Imaging of Bone Disease in Multiple Myeloma

Chapter 1 presents a general introduction on the pathophysiology, diagnosis, and treatment of multiple myeloma with an emphasis on myeloma-related bone disease. In Chapter 2 the results of a systematic review comparing MRI, 18F-FDG PET, CT with whole-body X-Ray or whole-body CT are presented. A comprehensive search of bibliographic databases resulted in 32 directly comparative studies. Methodological quality was assessed using QUADAS-criteria, the mean score was 7.1. The quality was hampered by a poor description of selection and execution criteria. All index tests had a higher detection rate when compared to whole-body X-Ray, with up to 80% more lesions detected, although the modern imaging techniques detected fewer lesions in the skull and ribs. CT and MRI performed equally with respect to detection rate and sensitivity. Chapter 3 describes the outcomes of a systematic review on the value of whole-body X-ray and 18F-FDG PET in staging and response assessment. Eighteen studies met the inclusion criteria. Methodological quality assessment using the QUADAS-criteria resulted in a mean of 8.5. In 7 studies concordance assessment between whole-body X-ray and 18F-FDG PET was possible, displaying a higher sensitivity of 18F-FDG PET in the detection of myeloma related bone lesions in 6 studies. The only study reporting the prognostic value at staging demonstrated that 18F-FDG-avid bone lesions are an independent prognostic parameter. Furthermore, the studies on response monitoring revealed superior clinical outcome in case of normalization of 18F-FDG PET, although limited in number. In Chapter 4 results on interobserver agreement in CT-reading are presented. Two datasets of newly diagnosed elderly myeloma patients were used. The first consists of 35 scans that were performed and analyzed before the introduction of whole-body low dose CT as the diagnostic standard. The second consists of 20 scans that were chosen at random from real world patients. Patient level analysis showed comparable levels of agreement between both datasets. The overall agreement was 90-94%, however, negative agreement was considerably lower with 75-80%, for which concomitant age-related skeletal comorbidity might be the cause. Therefore, there is disagreement on presence of bone disease in approximately 10% of cases. A correct diagnosis of bone disease is crucial to prevent incorrect treatment decisions. Specialized expert panels consisting of musculoskeletal radiologists and hematologists are of added value to prevent over- and undertreatment. Chapters 5 and 6 describe the results of a pilot study on in vivo bone formation in myeloma patients. In chapter 5 we compared 18F-Fluoride PET with MAR, the gold standard of bone formation, in myeloma patients. A significant correlation was found, indicating that 18F-Fluoride PET can serve as a surrogate marker for bone formation. Consequently, changes in bone formation could be determined following treatment with bortezomib revealing whole-body information. A pronounced inter- and intra-individual heterogeneity in 18F-Fluoride-uptake as well as response was observed. A more detailed analysis of the effect of multiple myeloma and anti-myeloma treatment on bone formation, is described in Chapter 6. For this purpose, 18F-FDG- and 18F-Fluoride-uptake in osteolytic bone lesions before and after treatment was measured. We demonstrated a spatio-temporal effect of myeloma cells on osteogenesis, with less bone formation in the active disease centers of lesions in comparison with the borders. Disease response was associated with bone formation, being more pronounced in the centers than in the borders. However, even before treatment, the 18F-Fluoride uptake was comparable with the 18F-Fluoride uptake in the non-affected bone. Although malignant plasma cells do suppress local bone formation, our findings challenge the paradigm that overall bone formation is suppressed in multiple myeloma. Therefore, we feel that whole-body 18F-Fluoride PET imaging will be helpful to unravel the complexity of bone formation in multiple myeloma.