MULTIPLE MYELOMA - A QUICK REFLECTION ON THE FAST PROGRESS Edited by Roman Hajek Multiple Myeloma - A Quick Reflection on the Fast Progress http://dx.doi.org/10.5772/56515 Edited by Roman Hajek Contributors Meral Beksac, Artur Jurczyszyn, Ana Muñoz, Cristina Riber, Katy Satue, Pablo Trigo, Manuel Gómez-Díez, Francisco Castejon, Lucie Rihova, Emine Ozyuvaci, Tolga Sitilci, Onat Akyol, Taner Demirer, Pervin Topcuoglu, Sinem Civriz Bozdag, Saad Usmani, Stephen Harding, Marie-Christine Kyrtsonis, Magdalena Cortes, Raul Vinet, Svachova, Plesner, Thomas Lund, Maja Hinge, Jean-Marie Delaisse, Klara Gadó, Elisabetta Ferrero, Nathalie Steimberg, Giovanna Mazzoleni, Marina Ferrarini, Daniela Belloni, Je-Jung Lee, Roman Hajek Published by InTech Janeza Trdine 9, 51000 Rijeka, Croatia Copyright © 2013 InTech All chapters are Open Access distributed under the Creative Commons Attribution 3.0 license, which allows users to download, copy and build upon published articles even for commercial purposes, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications. 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Publishing Process Manager Ana Pantar Technical Editor InTech DTP team Cover InTech Design team First published April, 2013 Printed in Croatia A free online edition of this book is available at www.intechopen.com Additional hard copies can be obtained from orders@intechopen.com Multiple Myeloma - A Quick Reflection on the Fast Progress, Edited by Roman Hajek p. cm. ISBN 978-953-51-1083-5 free online editions of InTech Books and Journals can be found at www.intechopen.com Contents Preface VII Chapter 1 Strategies for the Treatment of Multiple Myeloma in 2013: Moving Toward the Cure 1 Roman Hajek Chapter 2 Monoclonal Immunoglobulin 13 Marie-Christine Kyrtsonis, Efstathios Koulieris, Vassiliki Bartzis, Ilias Pessah, Eftychia Nikolaou, Vassiliki Karalis, Dimitrios Maltezas, Panayiotis Panayiotidis and Stephen J. Harding Chapter 3 Innovative Models to Assess Multiple Myeloma Biology and the Impact of Drugs 39 Marina Ferrarini, Giovanna Mazzoleni, Nathalie Steimberg, Daniela Belloni and Elisabetta Ferrero Chapter 4 Heterogeneity and Plasticity of Multiple Myeloma 61 Hana Šváchová, Sabina Sevcikova and Roman Hájek Chapter 5 Immunophenotyping in Multiple Myeloma and Others Monoclonal Gammopathies 93 Lucie Rihova, Karthick Raja Muthu Raja, Luiz Arthur Calheiros Leite, Pavla Vsianska and Roman Hajek Chapter 6 Monoclonal Gammopathy of Undetermined Significance 111 Magdalena Patricia Cortés, Rocío Alvarez, Jessica Maldonado, Raúl Vinet and Katherine Barría Chapter 7 Induction Therapy in Multiple Myeloma 133 Sule Mine Bakanay and Meral Beksac Chapter 8 Allogeneic Hematopoetic Cell Transplantation in Multiple Myeloma 165 Pervin Topcuoglu, Sinem Civriz Bozdag and Taner Demirer Chapter 9 Cellular Immunotherapy Using Dendritic Cells in Multiple Myeloma: New Concept to Enhance Efficacy 179 Je-Jung Lee, Youn-Kyung Lee, Hyun Ju Lee, Sung-Hoon Jung and Thanh-Nhan Nguyen-Pham Chapter 10 Novel Prognostic Modalities in Multiple Myeloma 199 Mariam Boota, Joshua Bornhorst, Zeba Singh and Saad Z. Usmani Chapter 11 Bone Disease in Multiple Myeloma 217 Maja Hinge, Thomas Lund, Jean-Marie Delaisse and Torben Plesner Chapter 12 Rare Manifestations of Multiple Myeloma 241 Artur Jurczyszyn Chapter 13 Pain and Multiple Myeloma 259 Emine Ozyuvaci, Onat Akyol and Tolga Sitilci Chapter 14 Quality of Life Issues of Patients with Multiple Myeloma 275 Klára Gadó and Gyula Domján Chapter 15 Multiple Myeloma in Horses, Dogs and Cats: A Comparative Review Focused on Clinical Signs and Pathogenesis 289 A. Muñoz, C. Riber, K. Satué, P. Trigo, M. Gómez-Díez and F.M. Castejón ContentsVI Preface Multiple myeloma is the second most common haematological malignancy. This book does not provide a comprehensive overview of the disease but offers a collection of chapters with in-depth information on distinct hot topics in the diagnostic, research and therapeutic fields. On the biological side, the authors show plasticity of myeloma cells and describe the innova‐ tive models to assess multiple myeloma biology. On the clinical side, the authors analyse current therapeutic development. Pharmacotherapy of multiple myeloma is an example of the fast introduction of scientific discoveries into clinics. The dynamics of testing new drugs for multiple myeloma treatment in clinical trials is breathtaking. Scientific discoveries have uncovered complicated pathogenesis of multiple myeloma; complicated reactions to treat‐ ment lead to creation of super cocktails. This strategy is most beneficial for the patient, but it is not yet personalized medicine. The curability of multiple myeloma is a question that is being discussed by the entire professional myeloma world. Regardless of your position in this debate, some professionals are missing the vital point in this debate - the incredible im‐ provement in treatment options. Consequently, improvement of prognosis is a fact which is most important from a patient’s perspective. This book will be of interest to medical professionals specializing in hematooncology, re‐ searchers, as well as many others. Prof. Roman Hajek Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Czech Republic Chapter 1 Strategies for the Treatment of Multiple Myeloma in 2013: Moving Toward the Cure Roman Hajek Additional information is available at the end of the chapter http://dx.doi.org/10.5772/55366 1. Introduction Multiple myeloma (MM) is a hematooncological disease, and in recent years, overall survival of patients has been significantly increased. Improvement of treatment results is connected not only to the introduction of autologous transplantation of hematopoietic cells into the treatment strategy for younger patients in the 90s but also to the introduction of new beneficial drugs into clinics; in the first decade of this century, bortezomib, thalidomide and lenalidomide were introduced in [1]. These new drugs have repeatedly proven their high treatment efficacy in clinics in all age groups of patients, in primotherapy as well as refractory disease. There are also newer drugs currently under investigation, such as new proteasome inhibitors (carfilzo‐ mib, MLN9708 and other peroral proteasome inhibitors) and other immunomodulatory drugs (pomalidomide) with the aim to improve or maintain treatment effects and decrease unfav‐ orable effects in [2]. Using drugs from both these groups together with glucocorticoids and alkylating cytostatics had a major impact on prolonging survival of our patients as previously published. On the other hand, it is clear that use of only one of the new efficient drugs in combination with glucocorticoids and alkylating cytostatics does not lead to a cure in [3-7]. Optimization of dosage in combination with other drugs and the length of treatment have been clarified for thalidomide and bortezomib. Current dosage levels are different from recorded dosages in registration studies which in certain cases led to common or higher level of side effects than is acceptable; these side effects are reduced after optimization. Side effects, especially the long-term ones, may fundamentally influence the quality of life of patients after successful treatment. Nowadays, optimization of thalidomide and bortezomib treatments is almost completed and lenalidomide optimization is currently being processed in [5]. It is logical to think that optimization of efficient drugs is a never ending process that waits for each new efficient drug, for example carfilzomib and pomalidomide in the near future. A © 2013 Hajek; 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. variety of new drugs are being tested in clinical studies at phases I/II. In MM treatment, modern target therapies are being tested, such as monoclonal antibodies, kinase inhibitors or inhibitors of other target molecules connected to one of the signaling pathways important for malignant cells. Although treatment results of this group of drugs failed to reach expectations, we feel that they will produce very promising results in the future. Current treatment strategies will lead to a cure – a topic which is being discussed very seriously. In this chapter, the current state of affairs as well as the potentials of pharmacotherapy in MM will be discussed. 2. Basic scientific data influencing current treatment strategies Our current treatment strategies originate from a variety of research data that may be shortly described as follows: a. Every MM is preceded by a precancerosis called monoclonal gammopathy of undeter‐ mined significance (MGUS) in [8]. Individual stages starting from the occurrence of first clonal plasmocyte to MGUS, MM, refractory MM up to plasmocellular leukemia are concurrent; in one individual, they may be described as disease progression changing in time. Many internal and external factors influence the phase when the initial plasmocyte will develop into hematological malignancy requiring therapy (Fig.1). MGUS or smoldering myeloma Asymptomatic Symptomatic ACTIVE MYELOMA M-protein (g/L) 20 50 100 1. RELAPSE 2. RELAPSE REFRACTORY RELAPSE First-line therapy Plateau remission Second-line Third-line Clonal expansion MGUS Late myeloma Plasma cell leukemia Early myeloma MGUS, monoclonal gammopathy of undetermined significance Figure 1. Natural history of multiple myeloma Multiple Myeloma - A Quick Reflection on the Fast Progress 2 [...]... the cell starts to synthesize Ig following the variable domain rearrangement On the coding DNA strand, the gene segments for the formation of the variable and the constant domains of the heavy chain are in order 5´ VDJ- - - 3- 1- 1- 2- 4- - 2- 3´ The RNA polymer‐ ase binds to the template strand of DNA and starts reading in 3´ to 5´ direction adding nucleotides to the 3´end of pre-mRNA transcript Alternative... Dose Melphalan; Results of a Randomized Phase III Trial Haematologica (2011) , 96(1), 3 1-1 1 [19] Cavo, M, Pantani, L, Patriarca, F, et al Superior Complete Response Rate (CR) and Progression-Free surfoval (PFS) with Bortezomib-Thalidomide-Dexamethasone (VTD) versus Thalidomide-Dexamethasone (TD) as Consolidation Therapy after Au‐ tologus Stem-cell Transplantation (ASCT in Multiple Myeloma (MM) Blood... 129 9-1 305 [37] San-miguel, J F, & Mateos, M V Can Multiple Myeloma Become a Curable Disease? Haematologica (2011) , 96(9), 124 6-8 Chapter 2 Monoclonal Immunoglobulin Marie-Christine Kyrtsonis, Efstathios Koulieris, Vassiliki Bartzis, Ilias Pessah, Eftychia Nikolaou, Vassiliki Karalis, Dimitrios Maltezas, Panayiotis Panayiotidis and Stephen J Harding Additional information is available at the end of the. .. monitoring international guidelines (IMWG 2011 concensus) recommend the use of total Ig nephelometric assays At gross concentrations these assay are suitable tools to monitor patients; however, as they are unable to distinguish between the monoclonal and polyclonal Igs they will be insensitive as the Ig concentration approaches the normal range One potentially useful addition to the laboratorian’s armatorarium... 541 2-5 417 9 10 Multiple Myeloma - A Quick Reflection on the Fast Progress [9] Fonseca, R, Bergsagel, P L, Drach, J, et al International Myeloma Working Group Molecular Classification of Multiple Myeloma: Spotlight Review Leukemia (2009) , 23(12), 221 0-2 1 [10] Munshi, N C, Anderson, K C, Bergsagel, P L, et al Consensus Recommendations for Risk Stratification in Multiple Myeloma: Report of the International... one novel agent as backbone together with glucocorticoids and alkylating cytostatics were used as high standard based on randomized trials (Tab 1) 3 4 Multiple Myeloma - A Quick Reflection on the Fast Progress Modern protocols of second decade use intensive treatment strategies in the clinical trials called “Multi Agent Sequential Therapy Targeting Different Clones” with at least two novel agens based... Bortezomib-Thalidomide-Dexamethasone over the Dual Combination of Thalido‐ mide-Dexamethasone in Patients with Multiple Myeloma Progressing or Relapsing after Autologous Transplantation: the MMVAR/IFM 200 5-0 4 Randomized Phase III Trial from the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation J Clin Oncol (2012) , 30(20), 247 5-8 2 [24] Gonsalves, W I, Gertz, M A, Lacy, M Q, et al Second Auto-SCT... tolerated thalidomide maintenance therapy for more than a year At this point, when there are less toxic drugs available for maintenance therapy, thalidomide is recommended as a part of short-term intensive consolidation therapies in [29,28,30] Lenalidomide was tested in two independent randomized clinical trials of phase III as maintenance treatment after autologous transplantation Both these trials, CALGB... enables the calculation of a ratio of the involved/uninvolved-polyclonal Igs (HLCR) [4 6-4 8] in the same manner as sFLC κ/λ ratios (FLCR) SPEP quantification of sFLC is inaccurate and for more than 150 years monoclonal FLC measurements relied upon urinalysis Collection, handling, renal function and variable light chain biochemistries make this a less than ideal medium for analysis In the last 10 years... BL and have been reported in other B-cell entities Almost 70% of mantle cell lymphoma (MCL) patients are genetically characterized by the chromosomal translocation t(11;14) In several cases, patients also have point mutations and / or deletion of the ATM (ataxia telangiectasia mutated) gene In addition, blastic forms or subtypes with more aggressive clinical behavior, may have additional mutations in . MULTIPLE MYELOMA - A QUICK REFLECTION ON THE FAST PROGRESS Edited by Roman Hajek Multiple Myeloma - A Quick Reflection on the Fast Progress http://dx.doi.org/10.5772/56515 Edited. Multiple Myeloma and Others Monoclonal Gammopathies 93 Lucie Rihova, Karthick Raja Muthu Raja, Luiz Arthur Calheiros Leite, Pavla Vsianska and Roman Hajek Chapter