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New drugs and novel mechanisms of action in multiple myeloma in 2013: a report from the International Myeloma Working Group (IMWG)

Leukemia volume 28, pages 525–542 (2014)Cite this article

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Abstract

Treatment in medical oncology is gradually shifting from the use of nonspecific chemotherapeutic agents toward an era of novel targeted therapy in which drugs and their combinations target specific aspects of the biology of tumor cells. Multiple myeloma (MM) has become one of the best examples in this regard, reflected in the identification of new pathogenic mechanisms, together with the development of novel drugs that are being explored from the preclinical setting to the early phases of clinical development. We review the biological rationale for the use of the most important new agents for treating MM and summarize their clinical activity in an increasingly busy field. First, we discuss data from already approved and active agents (including second- and third-generation proteasome inhibitors (PIs), immunomodulatory agents and alkylators). Next, we focus on agents with novel mechanisms of action, such as monoclonal antibodies (MoAbs), cell cycle-specific drugs, deacetylase inhibitors, agents acting on the unfolded protein response, signaling transduction pathway inhibitors and kinase inhibitors. Among this plethora of new agents or mechanisms, some are specially promising: anti-CD38 MoAb, such as daratumumab, are the first antibodies with clinical activity as single agents in MM. Moreover, the kinesin spindle protein inhibitor Arry-520 is effective in monotherapy as well as in combination with dexamethasone in heavily pretreated patients. Immunotherapy against MM is also being explored, and probably the most attractive example of this approach is the combination of the anti-CS1 MoAb elotuzumab with lenalidomide and dexamethasone, which has produced exciting results in the relapsed/refractory setting.

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Author information

Author notes

  1. S Usmani

    Present address: 31Current address: Levine Cancer Institute, Carolinas Healthcare System, Charlotte, NC, USA.,

  2. E M Ocio, P G Richardson, S V Rajkumar, A Palumbo, M V Mateos, R Orlowski, S Kumar, S Usmani, D Roodman, R Niesvizky, H Einsele, K C Anderson, M A Dimopoulos, H Avet-Loiseau, U-H Mellqvist, I Turesson, G Merlini, R Schots, P McCarthy, L Bergsagel, C S Chim, J J Lahuerta, J Shah, A Reiman, J Mikhael, S Zweegman, S Lonial, R Comenzo, W J Chng, P Moreau, P Sonneveld, H Ludwig, B G M Durie and J F S Miguel: See Appendix.

Authors and Affiliations

  1. Department of Hematology, University Hospital and Cancer Research Center, University of Salamanca-IBSAL, IBMCC (USAL-CSIC), Salamanca, Spain

    E M Ocio, M V Mateos & J F S Miguel

  2. Department of Medicine, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    P G Richardson & K C Anderson

  3. Department of Hematology, Mayo Clinic, Rochester, MN, USA

    S V Rajkumar & S Kumar

  4. Department of Hematology, University of Torino, Torino, Italy

    A Palumbo

  5. Department of Lymphoma/Myeloma, MD Anderson Cancer Center, Houston, TX, USA

    R Orlowski & J Shah

  6. M.I.R.T. UAMS, Little Rock, AR, USA

    S Usmani

  7. Director of Hematology/Oncology, Indiana University, Indianapolis, IN, USA

    D Roodman

  8. Department of Hematology, Weill Cornell Medical College, New York, NY, USA

    R Niesvizky

  9. Department of Internal Medicine, University of Wurzburg, Wurzburg, Germany

    H Einsele

  10. School of Medicine, University of Athens, Athens, Greece

    M A Dimopoulos

  11. Department of Hematology, University of Toulouse, Toulouse, France

    H Avet-Loiseau

  12. Department of Medicine, Section of Hematology, Sahlgrenska University Hospital, Gothenburg, Sweden

    U-H Mellqvist

  13. Department of Medicine, Section of Hematology, Skane University Hospital, Malmo, Sweden

    I Turesson

  14. Department of Molecular Medicine, Univeristy of Pavia, Pavia, Italy

    G Merlini

  15. Department of Clinical Hematology and Stem Cell Laboratory, University Ziekenhuis, Brussels, Belgium

    R Schots

  16. Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA

    P McCarthy

  17. Division of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ, USA

    L Bergsagel & J Mikhael

  18. Department of Hematology, Queen Mary Hospital, Hong Kong

    C S Chim

  19. Department of Hematology, Hospital Universitario 12 de Octubre, Madrid, Spain

    J J Lahuerta

  20. Department of Oncology, University of New Brunswick, Saint John Regional Hospital, St John, NB, Canada

    A Reiman

  21. Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands

    S Zweegman

  22. Department of Hematology and Medical Oncology, Shanghai Chang Zheng Hospital, Atlanta, GA, USA

    S Lonial

  23. Department of Hematology, Tufts Medical School, Boston, MA, USA

    R Comenzo

  24. Department of Hematology Oncology, National University Cancer Institute, Singapore

    W J Chng

  25. Department of Hematology, University Hospital, Nantes, France

    P Moreau

  26. Department of Hematology, Erasmus MC, Rotterdam, The Netherlands

    P Sonneveld

  27. Department of Medicine, Center for Oncology, Hematology and Palliative Care, Wilhelminenspital, Vienna, Austria

    H Ludwig

  28. Oschin Cancer Center, Los Angeles, CA, USA

    B G M Durie

  29. Department of Clinical and Translational Medicine, University of Navarra, Pamplona, Spain

    J F S Miguel

Authors
  1. E M Ocio
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  2. P G Richardson
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  3. S V Rajkumar
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  4. A Palumbo
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  5. M V Mateos
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  6. R Orlowski
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  7. S Kumar
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  8. S Usmani
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  9. D Roodman
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  10. R Niesvizky
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  11. H Einsele
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  12. K C Anderson
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  13. M A Dimopoulos
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  14. H Avet-Loiseau
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  15. U-H Mellqvist
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  16. I Turesson
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  17. G Merlini
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  18. R Schots
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  19. P McCarthy
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  20. L Bergsagel
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  21. C S Chim
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  22. J J Lahuerta
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  23. J Shah
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  24. A Reiman
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  25. J Mikhael
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  26. S Zweegman
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  27. S Lonial
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  28. R Comenzo
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  29. W J Chng
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  30. P Moreau
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  31. P Sonneveld
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  32. H Ludwig
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  33. B G M Durie
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  34. J F S Miguel
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Consortia

on behalf of the International Myeloma Working Group

Corresponding author

Correspondence to E M Ocio.

Ethics declarations

Competing interests

EMO—consultancy: Onyx, Bristol Myers Squibb, Array Pharmaceuticals; research funding: Celgene, Onyx, Pharmamar, Array Pharmaceuticals. PGR—consultancy: Celgene, Millennium Takeda, Johnson & Johnson, Novartis, Bristol Myer Squibb; research funding: Celgene and Millenium. SVR—no conflicts to disclose. AP—consultancy and honoraria: Amgen, Bristol Myers Squibb, Celgene, Janssen-Cilag, Millennium, ONYX. MVM—consultancy: Janssen-Cilag, Celgene, Millennium. RO—consultancy: Abbott Laboratories, Centocor Ortho Biotech, Cephalon, Millennium, Novartis, Onyx; research funding: Celgene, Johnson & Johnson, Millennium, Onyx. SK—consultancy: Millennium, Celgene, Onyx; research funding: Celgene, Millennium, Novartis, Celphalon, Sanofi, Onyx. SU—consultancy: Celgene; honoraria: Celgene, Onyx; research funding: Celgene, Onyx, Millennium. DR—honoraria: Amgen; research funding: Eli Lilly. RN—consultancy: Onyx, Millennium, Celgene; honoraria: Onyx, Millennium, Celgene; research funding: Onyx, Millennium, Celgene. HE—consultancy: Celgene, Janssen; honoraria: Celgene, Janssen; research funding: Celgene, Janssen. KCA—consultancy: Gilead, Sanofi-Aventis, Onyx, Celgene; stock ownership: Acetylon, Oncoprep. MAD—consultancy: Celgene, Ortho Biotech; honoraria: Celgene, Ortho Biotech; research funding: Celgene. HA—honoraria: Celgene, Janssen, Onyx. UHM—honoraria: Celgene, Janssen-Cilag. IT—No conflicts to disclose. GM—consultancy: Millennium Takeda, Neotype; honoraria: Millennium Takeda, Pfizer. RS—No conflicts to disclose. PM—consultancy: Celgene, Janssen; honoraria: Celgene, Janssen. PLB—honoraria: Onyx. CSC—No conflicts to disclose. JJL—honoraria: Celgene; research funding: Celgene, Janssen-Cilag. JS—research funding: Janssen-Cilag, Celgene, Onyx. AR—consultancy: Celgene; research funding: Celgene, Bristol Myers Squibb, Millennium, Astra Zeneca, Onyx. JM—research funding: Celgene, Onyx, Sanofi. SZ—research funding: Celgene, Janssen-Cilag, Millennium. SL—consultancy: Celgene, Millennium, Novartis, Bristol Myers Squibb, Onyx, Janssen-Cilag. RC—consultancy: Millennium; research funding: Millennium, Prothena Biotech. WJC—honoraria: Janssen, Celgene, Novartis; research funding: Celgene, Roche. PM—consultancy: Celgene, Janssen, Millennium; honoraria: Celgene, Janssen. PS—research funding: Janssen-Cilag, Celgene, Onyx. HL—honoraria: Celgene, Mundi Pharma, Janssen-Cilag; research funding: Celgene, Mundi Pharma, Janssen-Cilag. BD—honoraria: Celgene Corporation, Onyx Pharmaceutical, Millennium Pharmaceutical, The Takeda Company. JFSM—consultancy and honoraria: Janssen-Cilag, Millennium, Celgene, Onyx, Novartis, Bristol Myers Squibb.

Appendix

Appendix

The International Myeloma Working Group

  1. 1

    Niels Abildgaard, Syddansk Universitet, Odense, Denmark.

  2. 2

    Rafat Abonour, Indiana University School of Medicine, Indianapolis, Indiana, USA.

  3. 3

    Ray Alexanian, MD Anderson, Houston, TX, USA.

  4. 4

    Melissa Alsina, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.

  5. 5

    Kenneth C. Anderson, DFCI, Boston, MA, USA.

  6. 6

    Michel Attal, Purpan Hospital, Toulouse, France.

  7. 7

    Hervé Avet-Loiseau, Institute de Biologie, Nantes, France.

  8. 8

    Ashraf Badros, University of Maryland, Baltimore, MD, USA.

  9. 9

    Dalsu Baris, National Cancer Institute, Bethesda, MD, USA.

  10. 10

    Bart Barlogie, M.I.R.T. UAMS, Little Rock, AR, USA.

  11. 11

    Régis Bataille, Institute de Biologie, Nantes, France.

  12. 12

    Meral Beksaç, Ankara University, Ankara, Turkey.

  13. 13

    Andrew Belch, Cross Cancer Institute, Edmonton, AB, Canada.

  14. 14

    Dina Ben-Yehuda, Hadassah University Hospital, Hadassah, Israel.

  15. 15

    Bill Bensinger, Fred Hutchinson Cancer Center, Seattle, WA, USA.

  16. 16

    P. Leif Bergsagel, Mayo Clinic Scottsdale, Scottsdale, AZ, USA.

  17. 17

    Jenny Bird, Bristol Haematology and Oncology Center, Bristol, UK.

  18. 18

    Joan Bladé, Hospital Clinica, Barcelona, Spain.

  19. 19

    Mario Boccadoro, University of Torino, Torino, Italy.

  20. 20

    Jo Caers, Centre Hospitalier Universitaire de Liège, Liège, Belgium.

  21. 21

    Michele Cavo, Universita di Bologna, Bologna, Italy.

  22. 22

    Asher Chanan-Khan, Mayo Clinic, Jacksonville, FL, USA.

  23. 23

    Wen Ming Chen, MM Research Center of Beijing, Beijing, China.

  24. 24

    Marta Chesi, Mayo Clinic Scottsdale, Scottsdale, AZ, USA.

  25. 25

    Tony Child, Leeds General Hospital, Leeds, UK.

  26. 26

    James Chim, Department of Medicine, Queen Mary Hospital, Hong Kong.

  27. 27

    Wee-Joo Chng, National University Health System, Singapore.

  28. 28

    Ray Comenzo, Tufts Medical School, Boston, MA, USA.

  29. 29

    John Crowley, Cancer Research and Biostatistics, Seattle, WA, USA.

  30. 30

    William Dalton, H. Lee Moffitt, Tampa, FL, USA.

  31. 31

    Faith Davies, Royal Marsden Hospital, London, UK.

  32. 32

    Javier de la Rubia, Hospital Universitario La Fe, Valencia, Spain.

  33. 33

    Cármino de Souza, Univeridade de Campinas, Caminas, Brazil.

  34. 34

    Michel Delforge, University Hospital Gasthuisberg, Leuven, Belgium.

  35. 35

    Meletios Dimopoulos, University of Athens School of Medicine, Athens, Greece.

  36. 36

    Angela Dispenzieri, Mayo Clinic, Rochester, MN, USA.

  37. 37

    Johannes Drach, University of Vienna, Vienna, Austria.

  38. 38

    Matthew Drake, Mayo Clinic Rochester, Rochester, MN, USA.

  39. 39

    Brian G.M. Durie, Cedars-Sinai Samuel Oschin Cancer Center, Los Angeles, CA, USA.

  40. 40

    Hermann Einsele, Universitätsklinik Würzburg, Würzburg, Germany.

  41. 41

    Theirry Facon, Centre Hospitalier Regional Universitaire de Lille, Lille, France.

  42. 42

    Dorotea Fantl, Socieded Argentinade Hematolgia, Buenos Aires, Argentina.

  43. 43

    Jean-Paul Fermand, Hopitaux de Paris, Paris, France.

  44. 44

    Carlos Fernández de Larrea, Hospital Clínic de Barcelona, Barcelona, Spain.

  45. 45

    Rafael Fonseca, Mayo Clinic Arizona, Scottsdale, AZ, USA.

  46. 46

    Gösta Gahrton, Karolinska Institute for Medicine, Huddinge, Sweden.

  47. 47

    Ramón García-Sanz, University Hospital of Salamanca, Salamanca, Spain.

  48. 48

    Christina Gasparetto, Duke University Medical Center, Durham, NC, USA.

  49. 49

    Morie Gertz, Mayo Clinic, Rochester, MN, USA.

  50. 50

    Irene Ghobrial, Dana-Farber Cancer Institute, Boston, MA, USA.

  51. 51

    John Gibson, Royal Prince Alfred Hospital, Sydney, NSW, Australia.

  52. 52

    Peter Gimsing, University of Copenhagen, Copenhagen, Denmark.

  53. 53

    Sergio Giralt, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

  54. 54

    Hartmut Goldschmidt, University Hospital Heidelberg, Heidelberg, Germany.

  55. 55

    Philip Greipp, Mayo Clinic, Rochester, MN, USA.

  56. 56

    Roman Hajek, Brno University, Brno, Czech Republic.

  57. 57

    Izhar Hardan, Tel Aviv University, Tel Aviv, Israel.

  58. 58

    Parameswaran Hari, Medical College of Wisconsin, Milwaukee, WI, USA.

  59. 59

    Hiroyuki Hata, Kumamoto University Hospital, Kumamoto, Japan.

  60. 60

    Yutaka Hattori, Keio University School of Medicine, Tokyo, Japan.

  61. 61

    Tom Heffner, Emory University, Atlanta, GA, USA.

  62. 62

    Jens Hillengass, University of Heidelberg, Heidelberg, Germany.

  63. 63

    Joy Ho, Royal Prince Alfred Hospital, Sydney, NSW, Australia.

  64. 64

    Antje Hoering, Cancer Research and Biostatistics, Seattle, WA, USA.

  65. 65

    Jian Hou, Shanghai Chang Zheng Hospital, Shanghai, China.

  66. 66

    Vania Hungria, Clinica San Germano, Sao Paolo, Brazil.

  67. 67

    Shinsuke Ida, Nagoya City University Medical School, Nagoya, Japan.

  68. 68

    Andrzej J. Jakubowiak, University of Chicago, Chicago, IL, USA.

  69. 69

    Peter Jacobs, Constantiaberg Medi-Clinic, Plumstead, South Africa.

  70. 70

    Sundar Jagannath, Mt. Sinai Cancer Institute, New York, NY, USA.

  71. 71

    Hans Johnsen, Aalborg Hospital Science and Innovation Center, Aalborg, Denmark.

  72. 72

    Douglas Joshua, Royal Prince Alfred Hospital, Sydney, NSW, Australia.

  73. 73

    Artur Jurczyszyn, The Myeloma Treatment Foundation, Poland.

  74. 74

    Efstathios Kastritis, University of Athens, Athens, Greece.

  75. 75

    Jonathan Kaufman, Emory Clinic, Atlanta, GA, USA.

  76. 76

    Michio Kawano, Yamaguchi University, Ube, Japan.

  77. 77

    Eva Kovacs, Cancer Immunology Research-Life, Birsfelden, Switzerland.

  78. 78

    Amrita Krishnan, City of Hope, Duarte, CA, USA.

  79. 79

    Sigurdur Kristinsson, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden.

  80. 80

    Nicolaus Kröger, University Hospital Hamburg, Hamburg, Germany.

  81. 81

    Shaji Kumar, Department of Hematology, Mayo Clinic, Rochester, MN, USA.

  82. 82

    Robert A. Kyle, Department of Laboratory Med. and Pathology, Mayo Clinic, Rochester, MN, USA.

  83. 83

    Chara Kyriacou, Northwick Park Hospital, London, UK.

  84. 84

    Martha Lacy, Mayo Clinic Rochester, Rochester, MN, USA.

  85. 85

    Juan José Lahuerta, Grupo Español di Mieloma, Hospital Universitario 12 de Octubre, Madrid, Spain.

  86. 86

    Ola Landgren, National Cancer Institute, Bethesda, MD, USA.

  87. 87

    Jacob Laubach, Dana-Farber Cancer Institute, Boston, MA, USA.

  88. 88

    Garderet Laurent, Hôpital Saint Antoine, Paris, France.

  89. 89

    Fernando Leal da Costa, Instituto Portugues De Oncologia, Lisbon, Portugal.

  90. 90

    Jae Hoon Lee, Gachon University Gil Hospital, Incheon, Korea.

  91. 91

    Merav Leiba, Sheba Medical Center, Tel Hashomer, Israel.

  92. 92

    Xavier LeLeu, Hospital Huriez, CHRU Lille, France.

  93. 93

    Suzanne Lentzsch, Columbia University, New York, NY, USA.

  94. 94

    Henk Lokhorst, University Medical CenterUtrecht, Utrecht, The Netherlands.

  95. 95

    Sagar Lonial, Emory University Medical School, Atlanta, GA, USA.

  96. 96

    Heinz Ludwig, Wilhelminenspital Der Stat Wien, Vienna, Austria.

  97. 97

    Anuj Mahindra, Dana-Farber Cancer Institute, Massachusetts General Hospital, Boston, MA, USA.

  98. 98

    Angelo Maiolino, Rua fonte da Saudade, Rio de Janeiro, Brazil.

  99. 99

    María-Marivi Mateos, University Hospital of Salamanca-IBSAL, IBMCC (USAL-CSIC), Salamanca, Spain.

  100. 100

    Amitabha Mazumder, NYU Comprehensive Cancer Center, New York, NY, USA.

  101. 101

    Philip McCarthy, Roswell Park Cancer Institute, Buffalo, NY, USA.

  102. 102

    Jayesh Mehta, Northwestern University, Chicago, IL, USA.

  103. 103

    Ulf-Henrik Mellqvist, Sahlgrenska University Hospital, Gothenburg, Sweden.

  104. 104

    GiamPaolo Merlini, University of Pavia, Pavia, Italy.

  105. 105

    Joseph Mikhael, Mayo Clinic Arizona, Scottsdale, AZ, USA.

  106. 106

    Philippe Moreau, University Hospital, Nantes, France.

  107. 107

    Gareth Morgan, Royal Marsden Hospital, London, UK.

  108. 108

    Nikhil Munshi, Diane Farber Cancer Institute, Boston, MA, USA.

  109. 109

    Hareth Nahi, Karolinska University Hospital, Stockholm, Sweden.

  110. 110

    Ruben Niesvizky, Weill Cornell Medical College, New York, NY, USA.

  111. 111

    Amara Nouel, Hospital Rutz y Paez, Bolivar, Venezuela.

  112. 112

    Yana Novis, Hospital Sírio Libanês, Bela Vista, Brazil.

  113. 113

    Enrique Ocio, University Hospital of Salamanca-IBSAL, IBMCC (USAL-CSIC), Salamanca, Spain.

  114. 114

    Robert Orlowski, MD Anderson Cancer Center, Houston, TX, USA.

  115. 115

    Antonio Palumbo, Cathedra Ematologia, Torino, Italy.

  116. 116

    Santiago Pavlovsky, Fundaleu, Buenos Aires, Argentina.

  117. 117

    Linda Pilarski, University of Alberta, Edmonton, AB, Canada.

  118. 118

    Raymond Powles, Leukemia & Myeloma, Wimbledon, UK.

  119. 119

    Noopur Raje, Massachusetts General Hospital, Boston, MA, USA.

  120. 120

    S. Vincent Rajkumar, Mayo Clinic, Rochester, MN, USA.

  121. 121

    Donna Reece, Princess Margaret Hospital, Toronto, ON, Canada.

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    Paul G. Richardson, Dana Farber Cancer Institute, Boston, MA, USA.

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    Kenneth R. Romeril, Wellington Hospital, Wellington, New Zealand.

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    David Roodman, Indiana University, Indianapolis, IN, USA

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    Laura Rosiñol, Hospital Clinic, Barcelona, Spain.

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    Murielle Roussel, University of Toulouse, Toulouse, France.

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    Stephen Russell, Mayo Clinic, Rochester, MN, USA.

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    Jesús San Miguel, University Hospital of Salamanca-IBSAL, IBMCC (USAL-CSIC), Salamanca, Spain.

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    Rik Schots, Universitair Ziekenhuis Brussel, Brussels, Belgium.

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    Sabina Sevcikova, Masaryk University, Brno, Czech Republic.

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    Orhan Sezer, Universität Hamburg, Hamburg, Germany.

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    Jatin J. Shah, MD Anderson Cancer Institute, Houston, TX, USA.

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    John Shaughnessy, M.I.R.T. UAMS, Little Rock, AR, USA.

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    Seema Singhal, Northwestern University, Chicago, IL, USA.

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    Andrew Spencer, The Alfred Hospital, Melbourne, VIC, Australia.

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    Edward Stadtmauer, University of Pennsylvania, Philadelphia, PA, USA.

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    Keith Stewart, Mayo Clinic Arizona, Scottsdale, AZ, USA.

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    Evangelos Terpos, University of Athens School of Medicine, Athens, Greece.

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    Patrizia Tosi, Italian Cooperative Group, Istituto di Ematologia Seragnoli, Bologna, Italy.

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    Guido Tricot, Huntsman Cancer Institute, Salt Lake City, UT, USA.

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    Brian Van Ness, University of Minnesota, Minneapolis, MN, USA.

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    Isabelle Vande Broek, Vrije Universiteit Brussels, Brussels, Belgium.

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    Karin Vanderkerken, Vrije University Brussels VUB, Brussels, Belgium.

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    Michael Wang, MD Anderson, Houston, TX, USA.

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    Donna Weber, MD Anderson, Houston, TX, USA.

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    Jan Westin, Sahlgrenska University Hospital, Gothenburg, Sweden.

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    Keith Wheatley, University of Birmingham, Birmingham, UK.

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    Elena Zamagni, University of Bologna, Bologna, Italy.

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Ocio, E., Richardson, P., Rajkumar, S. et al. New drugs and novel mechanisms of action in multiple myeloma in 2013: a report from the International Myeloma Working Group (IMWG). Leukemia 28, 525–542 (2014). https://doi.org/10.1038/leu.2013.350

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