Cancer Treatment and Research Series Editor: Steven T Rosen Aldo M. Roccaro Irene M. Ghobrial Plasma Cell Dyscrasias Indexed in PubMed/Medline Cancer Treatment and Research Volume 169 Series editor Steven T Rosen, Duarte, CA, USA More information about this series at http://www.springer.com/series/5808 Aldo M Roccaro Irene M Ghobrial • Editors Plasma Cell Dyscrasias 123 Editors Aldo M Roccaro Department of Medical Oncology/Hematology ASST Spedali Civili di Brescia Brescia Italy ISSN 0927-3042 Cancer Treatment and Research ISBN 978-3-319-40318-2 DOI 10.1007/978-3-319-40320-5 Irene M Ghobrial Department of Medical Oncology Dana-Farber Cancer Institute Boston, MA USA ISSN 2509-8497 (electronic) ISBN 978-3-319-40320-5 (eBook) Library of Congress Control Number: 2016942532 © Springer International Publishing Switzerland 2016 This work is subject to copyright All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of 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published by Springer Nature The registered company is Springer International Publishing AG Switzerland Contents Part I Monoclonal Gammopathy of Undetermined Significance and Smoldering Myeloma MGUS and Smoldering Multiple Myeloma: Diagnosis and Epidemiology María-Victoria Mateos and Ola Landgren Part II Multiple Myeloma Vision Statement for Multiple Myeloma: Future Directions Kenneth C Anderson 15 Genomic Aberrations in Multiple Myeloma Salomon Manier, Karma Salem, Siobhan V Glavey, Aldo M Roccaro and Irene M Ghobrial 23 Epigenetics in Multiple Myeloma Siobhan V Glavey, Salomon Manier, Antonio Sacco, Karma Salem, Yawara Kawano, Juliette Bouyssou, Irene M Ghobrial and Aldo M Roccaro 35 Role of Endothelial Cells and Fibroblasts in Multiple Myeloma Angiogenic Switch Domenico Ribatti and Angelo Vacca Targeting the Bone Marrow Microenvironment Michele Moschetta, Yawara Kawano and Klaus Podar 51 63 Multiple Myeloma Minimal Residual Disease 103 Bruno Paiva, Ramón García-Sanz and Jesús F San Miguel Treatment of Newly Diagnosed Elderly Multiple Myeloma 123 Guillemette Fouquet, Francesca Gay, Eileen Boyle, Sara Bringhen, Alessandra Larocca, Thierry Facon, Xavier Leleu and Antonio Palumbo Management of Transplant-Eligible Patients with Newly Diagnosed Multiple Myeloma 145 Jacob Laubach and Shaji Kumar v vi Contents Treatment of Relapsed/Refractory Multiple Myeloma 169 Paola Neri, Nizar J Bahlis, Claudia Paba-Prada and Paul Richardson Treatment of MM: Upcoming Novel Therapies 195 Sagar Lonial Role of the Immune Response in Disease Progression and Therapy in Multiple Myeloma 207 Susan J Lee and Ivan Borrello Transplantation for Multiple Myeloma 227 Yogesh S Jethava and Frits van Rhee Bone Disease in Multiple Myeloma 251 Homare Eda, Loredana Santo, G David Roodman and Noopur Raje Part III Primary Amyloidosis, Systemic Light Chain and Heavy Chain Diseases, Plasmacytoma Immunoglobulin Light Chain Systemic Amyloidosis 273 Angela Dispenzieri and Giampaolo Merlini Part IV Waldenstrom’s Macroglobulinemia Waldenstrom Macroglobulinemia: Genomic Aberrations and Treatment 321 Prashant Kapoor, Stephen M Ansell and Esteban Braggio Part I Monoclonal Gammopathy of Undetermined Significance and Smoldering Myeloma MGUS and Smoldering Multiple Myeloma: Diagnosis and Epidemiology María-Victoria Mateos and Ola Landgren Abstract Monoclonal gammopathy of undetermined significance (MHUS) is characterized by the presence of a serum M-protein less than g/dL, less than 10 % clonal plasma cells in the bone marrow, and the absence of myeloma-defining event Smoldering multiple myeloma (SMM) is an asymptomatic disorder characterized by the presence of ≥3 g/dL serum M-protein and/or 10–60 % bone marrow plasma cell infiltration with no myeloma-defining event The risk of progression to multiple myeloma (MM) requiring therapy varies greatly for individual patients, but it is uniform and % per year for MGUS, while higher (10 % per year) and not uniform for SMM patients The definition of MM was recently revisited patients previously labeled as SMM with a very high risk of progression (80–90 % at years) were included in the updated definition of MM requiring therapy The standard of care is observation for MGUS patients and although this also applies for SMM, a recent randomized trial targeting high-risk SMM showed that early intervention was associated with better progression-free and overall survival Biomarkers have become an integrated part of diagnostic criteria for MM requiring therapy, as well as clinical risk stratification of patients with SMM This paper reviews and discusses clinical implications for MGUS and SMM patients Keywords Á Multiple myeloma requiring therapy Monoclonal gammopathy of undetermined significance Smoldering myeloma Á M.-V Mateos (&) University Hospital of Salamanca/IBSAL, Paseo San Vicente, 58-182, 37007 Salamanca, Spain e-mail: mvmateos@usal.es O Landgren Myeloma Service, Memorial Sloan-Kettering Cancer Center, New York, USA © Springer International Publishing Switzerland 2016 A.M Roccaro and I.M Ghobrial (eds.), Plasma Cell Dyscrasias, Cancer Treatment and Research 169, DOI 10.1007/978-3-319-40320-5_1 M.-V Mateos and O Landgren Introduction In 1978, Monoclonal gammopathy of undetermined significance (MGUS) was described by Kyle and Greipp and years later, based on a series of six patients who met the criteria for multiple myeloma (MM) but whose disease did not have an aggressive course, the same authors coined the term smoldering multiple myeloma (SMM) [1] In 2014, the International Myeloma Working Group (IMWG) updated the definition of multiple myeloma (MM) which in turn impacted the definition of both MGUS and SMM [2] MGUS diagnosis requires the presence of 5 × 106/L • Immunophenotyping characterization and immunoparesis: –≥ 95 % of aberrant plasma cells by flow within the plasma cell bone marrow compartment... They upregulate cytolytic T cell, natural killer cell, and natural killer cell- T cell anti-MM immunity, while at the same time inhibiting aberrant increased regulatory T cell function in myeloma