**Author details**

regard to markers of osteoblast activation and also bone matrix deposition [118;119]. Alkaline phosphatase was found to be significantly increased in patients who responded to bortezomib treatment [119]. In another clinical study bone-specific alkaline phophatase (bALP) and osteocalcin were found to be increased not only in responding patients, but also in patients who did not achieve an anti-myeloma response to treatment with bortezomib [120]. This result supports the assumption that bortezomib may have a bone anabolic effect independent of its anti-myeloma effect. Enhancement of bone matrix deposition after mono-therapy with bortezomib, has also been shown by the demonstration of increased serum levels of PINP (Procollagen Type-I N-terminal propeptide) [118]. Both bALP and osteocalcin were found to be increased after treatment with bortezomib in a clinical study of 34 relapsed myeloma patients in non-responders and responders but the increase was highest in responding patients. However no radiographic signs of healing of the baseline osteolytic lesions were observed six month post-treatment [112]. Radiologic evidence of healing of lytic lesions was observed in six out of 11 patients who responded to combination treatment with bortezomib, melphalan, and prednisone while none of the evaluated patients who had achieved a response to treatment with melphalan and prednisone without bortezomib showed radiological signs

Pomalidomide (originally CC-4047), is a derivative of thalidomide that is anti-angiogenic and acts as an immunomodulator. Pomalidomide is now tested in Phase III clinical trials and will hopefully soon become available treatment of patients with relapsed or refractory MM. The drug has been granted orphan status for the treatment of MM by the European Medicines Agency [122]. Pomalidomide has been shown to inhibit osteoclasts differentiation in bone marrow cultures which leads to a strong inhibition of bone resorption [123]. The inhibition of osteoclast formation seems to occur through a reduction of the PU.1 expression. PU.1 is a critical transcription factor in the development of mature osteoclasts. Lenalidomide, another thalidomide derivative, has been shown to inhibit both an early step in osteoclastogenesis through reduction of PU.1 expression and to reduce secretion of RANKL from bone marrow stroma cells derived from patients with MM [124]. In a clinical study including 20 MM patients with bone disease Breitkreuts *et al.* found a significant decrease in the serum levels of the RANKL/OPG ratio after two cycles of treatment with lenalidomide [124]. Likewise, treatment with thalidomide in combination with dexamethasone has a favourable effect on the RANKL/ OPG ratio [125]. Treatment with thalidomide in combination with dexamethasone can also decrease the levels of the bone resorption markers CTX, NTX and TRACP-5b, however the treatment does not increase the bone formation marker bALP or osteocalcin [126]. The failure to increase bone formations markers in serum, correlates with the observation that none of the responding patients in a clinical study of patients treated with a thalidomide/dexamethasone

combination, showed any radiological signs of healing of osteolytic lesions [125].

The pathophysiology in multiple myeloma bone disease is complex. There is evidence that not only osteoclast activity but also other cells and structures responsible for normal bone

of healing [121].

228 Multiple Myeloma - A Quick Reflection on the Fast Progress

**7. Conclusion**

Maja Hinge1\*, Thomas Lund2 , Jean-Marie Delaisse1 and Torben Plesner3

\*Address all correspondence to: maja.hinge@slb.regionsyddanmark.dk

1 Department of Clinical Cell Biology, Vejle/Lillebælt Hospital, University of Southern Denmark, Vejle, Denmark

2 Department of Haematology, Odense University Hospital, Odense, Denmark

3 Department of Internal Medicine, Division of Haematology, Vejle/Lillebælt Hospital, University of Southern Denmark, Denmark

#### **References**

[1] Kyle RA, Therneau TM, Rajkumar SV, Larson DR, Plevak MF, Melton LJ, III. Inci‐ dence of multiple myeloma in Olmsted County, Minnesota: Trend over 6 decades. Cancer 2004 Dec 1;101(11):2667-74.

[2] Kyle RA, Gertz MA, Witzig TE, Lust JA, Lacy MQ, Dispenzieri A, Fonseca R, Rajku‐ mar SV, Offord JR, Larson DR, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin.Proc. 2003 Jan;78(1):21-33.

[15] Hauge EM, Qvesel D, Eriksen EF, Mosekilde L, Melsen F. Cancellous bone remodel‐ ing occurs in specialized compartments lined by cells expressing osteoblastic mark‐

Bone Disease in Multiple Myeloma http://dx.doi.org/10.5772/55190 231

[16] Andersen TL, Soe K, Sondergaard TE, Plesner T, Delaisse JM. Myeloma cell-induced disruption of bone remodelling compartments leads to osteolytic lesions and genera‐ tion of osteoclast-myeloma hybrid cells. Br.J.Haematol. 2010 Feb;148(4):551-61.

[17] Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature

[18] Hofbauer LC, Schoppet M. Clinical implications of the osteoprotegerin/RANKL/ RANK system for bone and vascular diseases. JAMA 2004 Jul 28;292(4):490-5.

[19] Uneda S, Hata H, Matsuno F, Harada N, Mitsuya Y, Kawano F, Mitsuya H. Macro‐ phage inflammatory protein-1 alpha is produced by human multiple myeloma (MM) cells and its expression correlates with bone lesions in patients with MM. Br.J.Hae‐

[20] Han JH, Choi SJ, Kurihara N, Koide M, Oba Y, Roodman GD. Macrophage inflam‐ matory protein-1alpha is an osteoclastogenic factor in myeloma that is independent of receptor activator of nuclear factor kappaB ligand. Blood 2001 Jun 1;97(11):3349-53.

[21] Oba Y, Lee JW, Ehrlich LA, Chung HY, Jelinek DF, Callander NS, Horuk R, Choi SJ, Roodman GD. MIP-1alpha utilizes both CCR1 and CCR5 to induce osteoclast forma‐ tion and increase adhesion of myeloma cells to marrow stromal cells. Exp.Hematol.

[22] Bataille R, Chappard D, Marcelli C, Rossi JF, Dessauw P, Baldet P, Sany J, Alexandre C. Osteoblast stimulation in multiple myeloma lacking lytic bone lesions. Br.J.Hae‐

[23] Taube T, Beneton MN, McCloskey EV, Rogers S, Greaves M, Kanis JA. Abnormal bone remodelling in patients with myelomatosis and normal biochemical indices of

[24] Valentin-Opran A, Charhon SA, Meunier PJ, Edouard CM, Arlot ME. Quantitative histology of myeloma-induced bone changes. Br.J.Haematol. 1982 Dec;52(4):601-10.

[25] Pearse RN, Sordillo EM, Yaccoby S, Wong BR, Liau DF, Colman N, Michaeli J, Ep‐ stein J, Choi Y. Multiple myeloma disrupts the TRANCE/ osteoprotegerin cytokine axis to trigger bone destruction and promote tumor progression.

[26] Terpos E, Szydlo R, Apperley JF, Hatjiharissi E, Politou M, Meletis J, Viniou N, Yata‐ ganas X, Goldman JM, Rahemtulla A. Soluble receptor activator of nuclear factor kappaB ligand-osteoprotegerin ratio predicts survival in multiple myeloma: proposal

bone resorption. Eur.J.Haematol. 1992 Oct;49(4):192-8.

Proc.Natl.Acad.Sci.U.S.A 2001 Sep 25;98(20):11581-6.

for a novel prognostic index. Blood 2003 Aug 1;102(3):1064-9.

ers. J.Bone Miner.Res. 2001 Sep;16(9):1575-82.

2003 May 15;423(6937):337-42.

matol. 2003 Jan;120(1):53-5.

2005 Mar;33(3):272-8.

matol. 1990 Dec;76(4):484-7.


[15] Hauge EM, Qvesel D, Eriksen EF, Mosekilde L, Melsen F. Cancellous bone remodel‐ ing occurs in specialized compartments lined by cells expressing osteoblastic mark‐ ers. J.Bone Miner.Res. 2001 Sep;16(9):1575-82.

[2] Kyle RA, Gertz MA, Witzig TE, Lust JA, Lacy MQ, Dispenzieri A, Fonseca R, Rajku‐ mar SV, Offord JR, Larson DR, et al. Review of 1027 patients with newly diagnosed

[3] 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 Mar;20(3):

[4] Wisloff F, Hjorth M. Health-related quality of life assessed before and during chemo‐ therapy predicts for survival in multiple myeloma. Nordic Myeloma Study Group.

[5] Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and re‐

[6] Giuliani N, Ferretti M, Bolzoni M, Storti P, Lazzaretti M, Dalla PB, Bonomini S, Mar‐ tella E, Agnelli L, Neri A, et al. Increased osteocyte death in multiple myeloma pa‐ tients: role in myeloma-induced osteoclast formation. Leukemia 2012 Jun;26(6):

[7] Roodman GD. Cell biology of the osteoclast. Exp.Hematol. 1999 Aug;27(8):1229-41.

[8] Wada T, Nakashima T, Hiroshi N, Penninger JM. RANKL-RANK signaling in osteo‐

[9] Baron R, Neff L, Louvard D, Courtoy PJ. Cell-mediated extracellular acidification and bone resorption: evidence for a low pH in resorbing lacunae and localization of a 100-kD lysosomal membrane protein at the osteoclast ruffled border. J.Cell Biol. 1985

[10] Delaisse JM, Andersen TL, Engsig MT, Henriksen K, Troen T, Blavier L. Matrix met‐ alloproteinases (MMP) and cathepsin K contribute differently to osteoclastic activi‐

[11] Datta HK, Ng WF, Walker JA, Tuck SP, Varanasi SS. The cell biology of bone metabo‐

[12] Gavriatopoulou M, Dimopoulos MA, Christoulas D, Migkou M, Iakovaki M, Gkotza‐ manidou M, Terpos E. Dickkopf-1: a suitable target for the management of myeloma

[13] Khosla S, Westendorf JJ, Oursler MJ. Building bone to reverse osteoporosis and re‐

[14] Andersen TL, Sondergaard TE, Skorzynska KE, gnaes-Hansen F, Plesner TL, Hauge EM, Plesner T, Delaisse JM. A physical mechanism for coupling bone resorption and

sponse assessment of multiple myeloma. Leukemia 2009 Jan;23(1):3-9.

clastogenesis and bone disease. Trends Mol.Med. 2006 Jan;12(1):17-25.

ties. Microsc.Res.Tech. 2003 Aug 15;61(6):504-13.

pair fractures. J.Clin.Invest 2008 Feb;118(2):421-8.

bone disease. Expert.Opin.Ther.Targets. 2009 Jul;13(7):839-48.

formation in adult human bone. Am.J.Pathol. 2009 Jan;174(1):239-47.

lism. J.Clin.Pathol. 2008 May;61(5):577-87.

multiple myeloma. Mayo Clin.Proc. 2003 Jan;78(1):21-33.

Br.J.Haematol. 1997 Apr;97(1):29-37.

230 Multiple Myeloma - A Quick Reflection on the Fast Progress

487-93.

1391-401.

Dec;101(6):2210-22.


[27] Choi SJ, Cruz JC, Craig F, Chung H, Devlin RD, Roodman GD, Alsina M. Macro‐ phage inflammatory protein 1-alpha is a potential osteoclast stimulatory factor in multiple myeloma. Blood 2000 Jul 15;96(2):671-5.

[39] Abe M, Hiura K, Wilde J, Shioyasono A, Moriyama K, Hashimoto T, Kido S, Oshima T, Shibata H, Ozaki S, et al. Osteoclasts enhance myeloma cell growth and survival via cell-cell contact: a vicious cycle between bone destruction and myeloma expan‐

Bone Disease in Multiple Myeloma http://dx.doi.org/10.5772/55190 233

[40] Sprynski AC, Hose D, Caillot L, Reme T, Shaughnessy JD, Jr., Barlogie B, Seckinger A, Moreaux J, Hundemer M, Jourdan M, et al. The role of IGF-1 as a major growth factor for myeloma cell lines and the prognostic relevance of the expression of its re‐

[41] Tanaka Y, Abe M, Hiasa M, Oda A, Amou H, Nakano A, Takeuchi K, Kitazoe K, Ki‐ do S, Inoue D, et al. Myeloma cell-osteoclast interaction enhances angiogenesis to‐ gether with bone resorption: a role for vascular endothelial cell growth factor and

[42] Vanderkerken K, De LE, Shipman C, Asosingh K, Willems A, Van CB, Croucher P. Recombinant osteoprotegerin decreases tumor burden and increases survival in a

[43] Yaccoby S, Pearse RN, Johnson CL, Barlogie B, Choi Y, Epstein J. Myeloma interacts with the bone marrow microenvironment to induce osteoclastogenesis and is de‐

[44] Brincker H, Westin J, Abildgaard N, Gimsing P, Turesson I, Hedenus M, Ford J, Kan‐ dra A. Failure of oral pamidronate to reduce skeletal morbidity in multiple myeloma: a double-blind placebo-controlled trial. Danish-Swedish co-operative study group.

[45] Menssen HD, Sakalova A, Fontana A, Herrmann Z, Boewer C, Facon T, Lichinitser MR, Singer CR, Euller-Ziegler L, Wetterwald M, et al. Effects of long-term intrave‐ nous ibandronate therapy on skeletal-related events, survival, and bone resorption markers in patients with advanced multiple myeloma. J.Clin.Oncol. 2002 May

[46] Berenson JR, Lichtenstein A, Porter L, Dimopoulos MA, Bordoni R, George S, Lipton A, Keller A, Ballester O, Kovacs M, et al. Long-term pamidronate treatment of ad‐ vanced multiple myeloma patients reduces skeletal events. Myeloma Aredia Study

[47] Mhaskar R, Redzepovic J, Wheatley K, Clark OA, Miladinovic B, Glasmacher A, Ku‐ mar A, Djulbegovic B. Bisphosphonates in multiple myeloma: a network meta-analy‐

[48] Modi ND, Lentzsch S. Bisphosphonates as antimyeloma drugs. Leukemia 2012 Apr;

[49] Morgan GJ, Davies FE, Gregory WM, Cocks K, Bell SE, Szubert AJ, Navarro-Coy N, Drayson MT, Owen RG, Feyler S, et al. First-line treatment with zoledronic acid as

murine model of multiple myeloma. Cancer Res. 2003 Jan 15;63(2):287-9.

pendent on osteoclast activity. Br.J.Haematol. 2002 Feb;116(2):278-90.

sion. Blood 2004 Oct 15;104(8):2484-91.

ceptor. Blood 2009 May 7;113(19):4614-26.

Br.J.Haematol. 1998 May;101(2):280-6.

Group. J.Clin.Oncol. 1998 Feb;16(2):593-602.

sis. Cochrane.Database.Syst.Rev. 2012;5:CD003188.

1;20(9):2353-9.

26(4):589-94.

osteopontin. Clin.Cancer Res. 2007 Feb 1;13(3):816-23.


[39] Abe M, Hiura K, Wilde J, Shioyasono A, Moriyama K, Hashimoto T, Kido S, Oshima T, Shibata H, Ozaki S, et al. Osteoclasts enhance myeloma cell growth and survival via cell-cell contact: a vicious cycle between bone destruction and myeloma expan‐ sion. Blood 2004 Oct 15;104(8):2484-91.

[27] Choi SJ, Cruz JC, Craig F, Chung H, Devlin RD, Roodman GD, Alsina M. Macro‐ phage inflammatory protein 1-alpha is a potential osteoclast stimulatory factor in

[28] Terpos E, Politou M, Szydlo R, Goldman JM, Apperley JF, Rahemtulla A. Serum lev‐ els of macrophage inflammatory protein-1 alpha (MIP-1alpha) correlate with the ex‐ tent of bone disease and survival in patients with multiple myeloma. Br.J.Haematol.

[29] Hashimoto T, Abe M, Oshima T, Shibata H, Ozaki S, Inoue D, Matsumoto T. Ability of myeloma cells to secrete macrophage inflammatory protein (MIP)-1alpha and MIP-1beta correlates with lytic bone lesions in patients with multiple myeloma.

[30] Niida S, Kaku M, Amano H, Yoshida H, Kataoka H, Nishikawa S, Tanne K, Maeda N, Nishikawa S, Kodama H. Vascular endothelial growth factor can substitute for macrophage colony-stimulating factor in the support of osteoclastic bone resorption.

[31] Tanaka Y, Abe M, Hiasa M, Oda A, Amou H, Nakano A, Takeuchi K, Kitazoe K, Ki‐ do S, Inoue D, et al. Myeloma cell-osteoclast interaction enhances angiogenesis to‐ gether with bone resorption: a role for vascular endothelial cell growth factor and

[32] Edwards CM, Zhuang J, Mundy GR. The pathogenesis of the bone disease of multi‐

[33] Lentzsch S, Ehrlich LA, Roodman GD. Pathophysiology of multiple myeloma bone

[34] Edwards CM, Zhuang J, Mundy GR. The pathogenesis of the bone disease of multi‐

[35] Giuliani N, Bataille R, Mancini C, Lazzaretti M, Barille S. Myeloma cells induce im‐ balance in the osteoprotegerin/osteoprotegerin ligand system in the human bone

[36] Cheung WC, Van NB. Distinct IL-6 signal transduction leads to growth arrest and death in B cells or growth promotion and cell survival in myeloma cells. Leukemia

[37] Andersen TL, Boissy P, Sondergaard TE, Kupisiewicz K, Plesner T, Rasmussen T, Haaber J, Kolvraa S, Delaisse JM. Osteoclast nuclei of myeloma patients show chro‐ mosome translocations specific for the myeloma cell clone: a new type of cancer-host

[38] Yaccoby S, Wezeman MJ, Henderson A, Cottler-Fox M, Yi Q, Barlogie B, Epstein J. Cancer and the microenvironment: myeloma-osteoclast interactions as a model. Can‐

disease. Hematol.Oncol.Clin.North Am. 2007 Dec;21(6):1035-49, viii.

multiple myeloma. Blood 2000 Jul 15;96(2):671-5.

2003 Oct;123(1):106-9.

232 Multiple Myeloma - A Quick Reflection on the Fast Progress

Br.J.Haematol. 2004 Apr;125(1):38-41.

J.Exp.Med. 1999 Jul 19;190(2):293-8.

osteopontin. Clin.Cancer Res. 2007 Feb 1;13(3):816-23.

marrow environment. Blood 2001 Dec 15;98(13):3527-33.

ple myeloma. Bone 2008 Jun;42(6):1007-13.

ple myeloma. Bone 2008 Jun;42(6):1007-13.

partnership? J.Pathol. 2007 Jan;211(1):10-7.

cer Res. 2004 Mar 15;64(6):2016-23.

2002 Jun;16(6):1182-8.


compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a rando‐ mised controlled trial. Lancet 2010 Dec 11;376(9757):1989-99.

[61] Drake MT, Clarke BL, Khosla S. Bisphosphonates: mechanism of action and role in

Bone Disease in Multiple Myeloma http://dx.doi.org/10.5772/55190 235

[62] Belch AR, Bergsagel DE, Wilson K, O'Reilly S, Wilson J, Sutton D, Pater J, Johnston D, Zee B. Effect of daily etidronate on the osteolysis of multiple myeloma. J.Clin.Oncol.

[63] Lahtinen R, Laakso M, Palva I, Virkkunen P, Elomaa I. Randomised, placebo-control‐ led multicentre trial of clodronate in multiple myeloma. Finnish Leukaemia Group.

[64] Berenson JR, Lichtenstein A, Porter L, Dimopoulos MA, Bordoni R, George S, Lipton A, Keller A, Ballester O, Kovacs M, et al. Long-term pamidronate treatment of ad‐ vanced multiple myeloma patients reduces skeletal events. Myeloma Aredia Study

[65] Berenson JR, Lichtenstein A, Porter L, Dimopoulos MA, Bordoni R, George S, Lipton A, Keller A, Ballester O, Kovacs MJ, et al. Efficacy of pamidronate in reducing skele‐ tal events in patients with advanced multiple myeloma. Myeloma Aredia Study

[66] Rosen LS, Gordon D, Kaminski M, Howell A, Belch A, Mackey J, Apffelstaedt J, Hus‐ sein MA, Coleman RE, Reitsma DJ, et al. Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complica‐ tions in patients with advanced multiple myeloma or breast carcinoma: a random‐ ized, double-blind, multicenter, comparative trial. Cancer 2003 Oct 15;98(8):1735-44.

[67] Attal M, Harousseau JL, Leyvraz S, Doyen C, Hulin C, Benboubker L, Yakoub A, I, Bourhis JH, Garderet L, Pegourie B, et al. Maintenance therapy with thalidomide im‐ proves survival in patients with multiple myeloma. Blood 2006 Nov 15;108(10):

[68] Aviles A, Nambo MJ, Neri N, Castaneda C, Cleto S, Huerta-Guzman J. Antitumor ef‐ fect of zoledronic acid in previously untreated patients with multiple myeloma.

[69] Berendson J DMCY-M. Improved survival in patients wiht multiple myeloma and high bALP levels treated wiht zoledronic acid compared wiht pamidronate: univari‐ ate and multivariate models of hazard ratios. 48th ASH, Annual Meeting and Expo‐

sion 2006 December 9-12, Orlando, FL.Abstract 3589 . 2006. Ref Type: Abstract

in multiple myeloma. Br.J.Haematol. 2001 Jun;113(4):1035-43.

[70] McCloskey EV, Dunn JA, Kanis JA, MacLennan IC, Drayson MT. Long-term followup of a prospective, double-blind, placebo-controlled randomized trial of clodronate

[71] Mhaskar R, Redzepovic J, Wheatley K, Clark OA, Miladinovic B, Glasmacher A, Ku‐ mar A, Djulbegovic B. Bisphosphonates in multiple myeloma. Cochrane.Data‐

clinical practice. Mayo Clin.Proc. 2008 Sep;83(9):1032-45.

1991 Aug;9(8):1397-402.

3289-94.

Med.Oncol. 2007;24(2):227-30.

base.Syst.Rev. 2010;(3):CD003188.

Lancet 1992 Oct 31;340(8827):1049-52.

Group. J.Clin.Oncol. 1998 Feb;16(2):593-602.

Group. N.Engl.J.Med. 1996 Feb 22;334(8):488-93.


[61] Drake MT, Clarke BL, Khosla S. Bisphosphonates: mechanism of action and role in clinical practice. Mayo Clin.Proc. 2008 Sep;83(9):1032-45.

compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a rando‐

[50] Taube T, Beneton MN, McCloskey EV, Rogers S, Greaves M, Kanis JA. Abnormal bone remodelling in patients with myelomatosis and normal biochemical indices of

[51] Tian E, Zhan F, Walker R, Rasmussen E, Ma Y, Barlogie B, Shaughnessy JD, Jr. The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions

[52] Giuliani N, Colla S, Morandi F, Lazzaretti M, Sala R, Bonomini S, Grano M, Colucci S, Svaldi M, Rizzoli V. Myeloma cells block RUNX2/CBFA1 activity in human bone marrow osteoblast progenitors and inhibit osteoblast formation and differentiation.

[53] Eisenberger S, Ackermann K, Voggenreiter G, Sultmann H, Kasperk C, Pyerin W. Metastases and multiple myeloma generate distinct transcriptional footprints in os‐

[54] Abildgaard N, Glerup H, Rungby J, dix-Hansen K, Kassem M, Brixen K, Heicken‐ dorff L, Nielsen JL, Eriksen EF. Biochemical markers of bone metabolism reflect os‐ teoclastic and osteoblastic activity in multiple myeloma. Eur.J.Haematol. 2000 Feb;

[55] Abildgaard N, Brixen K, Eriksen EF, Kristensen JE, Nielsen JL, Heickendorff L. Se‐ quential analysis of biochemical markers of bone resorption and bone densitometry

[56] Terpos E, Palermos J, Tsionos K, Anargyrou K, Viniou N, Papassavas P, Meletis J, Ya‐ taganas X. Effect of pamidronate administration on markers of bone turnover and

[57] Lund T, Abildgaard N, Delaisse JM, Plesner T. Effect of withdrawal of zoledronic acid treatment on bone remodelling markers in multiple myeloma. Br.J.Haematol.

[58] Terpos E, Dimopoulos MA, Sezer O, Roodman D, Abildgaard N, Vescio R, Tosi P, Garcia-Sanz R, Davies F, Chanan-Khan A, et al. The use of biochemical markers of bone remodeling in multiple myeloma: a report of the International Myeloma Work‐

[59] Khan SA, Kanis JA, Vasikaran S, Kline WF, Matuszewski BK, McCloskey EV, Bene‐ ton MN, Gertz BJ, Sciberras DG, Holland SD, et al. Elimination and biochemical re‐ sponses to intravenous alendronate in postmenopausal osteoporosis. J.Bone

[60] Ramaswamy B, Shapiro CL. Bisphosphonates in the prevention and treatment of

bone metastases. Oncology (Williston.Park) 2003 Sep;17(9):1261-70.

disease activity in multiple myeloma. Eur.J.Haematol. 2000 Nov;65(5):331-6.

mised controlled trial. Lancet 2010 Dec 11;376(9757):1989-99.

in multiple myeloma. N.Engl.J.Med. 2003 Dec 25;349(26):2483-94.

bone resorption. Eur.J.Haematol. 1992 Oct;49(4):192-8.

teocytes in vivo. J.Pathol. 2008 Apr;214(5):617-26.

ing Group. Leukemia 2010 Oct;24(10):1700-12.

Miner.Res. 1997 Oct;12(10):1700-7.

in multiple myeloma. Haematologica 2004 May;89(5):567-77.

Blood 2005 Oct 1;106(7):2472-83.

234 Multiple Myeloma - A Quick Reflection on the Fast Progress

64(2):121-9.

2010 Oct;151(1):92-3.


[72] Mhaskar R, Redzepovic J, Wheatley K, Clark OA, Miladinovic B, Glasmacher A, Ku‐ mar A, Djulbegovic B. Bisphosphonates in multiple myeloma: a network meta-analy‐ sis. Cochrane.Database.Syst.Rev. 2012;5:CD003188.

[83] Freiberger JJ. Utility of hyperbaric oxygen in treatment of bisphosphonate-related os‐ teonecrosis of the jaws. J.Oral Maxillofac.Surg. 2009 May;67(5 Suppl):96-106.

Bone Disease in Multiple Myeloma http://dx.doi.org/10.5772/55190 237

[84] Montebugnoli L, Felicetti L, Gissi DB, Pizzigallo A, Pelliccioni GA, Marchetti C. Bi‐ phosphonate-associated osteonecrosis can be controlled by nonsurgical management.

[85] Cella L, Oppici A, Arbasi M, Moretto M, Piepoli M, Vallisa D, Zangrandi A, Di NC, Cavanna L. Autologous bone marrow stem cell intralesional transplantation repair‐ ing bisphosphonate related osteonecrosis of the jaw. Head Face.Med. 2011;7:16. [86] Agrillo A, Petrucci MT, Tedaldi M, Mustazza MC, Marino SM, Gallucci C, Iannetti G. New therapeutic protocol in the treatment of avascular necrosis of the jaws. J.Cranio‐

[87] Ripamonti CI, Maniezzo M, Campa T, Fagnoni E, Brunelli C, Saibene G, Bareggi C, Ascani L, Cislaghi E. Decreased occurrence of osteonecrosis of the jaw after imple‐ mentation of dental preventive measures in solid tumour patients with bone meta‐ stases treated with bisphosphonates. The experience of the National Cancer Institute

[88] Dimopoulos MA, Kastritis E, Bamia C, Melakopoulos I, Gika D, Roussou M, Migkou M, Eleftherakis-Papaiakovou E, Christoulas D, Terpos E, et al. Reduction of osteonec‐ rosis of the jaw (ONJ) after implementation of preventive measures in patients with multiple myeloma treated with zoledronic acid. Ann.Oncol. 2009 Jan;20(1):117-20. [89] Terpos E, Sezer O, Croucher PI, Garcia-Sanz R, Boccadoro M, San MJ, Ashcroft J, Blade J, Cavo M, Delforge M, et al. The use of bisphosphonates in multiple myeloma: recommendations of an expert panel on behalf of the European Myeloma Network.

[90] Durie BG. Use of bisphosphonates in multiple myeloma: IMWG response to Mayo

[91] Kyle RA, Yee GC, Somerfield MR, Flynn PJ, Halabi S, Jagannath S, Orlowski RZ, Roodman DG, Twilde P, Anderson K. American Society of Clinical Oncology 2007 clinical practice guideline update on the role of bisphosphonates in multiple myelo‐

[92] Lacy MQ, Dispenzieri A, Gertz MA, Greipp PR, Gollbach KL, Hayman SR, Kumar S, Lust JA, Rajkumar SV, Russell SJ, et al. Mayo clinic consensus statement for the use of bisphosphonates in multiple myeloma. Mayo Clin.Proc. 2006 Aug;81(8):1047-53.

[93] Corso A, Varettoni M, Zappasodi P, Klersy C, Mangiacavalli S, Pica G, Lazzarino M. A different schedule of zoledronic acid can reduce the risk of the osteonecrosis of the

[94] Lund T, Abildgaard N, Andersen TL, Delaisse JM, Plesner T. Multiple myeloma: changes in serum C-terminal telopeptide of collagen type I and bone-specific alkaline

jaw in patients with multiple myeloma. Leukemia 2007 Jul;21(7):1545-8.

Clinic consensus statement. Mayo Clin.Proc. 2007 Apr;82(4):516-7.

Oral Surg.Oral Med.Oral Pathol.Oral Radiol.Endod. 2007 Oct;104(4):473-7.

fac.Surg. 2006 Nov;17(6):1080-3.

of Milan. Ann.Oncol. 2009 Jan;20(1):137-45.

Ann.Oncol. 2009 Aug;20(8):1303-17.

ma. J.Clin.Oncol. 2007 Jun 10;25(17):2464-72.


[83] Freiberger JJ. Utility of hyperbaric oxygen in treatment of bisphosphonate-related os‐ teonecrosis of the jaws. J.Oral Maxillofac.Surg. 2009 May;67(5 Suppl):96-106.

[72] Mhaskar R, Redzepovic J, Wheatley K, Clark OA, Miladinovic B, Glasmacher A, Ku‐ mar A, Djulbegovic B. Bisphosphonates in multiple myeloma: a network meta-analy‐

[73] Terpos E, Sezer O, Croucher PI, Garcia-Sanz R, Boccadoro M, San MJ, Ashcroft J, Blade J, Cavo M, Delforge M, et al. The use of bisphosphonates in multiple myeloma: recommendations of an expert panel on behalf of the European Myeloma Network.

[74] Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular ne‐ crosis of the jaws: a growing epidemic. J.Oral Maxillofac.Surg. 2003 Sep;61(9):1115-7.

[75] Badros A, Weikel D, Salama A, Goloubeva O, Schneider A, Rapoport A, Fenton R, Gahres N, Sausville E, Ord R, et al. Osteonecrosis of the jaw in multiple myeloma pa‐

[76] Bamias A, Kastritis E, Bamia C, Moulopoulos LA, Melakopoulos I, Bozas G, Koutsou‐ kou V, Gika D, Anagnostopoulos A, Papadimitriou C, et al. Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors. J.Clin.On‐

[77] Zervas K, Verrou E, Teleioudis Z, Vahtsevanos K, Banti A, Mihou D, Krikelis D, Ter‐ pos E. Incidence, risk factors and management of osteonecrosis of the jaw in patients with multiple myeloma: a single-centre experience in 303 patients. Br.J.Haematol.

[78] Dimopoulos MA, Kastritis E, Anagnostopoulos A, Melakopoulos I, Gika D, Moulo‐ poulos LA, Bamia C, Terpos E, Tsionos K, Bamias A. Osteonecrosis of the jaw in pa‐ tients with multiple myeloma treated with bisphosphonates: evidence of ncreased

risk after treatment with zoledronic acid. Haematologica 2006 Jul;91(7):968-71.

treated with bisphosphonates. Leuk.Lymphoma 2008 Nov;49(11):2156-62.

of a prospective study. Photomed.Laser Surg. 2010 Apr;28(2):179-84.

[79] Montefusco V, Gay F, Spina F, Miceli R, Maniezzo M, Teresa AM, Farina L, Piva S, Palumbo A, Boccadoro M, et al. Antibiotic prophylaxis before dental procedures may reduce the incidence of osteonecrosis of the jaw in patients with multiple myeloma

[80] Bedogni A, Saia G, Bettini G, Tronchet A, Totola A, Bedogni G, Tregnago P, Valenti MT, Bertoldo F, Ferronato G, et al. Osteomalacia: the missing link in the pathogenesis of bisphosphonate-related osteonecrosis of the jaws? Oncologist. 2012;17(8):1114-9.

[81] Scoletta M, Arduino PG, Reggio L, Dalmasso P, Mozzati M. Effect of low-level laser irradiation on bisphosphonate-nduced osteonecrosis of the jaws: preliminary results

[82] Vescovi P, Merigo E, Meleti M, Manfredi M, Fornaini C, Nammour S. Surgical Ap‐ proach and Laser Applications in BRONJ Osteoporotic and Cancer Patients. J.Osteo‐

tients: clinical features and risk factors. J.Clin.Oncol. 2006 Feb 20;24(6):945-52.

sis. Cochrane.Database.Syst.Rev. 2012;5:CD003188.

Ann.Oncol. 2009 Aug;20(8):1303-17.

236 Multiple Myeloma - A Quick Reflection on the Fast Progress

col. 2005 Dec 1;23(34):8580-7.

2006 Sep;134(6):620-3.

poros. 2012;2012:585434.


phosphatase can be used in daily practice to detect imminent osteolysis. Eur.J.Hae‐ matol. 2010 May;84(5):412-20.

[108] Diamond T, Levy S, Day P, Barbagallo S, Manoharan A, Kwan YK. Biochemical, his‐ tomorphometric and densitometric changes in patients with multiple myeloma: ef‐ fects of glucocorticoid therapy and disease activity. Br.J.Haematol. 1997 Jun;97(3):

Bone Disease in Multiple Myeloma http://dx.doi.org/10.5772/55190 239

[109] Zavrski I, Krebbel H, Wildemann B, Heider U, Kaiser M, Possinger K, Sezer O. Pro‐ teasome inhibitors abrogate osteoclast differentiation and osteoclast function. Bio‐

[110] von M, I, Krebbel H, Hecht M, Manz RA, Fleissner C, Mieth M, Kaiser M, Jakob C, Sterz J, Kleeberg L, et al. Bortezomib nhibits human osteoclastogenesis. Leukemia

[111] Boissy P, Andersen TL, Lund T, Kupisiewicz K, Plesner T, Delaisse JM. Pulse treat‐ ment with the proteasome inhibitor bortezomib inhibits osteoclast resorptive activity

[112] Terpos E, Heath DJ, Rahemtulla A, Zervas K, Chantry A, Anagnostopoulos A, Pouli A, Katodritou E, Verrou E, Vervessou EC, et al. Bortezomib reduces serum dick‐ kopf-1 and receptor activator of nuclear factor-kappaB ligand concentrations and normalises indices of bone remodelling in patients with relapsed multiple myeloma.

[113] Zhao M, Qiao M, Oyajobi BO, Mundy GR, Chen D. E3 ubiquitin ligase Smurf1 medi‐ ates core-binding factor alpha1/Runx2 degradation and plays a specific role in osteo‐

[114] Garrett IR, Chen D, Gutierrez G, Zhao M, Escobedo A, Rossini G, Harris SE, Gallwitz W, Kim KB, Hu S, et al. Selective nhibitors of the osteoblast proteasome stimulate

[115] Giuliani N, Morandi F, Tagliaferri S, Lazzaretti M, Bonomini S, Crugnola M, Mancini C, Martella E, Ferrari L, Tabilio A, et al. The proteasome inhibitor bortezomib affects osteoblast differentiation in vitro and in vivo in multiple myeloma patients. Blood

[116] Oyajobi BO, Garrett IR, Gupta A, Flores A, Esparza J, Munoz S, Zhao M, Mundy GR. Stimulation of new bone formation by the proteasome inhibitor, bortezomib: implica‐

[117] Pennisi A, Li X, Ling W, Khan S, Zangari M, Yaccoby S. The proteasome inhibitor, bortezomib suppresses primary myeloma and stimulates bone formation in myelom‐

atous and nonmyelomatous bones in vivo. Am.J.Hematol. 2009 Jan;84(1):6-14. [118] Lund T, Soe K, Abildgaard N, Garnero P, Pedersen PT, Ormstrup T, Delaisse JM, Plesner T. First-line treatment with bortezomib rapidly stimulates both osteoblast ac‐ tivity and bone matrix deposition in patients with multiple myeloma, and stimulates

tions for myeloma bone disease. Br.J.Haematol. 2007 Nov;139(3):434-8.

bone formation in vivo and in vitro. J.Clin.Invest 2003 Jun;111(11):1771-82.

in clinically relevant conditions. Leuk.Res. 2008 Nov;32(11):1661-8.

blast differentiation. J.Biol.Chem. 2003 Jul 25;278(30):27939-44.

chem.Biophys.Res.Commun. 2005 Jul 22;333(1):200-5.

641-8.

2007 Sep;21(9):2025-34.

2007 Jul 1;110(1):334-8.

Br.J.Haematol. 2006 Dec;135(5):688-92.


[108] Diamond T, Levy S, Day P, Barbagallo S, Manoharan A, Kwan YK. Biochemical, his‐ tomorphometric and densitometric changes in patients with multiple myeloma: ef‐ fects of glucocorticoid therapy and disease activity. Br.J.Haematol. 1997 Jun;97(3): 641-8.

phosphatase can be used in daily practice to detect imminent osteolysis. Eur.J.Hae‐

[95] Body JJ, Facon T, Coleman RE, Lipton A, Geurs F, Fan M, Holloway D, Peterson MC, Bekker PJ. A study of the biological receptor activator of nuclear factor-kappaB li‐ gand inhibitor, denosumab, in patients with multiple myeloma or bone metastases

[96] Vij R, Horvath N, Spencer A, Taylor K, Vadhan-Raj S, Vescio R, Smith J, Qian Y, Yeh H, Jun S. An open-label, phase 2 trial of denosumab in the treatment of relapsed or

[97] Henry DH, Costa L, Goldwasser F, Hirsh V, Hungria V, Prausova J, Scagliotti GV, Sleeboom H, Spencer A, Vadhan-Raj S, et al. Randomized, double-blind study of de‐ nosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma.

[98] Vadhan-Raj S, von MR, Fallowfield LJ, Patrick DL, Goldwasser F, Cleeland CS, Hen‐ ry DH, Novello S, Hungria V, Qian Y, et al. Clinical benefit in patients with metastat‐ ic bone disease: results of a phase 3 study of denosumab versus zoledronic acid.

[99] Stopeck AT, Lipton A, Body JJ, Steger GG, Tonkin K, de Boer RH, Lichinitser M, Fuji‐ wara Y, Yardley DA, Viniegra M, et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a

[102] Morgan GJ, Wu P. Targeting bone in myeloma. Recent Results Cancer Res.

[103] Fulciniti M, Tassone P, Hideshima T, Vallet S, Nanjappa P, Ettenberg SA, Shen Z, Pa‐ tel N, Tai YT, Chauhan D, et al. Anti-DKK1 mAb (BHQ880) as a potential therapeutic

[105] Callander NS, Roodman GD. Myeloma bone disease. Semin.Hematol. 2001 Jul;38(3):

[106] Wahlin A, Holm J, Osterman G, Norberg B. Evaluation of serial bone X-ray examina‐

[107] Epstein J, Walker R. Myeloma and bone disease: "the dangerous tango".

randomized, double-blind study. J.Clin.Oncol. 2010 Dec 10;28(35):5132-9.

[100] http://www.cancer.gov/cancertopics/druginfo/fda-denosumab. 2012 Aug 8. [101] http://www.ema.europa.eu/docs/en\_GB/document\_library/EPAR\_-\_Summa‐ ry\_for\_the\_public/human/002173/WC500110385.pdf. 2012 Aug 28.

agent for multiple myeloma. Blood 2009 Jul 9;114(2):371-9.

tion in multiple myeloma. Acta Med.Scand. 1982;212(6):385-7.

[104] http://www.clinicaltrials.gov/.. 2012 Aug 29.

Clin.Adv.Hematol.Oncol. 2006 Apr;4(4):300-6.

plateau-phase multiple myeloma. Am.J.Hematol. 2009 Oct;84(10):650-6.

from breast cancer. Clin.Cancer Res. 2006 Feb 15;12(4):1221-8.

matol. 2010 May;84(5):412-20.

238 Multiple Myeloma - A Quick Reflection on the Fast Progress

J.Clin.Oncol. 2011 Mar 20;29(9):1125-32.

Ann.Oncol. 2012 Jul 31.

2012;192:127-43.

276-85.


osteoblast proliferation and differentiation in vitro. Eur.J.Haematol. 2010 Oct;85(4): 290-9.

**Chapter 12**

**Rare Manifestations of Multiple Myeloma**

Multiple myeloma (MM) or plasma cell myeloma, is a haematological disease representing 1-2% of all cancers and about 15% of haematological *malignancies*. The classic form of MM is characterized by generalized neoplastic changes in the bones accompanied by kidney damage, impaired haematopoiesis and susceptibility to infections. In laboratory tests, MM manifests it‐ self by the presence of monoclonal protein, called paraprotein, in serum or urine. This results from the fact that pathological plasma cells produce a complete immunoglobulin (Ig), usually IgG or IgA, or only the kappa or lambda light chains. Solitary myeloma (osseous or extraoss‐ eous), non-secretory myeloma and secretory myeloma are rarer forms of MM. Sometimes, however, the clinical picture of MM is quite different from the classic manifestation described

The atypical clinical and laboratory manifestations and paraneoplastic syndromes concomi‐ tant with a diagnosis of MM and described below, as are those that appear in the course of the disease, especially in progression. Although they do not represent a significant percent‐ age of cases, knowledge of the rare clinical and laboratory variants of MM may assist in

In addition to their low incidence, rare manifestations of MM share the lack of valid relevant scientific knowledge, which leads to difficulties in making firm therapeutic guidelines. In fact, most of the information on these conditions derives from case reports and/or small ser‐ ies studies, making it rather difficult to develop any uniform treatment approaches. As a re‐ sult, several of rare manifestations of MM can well be controlled with standard regimens used for classic MM, like for example non-secretory myeloma. However the satisfactory strategies to control some of those conditions, such as plasma cell leukemia, are still unsatis‐ factory. These issues are best illustrated in the present work in the chapter discussing PO‐

> © 2013 Jurczyszyn; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

in the textbooks. This can cause diagnostic difficulties, thereby delaying treatment.

Additional information is available at the end of the chapter

making a differential diagnosis in cases of doubt.

Artur Jurczyszyn

**1. Introduction**

EMS syndrome.

http://dx.doi.org/10.5772/53385

