Skip to main content Accessibility help
×
Hostname: page-component-78c5997874-v9fdk Total loading time: 0 Render date: 2024-11-03T01:15:56.582Z Has data issue: false hasContentIssue false

6 - DIAGNOSIS AND TREATMENT OF MYELOMA BONE DISEASE

Published online by Cambridge University Press:  11 July 2009

S. Vincent Rajkumar
Affiliation:
Mayo Clinic, Minnesota
Robert A. Kyle
Affiliation:
Mayo Clinic, Minnesota
Get access

Summary

INTRODUCTION

Multiple myeloma (MM) is the most common cancer to metastasize to bone, with up to 90% of patients developing bone lesions. The bone lesions are purely osteolytic in nature and do not heal in the vast majority of patients. Up to 60% of patients develop pathological fractures over the course of their disease. Bone disease is a hallmark of MM, and myeloma bone disease differs from bone metastasis caused by other tumors. Although myeloma and other osteolytic metastases induce increased osteoclastic bone destruction, in contrast to other tumors, once myeloma tumor burden exceeds 50% in a local area, osteoblast activity is either severely depressed or absent. The basis for this severe imbalance between increased osteoclastic bone resorption and decreased bone formation has been the topic of intensive investigation over the past several years. These studies have helped to identify novel targets for treating myeloma bone disease and are discussed subsequently in this chapter.

The clinical and economic impact of myeloma bone disease in patients with myeloma can be catastrophic. Saad and coworkers retrospectively evaluated data from patients on the control arms of randomized trials of zoledronic acid to assess the impact of pathological fractures on survival of patients with malignant disease. A total of 3049 patients with metastatic bone disease were included in this study, of which 513 had myeloma. Patients with myeloma had the highest incidence of fracture (43%) over the 21 months of the study compared to patients with breast cancer, prostate cancer, and lung cancer.

Type
Chapter
Information
Publisher: Cambridge University Press
Print publication year: 2008

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Roodman, GD.Pathogenesis of myeloma bone disease. Blood Cells Mol Dis 2004;32:290–2.CrossRefGoogle ScholarPubMed
Melton, LJ III, Kyle, RA, Achenbach, SJ, Oberg, AL, Rajkumar, SV.Fracture risk with multiple myeloma: a population-based study. J Bone Miner Res 2005;20:487–93.CrossRefGoogle ScholarPubMed
Taube, T, Beneton, MN, Mccloskey, EV, Rogers, S, Greaves, M, Kanis, JA.Abnormal bone remodelling in patients with myelomatosis and normal biochemical indices of bone resorption. Eur J Haematol 1992;49:192–8.CrossRefGoogle ScholarPubMed
Saad, F, Lipton, A, Cook, R, Chen, YM, Smith, M, Coleman, R.Pathologic fractures correlate with reduced survival in patients with malignant bone disease. Cancer 2007;110:1860–7.CrossRefGoogle ScholarPubMed
Schulman, KL, Kohles, J.Economic burden of metastatic bone disease in the U.S. Cancer 2007;109:2334–42.CrossRefGoogle ScholarPubMed
Kyle, RA, Therneau, TM, Rajkumar, SV, Larson, DR, Plevak, MF, Melton, LJ. Incidence of multiple myeloma in Olmsted County, Minnesota: trend over 6 decades. Cancer 2004; 101:2667–74.CrossRefGoogle ScholarPubMed
Oyajobi, BO.Multiple myeloma/hypercalcemia [review]. Arthritis Res Ther 2007;9 (suppl 1):S4.CrossRefGoogle Scholar
Sourbier, C, Massfelder, T.Parathyroid hormone-related protein in human renal cell carcinoma. Cancer Lett 2006;240:170–82.CrossRefGoogle ScholarPubMed
Horiuchi, T, Miyachi, T, Arai, T, Nakamura, T, Mori, M, Ito, H.Raised plasma concentrations of parathyroid hormone related peptide in hypercalcemic multiple myeloma. Horm Metab Res 1997;29:469–71.CrossRefGoogle ScholarPubMed
Wang, K, Allen, L, Fung, E, Chan, CC, Chan, JC, Griffith, JF.Bone scintigraphy in common tumors with osteolytic components [review]. Clin Nucl Med 2005;30:655–71.CrossRefGoogle Scholar
Collins, CD. Multiple Myeloma. In: Imaging In Oncology. Ed. By Husband, J. E. & Resnick, R. H.. Publisher: London; Boca Raton: Taylor & Francis. 2nd Edition, Vol. 2; Chapter 33, pp. 875–89, 2004.
Snapper, I, Khan, A. Myelomatosis: fundamentals and clinical features. University Park Press, Baltimore; 1971.
Mele, A, Offidani, M, Visani, G, et al. Technetium-99m sestamibi scintigraphy is sensitive and specific for the staging and the follow-up of patients with multiple myeloma: a multicentre study on 397 scans. Br J Haematol 2007;136:729–35.CrossRefGoogle ScholarPubMed
Moulopoulos, , Dimopoulos, MA, Smith, TL, et al. Prognostic significance of magnetic resonance imaging in patients with asymptomatic multiple myeloma. J Clin Oncol 1995;13:251–6.CrossRefGoogle ScholarPubMed
Lecouvet, FE, Vande Berg, BC, Malghem, J, Maldague, BE.Magnetic resonance and computed tomography imaging in multiple myeloma. Semin Musculoskelet Radiol 2001;5:43–55.CrossRefGoogle ScholarPubMed
D'Sa, S, Abildgaard, N, Tighe, J, Shaw, P, Hall-Craggs, M.Guidelines for the use of imaging in the management of myeloma. Br J Haematol 2007;137:49–63.CrossRefGoogle ScholarPubMed
Lecouvet, FE, Vande Berg, BC, Michaux, L, et al. Stage III multiple myeloma: clinical and prognostic value of spinal bone marrow MR imaging. Radiology 1998;209:653–60.CrossRefGoogle ScholarPubMed
Walker, R, Barlogie, B, Haessler, J.Magnetic resonance imaging in multiple myeloma: diagnostic and clinical implications. J Clin Oncol 2007;25:1121–8.CrossRefGoogle ScholarPubMed
Dimopoulos, MA, Moulopoulos, , Datseris, I, et al. Imaging of myeloma bone disease – implications for staging, prognosis and follow-up. Acta Oncol 2000;39:823–7.CrossRefGoogle ScholarPubMed
Moulopoulos, , Dimopoulos, MA, Weber, D, Fuller, L, Libshitz, HI, Alexanian, R.Magnetic resonance imaging in the staging of solitary plasmacytoma of bone. J Clin Oncol 1993;11:1311–15.CrossRefGoogle ScholarPubMed
Bredella, MA, Steinbach, L, Caputo, G, Segall, G, Hawkins, R.Value of FDG PET in the assessment of patients with multiple myeloma. Am J Roentgenol 2005;184:1199–204.CrossRefGoogle ScholarPubMed
Nanni, C, Zamagni, E, Farsad, M, et al. Role of 18F-FDG PET/CT in the assessment of bone involvement in newly diagnosed multiple myeloma: preliminary results. Eur J Nucl Med Mol Imaging 2006;33:525–31.CrossRefGoogle ScholarPubMed
Fogelman, I, Cook, G, Israel, O, Wall, H.Positron emission tomography and bone metastases [review]. Semin Nucl Med 2005;35:135–42.CrossRefGoogle Scholar
Kimmel, DB.Mechanism of action, pharmacokinetic and pharmacodynamic profile, and clinical applications of nitrogen-containing bisphosphonates [review]. J Dent Res 2007;86:1022–33.CrossRefGoogle Scholar
Berenson, JR, Lichtenstein, A, Porter, L, et al. Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. Myeloma Aredia Study Group. J Clin Oncol 1998;16:593–602.CrossRefGoogle ScholarPubMed
Rosen, LS, Gordon, D, Antonio, BS, Kaminski, M.Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial. Cancer J 2001;7:377–87.Google ScholarPubMed
Body, JJ, Diel, IJ, Lichinitser, MR, et al. Intravenous ibandronate reduces the incidence of skeletal complications in patients with breast cancer and bone metastases. Ann Oncol 2003;14:1399–405.CrossRefGoogle ScholarPubMed
Mccloskey, EV, Dunn, JA, Kanis, JA, et al. Long-term follow-up of a prospective, double-blind, placebo-controlled randomized trial of clodronate in multiple myeloma. Br J Haematol 2001;113:1035–43.CrossRefGoogle ScholarPubMed
Kyle, RA, Yee, GC, Somerfield, MR, et al. American Society of Clinical Oncology. American Society of Clinical Oncology 2007 clinical practice guideline update on the role of bisphosphonates in multiple myeloma. J Clin Oncol 2007;25:2464–72.CrossRefGoogle Scholar
Lacy, MQ, Dispenzieri, A, Gertz, MA, et al. Mayo clinic consensus statement for the use of bisphosphonates in multiple myeloma [review]. Mayo Clin Proc 2006;81:1047–53.CrossRefGoogle Scholar
Corso, A, Ferretti, E, Lazzarino, M.Zoledronic acid exerts its antitumor effect in multiple myeloma interfering with the bone marrow microenvironment [review]. Hematology 2005;10:215–24.CrossRefGoogle Scholar
Avcu, F, Ural, AU, Yilmaz, MI.The bisphosphonate zoledronic acid inhibits the development of plasmacytoma induced in BALB/c mice by intraperitoneal injection of pristane. Eur J Haematol 2005;74:496–500.CrossRefGoogle ScholarPubMed
Croucher, P, Jagdev, S, Coleman, R.The anti-tumor potential of zoledronic acid [review]. Breast 2003;12 (suppl 2):S30–6.CrossRefGoogle Scholar
Musto, P, Petrucci, MT, Bringhen, S, et al. Final analysis of a multicenter, randomized study comparing zoledronate vs. observation in patients with asymptomatic myeloma. Blood 2007;110:164a.Google Scholar
Musto, P, Falcone, A, Sanpaolo, G, et al. Pamidronate reduces skeletal events but does not improve progression-free survival in early-stage untreated myeloma: results of a randomized trial. Leuk Lymphoma 2003;44:1545–8.CrossRefGoogle Scholar
Wang, J, Goodger, NM, Pogrel, MA.Osteonecrosis of the jaws associated with cancer chemotherapy. J Oral Maxillofac Surg 2003;61:1104–7.CrossRefGoogle ScholarPubMed
Marx, RE.Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 2003;61:1115–17.CrossRefGoogle ScholarPubMed
Wyngaert, T, Huizing, MT, Vermorken, JB.Osteonecrosis of the jaw related to the use of bisphosphonates. Curr Opin Oncol 2007;19:315–22.CrossRefGoogle ScholarPubMed
Khosla, S, Burr, D, Cauley, J, et al. American Society for Bone and Mineral Research. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2007;22:1479–91.CrossRefGoogle ScholarPubMed
Badros, A, Evangelos, T, Goloubeva, T, et al. Long-term follow-up of multiple myeloma (MM) patients (pts) with osteonecrosis of the jaw (ONJ). Blood 2007;110:1030a.Google Scholar
Badros, A, Weikel, D, Salama, A, et al. Osteonecrosis of the jaw in multiple myeloma patients: clinical features and risk factors. J Clin Oncol 2006;24:945–52.CrossRefGoogle ScholarPubMed
Clarke, BM, Boyette, J, Vural, E, Suen, JY, Anaissie, EJ, Stack, BC. Bisphosphonates and jaw osteonecrosis: the UAMS experience. Otolaryngol Head Neck Surg 2007;136:396–400.CrossRefGoogle ScholarPubMed
Khamaisi, M, Regev, E, Yarom, N, et al. Possible association between diabetes and bisphosphonate-related jaw osteonecrosis. J Clin Endocrinol Metab 2007;92:1172–5.CrossRefGoogle ScholarPubMed
Corso, A, Varettoni, M, Zappasodi, P, et al. A different schedule of zoledronic acid can reduce the risk of the osteonecrosis of the jaw in patients with multiple myeloma. Leukemia 2007;21:1545–8.CrossRefGoogle ScholarPubMed
Lentzsch, S, Ehrlich, , Roodman, GD.Pathophysiology of multiple myeloma bone disease. Hematol Oncol Clin North Am 2007;21:1035–49.CrossRefGoogle ScholarPubMed
Li, J, Sarosi, I, Yan, XQ, et al. RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism. Proc Natl Acad Sci USA 2000;97:1566–71.CrossRefGoogle ScholarPubMed
Lacey, DL, Timms, E, Tan, HL, et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 1998;93:165–76.CrossRefGoogle ScholarPubMed
Pearse, RN, Sordillo, EM, Yaccoby, S, et al. Multiple myeloma disrupts the TRANCE/osteoprotegerin cytokine axis to trigger bone destruction and promote tumor progression. Proc Natl Acad Sci USA 2001;98:11581–6.CrossRefGoogle Scholar
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.CrossRefGoogle ScholarPubMed
Sezer, O, Heider, U, Zavrski, I, KüHne, CA, Hofbauer, LC.RANK ligand and osteoprotegerin in myeloma bone disease. Blood 2003;101(6):2094–8.CrossRefGoogle ScholarPubMed
Giuliani, N, Bataille, R, Mancini, C, Lazzaretti, M, Barillé, S.Myeloma cells induce imbalance in the osteoprotegerin/osteoprotegerin ligand system in the human bone marrow environment. Blood 2001;98:3527–33.CrossRefGoogle ScholarPubMed
Croucher, PI, Shipman, CM, Lippitt, J, et al. Osteoprotegerin inhibits the development of osteolytic bone disease in multiple myeloma. Blood 2001;98:3534–40.CrossRefGoogle ScholarPubMed
Vanderkerken, K, Leenheer, E, Shipman, C, et al. Recombinant osteoprotegerin decreases tumor burden and increases survival in a murine model of multiple myeloma. Cancer Res 2003;63:287–9.Google Scholar
Sordillo, EM, Pearse, RN.RANK-Fc: a therapeutic antagonist for RANK-L in myeloma [review]. Cancer 2003;97:802–12.CrossRefGoogle Scholar
Body, JJ, Facon, T, Coleman, RE, et al. A study of the biological receptor activator of nuclear factor-kappaB ligand inhibitor, denosumab, in patients with multiple myeloma or bone metastases from breast cancer. Clin Cancer Res 2006;12:1221–8.CrossRefGoogle ScholarPubMed
Body, JJ, Greipp, P, Coleman, RE, et al. A phase I study of AMGN-0007, a recombinant osteoprotegerin construct, in patients with multiple myeloma or breast carcinoma related bone metastases. Cancer 2003;97(suppl 3):887–92.CrossRefGoogle ScholarPubMed
Choi, SJ, Cruz, JC, Craig, F, et al. Macrophage inflammatory protein 1-alpha is a potential osteoclast stimulatory factor in multiple myeloma. Blood 2000;96:671–5.Google ScholarPubMed
Choi, SJ, Oba, Y, Gazitt, Y, et al. Antisense inhibition of macrophage inflammatory protein 1-alpha blocks bone destruction in a model of myeloma bone disease. J Clin Invest 2001;108:1833–41.CrossRefGoogle Scholar
Masih-Khan, E, Trudel, S, Heise, C, et al. MIP-1alpha (CCL3) is a downstream target of FGFR3 and RAS-MAPK signaling in multiple myeloma. Blood 2006;108:3465–71.CrossRefGoogle ScholarPubMed
Giuliani, N, Rizzoli, V, Roodman, GD.Multiple myeloma bone disease: Pathophysiology of osteoblast inhibition. Blood 2006;108:3992–6.CrossRefGoogle ScholarPubMed
Tian, E, Zhan, F, Walker, R, et al. The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med 2003;349:2483–94.CrossRefGoogle ScholarPubMed
Oshima, T, Abe, M, Asano, J, et al. Myeloma cells suppress bone formation by secreting a soluble Wnt inhibitor, sFRP-2. Blood 2005;106:3160–5.CrossRefGoogle ScholarPubMed
Edwards, CM, Edwards, JR, Lwin, ST, et al. Increasing Wnt signaling in the bone marrow microenvironment inhibits the development of myeloma bone disease and reduces tumor burden in bone in vivo. Blood 2008;111:2833–42.CrossRefGoogle ScholarPubMed
Yaccoby, S, Ling, W, Zhan, F, Walker, R, Barlogie, B, Shaughnessy, JD. Antibody-based inhibition of DKK1 suppresses tumor-induced bone resorption and multiple myeloma growth in vivo. Blood 2007;109:2106–11.CrossRefGoogle ScholarPubMed
Anderson, G, Gries, M, Kurihara, N, et al. Thalidomide derivative CC-4047 inhibits osteoclast formation by down-regulation of PU.1. Blood 2006;107:3098–105.CrossRefGoogle ScholarPubMed
Terpos, E, Mihou, D, Szydlo, R, et al. The combination of intermediate doses of thalidomide with dexamethasone is an effective treatment for patients with refractory/relapsed multiple myeloma and normalizes abnormal bone remodeling, through the reduction of sRANKL/osteoprotegerin ratio. Leukemia 2005;19:1969–76.CrossRefGoogle Scholar
Tosi, P, Zamagni, E, Cellini, C, et al. First-line therapy with thalidomide, dexamethasone and zoledronic acid decreases bone resorption markers in patients with multiple myeloma. Eur J Haematol 2006;76:399–404.CrossRefGoogle ScholarPubMed
Zangari, M, Esseltine, D, Cavallo, F, et al. Predictive value of alkaline phosphatase for response and time to progression in bortezomib-treated multiple myeloma patients. Am J Hematol 2007;82:831–3.CrossRefGoogle ScholarPubMed
Giuliani, N, Morandi, F, Tagliaferri, S, et al. The proteasome inhibitor bortezomib affects osteoblast differentiation in vitro and in vivo in multiple myeloma patients. Blood 2007;110:334–8.CrossRefGoogle ScholarPubMed
Zangari, M, Cavallo, F, Suza, L, et al. Prospective evaluation of the bone anabolic effect of bortezomib in relapsed multiple myeloma (MM) patients. Blood 2007;798a.Google Scholar
Terpos, E, Heath, DJ, Rahemtulla, A, et al. Bortezomib reduces serum dickkopf-1 and receptor activator of nuclear factor-kappaB ligand concentrations and normalizes indices of bone remodeling in patients with relapsed multiple myeloma. Br J Haematol 2006;135:688–92.CrossRefGoogle Scholar
Zavrski, I, Krebbel, H, Wildemann, B, et al. Proteasome inhibitors abrogate osteoclast differentiation and osteoclast function. Biochem Biophys Res Commun 2005;333:200–5.CrossRefGoogle ScholarPubMed
Deramond, H, Depriester, C, Galibert, P, Gars, D.Percutaneous vertebroplasty with polymethylmethacrylate. Technique, indications, and results. Radiol Clin North Am 1998;36:533–46.CrossRefGoogle ScholarPubMed
Bosch, A, Frias, Z.Radiotherapy in the treatment of Multiple Myeloma. Int J Radiat Oncol Biol Phys 1988;15:1363–9.CrossRefGoogle ScholarPubMed

Save book to Kindle

To save this book to your Kindle, first ensure [email protected] is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×