Handbook of Multiple Myeloma

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Editors Contributors
Mohamad Mohty MD, PhD Hervé Avet-Loiseau MD
Clinical Hematology and Cellular Joan Bladé MD, PhD
Therapy Department Eileen M Boyle MD
Université Pierre and Marie Curie Jill Corre PharmD, PhD
Hospital Saint-Antoine Michel Delforge MD, PhD
Paris, France Hélène Demarquette MB
Thierry Facon MD
Jean-Luc Harousseau MD Carlos Fernández de Larrea MD, PhD
Department of Hematology Stéphanie Guidez MD
Centre René Gauducheau Charles Herbaux MD
Nantes Atlantique (Saint-Herblain) Charline Legrand MB
France Xavier Leleu MD, PhD
Florent Malard MD, PhD
Evangelos Terpos MD, PhD

ISBN 978-3-319-18217-9 ISBN 978-3-319-18218-6 (eBook)

DOI 10.1007/978-3-319-18218-6
Springer Cham Heidelberg New York Dordrecht London

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 Contents
Author biographies vii
Abbreviationsxv
Introductionxxi

1 Pathophysiology1
Hervé Avet-Loiseau and Jill Corre
Chromosomal aberrations 1
Changes in gene expression 4
Bone marrow microenvironment and cytokine network 5
References11

2 Diagnosis and staging 15

Carlos Fernández de Larrea and Joan Bladé
Diagnostic criteria 15
Classification16
Prognosis19
Imaging21
Response criteria 21
Minimal residual disease  25
Acknowledgement27
References27

3 Treatment of transplant-eligible patients 29

Mohamad Mohty, Florent Malard, and Jean-Luc Harousseau
Induction therapy 29
Autologous transplantation 31
Consolidation32
Maintenance34
Allogeneic transplantation 36
References38

v
vi • co n te nts

4 Treatment of elderly patients with myeloma 41

Eileen M Boyle, Charline Legrand, Hélène Demarquette, Stéphanie Guidez
Charles Herbaux, Xavier Leleu, and Thierry Facon
Introduction41
Epidemiology41
Biological and clinical features 42
Defining aims 43
What to aim for?  44
Disease-specific treatment options 44
Tailoring the treatment to the patient  50
Supportive care 56
Conclusion and perspectives  58
References59

5 Treatment of relapsed multiple myeloma 65

Michel Delforge
General considerations 65
Immediate treatment initiation or watchful waiting 66
To re-treat or not  68
Role of allogeneic transplantation 70
Optimizing drug-based treatment at relapse 70
Supportive care 73
Conclusion74
References74

6 Bone disease 79
Evangelos Terpos
Introduction79
Biology of multiple myeloma bone disease 79
Therapy82
References88
Author Biographies
Hervé Avet-Loiseau, MD, is Head of the Laboratory for Genomics in
Myeloma in the University Cancer Center of Toulouse and has been since
September 2012. Before, he was Head of the Hematology Laboratory of
the University Hospital of Nantes, France, a position he has held since
2008. He received his medical degree with a specialization in Pediatric
Hematology in 1990. After pursuing a postdoctoral fellowship in the
laboratory of Dr Joe Gray in San Francisco, he moved into the area of
Biological Hematology in 1995 and subsequently specialized in cytogenet-
ics. He received his PhD in 1998 and became Professor of Hematology in
2001. Professor Hervé Avet-Loiseau is highly involved in the Intergroupe
Francophone du Myélome and is current Chairman where he leads all
biological studies. Most of these studies are based on the analysis of
genetic/genomic abnormalities observed in malignant plasma cells using
different technologies, including fluorescence in-situ hybridization, gene
expression profiling, single nucleotide polymorphism arrays, and next
generation sequencing.

Joan Bladé, MD, PhD, graduated from the Medical School of the
University of Barcelona. In 1981 he joined the staff at the Department
of Hematology of the Hospital Clínic de Barcelona/IDIBAPS, where he
is now Senior Consultant and Director of the Amyloidosis and Myeloma
Unit. He was Executive Secretary of the PETHEMA group, co-founder
of the PETHEMA Foundation, and co-founder of the Spanish Myeloma
Group. Dr Bladé chaired the group that developed the European Group
for Blood and Marrow Transplant (EBMT) response criteria, known today
as the Bladé Criteria. He has published over 350 papers on monoclonal
gammopathies and is the recipient of the 2010 Robert A Kyle Lifetime
Achievement Award, Joseph Michaelis 2012 Award for his myeloma
research, and he is current Secretary of the International Myeloma Society.

vii
VIII • AUTHOR BIOGRAPHIES

Eileen M Boyle, MD, completed her medical degree at the Lyon University
School of Medicine in France in 2008. She received a master’s degree
in cell biology in 2014 having done research at the Institute of Cancer
research under the supervision of Professor Gareth Morgan. She cur-
rently serves as a Senior Registrar in the Department of Hematology,
Hôpital Claude Huriez, CHRU, Lille, and in the Lille University School
of Medicine. Her main topic of interest is the genetic make-up of mature
lymphoid neoplasms including myeloma and lymphoma.

Jill Corre, PharmD, PhD, graduated from the Pharmaceutical Faculty of

the François Rabelais University of Tours in France. She moved to Toulouse
where she completed her training as a resident in Medical Biology and
specialized in Hematology in the University Hospital. In 2007, she joined
the staff at the Hematology Laboratory of the University Toulouse Hospital
where she is now Assistant Professor. Her doctoral thesis was on myeloma
microenvironment, in particular on mesenchymal stromal cells. In 2012,
she also joined Professor Hervé Avet-Loiseau in the Unit for Genomics
in Myeloma, which is now located at the University Cancer Institute of
Toulouse Oncopole. Her research activity takes place in the pharmacog-
enomics of myeloma team, from the Cancer Research Center of Toulouse.
She is currently a member of the Intergroupe Francophone du Myélome.

Michel Delforge, MD, PhD, is Professor of Medicine at the Department

of Hematology, Catholic University in Leuven, Belgium. He was trained in
Leuven and at the University of Minnesota, USA, and obtained a doctoral
degree in biomedical sciences. He directs the myeloma and myelodys-
plasia clinic of the Department of Hematology at the University Hospital
Leuven. He is a Senior Clinical Investigator and Professor of Medicine
at the Catholic University Leuven, Belgium. Professor Delforge is a
member of the executive committee of the Stem Cell Institute Leuven and
holds the CAF-DCF (Belgian Red Cross) Chair in Hematology. Professor
Delforge is an active member of the Belgian Myeloma Working Party,
Intergroupe Francophone du Myélome, the Hemato Oncology Foundation
 AUTHOR BIOGRAPHIES • Ix

for Adults in the Netherlands and International Myeloma Working Group.

His topics of interest include: side-effect management of new drugs in
myeloma, translational research and new drug development. Professor
Delforge has authored or co-authored more than 50 manuscripts in
peer-reviewed journals.

Hélène Demarquette, MB, completed her medical degree at the Lille

University School of Medicine in France. She currently serves as a Senior
Registrar in the Department of Hematology, Hôpital Claude Huriez,
CHRU, Lille, where she is currently completing dual training in hematol-
ogy and infectious diseases. Her main field of interest is myeloma and
infectious disease.

Thierry Facon, MD, completed his medical degree at the Lille University
School of Medicine in France. He currently serves as Professor of
Hematology in the Department of Hematology at Lille University Hospital.
Professor Facon is a member of the Intergroupe Francophone du Myélome
and was President of the Intergroupe Francophone du Myélome from 2003
to 2006. In 2006, Professor Facon was a key speaker at the plenary session
of the American Society of Clinical Oncology in Atlanta, Georgia. He was
former Vice President of the French Society of Hematology. Professor
Facon’s main areas of expertise and fields of interest are the biology and
treatment of multiple myeloma and chronic myeloid leukemia, and he
has published numerous clinical papers in the peer-reviewed literature
about different treatment approaches for these conditions.

Carlos Fernández de Larrea, MD, PhD, studied medicine at the Central

University of Venezuela in Caracas, obtaining the distinction Summa
Cum Laude. He moved to Barcelona where he completed his training in
Hematology at the Hospital Clínic. His doctoral thesis was on complete
remission in multiple myeloma, obtaining the Extraordinary Award of
the University of Barcelona in 2012. He has spent training periods at
the Institut Pasteur in Paris, the Centre for Systemic Amyloidosis of
x • AUTHOR BIOGRAPHIES

Pavia, and the National Cancer Institute (NIH) in Bethesda. He is cur-

rently a member of the medical staff of the Department of Hematology,
and a member of the Amyloidosis and Myeloma Unit, at the Hospital
Clínic de Barcelona/IDIBAPS.

Stéphanie Guidez, MD, completed her medical degree at the Lille

University School of Medicine in 2009. She received a master’s degree in
cell biology in 2014 having done research at the Lille Institute of Cancer
research (IRCL) under the supervision of Dr Céline Berthon. She currently
serves as a Senior Registrar in the Department of Hematology, Hôpital
Claude Huriez, CHRU, Lille, France, and in the Lille University School
of Medicine. Her main field of interest is mature myeloma, lymphoma,
leukemia, and bone-marrow transplant.

Jean-Luc Harousseau, MD, is Professor of Hematology at the University of

Nantes in France. He has been Chairman of the French National Authority
for Health since February 2011 and Chair of its Economic and Public Health
Evaluation Committee since February 2014. He headed the Department
of Clinical Hematology in Nantes teaching Hospital for 24 years and was
Director of the Cancer Center René Gauducheau in Nantes from October
2008 to January 2011. In his previous position, he was a member of the
Scientific Advisory Board of the French National Cancer Institute and
President of the Clinical Research in Oncology National Committee
from October 2008 to January 2011. He was a founding member of the
Groupe Ouest-Est Leucémies Aigues et Maladies du Sang and of the
Intergroupe Français du Myélome, and President of this internationally
renowned cooperative group from June 2009 to January 2011. Professor
Harousseau is a member of the European Hematology Association, the
European Group for Blood and Marrow Transplantation, the American
Society of Hematology and the American Society of Clinical Oncology.
He was member of the Scientific Advisory Board for the Multiple Myeloma
Research Foundation and the International Myeloma Foundation. His
areas of research interest concern the therapy of acute myeloid leukemia
 AUTHOR BIOGRAPHIES • xI

and multiple myeloma. He received the 2005 Waldenström Award and

the 2009 Robert A Kyle Award for his scientific contribution in the field
of multiple myeloma. Professor Harousseau has contributed to more than
500 peer-reviewed publications.

Charles Herbaux, MD, completed his medical degree at the Lille

University School of Medicine in 2008. He currently serves as an Assistant
Professor in the Department of Hematology, Hôpital Claude Huriez,
CHRU, Lille, and in the Lille University School of Medicine. He received
a master’s degree in cell biology in 2013 having done research at the Lille
Institute of Cancer research (IRCL) under the supervision of Dr Xavier
Leleu. His main field of interest is mature lymphoid neoplasm includ-
ing Waldenstrom’s macroglobulinemia and pro-lymphocytic leukemia.

Charline Legrand, MB, completed her medical degree at Anger University

School of Medicine in France in 2014. She currently serves as a Junior
Registrar in the Department of Hematology, Hôpital Claude Huriez,
CHRU, Lille, and in the Lille University School of Medicine. Her main
fields of interest are leukemia, myeloma, and lymphoma.

Xavier Leleu, MD, PhD, completed his medical degree at the Bordeaux
University School of Medicine in France. He currently serves as an Associate
Professor in the Department of Hematology at Hôpital Claude Huriez,
part of the academic hospital of Lille (CHRU), France. He received a
master's degree in cell biology at the University of Medicine of Lille in
2001 and completed his PhD in 2007 having done his research at the
Dana-Farber Cancer Institute, affiliated with Harvard Medical School,
Boston, MA, USA. His main topic of research was the preclinical devel-
opment of novel agents in Waldenström’s macroglobulinemia and mul-
tiple myeloma. Professor Leleu is a member member of many scientific
societies including the American Society of Hematology, the European
Hematology Association, the International Myeloma Working Group, and
the International Waldenström’s Macroglobulinemia Foundation (IWMF).
xII • AUTHOR BIOGRAPHIES

Professor Leleu is a member of the Intergroupe Francophone du Myélome

(IFM) and on the board of directors; he recently entered the bureau as the
Treasurer of IFM. Professor Leleu is a reviewer and on the editorial board
of several journals in the field of hematology including Blood, Journal of
Clinical Oncology, The Lancet Oncology, the British Journal of Haematology,
Clinical Cancer Research, Haematologica, and Leukemia, amongst others.

Florent Malard, MD, PhD, studied medicine at the University of Nantes,

France and obtained his PhD degree at the University Pierre and Marie
Curie in Paris, France. He works as a postdoctoral Fellow in the French
National Institute for Medical Research in Nantes on the pathophysiology
of acute and chronic graft-versus-host disease after allogeneic stem-cell
transplantation. His clinical research is focused on multiple myeloma
and allogeneic stem-cell transplantation and so far he has published over
30 publications on these topics.

Mohamad Mohty, MD, PhD, is Professor of Hematology and Head of

the Hematology and Cellular Therapy Department at the Saint-Antoine
Hospital and University Pierre and Marie Curie (Paris, France). Professor
Mohty obtained his medical degree from the University of Montpellier,
France, and his PhD from the University of Marseille, France. Before
moving to Paris, he was head of the Transplant Program at the University-
Hospital of Nantes, France. He also undertook post-doctoral work at the
Hematology Department, Imperial College, Hammersmith Hospital,
London, UK. Professor Mohty is also currently Head of a translational
research team (INSERM team N°7) at the Saint-Antoine Research centre
in Paris and his research is focused on the pathophysiology and immuno-
biology of normal and pathological antigen-presenting cells, especially
the impact of novel immunomodulatory agents such as proteasome
inhibitors, IMiDs, and hypomethylating agents. He has a special clini-
cal focus on the development of reduced-toxicity conditioning regimens,
immunotherapy, and different aspects of therapy of acute leukemia
and multiple myeloma. Professor Mohty is currently President of the
 AUTHOR BIOGRAPHIES • xIII

European Society for Blood and Marrow Transplantation (EBMT). He

serves on the board of the EBMT, and the Intergroupe Francophone du
Myelome (IFM). He is a member of the American Society of Hematology,
American Society for Clinical Oncology, American Society for Blood and
Marrow Transplantation, European Hematology Association, International
Society for Experimental Hematology, and EBMT. Professor Mohty has
published more than 320 peer-reviewed articles in the field of stem cell
transplantation, leukemia, and myeloma, in different hematology and
immunology journals. He also serves as Editor-in-Chief of the journal
Bone Marrow Transplantation, as Associate Editor for Leukemia, European
Journal of Haematology, and Blood Cancer Journal, as a member of the
editorial board of Haematologica, and as a regular reviewer in different
immunology, hematology, and cancer journals such as Blood, The Lancet,
and Nature Reviews.

Evangelos Terpos, MD, PhD, is an Associate Professor of Hematology

in the Department of Clinical Therapeutics in the University of Athens,
School of Medicine, Athens, Greece. He has also been appointed as
Honorary Senior Lecturer in the Department of Hematology, Faculty of
Medicine Imperial College London, UK. His main research interest is the
biology of plasma cell dyscrasias and especially the biology of bone disease
in multiple myeloma (MM). In more than 300 papers in peer-reviewed
journals, Professor Terpos has reported the significant role of RANKL
and osteoprotegerin axis, CCL-3 (MIP-1α), Wnt and TGF-beta signalling
in myeloma bone disease and myeloma cell growth. He has studied the
predictive value of markers of bone remodeling and osteoclast function
in myeloma progression and patients’ survival. He has evaluated the
effect of bisphosphonates and different anti-myeloma therapies includ-
ing ASCT, IMiDs- and bortezomib-based regimens on bone metabolism.
He has studied the biology and prevalence of osteonecrosis of the jaw in
myeloma patients who receive bisphosphonates. Professor Terpos also
works on the role of modern imaging for MM, of angiogenesis in MM and
Waldenström’s macroglobulinemia, and of renal impairment in MM. In
xIV • AUTHOR BIOGRAPHIES

the clinical research era, Professor Terpos participates in all important

clinical trials with novel agents (pomalidomide, carfilzomib, ixazomib,
and daratumumab) in the field of multiple myeloma. Professor Terpos is
co-chairing the Bone Subgroup of the International Myeloma Working
Group. He participates in several clinical trials with novel antimyeloma
agents in the field of multiple myeloma. Dr Terpos has given lectures
at the European Hematology Association (EHA) and American Society
of Hematology (ASH) meetings, International Myeloma Workshops,
International Meetings on Cancer-Induced Bone Disease and in several
national meetings. He is reviewer of scientific papers in more than 50
medical journals and has reviewed abstracts for EHA and ASH meetings.
He is a member of the editorial board of Haematologica.
Abbreviations
ABMTR Autologous Blood and Marrow Transplant Registry
Allo-SCT Allogeneic stem cell transplantation
AMM Asymptomatic MM
APRIL A proliferation-inducing ligand
ASCT/auto-SCT Autologous stem cell transplant
BAD BCL-XL associated death promoter
BAFF B-cell activating factor
bALP Bone specific alkaline phosphatase
bFGF Basic fibroblast growth factor
BMECs Bone marrow endothelial cells
BMMe Bone marrow microenvironment
BMSCs Bone marrow stromal cells
BRAF v-raf murine sarcoma viral oncogene homolog B1
CALGB Cancer and Leukemia Group B
CAMDR Cell adhesion-mediated drug resistance
CCL3 CC chemokine ligand 3
CCND1 Cyclin D1 gene
CD138 Syndecan-1
CIBMTR International Center for Blood and Marrow
Transplant Research
CIRS Cumulative Illness Rating Scale
CLO Clodronate
CR Complete response/complete remission
CRAB Calcium, renal insufficiency, anemia, or bone lesions
CrCl Creatinine clearance
CRDa Cyclophosphamide-lenalidomide-dexamethasone
CT Computed tomography
CTD Cyclophosphamide-thalidomide-dexamethasone
CTX C-terminal cross-linking telopeptide of type-1
collagen

xv
xVI • ABBREVIATIONS

CVAD Cyclophosphamide-vincristine-doxorubicin-
dexamethasone
dex Dexamethasone
DKK1 Dickkopf 1
DLI Donor lymphocyte infusion
DVT Deep vein thrombosis
DXA Dual energy X-ray absorptiometry
EM Extramedullary involvement
EBMT European Society for Blood and Marrow
Transplantation
ECIL European Conference on Infections in Leukemia
EFS Event-free survival
EMA European Medicines Agency
ERK Extracellular signal-regulated kinase
Exp Experimental
FasL Apo-1/CD95 ligand
FGFR3 Fibroblast growth factor receptor 3 gene
FISH Fluorescence in situ hybridization
FKHR Forkhead in rhabdomyosarcoma
FLC Free light chain
FRP2 Frizzle related-protein 2
GDF15 Growth differentiation factor 15
GSK3β Glycogen synthase kinase 3β
GVM Graft-versus-myeloma effect
Has1 Hyaluronan synthase 1
Hb Hemoglobin
HDAC Histone deacetylase
HDM High-dose melphalan
HDT High-dose treatment
HGF Hepatocyte growth factor
HIV Human immunodeficiency virus
HMCLs Human myeloma cell lines
HoxB Homeobox protein B
 xVII • ABBREVIATIONS

IAPs Inhibitor of apoptosis proteins

IBMTR International Bone Marrow Transplant Registry
ICAM1 Intercellular adhesion molecule 1
ICTP C-terminal cross-linking telopeptide of type-1
collagen generated by metalloproteinase
IFM Intergroupe Francophone du Myélome
IGF1 Insulin-like growth factor 1
IgA/D/E/G/M Immunoglobulin A/D/E/G/M
IGH Immunoglobulin H gene
IKK-α IkappaB kinase alpha
IL-1β/3/6/7 Interleukin 1β /3/6/7
IMiD Immunomodulatory drug
IMWG International Myeloma Working Group
INFα Interferon α
ISS International Staging System
IV Intravenous
JAK2 Janus kinase 2
KRAS Kirsten rat sarcoma viral oncogene homolog
LDH Lactate dehydrogenase
LFA1 Leukocyte/lymphocyte function-associated antigen 1
MAA Marketing authorization application
MAC Myeloablative conditioning
MAF Avian musculoaponeurotic fibrosarcoma
proto-oncogene
MAPK Mitogen-activated protein kinase
MCL1 Myeloid cell leukemia sequence 1
M-CSF Macrophage colony-stimulating factor
MFC Multiparametric flow cytometry
MEK Mitogen-activated protein kinase kinase
Mel100 Melphalan 100 mg/m2
MGUS Monoclonal gammopathy of undetermined
significance
MIP1 α Macrophage inflammatory protein 1α
xVIII • ABBREVIATIONS

MM Multiple myeloma
MMP1/2/3 Matrix metalloproteinase 1/2/3
MMSET MM set domain
MoAb Monoclonal antibodies
MP Melphalan-prednisone
MPR Melphalan-prednisone-lenalidomide
MPT Melphalan-prednisone-thalidomide
MPV Melphalan-prednisone-bortezomib
MRD Minimal residual disease
MRI Magnetic resonance imaging
MSCs Mesenchymal stem cells
mTOR Mammalian target of rapamycin
n/a Non-applicable
NCAM Neuronal adhesion molecule
n-CR Near-complete response
NFκB Nuclear factorκB
NGS Next generation sequencing
NRM Non-relapse mortality
ns Not significant
NTX N-terminal cross-linking telopeptide of type-1
collagen
OC Osteocalcin
ONJ Osteonecrosis of the jaw
OPG Osteoprotegerin
OS Overall survival
PAD Bortezomib-doxorubicin-dexamethasone
PAM Pamidronate
PCL Plasma cell leukemia
PET positron emission tomography
PFS Progression-free survival
PIK3 Phosphatidylinositol 3-kinase
PINI Prognostic Inflammatory and Nutritional Index
 xIx • ABBREVIATIONS

POEMS Polyneuropathy, organomegaly, endocrinopathy,

monoclonal gammopathy, and skin changes
Pom Pomalidomide
PSGL1 P-selectin glycoprotein ligand 1
QOL Quality of life
RANKL Receptor activator of NFκB ligand
Rd Lenalidomide-dexamethasone
Rd18 Lenalidomide-dexamethasone to a fixed duration of
18 cycles
RIC Reduced intensity conditioning
RUNX2 Runt-related transcription factor 2
SC Subcutaneous
SCC Spinal cord compression
SCF Stem cell factor
sCR Stringent complete remission
SDF-1α Stromal cell-derived factor 1α
SLAMF7 Signaling lymphocyte adhesion molecule family 7
sNDA Supplemental new drug application
SNP Single nucleotide polymorphism
SREs Skeletal-related events
STAT3 Signal transducer and activator of transcription 3
std Standard
TAD Thalidomide-doxorubicin-dexamethasone
TD Thalidomide-dexamethasone
TGFβ Transforming growth factor β
Thal Thalidomide
TNFα Tumor necrosis factor α
TP53 Tumor protein 53
TRACP-5b Tartrate-resistant acid phosphatase isoform 5b
TTP Time to progression
VAD Vincristine-doxorubicin-dexamethasone
VBAD Vincristine-carmustine-doxorubicin-dexamethasone