**Author details**

Marie-Christine Kyrtsonis1\*, Efstathios Koulieris1 , Vassiliki Bartzis1 , Ilias Pessah1 , Eftychia Nikolaou1 , Vassiliki Karalis1 , Dimitrios Maltezas1 , Panayiotis Panayiotidis1 and Stephen J. Harding2\*

\*Address all correspondence to: mck@ath.forthnet.gr; Stephen.harding@bindingsite.co.uk

1 Haematology Section of 1st Department of Propaedeutic Internal Medicine, Athens Medical School, Athens, Greece

2 The Binding Site Group Ltd, Birmingham, UK

## **References**


[4] Gay D, Saunders T, Camper S, Weigert M. Receptor editing: an approach by autor‐ eactive B cells to escape tolerance. J.Exp.Med 1993;177 999-1008.

[19] Liu Y-J, de Bouteiller O, Arpin C, et al. Normal human IgD+IgM- germinal center B cells can express up to 80 mutations in the variable region of their IgD transcripts.

Monoclonal Immunoglobulin http://dx.doi.org/10.5772/55855 31

[20] Seifert M, Steimle-Grauer SA, Goossens T, et al. A model for the development of hu‐ man IgD-only B cells: Genotypic analyses suggest their generation in superantigen

[21] Tangye SG, Avery DT, Deenick EK, Hodgkin PD. Intrinsic differences in the prolifer‐ ation of naive and memory human B cells as a mechanism for enhanced secondary

[22] Swerdlow SH, Campo E, Harris NL, et al, editors. WHO classification of tumours of haematopoietic and lymphoid tissues. IARC Press, Geneva, Switzerland; 2008.

[23] Rajkumar SV, Kyle RA, Buadi FK. Advances in the diagnosis, classification, risk stratification and management of monoclonal gammopathy of undetermined signifi‐ cance: Implications for recategorizing disease entities in the presence of evolving sci‐

[24] Kyrtsonis M-C, Bartzis V, Papanikolaou X, et al. Genetic and Molecular Advances in Multiple Multiple Myeloma: A Route to Better Understand Disease Heterogeneity.

[25] Bergsagel PL, Kuehl WM. Chromosome translocations in multiple myeloma. Onco‐

[26] Bosch F, Jares P, Campo E, et al. PRAD1/cyclinD1 gene overexpression in chronic lymphoproliferative disorders: a high specific marker of mantle cell lymphoma.

[27] Santra M, Zhan F, Tian E et al. A subset of multiple myeloma harbouring the t(4;14) (p16;q32) translocation lacks FGFR3 expression but maintains an IGH/MMSET fusion

[28] Walker BA, Wardell CP, Melchor L, et al. Intraclonal heterogeneity and distinct mo‐ lecular mechanisms characterize the development of t(4;14) and t(11;14) myeloma.

[29] Keats JJ, Chesi M, Egan JB, et al. Clonal competition with alternating dominance in

[30] Dang CV. c-Myc Target Genes Involved in Cell Growth, Apoptosis, and Metabolism.

[31] Guikema JE, de Boer C, Haralambieva E. IGH switch breakpoints in Burkitt lympho‐ ma: exclusive involvement of non-canonical class switch recombination. Genes chro‐

driven immune responses. Mol. Immunol 2009;46(4) 630-639.

immune responses. J.Immunol 2003;170 686-694.

entific evidence. Mayo Clin Proc 2010;85(10) 945-948.

The Application Of Clinical Genetics 2010;3 41-51.

gene 2001;20(40) 5611-5622.

Blood 1994;84 2726-2732.

Blood 2012;120(5) 1077-86.

Mol Cell Biol 1999;19(1) 1-11.

mosomes Cancer 2006;45 808-819.

transcript. Blood 2003;101(6) 2374-2376.

multiple myeloma. Blood 2012;120(5) 1067-1076.

Immunity 1996;4 603-613.


[19] Liu Y-J, de Bouteiller O, Arpin C, et al. Normal human IgD+IgM- germinal center B cells can express up to 80 mutations in the variable region of their IgD transcripts. Immunity 1996;4 603-613.

[4] Gay D, Saunders T, Camper S, Weigert M. Receptor editing: an approach by autor‐

[5] Monroe JG, Dorshkind K. Fate decisions regulating bone marrow and peripheral B

[6] Sims GP, Enger R, Shirota Y, et al. Identification and characterization of circulating

[7] Bende RJ. B-cell biology and the development of mature B cell lymphomas. PhD The‐

[8] Schettino EW, Chai SK, Kasaian MT, et al. VHDJH gene sequences and an\_gen reac‐ tivity of monoclonal antibodies produced by human B-1 cells, evidence for somatic

[9] Bikah G, Carey J, Ciallella JR, Tarakhovsky A, Bondada S. CD5-mediated negative regulation of antigenreceptor-induced growth signals in B-1 B-cells. Science 1996;274

[10] Chen ZJ., Wheeler CL, Shi W, Wu AJ, Yarboro CH, Gallagher M, Notkins AL. Poly‐ reactive antigen-binding B cells are the predominant cell type in the newborn B cell

[11] Tsuiji M, Yurasov S, Velinzon K, et al. A checkpoint for autoreactivity in human IgM

[12] Berek C, Berger A, Apel M. Maturation of the immune response in germinal centers.

[13] Lindhout E, Koopman G, Pals ST, de Groot C. Triple check for antigen specificity of B

[14] Liu YJ, Malisan F, de Bouteiller O, et al. Within germinal centers, isotype switching of immunoglobulin genes occurs after the onset of somatic mutation. Immunity 1996;4

[15] Schwartz RS. Jumping genes and the immunoglobulin gene system. N Engl J Med

[16] Küppers R, Klein U, Hansmann ML, Rajewsky K. Cellular origin of human B-cell

[17] Muramatsu M, Kinoshita K, Fagarasan S, et al. Class switch recombination and hy‐ permutation require activation-induced cytidine deaminase (AID), a potential RNA

[18] MacLennan ICM. Germinal centers. Annu.Rev.Immunol 1994;12 117-139.

cells during germinal centre reactions. Immunol.Today 1997;18 573-577.

eactive B cells to escape tolerance. J.Exp.Med 1993;177 999-1008.

lymphocyte development. Adv.Immunol 2007;95 1-50.

human transitional B cells. Blood 2005;105 4390-4398.

sis. Faculty of Medicine Amsterdam; 2010.

30 Multiple Myeloma - A Quick Reflection on the Fast Progress

selection. J.Immunol 1997;158 2477-2489.

repertoire. Eur.J.Immunol 1998;28 989-994.

Cell 1991;67(6) 1121-1129.

+ memory B cell development. J.Exp.Med 2006;203 393-400.

lymphomas. N Engl J Med 1999;341(20) 1520-1529.

editing enzyme. Cell 2000;102 553-563.

1906-1909.

241-250.

1995;333 42-44.


[32] Williams ME, Whitefield M, Swerdlow SH. Analysis of the cyclin-dependent kinase inhibitors p18 and p19 in the Mantle cell lymphoma and chronic lymphocytic leuke‐ mia. Ann Oncol 1997;8;Suppl 2 71-73.

[47] Keren DF. Heavy/Light-Chain Analysis of monoclonal gammopathies. Clin Chem

Monoclonal Immunoglobulin http://dx.doi.org/10.5772/55855 33

[49] Bradwell AR, Carr-Smith HD, Mead GP, et al. Highly sensitive, automated immuneassay for immunoglobulin free light chains in serum and urine. Clin Chem 2001;47: 4

[50] Morabito F, De Filippi R, Laurenti L, et al. The cumulative amount of serum-free light chain is a strong prognosticator in chronic lymphocytic leukemia. Blood

[51] Kyle RA, Therneau TM, Rajkumar SV et al. Prevalence of monoclonal gammopathy

[52] Waldenstrom J. Studies on conditions associated with disturbed gamma globulin for‐

[53] Kyle RA. Monoclonal gammopathy of undetermined significance: natural history in

[54] Kyle RA, Durie BG, Rajkumar SV, et al; International Myeloma Working Group. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management. Leukemia 2010;24(6)

[55] Korde N, Kristinsson SY, Landgren O. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM): novel biological in‐ sights and development of early treatment strategies. Blood 2011;117(21) 5573–5581.

[56] Kyle RA, Therneau TM, Rajkumar SV et al. A long-term study of prognosis in mono‐ clonal gammopathy of undetermined significance. N Engl J Med 2002;346(8) 564–569.

[57] Kyle RA, Therneau TM, Rajkumar SV et al. Long-term follow-up of IgM monoclonal gammopathy of undetermined significance. Semin Oncol 2003;30(2) 169–171.

[58] Dispenzieri A, Katzmann JA, Kyle RA et al. Prevalence and risk of progression of light-chain monoclonal gammopathy of undetermined significance: a retrospective

[59] Rajkumar SV, Kyle RA, Therneau TM et al. Serum free light chain ratio is an inde‐ pendent risk factor for progression in monoclonal gammopathy of undetermined sig‐

[60] Perez-Persona E. Vidriales MB, Mateo G et al. New criteria to identify risk of pro‐ gression in monoclonal gammopathy of uncertain significance and smoldering multi‐ ple myeloma based on multiparameter flow cytometry analysis of bone marrow

population-based cohort study. Lancet 2010;375(9727) 1721–1728.

[48] Bradwell AR. Serum free light chain analysis (plus Hevylite). 5th ed. 2008.

2011;118(24) 6353-6361 doi:10.1182/blood-2011-04-345587

mation (gammopathies). Harvey Lect 1960;56 211–231.

241 cases. Am J Med 1978;64(5) 814–826.

1121-1127. doi:10.1038/leu.2010.60

nificance. Blood 2005;106(3) 812–817.

plasma cells. Blood 2007;110(7) 2586–2592.

of undetermined significance. N Eng J Med 2006;354(13) 1362-1369.

2009;55 1606–1608.

673-80.


[32] Williams ME, Whitefield M, Swerdlow SH. Analysis of the cyclin-dependent kinase inhibitors p18 and p19 in the Mantle cell lymphoma and chronic lymphocytic leuke‐

[33] Fu K, Weisenburger DD, Greiner TC, et al. Cyclin D1–negative mantle cell lympho‐ ma: a clinicopathologic study based on gene expression profiling. Blood 2005;106

[34] Potter M. Pathogenetic mechanisms in B-cell non-Hodgkin's lymphomas in humans.

[35] Tomita N, Tokunaka M, Nakamura N, et al. Clinicopathological features of lympho‐ ma/leukemia patients carrying both bcl2 and myc translocations. Haematologica

[36] Iqbal J, Neppalli T, Wright G, et al. BCL2 expression is a prognostic marker for the activated B-cell-like type of diffuse large B-cell lymphoma. Journal of Clinical Oncol‐

[37] Du M-Q. MALT Lymphoma: Recent Advances in Aetiology and Molecular Genetics.

[38] Attaelmannan M, Levinson SS. Understanding and Identifying Monoclonal Gammo‐

[39] Matsuda F, Ishii K, Bourvagnet P, et al. The complete nucleotide sequence of the hu‐ man immunoglobulin heavy chain variable region locus. J Exp Med 1998;188

[40] Janeway C. Immunobiology, 5th edition. The Immune System in Health and Disease.

[41] Litman GW, Rast JP, Shamblott MJ, Haire RN, Hulst M, Roess W et al. Phylogenetic diversification of immunoglobulin genes and the antibody repertoire. Mol. Biol. Evol

[43] Pier GB, Lyczak JB, Wetzler LM. Immunology, Infection and Immunity. ASM Press,

[44] Rus H, Cudrici C, Niculescu F. The role of the complement system in innate immuni‐

[46] Harding SJ, Mead GP, Bradwell AR, Berard AM. Serum free light chain immunoas‐ say as an adjunct to serum protein electrophoresis and immunofixation electrophore‐ sis in the detection of multiple myeloma and other B-cell malignancies. Clin Chem

[42] Ravetch J, Bolland S. IgG Fc receptors. Annu Rev Immunol 2001;19(1) 275–290.

[45] Merlini G, Stone MJ. Dangerous small B-cell clones. Blood 2006;108 2520.

Lab Med 2009;47(3) 302-304 doi:10.1515/CCLM.2009.084

mia. Ann Oncol 1997;8;Suppl 2 71-73.

32 Multiple Myeloma - A Quick Reflection on the Fast Progress

Cancer Research 1992;52 5522-5528.

J Clin Exp Hematopathol 2007;47(2) 31-42.

pathies. Clin Chem. 2000;46(8 Pt 2) 1230-1238.

Garland Publishing, New York, USA; 2001

4315-4321.

2151-2162.

1993;10(1) 60–72.

Washington DC, USA; 2004

ty. Immunol Res 2005;33(2) 103–112.

2009;94(7) 935-943.

ogy 2006;24(6) 961-968.


[61] Katzmann JA, Clark R, Kyle RA et al. Suppression of uninvolved immunoglobulins defined by heavy/light chain pair suppression is a risk factor for progression of MGUS. Leukemia 2012. doi:10.1038/leu.2012.189

[74] Koulieris E, Bartzis V, Tzenou T, Kafasi N, Efthymiou A, Mpitsanis C et al. Free light chain clonal escape reflects relapse in intact immunoglobulin multiple myeloma.

Monoclonal Immunoglobulin http://dx.doi.org/10.5772/55855 35

[75] Kühnemund A, Liebisch P, Bauchmüller K, et al. 'Light-chain escape-multiple myelo‐ ma'-an escape phenomenon from plateau phase: report of the largest patient series

[76] Durie BG, & Salmon SE. A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treat‐

[77] Kyrtsonis M-C, Maltezas D, Koulieris E, et al. The Contribution of Prognostic Factors to the Better Management of Multiple Myeloma Patients. Book Chapter In "Multiple

[78] Kyrtsonis M-C, Maltezas D, Tzenou T, Koulieris E, & Bradwell AR. Staging Systems and Prognostic factors as a Guide to Therapeutic Decisions in Multiple Myeloma.

[79] Drayson M, Begum G, Basu S, et al. Effects of paraprotein heavy and light chain type and free light chain load on survival in myeloma: An analysis of patients receiving conventional dose chemotherapy in Medical Research Council UK Multiple Myelo‐

[80] Kyrtsonis M-C, Vassilakopoulos TP, Kafasi N, et al. Prognostic value of serum free light chain ratio at diagnosis in multiple myeloma. Br J of Haematol 2007;137(3),

[81] Snozek CL, Katzmann JA, Kyle RA, et al. Prognostic value of the serum free light chain ratio in newly diagnosed myeloma: proposed incorporation into the interna‐

[82] Kumar S, Zhang L, Dispenzieri A, et al. Relationship between elevated immunoglo‐ bulin free light chain and the presence of IgH translocations in multiple myeloma.

[83] Maltezas D, Dimopoulos MA, Katodritou I, et al. Re-evaluation of prognostic mark‐ ers including staging, serum free light chains or their ratio and serum lactate dehy‐ drogenase in multiple myeloma patients receiving novel agents. Hematol Oncol 2012

[84] Koulieris E, Panayiotidis P, Harding SJ, et al. Ratio of involved/uninvolved immuno‐ globulin quantification by Hevylite™ assay: Clinical and prognostic impact in multi‐

[85] Bradwell A, Harding S, Fourrier N, et al. Prognostic utility of intact immunoglobulin

ple myeloma. Experimental Hematology & Oncology 2012;1(9)

Ig'κ/Ig'λ ratios in multiple myeloma patients. Leukemia 2012;27 :202-7

using LC-monitoring. J Cancer Res Clin Oncol. 2009;135(3) 477-84.

Haematologica 2011;96(s1) P-414

ment, and survival. Cancer 1975;36(3) 842–854.

Myeloma". InTech - Open Access Publisher 2012.

tional staging system. Leukemia. 2008;22(10) 1933-1937.

Semin Hematol; 2009;46(2) 110–117.

ma trials. Blood 2006;108(6) 2013-2019.

Leukemia 2010;24(8) 1498-1505.

240-243.


[74] Koulieris E, Bartzis V, Tzenou T, Kafasi N, Efthymiou A, Mpitsanis C et al. Free light chain clonal escape reflects relapse in intact immunoglobulin multiple myeloma. Haematologica 2011;96(s1) P-414

[61] Katzmann JA, Clark R, Kyle RA et al. Suppression of uninvolved immunoglobulins defined by heavy/light chain pair suppression is a risk factor for progression of

[62] Brown LM, Gridley G, Check D, Landgren O. Risk of multiple myeloma and mono‐ clonal gammopathy of undetermined significance among white and black male Unit‐ ed States veterans with prior autoimmune, infectious, inflammatory, and allergic

[63] Rubin L, Urowitz MB, Pruzanski W. Systemic lupus erythematosus with paraprotei‐

[64] Garton MJ, Keir G, Dickie A, Steven M, Rennie JA. Prevalence and long-term signifi‐ cance of paraproteinaemia in rheumatoid arthritis. Rheumatology 2006;45(3) 355-356.

[65] Durie BG. Staging and kinetics of multiple myeloma. Semin Oncol. 1986;13(3)

[66] Nau K, Lewis W. Multiple Myeloma: Diagnosis and Treatment. Am Fam Physician

[67] Rajkumar SV, Kyle RA. Multiple myeloma: diagnosis and treatment. Mayo Clin Proc

[68] International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International

[69] Drayson M, Tang LX, Drew R, Mead GP, Carr-Smith H, Bradwell AR. Serum free light-chain measurements for identifying and monitoring patients with nonsecretory

[70] Blade J, Samson D, Reece D, et al. Criteria for evaluating disease response and pro‐ gression in patients with multiple myeloma treated by high-dose therapy and hemo‐ poietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant. Br J Haematol 1998;102(5) 1115–1123. doi:

[71] Durie BG, Harousseau JL, Miguel JS, et al. International Myeloma Working Group. International uniform response criteria for multiple myeloma. Leukemia 2006;20(9)

[72] Gay F, Larocca A, Wijermans P, et al. Complete response correlates with long-term progression-free and overall survival in elderly myeloma treated with novel agents:

[73] Ludwig H, Milosavljevic D, Zojer N, edt al. Immunoglobulin heavy/light chain ratios improve paraprotein detection and monitoring, identify residual disease and corre‐

late with survival in multiple myeloma patients. Leukemia 2012 ;27 : 213-219.

multiple myeloma. Blood 2001;97(9) 2900-2902. doi:10.1182/blood.V97.9.2900

Myeloma Working Group. Br J Haematol 2003;121(5) 749–757.

MGUS. Leukemia 2012. doi:10.1038/leu.2012.189

disorders. Blood 2008;111(7) 3388-3394.

34 Multiple Myeloma - A Quick Reflection on the Fast Progress

300-309.

2008;78 853-859.

2005;80(10) 1371–1382.

10.1046/j.1365-2141.1998.00930

analysis of 1175 patients. Blood 2010;117 3025-3031.

1467-1473.

nemia. Arthritis Rheum. 1984;27(6) 638-644.


[86] Dingli D, Kyle RA, Rajkumar SV et al. Immunoglobulin free light chains and solitary plasmacytoma of bone. Blood 2006;108(6) 1979-1983

Course. Sixth International Workshop On Waldenstrom's Macroglobulinemia. 2010,

Monoclonal Immunoglobulin http://dx.doi.org/10.5772/55855 37

[99] Koulieris E, Kyrtsonis M-C, Maltezas D, et al. Quantification of serum IgM kappa and IgM lambda in Patients with Waldenstrom's Macroglobulinemia. Hematology

[100] Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working

[101] Pratt G, Harding S, Holder Ret al. Abnormal serum free light chain ratios are associ‐ ated with poor survival and may reflect biological subgroups in patients with chron‐

[102] Yegin ZA, Ozkurt ZN, Yağci M. Free light chain: a novel predictor of adverse out‐ come in chronic lymphocytic leukemia. Eur J Haematol 2010;84(5) 406-411 doi:

[103] Maurer MJ, Cerhan JR, Katzmann JA, et al. Monoclonal and polyclonal serum free light chains and clinical outcome in chronic lymphocytic leukemia. Blood

[104] Leleu X, Moreau AS, Hennache B, et al. Serum Free Light Chain Immunoassays Measurements for Monitoring Solitary Bone Plasmacytoma. Haematologica 2005;

[105] Charafeddine KM, Jabbour MN, Kadi RH, Daher RT. Extended use of serum free light chain as a biomarker in lymphoproliferative disorders: a comprehensive re‐

[106] Landgren O, Goedert JJ, Rabkin CS, et al. Circulating serum free light chains as pre‐ dictive markers of AIDS-related lymphoma. J Clin Oncol 2010;28(5) 773-779

[107] Maurer MJ, Micallef IN, Cerhan JR, et al. Elevated serum free light chains are associ‐ ated with event-free and overall survival in two independent cohorts of patients with

Group 1996 guidelines. Blood 2008;111(12) 5446-5456

ic lymphocytic leukaemia. Br J Haematol 2009;144(2) 217-22

October 6-10, Venice, Italy

10.1111/j.1600-0609.2010.01412.x

view. Am J Clin Pathol 2012;137 890-897.

diffuse large B-cell lymphoma. J Clin Oncol 2011;29

2011;118(10) 2821-2826.

90(1): 110

Reports 2010;2: F63a.


Course. Sixth International Workshop On Waldenstrom's Macroglobulinemia. 2010, October 6-10, Venice, Italy

[99] Koulieris E, Kyrtsonis M-C, Maltezas D, et al. Quantification of serum IgM kappa and IgM lambda in Patients with Waldenstrom's Macroglobulinemia. Hematology Reports 2010;2: F63a.

[86] Dingli D, Kyle RA, Rajkumar SV et al. Immunoglobulin free light chains and solitary

[87] Lachmann HJ, Gallimore R, Gillmore JD, Carr-Smith HD, Bradwell AR, Pepys MB, Hawkins PN. Outcome in systemic AL amyloidosis in relation to changes in concen‐ tration of circulating free immunoglobulin light chains following chemotherapy. Br J

[88] Dispenzieri A, Lacy MQ, Katzmann JA, et al. Absolute values of immunoglobulin free light chains are prognostic in patients with primary systemic amyloidosis under‐

[89] Palladini G, Foli A, Milani P, et al. Best use of cardiac biomarkers in patients with AL amyloidosis and renal failure. Am J Hematol 2012;87(5) 465-471 doi: 10.1002/ajh.

[90] Kumar S, Dispenzieri A, Lacy MQ, et al. Revised prognostic staging system for light chain amyloidosis incorporating cardiac biomarkers and serum free light chain meas‐

[91] Wechalekar AD, Harding S, Lachmann HJ, et al. Serum immunoglobulin heavy/light chain ratios (Hevylite) in patients with systemic AL amyloidosis. Amyloid 2010;17

[92] Kyrtsonis M-C, Vassilakopoulos TP, Angelopoulou et al. Waldenstrom's macroglo‐ bulinemia: Clinical course and prognostic factors in 60 patients. Experience From a

[93] Pangalis GA, Kyrtsonis M-C, Kontopidou FN, et al. Differential Diagnosis Of Wal‐ denstrom's Macroglobulinemia And Other B-Cell Disorders. Clin Lymphoma 2005;5

[94] Weber D, Treon SP, Emmanuilides C, et al. Uniform response criteria in Walden‐ strom's macroglobulinemia: Consensus Panel Recommendations from the Second In‐ ternational Workshop on Waldenstrom's Macroglobulinemia. Seminars in Oncology

[95] Morel P, Duhamel A, Gobbi P et al. International prognostic scoring system for Wal‐

[96] Leleu X, Koulieris E, Maltezas D. et al. Novel M-component based biomarkers in Waldenstrom Macroglobulinemia (WM). Clin Lymphoma Myeloma Leukemia

[97] Itzykson R, Le Garff-Tavernier M, Katsahian S, Diemert MC, Musset L, Leblond V. Serum-free light chain elevation is associated with a shorter time to treatment in Wal‐

[98] Maltezas D, Tzenou T, Kafassi N, et al. Clinical Impact of Increased Serum Free Light Chains (sFLCs) or Their Ratio (FLCR) on WM at Diagnosis and During Disease

urements. J Clin Oncol 2012;30(9) 989-995. doi:10.1200/JCO.2011.38.5724

Single Haematology Unit. Annals of Haematology 2001;80 722-727.

denström macroglobulinemia. Blood 2009;113 4163–4170.

denstrom's macroglobulinemia. Haematologica 2008;93 793-794

going peripheral blood stem cell transplantation. Blood 2006;107 3378-3383.

plasmacytoma of bone. Blood 2006;108(6) 1979-1983

36 Multiple Myeloma - A Quick Reflection on the Fast Progress

23141

186a.

235-240.

2003;30 127-131.

2011;11 164-167.

Haematol 2003;122 78-84 doi:10.1046/j.1365-2141.2003.04433.x


**Chapter 3**

**Innovative Models to Assess Multiple**

Marina Ferrarini, Giovanna Mazzoleni, Nathalie Steimberg, Daniela Belloni and

Additional information is available at the end of the chapter

Elisabetta Ferrero

**1. Introduction**

therapeutic target [4].

http://dx.doi.org/10.5772/54312

**Myeloma Biology and the Impact of Drugs**

Tumor and its embedding microenvironment form a unique, dynamic system, largely orch‐ estrated by cellular players, including fibroblasts and endothelial cells (EC), and surround‐ ing extracellular matrix (ECM) with its distinctive physical, biochemical, and biomechanical properties. There is a general consensus that, beyond genetic mutations and epigenetic mod‐ ifications, the dialogue that occurs between tumor and its microenvironment, through solu‐ ble factors and molecular interactions, may affect tumor cells survival, growth, proliferation, response to chemical/physical factors, and lies the basis for metastatization to distant, specif‐ ic organs. This theory was proposed by Paget in the 1880s [1], who underlined the need, for investigating and targeting tumor, to focus not only on the cancer cell, "the seed", but also on the "soil" where tumor homes and in which it derives its nutrients, oxygen and signals [2, 3]. Accordingly, tight links between tumor and surrounding microenvironment could de‐ termine the overall sensitivity to anti-cancer drugs and therefore represent an attractive

Tumor microenvironment plays a critical role also in development and progression of hae‐ matological malignancies [5,6]. In this regard, Multiple Myeloma (MM) represents a para‐ digmatic condition [5,6]. Indeed, MM plasma cells almost exclusively home and thrive inside Bone Marrow (BM) microenvironment, which confers anti-apoptotic and pro-survival signals and resistance to drugs. In turn, tumor cell interactions with BM cells and matrix re‐

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

© 2013 Ferrarini et al.; 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, distribution, and reproduction in any medium, provided the original work is properly cited.

© 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,
