calculated for both tracers. Immunohistochemistry was performed on representative tissue from all groups for LAT1 and glucose transporter 1 (GLUT1) expression. Results: Melphalan therapy induced a statistically significant reduction in lesion avidity and uptake for both 18F-FDG and 18F-FDOPA. There was no visible effect on GLUT1 expression, but LAT1 density increased in the week 2 treated group. Longitudinal imaging of the week 3 treated group showed variable changes in 18F-FDG and 18F-FDOPA uptake, with an increase in 18F-FDOPA lesion avidity in the second week relative to baseline. LAT1 and GLUT1 surface density in the untreated and week 3 treated groups were qualitatively similar. Conclusion: 18F-FDOPA PET/CT complemented 18F-FDG PET/CT in imaging melphalan therapy response in preclinical extramedullary MM. 18F-FDOPA uptake was linked to LAT1 expression and melphalan response, with longitudinal imaging suggesting stabilization of LAT1 levels and melphalan tumor cytotoxicity. Future work will explore additional MM cell lines with heterogeneous LAT1 expression and response to melphalan therapy.
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Project description:Purpose[18F]FDG PET/CT is the elective imaging modality for treatment monitoring in multiple myeloma (MM). However, MM is a heterogeneous disease from an imaging point of view, raising challenges in interpretation of PET/CT. We herein investigated the prognostic role of the novel Italian Myeloma criteria for PET Use (IMPeTUs) in MM patients undergoing high-dose chemotherapy (HDT) followed by autologous stem cell transplantation (ASCT).MethodsForty-seven patients with newly diagnosed MM underwent [18F]FDG PET/CT before commencement of treatment (baseline PET/CT). Thirty-four of them (72.3%) were also examined after completion of ASCT (follow-up PET/CT). PET/CT analysis was based on the IMPeTUs criteria, which take into consideration-among others-the metabolic state of the bone marrow based on the 5-point Deauville score (DS), the number and metabolic state of focal [18F]FDG-avid lesions, as well as the presence of paramedullary disease (PMD) and extramedullary disease (EMD). We analyzed whether parameters from IMPeTUs correlate with clinically relevant parameters and patients' outcome, as assessed by progression-free survival (PFS).ResultsMedian follow-up from baseline and follow-up PET/CT were 85.1 months and 76.7 months, respectively. The number of focal, [18F]FDG-avid lesions significantly correlated with the bone marrow infiltration rate and the R-ISS stage, while the presence of PMD was associated with LDH. After univariate survival analysis, the number of focal, [18F]FDG-avid lesions both before and after therapy as well as the presence of PMD and EMD before therapy adversely affected PFS. Multivariate survival analysis for baseline parameters confirmed that the number of focal, [18F]FDG-avid lesions and the presence of EMD are associated with adverse prognosis, irrespective of the ISS stage and/or the presence of high-risk cytogenetic abnormalities. The 5-point DS of [18F]FDG uptake in reference bone marrow and focal lesions showed a significant decrease as response to treatment, but it did not affect PFS.ConclusionSeveral parameters utilized in IMPeTUs predict PFS in MM patients, suggesting the potentially significant role of the new criteria in patient stratification and response assessment. Additional studies are warranted for the further evaluation of IMPeTUs in the direction of establishment of robust cut-off values with a prognostic significance in the disease.
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Project description:Studies indicate that the radiotracer 2-[18F]fluoro-2-deoxy-D-glucose (2-[18F]FDG) can be metabolized beyond 2-[18F]FDG-6-phosphate (2-[18F]FDG-6-P), but its metabolism is incompletely understood. Most importantly, it remains unclear whether downstream metabolism affects tracer accumulation in vivo. Here we present a fingerprint of 2-[18F]FDG radiometabolites over time in cancer cells, corresponding tumor xenografts and murine organs. Strikingly, radiometabolites representing glycogen metabolism or the oxPPP correlated inversely with tracer accumulation across all examined tissues. Recent studies suggest that not only hexokinase, but also hexose-6-phosphate dehydrogenase (H6PD), an enzyme of the oxidative pentose phosphate pathway (oxPPP), determines 2-[18F]FDG accumulation. However, little is known about the corresponding enzyme glucose-6-phosphate dehydrogenase (G6PD). Our mechanistic in vitro experiments on the role of the oxPPP propose that 2-[18F]FDG can be metabolized via both G6PD and H6PD, but data from separate enzyme knockdown suggest diverging roles in downstream tracer metabolism. Overall, we propose that tissue-specific metabolism beyond 2-[18F]FDG-6-P could matter for imaging.
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Project description:Chemokine (C-X-C motif) receptor 4 (CXCR4) is a key factor for tumor growth and metastasis in several types of human cancer including multiple myeloma (MM). Proof-of-concept of CXCR4-directed radionuclide therapy in MM has recently been reported. This study assessed the diagnostic performance of the CXCR4-directed radiotracer [68Ga]Pentixafor in MM and a potential role for stratifying patients to CXCR4-directed therapies. Thirty-five patients with MM underwent [68Ga]Pentixafor-PET/CT for evaluation of eligibility for endoradiotherapy. In 19/35 cases, [18F]FDG-PET/CT for correlation was available. Scans were compared on a patient and on a lesion basis. Tracer uptake was correlated with standard clinical parameters of disease activity. [68Ga]Pentixafor-PET detected CXCR4-positive disease in 23/35 subjects (66%). CXCR4-positivity at PET was independent from myeloma subtypes, cytogenetics or any serological parameters and turned out as a negative prognostic factor. In the 19 patients in whom a comparison to [18F]FDG was available, [68Ga]Pentixafor-PET detected more lesions in 4/19 (21%) subjects, [18F]FDG proved superior in 7/19 (37%). In the remaining 8/19 (42%) patients, both tracers detected an equal number of lesions. [18F]FDG-PET positivity correlated with [68Ga]Pentixafor-PET positivity (p=0.018). [68Ga]Pentixafor-PET provides further evidence that CXCR4 expression frequently occurs in advanced multiple myeloma, representing a negative prognostic factor and a potential target for myeloma specific treatment. However, selecting patients for CXCR4 directed therapies and prognostic stratification seem to be more relevant clinical applications for this novel imaging modality, rather than diagnostic imaging of myeloma.
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Project description:The combination of visual assessment of whole body [18F]FDG PET images and evaluation of bone marrow samples by Multiparameter Flow Cytometry (MFC) or Next-Generation Sequencing (NGS) is currently the most common clinical practice for the detection of Measurable Residual Disease (MRD) in Multiple Myeloma (MM) patients. In this study, radiomic features extracted from the bone marrow biopsy locations are analyzed and compared to those extracted from the whole bone marrow in order to study the representativeness of these biopsy locations in the image-based MRD assessment. Whole body [18F]FDG PET of 39 patients with newly diagnosed MM were included in the database, and visually evaluated by experts in nuclear medicine. A methodology for the segmentation of biopsy sites from PET images, including sternum and posterior iliac crest, and their subsequent quantification is proposed. First, starting from the bone marrow segmentation, a segmentation of the biopsy sites is performed. Then, segmentations are quantified extracting SUV metrics and radiomic features from the [18F]FDG PET images and are evaluated by Mann-Whitney U-tests as valuable features differentiating PET+/PET- and MFC+ /MFC- groups. Moreover, correlation between whole bone marrow and biopsy sites is studied by Spearman ρ rank. Classification performance of the radiomics features is evaluated applying seven machine learning algorithms. Statistical analyses reveal that some images features are significant in PET+/PET- differentiation, such as SUVmax, Gray Level Non-Uniformity or Entropy, especially with a balanced database where 16 of the features show a p value < 0.001. Correlation analyses between whole bone marrow and biopsy sites results in significant and acceptable coefficients, with 11 of the variables reaching a correlation coefficient greater than 0.7, with a maximum of 0.853. Machine learning algorithms demonstrate high performances in PET+/PET- classification reaching a maximum AUC of 0.974, but not for MFC+/MFC- classification. The results demonstrate the representativeness of sample sites as well as the effectiveness of extracted features (SUV metrics and radiomic features) from the [18F]FDG PET images in MRD assessment in MM patients.
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Project description:The International Myeloma Working Group recently fully incorporated 18F-FDG PET into multiple myeloma (MM) diagnosis and response evaluation. Moreover, a few studies demonstrated the prognostic value of several biomarkers extracted from this imaging at baseline. Before these 18F-FDG PET biomarkers could be fully endorsed as risk classifiers by the hematologist community, further characterization of underlying molecular aspects was necessary. Methods: Reported prognostic biomarkers (18F-FDG avidity, SUVmax, number of focal lesions, presence of paramedullary disease [PMD] or extramedullary disease) were extracted from 18F-FDG PET imaging at baseline in a group of 139 patients from CASSIOPET, a companion study of the CASSIOPEIA cohort (ClinicalTrials.gov identifier NCT02541383). Transcriptomic analyses using RNA sequencing were realized on sorted bone marrow plasma cells from the same patients. An association with a high-risk gene expression signature (IFM15), molecular classification, progression-free survival, a stringent clinical response, and minimal residual disease negativity were explored. Results:18F-FDG PET results were positive in 79.4% of patients; 14% and 11% of them had PMD and extramedullary disease, respectively. Negative 18F-FDG PET results were associated with lower levels of expression of hexokinase 2 (HK2) (fold change, 2.1; adjusted P = 0.04) and showed enrichment for a subgroup of patients with a low level of bone disease. Positive 18F-FDG PET results displayed 2 distinct signatures: either high levels of expression of proliferation genes or high levels of expression of GLUT5 and lymphocyte antigens. PMD and IFM15 were independently associated with a lower level of progression-free survival, and the presence of both biomarkers defined a group of "double-positive" patients at very high risk of progression. PMD and IFM15 were related neither to minimal residual disease assessment nor to a stringent clinical response. Conclusion: Our study confirmed and extended the association between imaging biomarkers and transcriptomic programs in MM. The combined prognostic value of PMD and a high-risk IFM15 signature may help define MM patients with a very high risk of progression.
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