Quantitative in-vivo monitoring of bone formation in multiple myeloma patients following treatment with bortezomib: A pilot study

Background: Continuous suppression of bone formation, even after treatment, is a major concern in multiple myeloma (MM) patients. The proteasome inhibitor bortezomib has been found to stimulate bone formation. Although this has been supported by measurements of biochemical markers of bone remodelling, only in a limited number of patients an actual increase in osteoblasts has been shown. Moreover, the gold standard for quantification of bone formation is the mineral apposition rate (MAR) in non-decalcified bone biopsies. A non-invasive alternative could be [18F] Fluoride PET scan, in which uptake reflects osteoblastic activity. Objective: In this pilot study we aimed to validate the ability of [18F] Fluoride PET scan for quantitative measurement of in-vivo and on-site bone formation in MM patients by comparing the mean standard uptake value (SUVmean) with the gold standard: MAR. Methods and Results: In 5 bortezomib-naive patients with relapsed MM a total of 8 [18F] Fluoride PET-CT scans, [18F] FDG PET-CT scans and bone biopsies were performed: in 5 patients before and in 3 patients following 4 cycles of bortezomib monotherapy. [18F] Fluoride PET scans were performed 60 minutes after injection of 2.1 MBq [18F] Fluoride/kg, [18F] FDG PET scans were performed after injection of 6.9 MBq [18F] FDG/kg/minutes-bed position. Low dose (30mAs) CT was performed both for attenuation correction and imaging of the bone. Bone biopsies of the left spina iliaca posterior were taken after tetracycline labelling (2-10-2). They were included in methylmethacrylate without decalcification. Measurements of MAR were made on unstained sections. Patients did not receive steroids or bisphosphonates during participation in the study. We found a significant correlation between the SUVmean of the left spina iliaca posterior and the MAR (correlation coefficient 0.751, p=0.046). In 3 patients, who received a minimum of 4 cycles of bortezomib, the effect of bortezomib on bone remodelling was evaluated by [18F] Fluoride PET at the active disease sites, defined as [18F] FDG positive-localisations before treatment. These results were compared with response rate as defined by the IMWG criteria and [18F] FDG PET-CT scans after 4 cycles of bortezomib. In 1 patient with extensive bone disease and a large plasmacytoma of costa 9, in all lesions there was a decrease in FDG-uptake following therapy, simultaneously [18F]-Fluoride uptake increased. Moreover, there was a pronounced and biologically significant increase in MAR from 1.04 μm/day to 1.26 μm/day. In the other 2 patients the comparison between [18F] FDG and [18F] Fluoride was hampered by a concomitant rib fracture and by a heterogeneous response. However, there was a correlation between the changes in MAR and SUV. Moreover, in one patient there was an increase in [18F]-Fluoride uptake, with a similar increase in MAR in the unaffected spinal bone, suggesting effect of bortezomib, independent of response. Conclusion: We found a significant correlation between quantification of bone formation by [18F] Fluoride PET and MAR, strongly suggesting that this non-invasive imaging technique can replace the invasive gold standard. Moreover, the [18F] Fluoride PET-CT scan was found to provide insight in bone remodelling in the whole body, being important because of heterogeneous responses. Despite the small number of patients included in this study, bortezomib was found to affect [18F] Fluoride indeed. In addition, our data suggest that the results of [18F] Fluoride PET-CT are not necessarily in line with the remission status according to the IMWG or the [18F] FDG PET-CT.