In this study, we have evaluated the visual and semi-quantitative performance of [18F]fluciclovine PET compared to [18F]FDG PET for newly diagnosed MM patients. Although the study size is limited (N = 13), [18F]fluciclovine PET appears to outperform [18F]FDG PET, with a higher number of subjects characterised as positive (92 vs 69%, respectively). Accordingly, higher tumour SUVs and tumour to normal tissue ratios were also observed.
Through investigations of imaging at different time points, we found acquisitions performed rapidly after injection of [18F]fluciclovine to be optimal (Fig. 2). This is probably due to the bidirectional properties of the cellular transport system of leucine (29). While [18F]fluciclovine imaging for prostate cancers was performed almost immediately after injection (30), the optimal time point for brain tumours is more uncertain and probably delayed (31). [11C]methionine PET for MM appears to usually be performed at 20 min p.i. (20, 22, 32), but we were unable to find reports investigating different timing. Here, the [18F]fluciclovine whole body images were obtained at 15 min p.i., but investigations of more immediate acquisitions could be interesting to pursue in a later study. The possibility of acquiring images earlier after administration of the radiopharmaceutical is nevertheless beneficial for several reasons. These include logistics for both patients and the nuclear medicine department as the time spent per patient is decreased. Furthermore, it will improve the image quality obtained for a certain absorbed dose, as early imaging allows decreased injected activity and/or acquisition time. Since the effective dose from the [18F]fluciclovine administration was already lower than for the [18F]FDG administration, we chose in our study to use a short acquisition time of 1 min per bed position, but this trade-off is open for optimisation.
The differences in visual appearance between [18F]fluciclovine and [18F]FDG PET were striking for many of the patients in the current study. While the IMPeTUs criteria can serve as guidance for the assessment of [18F]FDG PET (28), there are still many challenges associated with image interpretation. Only 9/13 patients were assessed positive on [18F]FDG PET in our study. Furthermore, the evaluations were, in several cases, not straightforward. The [18F]fluciclovine PET images were deemed positive in 12/13 patients and scored as easier to interpret than the according [18F]FDG PET scans for all positive cases. For the single subject assessed negative on both examinations, it should be noted that the [18F]FDG PET scan, unfortunately was performed 3 weeks before the [18F]fluciclovine scan. Theoretically, this subject could have turned [18F]FDG positive over the following weeks. For the rest of the population, the examinations were performed within 1 week of each other, in random order, and will most likely be highly comparable. One of the main limitations of the current work, besides the study size, is the lack of standardised assessment criteria for [18F]fluciclovine in MM. This is of course to be expected, as this pilot study is the first to explore the potential for this tracer. Still, especially pathological bone marrow uptake was challenging to characterise in a couple of cases, as normal physiological uptake of [18F]fluciclovine is expected in the marrow (30). This may also have a heterogeneous nature. Our institution has an extensive experience with [18F]fluciclovine for prostate cancer, and drew on this expertise for the current evaluations. While the majority of the [18F]fluciclovine images were easy to characterise, it should be noted that a few cases were borderline (especially subject 04). A set of evaluation criteria for MM, possibly also relaying on measurements of bone marrow heterogeneity and uptake structure, should be established if this tracer is to be used more routinely.
The approximate numbers of lesions were clearly different between the tracers (Table 2 and Fig. 1). While this number will not alter the positive/negative status, a study has reported a higher number of [18F]FDG foci to be associated with a less favourable prognosis (4), and an improved resolution of this number may therefore be relevant for stratification purposes. The semi-quantitative analyses for [18F]fluciclovine compared to [18F]FDG also support the visual results (Fig. 3) with significantly higher SUVs for [18F]fluciclovine vs [18F]FDG. Even though lesion selection for semi-quantitative measurements was done on both [18F]fluciclovine and [18F]FDG PET exams, choosing the lesions with highest uptake on each scan separately and then measuring the SUVs on both scans, all but one lesion had higher [18F]fluciclovine SUVs than [18F]FDG SUVs. This means that even the most visually striking lesions on [18F]FDG PET will probably have an even higher [18F]fluciclovine uptake. While no targeted biopsies were obtained to confirm that the lesions were indeed multiple myeloma, the follow-up [18F]fluciclovine examinations at 3 months after ASCT showed normalised uptake for all subjects. This, together with the improvement of the patients’ myeloma disease status, indicates that the lesions were actually myeloma. In this study, the mean SUVs for [18F]fluciclovine were more than twice as high as for [18F]FDG (8.2 vs 3.8, respectively). The ratios of the tumour to background tissue are also just as important for the assessments. Here, the tumour to blood ratio was more than three times higher for [18F]fluciclovine than [18F]FDG, and the tumour to bone marrow ratio was more than 40% higher for [18F]fluciclovine compared to [18F]FDG PET; further emphasising a beneficial [18F]fluciclovine uptake pattern. The liver is involved in the excretion of [18F]fluciclovine and, therefore, not a relevant tissue for thresholding. However, the ratio of tumour to liver for [18F]fluciclovine was still comparable, or even slightly higher, than that of [18F]FDG.
We here found a significant correlation between [18F]fluciclovine SUV measured in os ilium and the percentage of plasma cells in the biopsies, indicating that the PET examination represents a quantitative measure of tumour burden. No correlations were found for a similar investigation of [18F]FDG SUV. This is somewhat surprisingly, as earlier studies have found correlations also between biopsy results and [18F]FDG SUVs (33), but it may be that the study size in our investigation was too small to reveal a weak correlation for [18F]FDG. This is supported by an earlier study of [18F]FDG vs [11C]Methionine that found higher correlation coefficients for [11C]methionine PET (r = 0.6 for [18F]FDG vs r = 0.9 for [11C]methionine (33)). Although the biopsy data is from untargeted iliac crest marrow, introducing a potential uncertainty (especially for patients with patchy bone marrow pattern), this is no different from the previous study mentioned and should also not impact the correlation for each tracer differently.
Earlier studies have investigated alternative “non-[18F]FDG” tracers for MM, although also with a limited patient population, and in various clinical scenarios ranging from diagnosis to relapse. Since comparisons with [18F]FDG commonly has formed the basis for the investigations, direct evaluations between non-[18F]FDG tracers are challenging. While some tracers have shown somewhat disappointing results, such as [18F]FPRGD2 for integrin imaging (34) and Na[18F]F (9, 15), the investigation of others, such as [11C]acetate (14), seems to have been discontinued without apparent reasons. Carbon-11 or fluorine-18 labeled choline has been investigated in retrospective studies of relapse, progression, or for follow-up (18–20). While choline performed better than [18F]FDG (18, 19), it has later been shown inferior to [11C]Methionine is one of the rare studies comparing two non-[18F]FDG tracers (20). The amino acid-based [11C]Methionine has become an increasingly popular non-[18F]FDG tracer for MM and has, in several studies, shown higher sensitivity than [18F]FDG for detection of both intra- and extramedullary MM (21, 22, 33, 35). The combined evidence of [11C]methionine as a suitable MM tracer also holds promise for [18F]fluciclovine, as both tracers are amino acid-based, and the transporter system for [11C]Methionine (the L system) is also involved in cellular uptake of [18F]fluciclovine (24, 29). Our results support this theoretical notion and demonstrate that [18F]fluciclovine is indeed a promising tracer for MM. A recent study investigated [11C]methionine vs [18F]FDG in a study of 22 newly diagnosed, treatment-naïve symptomatic MM, finding that [11C]methionine is a more sensitive marker than [18F]FDG (22). While this study can be considered relatively comparable to ours, the high positive rate in both precludes speculations on which of the two amino acid-based tracers, [11C]methionine or [18F]fluciclovine, performs best. However, [11C]-Methionine is only feasible at centres with a cyclotron due to the short half-life of carbon-11. [18F]fluciclovine, being a fluorine-18-based tracer like [18F]FDG, is amenable to transport. Another amino acid-based tracer, [18F]fluoro-ethyl-tyrosine ([18F]FET), has also been investigated, although in a mixed population and only compared with CT imaging (36).
A potential disadvantage of [18F]fluciclovine and other amino acid-based tracers is the unavailability for theragnostic applications; replacing the positron emitter with a therapeutic nuclide. Tracers such as the CXCR4-targeting [68 Ga]Ga-pentixafor (13), PSMA tracers (currently under investigation), and the CD38-targeted daratumumab (16) have this potential. However, many theragnostic tracers, especially antibody-based, can be subject to downregulation. A broader selection of tracers, including [18F]fluciclovine or other amino acid-based tracers, should therefore be available to allow the best choice based on the clinical setting and stage.