Pathophysiology and diagnosis of multiple myeloma bone disease
Evangelos Terpos, University of Athens School of Medicine, Greece
Osteolytic bone disease is the most common complication of MM and is seen in up to 80% of patients at the time of diagnosis. One quarter of patients with MM bone disease develop pathological fractures, and 5% of patients end up having surgery to bone. Dr Evangelos Terpos from the University of Athens School of Medicine in Greece presented an overview of the biology of MM bone disease and outlined potential targets for intervention.
Normal bone metabolism is a balance between formation of bone by osteoblasts and resorption of bone by osteoclasts.1, 2 Osteoblasts are to a large extent regulated via the Wnt signalling pathway3 with Dickkopf (Dkk) proteins and sclerostin as important inhibitors.4 The most important activator of osteoclast activity is the receptor activator of nuclear factor kappa-B ligand (RANKL).5 Osteoblasts produce osteoprotegerin (OPG) which is an inhibitor of RANKL.5-7 In MM, binding of myeloma cells to bone marrow stromal cells (BMSC) results in overproduction of chemokines with osteoclast activity such as IL-11 and TNFα, as well as overproduction of RANKL and downregulation of OPG which in turn leads to activated osteoclasts and increased bone resorption.8, 9 This shift in the RANKL/OPG ratio correlates with markers of bone resorption, osteolytic lesions, and markers of disease activity and is a predictor of survival in patients with newly-diagnosed MM.10 Another marker that has been found to be elevated in MM and which is a predictor of survival is serum macrophage inflammatory protein-1 alpha (MIP-1a) with a 3-year OS rate of 85% and 44%, respectively, in patients with MIP-1a levels below and above 48 pg/ml respectively (p=0.021).11, 12
Bisphosphonates inhibit osteoclast activity and thereby restore the RANKL/OPG balance by promoting osteoclast apoptosis.13, 14 Another inhibitor of osteoclast function is denosumab, monoclonal antibody which prevents the development of osteoclasts by acting as a RANKL inhibitor.5 A randomised phase 3 trial was recently completed which compared denosumab with zolendronate for the treatment of MM bone disease; the results will be available later this year. Other drugs that may be potential candidates for MM bone disease include romosozumab, a monoclonal antibody against sclerostin,15 and sotatercept which targets activing A, a promoter of osteoclastogenesis and inhibitor of osteoblast differentiation in MM.16, 17
Conventional X-ray was long the gold standard for diagnosing and monitoring osteolytic bone lesions in MM.18, 19 However, whole-body low-dose CT is a more sensitive imaging technique and has been shown detect up to 74 times more lesions than X-ray20 and is recommended as a new standard procedure for diagnosing lytic lesions in MM.21 Other novel techniques that are used include magnetic resonance imaging (MRI) and PET/CT.19 MRI can provide detailed information about bone marrow involvement in MM bone disease and is significantly more sensitive than conventional x-ray for detecting focal lesions.22 Focal lesions on MRI pre- and post-therapy have been found to predict OS and PFS in patients undergoing SCT.22, 23 PET/CT is also significantly more sensitive than conventional x-ray, although it is less sensitive than MRI.24 The number of focal lesions detected and the standardised uptake values (SUVs) on PET/CT have prognostic significance for PFS in SCT patients25 and PET/CT is the preferred method for follow-up. Defining the cut-off value for PET/CT positivity remains an open issue; a set of criteria have been proposed based on the type, number and location of lesions graded on the Deauville five-point scale,26 but as this system is very complex its use in clinical practice may be limited. Other open issues include how best to define stringent complete response and how often to perform PET/CT during follow-up.
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- Terpos E, Szydlo R, Apperley JF, et al. Soluble receptor activator of nuclear factor kappaB ligand-osteoprotegerin ratio predicts survival in multiple myeloma: proposal for a novel prognostic index. Blood 2003;102:1064-9.
- Terpos E, Politou M, Szydlo R, et al. Serum levels of macrophage inflammatory protein-1 alpha (MIP-1alpha) correlate with the extent of bone disease and survival in patients with multiple myeloma. Br J Haematol 2003;123:106-9.
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- Terpos E, Kleber M, Engelhardt M, et al. European Myeloma Network guidelines for the management of multiple myeloma-related complications. Haematologica 2015;100:1254-66.
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