EHA 2016: Pathophysiology and diagnosis of multiple myeloma bone disease. The chair of this year’s EHA educational session on myeloma, Professor Roman Hajek (University of Ostrava, Czech Republic), discusses highlights from the session.

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.

 

References

  1. Seeman E, Delmas PD. Bone quality–the material and structural basis of bone strength and fragility. N Engl J Med 2006;354:2250-61.
  2. van Bezooijen RL, ten Dijke P, Papapoulos SE, et al. SOST/sclerostin, an osteocyte-derived negative regulator of bone formation. Cytokine Growth Factor Rev 2005;16:319-27.
  3. Logothetis CJ, Lin SH. Osteoblasts in prostate cancer metastasis to bone. Nat Rev Cancer 2005;5:21-8.
  4. Piters E, Boudin E, Van Hul W. Wnt signaling: a win for bone. Arch Biochem Biophys 2008;473:112-6.
  5. Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature 2003;423:337-42.
  6. Hofbauer LC, Schoppet M. Clinical implications of the osteoprotegerin/RANKL/RANK system for bone and vascular diseases. JAMA 2004;292:490-5.
  7. Lacey DL, Timms E, Tan HL, et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 1998;93:165-76.
  8. Terpos E, Dimopoulos MA. Myeloma bone disease: pathophysiology and management. Ann Oncol 2005;16:1223-31.
  9. Moreau M, Mourah S, Dosquet C. beta-Catenin and NF-kappaB cooperate to regulate the uPA/uPAR system in cancer cells. Int J Cancer 2011;128:1280-92.
  10. 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.
  11. 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.
  12. Roussou M, Tasidou A, Dimopoulos MA, et al. Increased expression of macrophage inflammatory protein-1alpha on trephine biopsies correlates with extensive bone disease, increased angiogenesis and advanced stage in newly diagnosed patients with multiple myeloma. Leukemia 2009;23:2177-81.
  13. Sato M, Grasser W, Endo N, et al. Bisphosphonate action. Alendronate localization in rat bone and effects on osteoclast ultrastructure. J Clin Invest 1991;88:2095-105.
  14. Coxon FP, Thompson K, Roelofs AJ, et al. Visualizing mineral binding and uptake of bisphosphonate by osteoclasts and non-resorbing cells. Bone 2008;42:848-60.
  15. McClung MR, Grauer A, Boonen S, et al. Romosozumab in postmenopausal women with low bone mineral density. N Engl J Med 2014;370:412-20.
  16. Vallet S, Mukherjee S, Vaghela N, et al. Activin A promotes multiple myeloma-induced osteolysis and is a promising target for myeloma bone disease. Proc Natl Acad Sci U S A 2010;107:5124-9.
  17. Abdulkadyrov KM, Salogub GN, Khuazheva NK, et al. Sotatercept in patients with osteolytic lesions of multiple myeloma. Br J Haematol 2014;165:814-23.
  18. Dimopoulos M, Terpos E, Comenzo RL, et al. International myeloma working group consensus statement and guidelines regarding the current role of imaging techniques in the diagnosis and monitoring of multiple Myeloma. Leukemia 2009;23:1545-56.
  19. Terpos E, Moulopoulos LA, Dimopoulos MA. Advances in imaging and the management of myeloma bone disease. J Clin Oncol 2011;29:1907-15.
  20. Pianko MJ, Terpos E, Roodman GD, et al. Whole-body low-dose computed tomography and advanced imaging techniques for multiple myeloma bone disease. Clin Cancer Res 2014;20:5888-97.
  21. 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.
  22. Walker R, Barlogie B, Haessler J, et al. Magnetic resonance imaging in multiple myeloma: diagnostic and clinical implications. J Clin Oncol 2007;25:1121-8.
  23. Usmani SZ, Mitchell A, Waheed S, et al. Prognostic implications of serial 18-fluoro-deoxyglucose emission tomography in multiple myeloma treated with total therapy 3. Blood 2013;121:1819-23.
  24. Zamagni E, Nanni C, Patriarca F, et al. A prospective comparison of 18F-fluorodeoxyglucose positron emission tomography-computed tomography, magnetic resonance imaging and whole-body planar radiographs in the assessment of bone disease in newly diagnosed multiple myeloma. Haematologica 2007;92:50-5.
  25. Zamagni E, Patriarca F, Nanni C, et al. Prognostic relevance of 18-F FDG PET/CT in newly diagnosed multiple myeloma patients treated with up-front autologous transplantation. Blood 2011;118:5989-95.
  26. Nanni C, Zamagni E, Versari A, et al. Image interpretation criteria for FDG PET/CT in multiple myeloma: a new proposal from an Italian expert panel. IMPeTUs (Italian Myeloma criteria for PET USe). Eur J Nucl Med Mol Imaging 2016;43:414-21.