Background
There has been an increasing interest over the past few years regarding the role of imaging in multiple myeloma (MM). This interest has been driven by the considerable technological advances, mostly in cross sectional imaging, that have taken place and by the recent introduction of some very effective novel therapeutic agents in the oncologist’s armamentarium, which have led to unparalleled levels of response in the disease. In this context, the role of molecular imaging with PET has gained significant importance in MM.
In the last years, the position of
18F-FDG PET/CT has been drastically upgraded in the management of MM. A number of studies have highlighted the diagnostic and prognostic value of the modality as well as its excellent performance in treatment response evaluation [
1‐
6]. Most recently, the International Myeloma Working Group (IMWG) has recommended the use of
18F-FDG PET/CT as a diagnostic tool in patients with active MM, smoldering MM (SMM), and solitary plasmacytoma [
7].
Although the vast majority of functional PET imaging studies is performed with
18F-FDG, this tracer carries some serious limitations in MM imaging: it demonstrates a false negativity incidence of approximately 11% which is associated with low hexokinase-2 expression in some MM patients, and it shows lower sensitivity than MRI in diffuse bone marrow infiltration, leading potentially to patient misclassifications if used as the only functional imaging technology [
1,
8]. Moreover,
18F-FDG, as a glucose analog, is generally restricted in oncological imaging by both false positive (inflammation, post-surgical areas, recent use of chemotherapy, fractures, etc.) and false negative results (hyperglycemia, recent administration of high-dose steroids, etc.).
According to the previous, there is a—still unmet—need for myeloma-specific radiotracers. 3′-Deoxy-3′-[
18F]fluorothymidine (
18F-FLT) is the most studied cellular proliferation PET agent [
9].
18F-FLT is taken up by cells, phosphorylated by thymidine kinase 1, which is upregulated by about tenfold during the S-phase of the cell cycle, and remains trapped intracellularly without being incorporated into DNA. Its kinetics can be described, as in the case of
18F-FDG, with a three-compartment model [
10‐
12]. A recent systematic review has shown that
18F-FLT PET seems to be a good predictor of early response to systemic-, radio-, and concurrent chemoradiotherapy and that the modality may be developed into a tool for guiding individualization of treatment strategies [
13]. Moreover,
18F-FLT is considered a potentially new myeloma functional imaging tracer [
14].
The aim of this pilot study was to evaluate18F-FLT PET/CT in imaging of MM patients, in the context of its combined use with 18F-FDG PET/CT.
Discussion
Functional imaging with PET provides the potential of investigating tumor biology at the molecular level after application of several radiotracers.
18F-FDG, the workhorse of PET imaging, is a surrogate of glucose utilization. The rationale of
18F-FDG application in tumor diagnostics is based on the “Warburg effect,” according to which most cancer cells rely on aerobic glycolysis to generate the energy needed for cellular processes in contrast to normal differentiated cells, which rely primarily on mitochondrial oxidative phosphorylation [
25]. Nowadays,
18F-FDG PET/CT has become the mainstay for imaging evaluation of several tumor entities. In particular in the case of MM,
18F-FDG PET/CT is considered a valuable tool in the work-up of patients with the disease [
7,
26]. Nevertheless, as already mentioned,
18F-FDG has some well-documented disadvantages that limit its performance in MM evaluation. Thus, the development of myeloma-specific diagnostic imaging agents that could potentially lead to personalized patient management represents a considerable need [
27].
Tumor proliferation is a hallmark of the cancer phenotype and one of the useful markers for treatment response evaluation and prognosis in clinical oncology [
28]. The radiolabeled thymidine analog
18F-FLT can allow noninvasive assessment of tumor proliferation [
10].
18F-FLT is incorporated into cells and undergoes phosphorylation by the enzyme thymidine kinase 1, producing
18F-FLT monophosphate (
18F-FLT-MP), which can then be sequentially phosphorylated to form
18F-FLT diphosphate (
18F-FLT-DP) and
18F-FLT triphosphate (
18F-FLT-TP); these phosphorylated products are metabolically trapped inside cells and are not incorporated into DNA. The tracer retention within cells reflects, in part, thymidine kinase activity and is often positively correlated with cellular proliferation [
29]. Although its role in everyday clinic has not been yet established,
18F-FLT PET has been studied and found to be of clinical significance in several human cancers in diagnosis and treatment response assessment [
30‐
35].
The knowledge regarding application of
18F-FLT PET in MM is limited. Up to now, the only existing results have been published by Agool et al., who studied a group of 18 patients with different hematologic disorders, among which, two patients with MM. The authors found that the affected osteolytic areas in these two MM patients demonstrated a low
18F-FLT uptake [
36]. Despite this lack in literature concerning its use in MM,
18F-FLT is considered a promising myeloma functional imaging tracer [
14,
37].
The aim of this pilot study was to evaluate
18F-FLT PET/CT in imaging of MM patients, in the context of its combined use with
18F-FDG PET/CT. Our results show that, if it were used as the only functional imaging modality,
18F-FLT PET/CT would have characterized only two patients as demonstrating myeloma-associated, skeletal manifestations. In contrary,
18F-FDG PET/CT could reveal skeletal lesions in five of the included patients. Moreover, the number of myeloma-indicative lesions was significantly higher for
18F-FDG PET/CT than for
18F-FLT PET/CT. An interesting finding of our analysis, which is in line with the results published by Agool et al. [
36], is that several affected osteolytic areas demonstrated a tracer mismatch of increased
18F-FDG uptake and reduced
18F-FLT uptake, indicating a phenomenon of synchronous increased glucose utilization and low proliferation rate in active myeloma lesions (Fig.
5). An explanation for this finding is the fact that MM is in general a tumor with low proliferation rate with a very small fraction of proliferating cells [
38]. In agreement with this knowledge,
18F-FLT PET/CT showed increased tracer accumulation in a patient with two lesions showing extramedullary expansion to the soft tissue of the chest wall after disrupting the cortical bone (Fig.
4). Given the fact that extramedullary expansion of MM is associated with increased proliferation [
39,
40], the demonstration of increased
18F-FLT uptake—not only in extramedullary but also in several medullary lesions—indicates an increased proliferation in the myeloma cells of this patient and suggests
18F-FLT PET/CT as a potential tool for highlighting the subgroup of MM patients with a hyperproliferative tumor. Unfortunately, no cytogenetic data, potentially demonstrating prognostic unfavorable abnormalities, were available in the particular patient.
Another finding of our analysis is the high background
18F-FLT activity in the bone marrow compartment, which further complicates the evaluation of bone marrow lesions in
18F-FLT PET/CT. In particular, a diffuse bone marrow infiltration would remain undetected by
18F-FLT PET/CT, as observed in our analysis, where two patients showed a diffuse pattern of
18F-FDG uptake. Although several causes, such as recent administration of chemotherapy or granulocyte-colony stimulating factor (G-CSF) and anemia, can lead to the diffusely increased bone marrow,
18F-FDG uptake is still a finding in PET/CT imaging, which is of particular interest in the case of MM due to the nature of the disease. Nevertheless, its interpretation should be cautious; MRI remains the gold standard for assessment of the degree of bone marrow plasma cell infiltration [
41].
Semi-quantitative evaluations showed that tracer uptake, reflected by SUV values, was significantly higher in myeloma-indicative lesions than in reference bone marrow for both 18F-FDG and 18F-FLT. Moreover, in these cases where lesions were detectable with both tracers (17 lesions), SUVmean and SUVmax were significantly higher for 18F-FLT than for 18F-FDG.
A part of our study focused on the evaluation of the dynamic
18F-FDG and
18F-FLT PET/CT scans. As already mentioned, a three-compartment model is a reliable approach for characterization of the quantitative behavior of both tracers [
11,
18‐
21]. Unfortunately, due to the small number of MM lesions detected in the pelvic area (particularly for
18F-FLT PET/CT), where the dynamic PET acquisition took place, no statistical evaluations regarding tracers’ kinetics were performed.
Limitations exist in this small pilot study. Firstly, the number of patients analyzed does not allow for safe conclusions to be drawn, and further studies with a larger study population are warranted to generalize the herein presented results. Nevertheless, the first results of the trial are not encouraging regarding the application of 18F-FLT PET/CT in myeloma diagnostics. Secondly, most of the PET/CT positive findings were not histopathologically confirmed. However, this is usually not possible in the clinical setting. Finally, the dynamic PET/CT studies were confined in the anatomic area of the lower abdomen and pelvis, since whole-body dynamic studies cannot be yet performed. A two-bed position protocol for the dynamic PET acquisition was used, which allows the study of a relatively large field of view of 43.2 cm. Nevertheless, new PET/CT scanners allow dynamic studies over several bed positions by using a continuous bed movement, thus facilitating the use of dynamic protocols and reducing the whole acquisition time.