Release Date: September 20, 2004
Expiration Date: September 30, 2005
This activity is jointly sponsored by the
Institute for Continuing
Healthcare Education
and the
International Myeloma Foundation.
A Comprehensive
Guide to Torino
International Myeloma Foundation
International Headquarters
12650 Riverside Drive, Suite 206
North Hollywood, California 91607
Multiple Myeloma
800 452 CURE (2873) Fax: 818 487 7454
TheIMF@myeloma.org
www.myeloma.org
2004 Conference
A Publication of the International Myeloma Foundation
Dedicated to improving the quality of life of myeloma patients while working toward prevention and a cure.
© 2004 International Myeloma Foundation
Proceedings from the live conference in Torino, Italy: April 22-24, 2004.
Accreditation:
This activity has been planned and implemented in accordance with the Essential Areas and
Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the
joint sponsorship of the Institute for Continuing Healthcare Education and the International
Myeloma Foundation. The Institute for Continuing Healthcare Education is accredited by the
ACCME to provide continuing medical education for physicians.
The Institute for Continuing Healthcare Education designates this educational activity for a
maximum of 3.5 category 1 credits toward the AMA Physician's Recognition Award. Each
physician should claim only those credits that he/she actually spent in the activity.
Target Audience:
This activity has been designed to meet the educational needs of hematologists, hematologic
oncologists, and physicians treating patients with multiple myeloma.
Commercial Support:
This activity is supported by educational grants from Tibotec Therapeutics, Celgene, and Millennium.
Disclaimer:
The opinions expressed in this publication are those of the participating faculty and not
that of the Institute for Continuing Healthcare Education, the IMF or any manufactures of
products mentioned herein.
The information is provided for general medical education purposes only and is not meant to
substitute for the independent medical judgment of a health-care professional.
A Comprehensive
Guide to Torino
Multiple Myeloma
2004 Conference
Proceedings from the live conference in
Torino, Italy: April 22-24, 2004.
This activity is jointly sponsored by the
Institute for Continuing Healthcare Education
and the
International Myeloma Foundation.
Release Date: September 20, 2004
Expiration Date: September 30, 2005
A Publication of the International Myeloma Foundation
Dedicated to improving the quality of life of myeloma patients while working toward prevention and a cure.
© 2004 International Myeloma Foundation
Faculty
Joan Bladé, MD
Nikhil C. Munshi, MD, MS
Hospital Clinic,
Associate Director, Jerome Lipper Multiple
Biomedical Investigation Institute
Myeloma Center
Barcelona, Spain
Dana-Farber Cancer Institute
Harvard Medical School
Gösta Gahrton
Boston, Massachusetts
Professor, Department of Medicine
Karolinska University Hospital,
Antonio Palumbo, MD
Huddinge Stockholm, Sweden
Professor of Medicine
Department of Hematology
Sundar Jagannath, MD
Ospedale Molinette
Professor of Medicine
Turin, Italy
Chief, Multiple Myeloma Service
Chief, Bone Marrow and
Brian Van Ness, PhD
Blood Stem cell Transplantation
Professor, Department of Genetics,
St. Vincents Comprehensive Cancer Institute
Cell Biology, and Development
New York Medical College
University of Minnesota
New York, New York
Minneapolis, Minnesota
Douglas E, Joshua, MD
Ivan Van Riet, MD
Professor and Head, Institute of Hematology
Academic Hospital Free University Brussels
Royal Prince Alfred Hospital,
(AZ-VUB)
Camperdown, Australia
Department of Medical Oncology and
Hematology - Stem Cell Laboratory
Robert A. Kyle, MD
Brussels, Belgium
Professor of Medicine & Laboratory Research
Mayo Clinic
Rochester, Minnesota
Heinz Ludwig, MD
Head, Department of Medicine and
Medical Oncology
Director, Myeloma Reference Center
Wilhelminen Hospital
Vienna, Austria
Activity Instructions
Readers of this monograph should review all accreditation and disclosure information,
learning objectives, and all 10 overviews, including tables, figures, and references. Readers
should then complete the post-test, found at the back of this monograph, filling in their
answers on the post-test answer key; the registration for credit; and the evaluation form. To
receive a certificate of credit, a score of 70% or higher is required on the post-test. This
activity is valid until September 30, 2005. It should take approximately 3.5 hours to complete
this activity as designed.
Learning Objectives
After reading this monograph, the reader
expression as tools to assess progression in patients
should be able to do the following:
with MGUS and/or smoldering multiple myeloma.
Session 1
Session 6
· Describe how analyses of molecular pathogenesis in
· Assess approaches for treating skeletal lesions and
multiple myeloma are revealing new information
anemia in patients with multiple myeloma.
concerning initiation and progression of disease.
· Identify the needs of special populations including
· Discuss the importance of combined analyses of
the elderly and patients with Waldenström's
chromosomal translocations; the roles of different
macroglobulinemia and AL amyloidosis.
receptors, gene groupings, and expressions; and how
retrospective and prospective study of genetic variants
Session 7
may have impact on the course of disease.
· Discuss the place of autologous stem-cell
transplantation in multiple myeloma, for both younger
Session 2
and older patients, including what benefit may be
·
Discuss
the
phenotypic
and
functional
achieved using tandem transplantation.
abnormalities associated with multiple myeloma and
· Describe how the introduction of drug agents--such
the early response of the immune system to
as thalidomide, IMiDs, and bortezomib--into current
monoclonal gammopathies.
induction and maintenance regimens may constitute an
· Explain the value of immunophenotyping in MGUS
important step forward in improving the long-term
and multiple myeloma and the role played by the
outcomes of patients with multiple myeloma.
myelomatous environment, and discuss the importance
of controlling bone resorption and hyaluronan
Session 8
synthases in managing multiple myeloma.
· Examine the place of allogeneic stem-cell
transplantation
following
myeloablative
or
Session 3
nonmyeloablative conditioning in multiple myeloma,
·
Identify the important interactions between
and detail data supporting or refuting the concept of
multiple myeloma tumor cells and the bone-marrow
graft versus myeloma as an important mechanism for
microenvironment.
reducing
transplant-related
morbidities
while
· Discuss the roles of cells expressing different clusters
decreasing rates of relapse.
of differentiation and the importance of different
· Compare and contrast peripheral blood stem cells
growth factors and growth factor pathways, and
and bone marrow as sources of cells for transplantation,
summarize the possible roles played by hypoxia,
and evaluate the role of donor-lymphocyte transfusions
osteoprotegerin, and RANKL in patients with
as supportive treatment.
multiple myeloma.
Session 9
Session 4
· Describe how 40 years after the introduction of
· Relate the many clinical indications suggesting the
melphalan and 15 years since the beginning of
significance of immunosurveillance and host-tumor
autologous transplantation, the discovery and
interactions in maintaining the stability of disease in
application of new drugs and new ways of
multiple myeloma and the potential central influence
thinking about tumor-host interactions might
of high-potency dendritic cells and idiotype-specific
significantly improve the treatment of patients
T-cell immunity.
with multiple myeloma.
Session 5
Session 10
· Explain the importance of the size of M-protein
· Provide an update on current advances in vaccine
spike, rearrangement of t(14q32), use of fluorine-
immunotherapy as treatment for patients with
18­labeled
deoxyglucose/positron
emission
multiple myeloma.
tomography (FDG/PET) scans, and COX-2
General Disclosure
These proceedings have been developed based on the
Brian Van Ness
63 presentations given at the live Multiple Myeloma
Dr. Van Ness has disclosed that he has no significant
Conference held in Turin, Italy, on April 22­24,
relationships with the grantors or any other
2004. Ten expert faculty members, who participated
commercial company whose products and services
in this conference, have summarized the presenta-
are discussed in his material.
tions given by their colleagues and have written a
comprehensive overview of the meeting's scientific
Nikhil Munshi
sessions. Therefore, these proceedings include the
Dr. Munshi has received honoraria related to speaker
discussion of unlabeled uses of commercial products
bureau activities from Celgene Corporation,
and/or products that have not yet been approved by
Millennium Pharmaceuticals, CTI, and Novartis
the FDA for use in the United States for any purpose.
Pharmaceuticals Corporation. He has also received
honoraria related to the development of educational
The opinions expressed in this publication are those
materials from Celgene Corporation.
of the participating faculty and not that of the
Douglas E. Joshua
Institute for Continuing Healthcare Education, the
Dr. Joshua has disclosed that he has no significant
International Myeloma Foundation, or any manufac-
relationships with the grantors or any other
turers of products mentioned herein.
commercial company whose products and services
are discussed in his material.
The information is provided for general medical edu-
cation purposes only and is not meant to substitute
Ivan Van Riet
for the independent medical judgment of a health-
Dr. Van Riet has disclosed that he has no significant
care professional relative to diagnostic and treatment
relationships with the grantors or any other
options of a specific patient's medical condition.
commercial company whose products and services
are discussed in his material.
Readers are encouraged to consult the package insert
for all products for updated information and
Sundar Jagannath
changes regarding indications, dosage, and con-
Dr. Jagannath has received honoraria related to
traindications. This recommendation is particularly
formal advisory and research activities, speaker
important with new or infrequently used products.
bureau, and the development of educational
materials from Millennium Pharmaceuticals and
Celgene Corporation.
Financial Disclosure
Antonio Palumbo
Dr. Palumbo has disclosed that he has no significant
Heinz Ludwig
relationships with the grantors or any other
Dr. Ludwig has disclosed that he has no significant
commercial company whose products and services
relationships with the grantors or any other
are discussed in his material.
commercial company whose products and services
are discussed in his material.
Joan Bladé
Dr. Blade has received honoraria related to the
Robert A. Kyle
development of academic content for a formal
Dr. Kyle has received honoraria related to formal
advisory activity from Millennium Pharmaceuticals.
advisory activities from Aeterna Zeutaris Inc.; Roche
Pharmaceuticals Inc.; Novartis Pharmaceuticals
Gösta Gahrton
Corporation;
Celgene
Corporation;
NeoRx
Dr. Gahrton has disclosed that he has no significant
Corporations;
Millennium
Pharmaceuticals;
relationships with the grantors or any other
Genentech, Inc.; Callisto Pharmaceuticals, Inc.; and
commercial company whose products and services
NexCura, Inc.
are discussed in his material.
Table of Contents
Session 1:
Page 1
Molecular Pathogenesis
Brian Van Ness: Minneapolis, Minnesota, USA
Session 2:
Page 4
Phenotype and Functional Abnormalities
Douglas E. Joshua: Sydney, Australia
Session 3:
Page 6
Microenvironment
Ivan Van Riet: Brussels, Belgium
Session 4:
Page 9
Role of Immunosurveillance
Douglas E. Joshua: Sydney, Australia
Session 5:
Page 11
Prognosis
Robert A. Kyle: Rochester, Minnesota, USA
Session 6:
Page 14
Supportive Therapy
Heinz Ludwig: Vienna, Austria
Session 7:
Page 21
Round Table on Autologous Transplantation
Joan Bladé: Barcelona, Spain
Session 8:
Page 25
Round Table on Allogeneic Transplantation
Gösta Gahrton: Stockholm, Sweden
Session 9:
Page 29
New Drugs
Sundar Jagannath: New York, New York, USA
Session 9:
Page 34
New Drugs
Antonio Palumbo: Turin, Italy
Session 10:
Page 37
Immunotherapy
Nikhil C. Munshi: Boston, Massachusetts, USA
Intentionally Left Blank
Session 1:
Molecular Pathogenesis
Brian Van Ness
and phenotypes. The model Dr. Bergsagel proposed
Minneapolis, Minnesota, USA
suggests that primary translocation events render
the cells more sensitive to proliferative signals
In 2000 there was a shift in defining cancer: Dr.
within the bone marrow (BM) compartment.2
Richard Klausner, Director of the National Cancer
Secondary
chromosomal
translocations
(eg,
Institute, issued a Director's Challenge to define
involving c-myc) lead to tumor progression.
cancer as a genetic disease. Given the many cellular
Further mutations or deletions of cell-cycle
pathways
that
contribute
to
proliferation,
regulators ­ such as K- or N-Ras, FGFR3, and
migration, and resistance to cell death, it is not at all
p53­ are associated with more advanced MM or
surprising to define plasma cell malignancy as a
late stage in the course of the disease.
genetically heterogeneous disease. Indeed, among a
Dr. Bergsagel's presentation highlighted the
group of patients with multiple myeloma (MM),
combined analysis of chromosomal translocations
there is wide variation in progression of disease and
and expression profiles that provided not only
therapeutic responses. It is very likely that initiation
models for initiation of disease but also a paradigm
of disease results from a multitude of possible
for molecular subgrouping for progression of MM.2
deregulated pathways in both the plasma cell and
the microenvironment.
Dr. Bernard Klein (INSERM, France) highlighted
approaches to genetically distinguish malignant
The first session of the Turin Multiple Myeloma
plasma cells from their normal counterparts.3 His
Congress highlighted various genetic approaches to
work also highlighted the important role of the BM
define plasma cell malignancy, not only to develop
microenvironment for myeloma cell survival and
an understanding of key transforming events but
proliferation. Using gene expression microarrays,
genetic events that have impact on progression of
Dr. Klein identified genes that work in synergy with
disease and response. Dr. Leif Bergsagel (Cornell
the well-known growth-promoting activities of
University, USA) and colleagues Drs. Marta Chesi
interleukin-6 (IL-6). ErbB and the epidermal
(Cornell) and Michael Kuehl (National Cancer
growth factor (EGF) family of genes were identified
Institute) have been long recognized for their
as important growth-promoting factors and
pioneering work in identifying genetic instability
represent new potential therapeutic targets. Recently
leading to a series of chromosomal translocations
2 genes encoding for BAFF/APRIL receptors, TACI
among monoclonal gammopathy of undetermined
and BCMA, have received significant interest,
significance
(MGUS),
smoldering
multiple
demonstrating key interactions of ligands produced
myeloma (SMM), intramedullary MM, and plasma
in the microenvironment and their receptors found
cell leukemias.1 The central theme of their work is
on myeloma cells. Thus, although gene expression
the characterization of 5 chromosomal partners
profiling provides a large comprehensive analysis of
(oncogenes) that are involved in translocations to
cellular activities, key areas of focus are coming to
the IgH locus: 11q13 (cyclin D1), 6p21 (cyclin
light through the directed analysis of the large
D3), 4p16 (FGFR3 and MMSET), 16q23 (c-maf ),
database created by Dr. Klein's group.
and 20q11 (mafB). The combined prevalence of
these 5 translocations is about 40%. Dr. Bergsagel
Drs. Hervé Avet-Loiseau and S. Wuilleme
has proposed models implicating translocations
(University
Hospital,
Nantes,
France)
also
involving cyclin D genes as an important initiating
highlighted the association of genetic heterogeneity
event.
Combining the characterization of
in MM and disease outcome.4 With the application
chromosomal translocations with gene expression
of sensitive techniques, such as fluorescent in situ
profiling, he identified homogeneous groups of
hybridization (FISH), hyperdiploidy is likely
tumors with distinctive gene expression patterns
present in more than 50% of patients with MM.
1
Identifying the hyperdiploid patients is likely of
independent of the cytogenetic abnormalities.
clinical value, as patients with hyperdiploidy
Further analysis has demonstrated that ZHX-2
generally have longer survival; however, the paradox
expression is inversely associated with a number
remains
concerning
the
impact
of
such
of proliferation genes. Thus, Dr. Shaughnessy's
chromosomal abnormalities on initiation of disease.
presentation
provided
novel
insights
and
Dr. Avet-Loiseau's group defined the prognostic
potential
targets
derived
from
such
a
value of chromosomal 13 deletions.5 He also noted
comprehensive genetic analysis.
the
novel
level
of
heterogeneity
involving
chromosomal 14 translocations delineating 2
Although defining the genetic alterations within the
different clinical and morphologic characteristics.
malignant plasma cell is key to our understanding of
There was a tight correlation between del(13) and
MM, it is likely that germline genetic variations
t(4;14). Thus, the presentation focused on defining
among the patient population contribute to the
several myeloma subgroups: hyperdiploidy, with low
course and response of the disease. Dr. Brian Van
incidence of del(13) and t(14q32), displaying longer
Ness (University of Minnesota, USA) presented a
survival; nonhyperdiploidy, with high incidence of
study initiated through the International Myeloma
del(13) and t(14q32), displaying poor response and
Foundation called Bank on a Cure.8 The goal of this
shorter survival; and variations of the first 2 groups
study is to develop international partnerships to
that lead to much of the variability in disease
establish a DNA bank from patients with MM and
progression and response.
controls. The ultimate goal is to develop
retrospective and prospective studies of genetic
In arguably the largest cohort of patients analyzed by
variations among the patient population and their
gene expression profiling, Dr. John Shaughnessy
impact on the disease, through the analysis of
(University of Arkansas, USA) has developed new
germline genetic polymorphisms, especially single
analytic tools and insights into the characterization
nucleotide polymorphisms (SNPs). Given the roles
of malignant plasma cells.6 Notably, the common
of numerous cytokines, metabolic pathways,
translocations are also clustered in defined gene
microenvironmental factors, bone metabolic factors,
expression subgroups that have distinct clinical
and so forth, genetic variations in the population
features. This suggests that there may be multiple
that affect levels of production or function may have
but limited common pathways associated with
a significant impact on clinical outcomes. This
survival and progression of MM. To identify a
concept was highlighted in analysis of cytokine gene
minimal number of genes capable of predicting early
polymorphisms in 1 Eastern Cooperative Oncology
mortality and potential therapeutic targets, Cox
Group (ECOG) phase 3 trial, demonstrating
regression modeling was used on gene profiles from
associations of survival, response, and incidence of
more than 220 patients. Dr. Shaughnessy provided
second
malignancies
with
different
genetic
evidence that a 3-gene model could identify 3 highly
polymorphisms (eg, TNF, IL-10, IFN, IL-1). The
distinct prognostic groups.7 The 3 genes presented
data presented were consistent with the hypothesis
were RAN, encoding a nuclear transport; ZHX-2,
that patients homozygous for high-producer alleles
encoding a transcription factor that represses NFY
of growth-promoting genes have adverse clinical
(that in turn regulates cyclins); and CHC1L,
outcomes. These studies establish a framework to
encoding a chromosomal remodeling factor that
expand the database, both in terms of patient
may regulate RAN.
samples and candidates for SNP.
Dr. Shaughnessy demonstrated that within his
Advances in genetic techniques have led to an
myeloma study group, these genes can account for
explosion of large databases. This, in turn, has led to
about 70% of the variability in survival and are
the development of new definitions of diseases such
2
as MM. Despite the different approaches presented,
7. Zhan F, Huang Y, Sawyer J, et al.
The
common themes are emerging.
Chromosomal
transcriptome of multiple myeloma defines disease
abnormalities, although diverse in MM, are resulting
subgroups with distinct genetic and clinical features.
in cyclin alterations that appear key to initiating a
In: Boccadoro M, Pileri A, eds. Multiple Myeloma
proliferative state. Thousands of genes are being
2004. Turin, Italy; 2004:17-19.
assessed, and key genes are being identified that are
8. Van Ness B. Genetic variants associated with
coalescing to some common pathways. Not only do
clinical response: a study through Bank On A Cure.
such studies redefine the disease but they redefine
In: Boccadoro M, Pileri A, eds. Multiple Myeloma
signatures of response and, more importantly, reveal
2004. Turin, Italy; 2004:14-15.
novel targets for new therapeutic agents. Given the
clear genetic heterogeneity in MM, defining these
targets will provide more rational and individualized
therapies in the very near future.
References
1. Bergsagel PL, Kuehl WM. Critical roles for
immunoglobulin translocations and cyclin D
dysregulation in multiple myeloma. Immunol Rev.
2003;194:96-104,.
2. Bergsagel L, Chesi M, Kuehl M. IgH
translocations in multiple myeloma. In: Boccadoro
M, Pileri A, eds. Multiple Myeloma 2004. Turin,
Italy; 2004:11-13.
3. Klein B. Intercellular communication signals in
human multiple myeloma (MM). In: Boccadoro M,
Pileri A, eds. Multiple Myeloma 2004. Turin, Italy;
2004:16.
4.
Avet-Loiseau
H,
Wuilleme
S.
Genetic
heterogeneity in multiple myeloma. In: Boccadoro
M, Pileri A, eds. Multiple Myeloma 2004. Turin,
Italy; 2004:20-22.
5. Avet-Loiseau H, Facon T, Grosbois B, et al.
Oncogenesis of multiple myeloma: 14q32 and 13q
chromosomal abnormalities are not randomly
distributed, but correlate with natural history,
immunological features, and clinical presentation.
Blood. 2002;99 (6):2185-2191.
6. Zhan F, et al. Global gene expression profiling of
multiple myeloma, monoclonal gammopathy of
undetermined significance and normal bone marrow
plasma cells. Blood. 2002;99(5):1745-1757..
3
Session 2: Phenotype and
Functional Abnormalities
Douglas E. Joshua
the presence of CD45-positive cells correlates with
Sydney, Australia
stable or progressive disease. Furthermore, CD45-
positive cells can respond directly to interleukin-6
The interaction between the phenotype of plasma
(IL-6), and the expression of CD45 is essential for
cells and the surrounding stoma cells in the bone
IL-6 induced proliferation. CD45-positive immature
marrow (BM) environment, and the functional
plasma cells increase in BM along with progression of
relationship between plasma cells and bone in
disease from MGUS to smoldering myeloma and to
multiple myeloma (MM) is of great therapeutic
clinically progressive myeloma. These data reinforce
importance. The immunologic environment of the
previous data on immature plasma cells and their
BM in MM has been studied by a number of
relation to disease behavior.
investigators who have demonstrated that there are
abnormalities in the T-cell environment of the BM as
New
techniques,
such
as
multiparametric
well in the peripheral blood in MM. Oligoclonal T-
immunophenotyping by flow cytometry, have
cell expansion in the BM consists of both CD4 and
allowed the identification of malignant plasma cells
CD8 expansions but is typically CD28 negative and
and their discrimination from other cells present in
shows increased production of interferon gamma.
the BM and normal plasma cells. The presence of
This is another line of evidence that infiltration of the
hypodiploid DNA content (identified by propidium
BM by tumor-infiltrating lymphocytes may represent
iodide
staining)
is
another
important
a host­tumor interaction in MM but one whose
multiparametric parameter that can be measured.
antitumor effect is unsuccessful. To explore the
possible reasons for the inability of T cells to control
A panel consisting of monoclonal antibodies to
tumor proliferation, phenotypic differences between
CD19, CD20, CD28, CD33, CD45, CD56,
malignant and normal plasma cells have been
CD117,
together
with
CD38,
allows
the
determined.
The
immunophenotype
of
the
identification of phenotypic aberrations in myeloma
malignant plasma cell of MM cells differs compared
plasma cells and permits a clear discrimination
with those from monoclonal gammopathy of
between malignant and normal cells. Such analysis is
undetermined significance (MGUS), plasma cell
useful for identification of minimal residual disease
leukemia, and normal plasma cells. Malignant
and has demonstrated that abnormal plasma cell
plasma cells have consistently abnormal higher levels
populations are always low in patients with MGUS
of CD56, CD8, CD86, and CD126 with lower
and always high in patients with overt MM. It also
levels of CD38. In addition, in some patients with
provides predictive information of the risk of relapse
MGUS, abnormally high levels of beta 2-
after BM transplantation (BMT).
microglobulin are expressed. These results suggest
that there is an increased antigen-presenting capacity
Novel data concerning RHAMM, a key receptor for
of plasma cells in MGUS that progressively
hyalunronan synthase, have demonstrated that
deteriorates as cells become more malignant; this may
RHAMM is overexpressed in all patients with MM.
be an explanation for the failure of the tumor-
RHAMM (CD168) occurs on the cell surface and
infiltrating T cells to control the disease effectively.
inside the cell. Cell surface RHAMM mediates the
motility of malignant MM B cells, and intracellular
One of the most important molecules expressed on
RHAMM is a centrosomal component that
the surface of MM cells is CD45. It has previously
participates in effective mitosis. Overexpression of
been demonstrated that MM cells can be split into
RHAMM leads to centrosomal abnormalities and
functionally mature, immature, and highly immature
stalled mitosis; both over- and underexpression of
plasma cells on the basis of CD45 expression. The
RHAMM have severe consequences in the cell cycle.
proliferative plasma cell is a CD45-positive cell, and
This suggests a mechanistic relationship between
4
overexpression of RHAMM and the extensive
In summary, immunophenotypic markers demonstrate
chromosomal instability present in MM. The
abnormalities of MM plasma cells and the
relationship between RHAMM and its receptor
surrounding T-cell environment. Surface markers,
hyalunronan synthase may serve as important
such as CD45, are crucial in behavior of the disease,
investigative tools in enhancing our understanding
and other molecules, such as RHAMM and
malignancy and may be critical regulators of
hyalunronan synthase, may be associated with genetic
malignant spread, thus providing important
instability. It is now clear that osteoclast and MM cells
therapeutic targets.
have important interactions and targeting these
interactions may serve an important therapeutic role.
The relationship between osteoclastic bone disease
and MM has been investigated in a number of
Bibliography
animal models. The 5T2MM model is a mouse
model of MM and investigations using RANKL and
Croucher P. Targeting osteoclastic bone resorption
recombinant osteoprotegerin have clearly shown that
and the treatment of myeloma bone disease: studies
osteolytic bone disease in the 5T2MM-bearing
in the 5T2MM model. In: Boccadoro M, Pileri A,
animals can be prevented with osteoprotegerin or
eds. Multiple Myeloma 2004. Turin, Italy;
zolendronic acid; further, these 2 agents can reduce
2004:38-39.
tumor load. These data demonstrate that targeting
the RANKL system and inhibiting osteoclastic bone
Epstein J. Myeloma and functional abnormalities in
absorption may prevent the development of
the myelomatous microenvironment: relationship to
disease development and progression. In: Boccadoro
myeloma bone disease and possess an antitumor
M, Pileri A, eds. Multiple Myeloma 2004. Turin,
effect. Thus, the relationship between BM stroma
Italy; 2004:34-37.
MM cells and bone disease in MM is an interactive
one in which there exists an important influence by
Kawano MM. Heterogenous expression of CD45
the bone environment on the disease process. The
on myeloma cells and its biological significance. In:
adhesion of MM cells to stroma cells can protect
Boccadoro M, Pileri A, eds. Multiple Myeloma
MM cells from apoptosis and cytokine-induced
2004. Turin, Italy; 2004:27-30.
osteoclast maturation. Studies on the relationship
between myeloma cells and osteoclasts show that
Mateo G, Gutiérrez NC, López-Berges MC, et al.
mature functional osteoclasts can extend the survival
Current role of immunophenotyping in multiple
and sustain proliferation of freshly purified primary
myeloma. In: Boccadoro M, Pileri A, eds. Multiple
MM cells. Gene profiling studies on MM cells
Myeloma 2004. Turin, Italy; 2004:31-33.
exposed in co-culture to osteoclasts demonstrated 2
Perez-Andres M, Almeida J, Martin-Ayuso M, et al.
distinct groups of MM cells: one that resembles MM
Interaction between clonal plasma cells and the
cell lines and includes cells from patients with
immunological environment in multiple myeloma
extramedullary disease and a second group that had a
as compared to other monoclonal gammopathies.
gene profile similar to normal plasma cells. These
In: Boccadoro M, Pileri A, eds. Multiple Myeloma
observations provide support for the concept that
2004. Turin, Italy; 2004:25-26.
extramedullary myelomas are not dependant on
interaction
with
osteoclasts,
whereas,
in
Pilarski LM, Adamia S, Maxwell CJ, Reiman T,
intramedullary myeloma, BM stroma plays a very
Belch AR. RHAMM and hyaluronan synthases
important interactive role. Investigations elucidating
(HASs) in multiple myeloma: mechanistic basis for
which molecules may be important in MM
novel predictive indicators of disease outcome. In:
cell­osteoclast interactions suggest that chrondroitin
Boccadoro M, Pileri A, eds. Multiple Myeloma
synthase is one important factor.
2004. Turin, Italy; 2004:40-41.
5
Session 3: Role of the
Microenvironment
Ivan Van Riet
(CD34+/CD133+) cells in BM of patients with MM
Brussels, Belgium
and on the capacity of these cells to contribute to the
tumor-induced formation of new blood vessels. He
A central issue in the biology of multiple myeloma
also mentioned that these EC precursors could be
(MM) is the complex interactive network between the
found in the peripheral blood of patients with MM
tumor
cells
and
the
bone
marrow
(BM)
after stem-cell mobilization with granulocyte colony-
microenvironment, in which stromal fibroblasts,
stimulating factor (G-CSF). He found that EC from
osteoclasts, and endothelial cells (EC) represent
BM of patients with MM (MM-EC) not only
important cellular components. During the Turin
express the vascular endothelial growth factor
Multiple Myeloma congress, several speakers
(VEGF) receptor, VEGFR-2, but also produce its
presented data that contribute to the further
ligand VEGF-A, suggesting the existence of an
unraveling of this intriguing molecular interplay
autocrine angiogenesis-stimulating loop in MM. Dr.
between the malignant cells and their host.
Vacca's team also found that binding of VEGF-A to
MM-EC could be inhibited by exposure of the cells
A major role of the BM microenvironment is to
to semaphorin 3 (Sema3), a natural tumor
support MM cell proliferation and survival. BM
suppressor. This observation indicates that Sema3
stromal cells produce several MM growth-promoting
might be used for anti-angiogenesis intervention in
factors, of which interleukin-6 (IL-6) and, more
MM. He showed that MM-EC produce different
recently, insulin-like growth factor-1 (IGF-1) have
chemokines, which have the potential to bind to
been identified as the most important ones. Dr.
specific receptors that are expressed to a variable
Martine Amiot (Institut de Biologie, France) provided
extent by MM plasma cells.
information on the involvement of the IGF-1/IGF-1
receptor pathway in MM cell proliferation and its
Dr. Vacca assumed that some chemokine/chemokine-
potential as a therapeutic target. She showed that
receptor interactions, such as IL-8/CXCR1 and SDF-
patients with MM and plasma cells that are negative
1/CXCR4, favor MM progression by stimulating
for the surface glycoprotein CD45 have poor
chemotaxis and proliferation of MM plasma cells. He
prognoses and progressive disease. Dr. Amiot
also presented data showing that thalidomide has a
explained how CD45 affects the IGF-1­mediated
strong downregulating effect on several genes
activation of the Akt/PI-3 kinase (Akt/PI-3K)
(including VEGF-A, basic fibroblast growth factor
pathway that stimulates MM cell proliferation. She
[bFGF], hepatocyte growth factor [HGF], and IGF-
illustrated that IGF-1­induced activation of Akt is
1) that are involved in neovascularization and/or
much more pronounced in CD45-negative MM cells
myeloma cell proliferation. He concluded that one of
compared with CD45-positive MM cells. Dr. Amiot
the therapeutic effects of this drug in MM might
proposed a potential therapeutic strategy that blocks
relate to direct inhibition of EC proliferation.2
IGF-R1 signalling and consequently the Akt/PI-3K
pathway, which could be of particular interest for the
Dr. Ivan Van Riet (Free University Brussels, Belgium)
treatment of patients with MM and CD45-negative
discussed
the
importance
of
MM
cell­EC
tumor cells.1
interactions in mediating the BM homing of tumor
cells. BM-EC have the capacity to upregulate the
Dr. Angelo Vacca (University of Bari Medical School,
expression of different molecules (such as the 67kD
Italy) discussed the role of angiogenesis in MM and
laminin receptor and metalloproteinase MMP-9) that
showed data related to further identification of the
are directly involved in tumor-cell migration. In
molecular interactions between MM cells and bone
addition, BM-EC produce several molecules
marrow endothelial cells (BM-EC). He provided
(laminin, IGF-1, and monocyte chemotactic protein
information on the existence of angioblastic
1 [MCP-1]) that serve as chemotactic factors for
6
myeloma cells. However, myeloma cells secrete
Dr. Federico Caligaris-Cappio (University of Vita-
factors that have the potential to stimulate EC to
Salute San Raffaele, Italy) discussed the involvement
produce new blood vessels. These factors include
of hypoxia in the environmental regulation of
VEGF and bFGF, in addition to platelet-derived
myeloma cell growth. Hypoxia­a reduction in the
growth factor (PDGF), all of which bind to receptor
normal level of tissue oxygenation­induces the
tyrosine kinases. Dr. Van Riet presented results of a
expression of several molecules that stimulate
study in 5TMM mouse models in which tumor-
angiogenesis and affect tumor progression. A major
bearing mice were injected with a series of receptor
regulator of hypoxia-responsive genes is the
tyrosine kinase (RTK) inhibitors with different
transcription factor hypoxia-inducible factor-1 (HIF-
specificity. This study demonstrated that in vivo
1). Dr. Caligaris-Cappio indicated that the expression
targeting of VEGF- and/or PDGF-RTK induces an
of HIF-1a (a protein that, together with HIF-1b,
impressive reduction in myeloma cell­induced
constitutes the functional HIF heterodimeric protein)
blood vessel formation. In this model, simultaneous
is upregulated in EC and not in other stromal cells.
blocking of VEGF- and PDGF-RTK also resulted in
He also presented data on the proteasome inhibitor
a highly significant increase in survival. Ongoing
MG132 and its ability to induce apoptosis in the
research must clarify whether this promising
U266 myeloma cell line as well as in primary
therapeutic effect is exclusively due to inhibition of
myeloma cells obtained from patient samples. The
neovascularization or also includes other (more
apoptotic effect of MG132 in myeloma cells could
direct) antimyeloma activities.3
not be prevented when the tumor cells were exposed
to BM stroma. Other in vitro experiments revealed
Dr. Constantine Mitsiades (Dana-Farber Cancer
that EC are sensitive to MG132-induced apoptosis.5
Institute, USA) characterized 3 different molecular
targets involved in the microenvironment-mediated
Dr. Nicola Giuliani (University of Parma, Italy)
support of MM cell growth. MM cell­BM milieu
discussed myeloma cell­osteoclast interactions,
interactions were studied using human MM cells in
focusing on the imbalance of osteoprotegerin (OPG)
either an in vitro coculture system or an in vivo
and the receptor activator of NF-kB ligand (RANKL)
severe combined immunodeficient (SCID)/nonobese
in MM. He referred to recent studies, all indicating
diabetic (NOD) mouse model. In both, Dr.
that RANKL expression is increased in both serum
Mitsiades
demonstrated
that
bidirectional
and cultured BM stromal cells from patients with
interactions between MM cells and BM stroma
MM and also showed that RANKL is not produced
enhance BM stromal-cell expression of various
directly by myeloma plasma cells. He discussed the
cytokines including IGF and proteasome subunits.
role of T cells in bone resorption and showed that
In addition, this interplay triggers in MM cells (1)
RANKL is increased in CD8-positive T cells in
the activation of different signalling pathways
patients with MM. Dr. Giuliani also presented data
(including activation of Akt/PI-3K); (2) increased
demonstrating that myeloma cells enhance RANKL
expression of heat shock proteins including heat
expression by T cells through secretion of interleukin-
shock protein 90 (hsp90); and (3) upregulation of
7 (IL-7). Accordingly, he found that neutralization of
proteasome subunits. All these events contribute
IL-7 could inhibit, at least in vitro, MM-induced
to stimulation of MM cell proliferation. Dr.
osteoclastogenesis. He concluded that restoring the
Mitsiades presented preclinical data demonstrating
balance between OPG and RANKL by using
how these molecules can be successfully targeted
RANKL inhibitors, OPG, or RANK-Fc not only
by small-molecule inhibitors and indicated that a
inhibits bone destruction but may decrease tumor
phase 1 clinical trial is under way to further
burden in patients with MM as well.6
evaluate these inhibitors.4
7
References
1. Bataille R, Robillard N, Pellat-Deceunynck C,
Amiot M. A cellular model for myeloma cell growth
and maturation based on intraclonal CD45 hierarchy.
Immunol Rev. 2003; 194:105-111.
2. Vacca A, Ria R, Semeraro F, et al. Endothelial cells
in the bone marrow of patients with multiple
myeloma. Blood. 2003; 102 (9):3340-3348.
3. Vande Broek I, Asosingh K, Allegaert V, et al. Bone
marrow endothelial cells increase the invasiveness of
human multiple myeloma cells through upregulation
of MMP-9: evidence for a role of hepatocyte growth
factor. Leukemia. 2004; 18(5):976-982.
4. Mitsiades CS, Mitsiades NS, McMullan CJ, et
al. Inhibition of the insulin-like growth factor
receptor-1 tyrosine kinase activity as a therapeutic
strategy for multiple myeloma, other hematologic
malignancies, and solid tumors. Cancer Cell. 2004;
Mar;5(3):221-230.
5. Ghia P, Granziero L, Chilosi M, Caligaris-Cappio
F. Chronic B cell malignancies and bone marrow
microenvironment. Semin Cancer Biol. 2002; 12
(2):149-155.
6. Giuliani N, Colla S, Rizzoli V, Barille-Nion S,
Bataille R. Do human myeloma cells directly
produce the receptor activator of nuclear factor
kappaB ligand (RANKL) or induce RANKL in the
bone marrow microenvironment? Cancer Res.
2004; 64 (2):772-773.
8
Session 4: Role of
Immunosurveillance
Douglas E. Joshua
associated with good prognoses and suggest that the
Sydney, Australia
therapeutic effects of interferon in MM are not
directly related to its immunomodulatory actions.
There are many clinical indications suggesting
significant immunosurveillance and host tumor
Other evidence reinforcing the immunoregulatory
interactions
in
multiple
myeloma
(MM).
role of CD4 and CD8 T cells is the detection of
Immunosurveillance
mechanisms
have
been
idiotypic reactive T cells. Patients with MM have
detected for natural killer (NK) T cells, CD4-
been found to contain both CD4 and CD8 T cells,
positive and cytotoxic CD8-positive T cells, and
which recognize the idiotype and predominantly
gamma delta T cells. In addition, idiotype reactive T
produce a TH 1 response. These cells are found
cells have been found in patients with MM, and
generally to have low affinity for binding to
these findings ­ together with the clinical
idiotype, but data indicate that some patients with
observations of the stability of the malignant clone
MM spontaneously mount CD4 and CD8 idiotype-
in smoldering myeloma, monoclonal gammopathy
specific T-cell immunity. These findings have been
of undetermined significance (MGUS), and plateau-
the basis for a number of idiotypic vaccination
phase disease ­ suggest that the malignant B-cell
protocols using various adjuvants to augment or
clone can be maintained in a nonprogressive state by
initiate
idiotype-induced
cellular
responses.
such mechanisms. One of the most pertinent
Idiotypic
immunization
protocols
clearly
observations
supporting
the
idea
of
demonstrate that patients can mount a cellular
immunosurveillance is the finding that expanded
response against the idiotype. Unfortunately,
CD8-positive clonal cells present in a significant
however, at this stage, clinical responses remain
number of patients with MM are related to
infrequent. Methods of immunization need to be
favorable prognostic outcomes, both at diagnosis
further explored, and, although the idiotype fills
and if found at any stage of the disease. Such CD8-
several criteria for being an ideal tumor antigen,
positive clones have the phenotype of cytotoxic
bioinformatic modeling programs of idiotypic
effector T cells: that is, they are CD8 positive, CD45
peptide sequences suggest that, in a majority of
RA positive, CD57 positive, CD28 negative, and
patients, it may not be an "optimal" antigen because
perforin positive. T-cell receptor CDR3 segment
of inadequate major histocompatibility complex
analysis and nucleotide sequencing have shown that
(MHC) peptide binding. Therefore, the search for
the
CD8-positive
CD57-positive
expanded
other antigens continues.
populations are clonal, whereas CD8-positive
CD57-negative expansions are polyclonal. Although
NK T cells, which are distinct lymphocytes that
aged-matched normal control populations also
recognize glycolipid antigens in the context of
contain expanded T-cell populations, these are
antigen-presenting CD1d molecules, may play a
almost exclusively CD4-positive T cells.
The
role in immunosurveillance of MM. A number of
differentiation stage of these clones in MM is either
studies have shown that freshly isolated human
CD27 negative, CD28 negative (late) or CD27
NK T cells can be readily quantified by ELISPOT
positive, CD28 negative (intermediate). It appears
assay. They have a TH 1 profile, and, after
that patients with "late" expanded T-cell clones have
stimulation
by
their
natural
ligand
a significantly improved survival over those patients
galactosylceramide via dendritic cells, killing of
who develop "intermediate" stage clonal T cells.
autologous myeloma cells can be documented.
Gene array studies comparing the 2 subpopulations
Patients with nonprogressive MM have deficiency
of T cells have shown a significant upregulation of
of ligand-dependent interferon production in the
interferon regulator factor 5 and downregulation of
NK T cells. However, this can be overcome using
interferon-alfa in the "late" stage T cells, which are
dendritic cells pulsed with the NK T ligand. It has
9
been hypothesized that in progressive disease, NK T
cytotoxic cells against the autologous tumor. The
cells are rendered dysfunctional by tumor-derived
potential to increase activity of NK T cells and
glycoprotein expressed by myeloma cells. An
gamma delta T cells to allow successful immune
immunotherapy approach targeting this population
control of the tumor is under active investigation.
of NK T cells may be of therapeutic benefit in
patients with MM.
References
Other important cells involved with tumor
1. Dhodapkar M. Role of glycolipid antigens and
immunosurveillance are circulating V9/V2 T cells,
natural killer T cells in myeloma. In: Boccadoro
which naturally recognize nonpeptide compounds
M, Pileri A, eds. Multiple Myeloma 2004. Turin,
derived from a variety of microbes and plants.
Italy; 2004:59.
Aminobisphosphonates,
including
the
aminobisphosphonate zoledronic acid, can induce
2. Joshua D. Immunobiology of T cells and
expansion of these T cells in the presence of low-dose
dendritic cells in myeloma. In: Boccadoro M,
interleukin-2 (IL-2). Upon expansion, these T cells
Pileri A, eds. Multiple Myeloma 2004. Turin,
display activity against human myeloma cell lines
Italy; 2004:64-66.
and primary myeloma cells in vitro. Furthermore, it
has been shown that the exposure of these cells to
3. Massaia M, Mariani S, Muraro M, et al. Role of
zoledronic acid and IL-2 can switch them from a
mevalonate metabolites and gamma/delta T cells.
naive memory phenotype to an effector phenotype.
In: Boccadoro M, Pileri A, eds. Multiple Myeloma
Such data indicate that immune dysregulation of
2004. Turin, Italy; 2004:62-63.
myeloma not only involves B cells and CD4 and
CD8 T cells but also gamma delta T cells; the
4. Mellstedt H. Natural and adaptive idiotype
mechanism of the immunomodulatory activity of
reactive T cells: application of various techniques for
bisphosphonates may involve such cells.
detection. In: Boccadoro M, Pileri A, eds. Multiple
Myeloma 2004. Turin, Italy; 2004:60-61.
Finally, in any platform for immunization protocols,
the function of high-potency dendritic cells needs to
be analyzed. Studies have shown that in MM the
high-potency
circulating
dendritic
cell
is
dysfunctional as it fails to upregulate CD80 on
exposure to CD40 ligand; however, this dysfunction
can be reversed by exposure to IL-12. Thus, for an
immunization program to be successful, more
optimal choice of antigen is required. Immunization
programs that use high-potency dendritic cells must
have their dysfunction corrected by cytotoxins such
as IL-2. Also, methods to stimulate both NK T cells
and gamma delta T cells need to be evaluated.
Immunosurveillance in MM is an extremely
significant factor in maintaining stability of the
disease. The presence of idiotypic reactive T cells
detected by both ELISPOT techniques and by
tetramer staining shows that it is possible to raise
10
Session 5: Prognosis
Robert A. Kyle
and/or BM containing 10% or more plasma cells
Rochester, Minnesota, USA
and no evidence of end organ damage. A total of
241 patients with MGUS evaluated at Mayo Clinic
Monoclonal
gammopathy
of
undetermined
from 1956 through 1970 were followed for 1 to 39
significance (MGUS) progresses to multiple
years. Twenty-seven percent developed MM,
myeloma (MM) or a related disorder at a rate of
macroglobulinemia,
amyloidosis,
or
a
approximately 1% per year. The size of the
lymphoproliferative disorder. The interval from
monoclonal protein (M protein) is the most
recognition of MGUS to progression ranged from 1
important prognostic feature. The prevalence of
to 32 years (median 10.4 years). The actuarial risk of
MGUS is approximately 3% of the population 50
progression was 17% at 10 years, 34% at 20 years,
years of age or older. The cumulative probability of
and 39% at 25 years. Long-term follow-up was
evolution to lymphoid malignancy at 5 and 10 years
obtained for 1384 patients with MGUS from the 11
was 8% and 25%, respectively, in a series of 384
counties of southeastern Minnesota evaluated at
patients with an asymptomatic IgM MGUS.
Mayo Clinic from 1960 through 1994. The number
Rearrangement of 14q32 occurs in almost one half
of patients with progression to a plasma cell disorder
of patients with MGUS or smoldering multiple
(115) was 7 times the number expected on the basis
myeloma (SMM) compared with more than 70% of
of the incidence rates for these conditions. The risk
patients with MM. In a group of 72 patients with
of MM was increased 25-fold, Waldenström's
SMM, the presence of an abnormal magnetic
macroglobulinemia (WM) 46-fold, and primary
resonance imaging (MRI) scan indicated a shorter
amyloidosis 8.4-fold. The risk of progression was
time to progression (TTP). A fluorine-18­labeled
approximately 1% per year. The size of the M-
deoxyglucose/positron
emission
tomography
protein spike at the time of recognition of MGUS
(FDG/PET) scan was normal in all 16 patients with
was the most important predictor of progression.
MGUS, but all 21 patients with active MM had
Patients with IgM or IgA M protein had greater risks
positive
scans.
Cyclooxygenase-2
(COX-2)
of progression than those with IgG M protein.
expression was found in 16% of patients with
Reduction of 1 or 2 uninvolved immunoglobulins
MGUS and in 35% of patients with MM at
or the presence of a monoclonal light chain in the
diagnosis. All 16 patients with negative polymerase
urine did not alter progression.
chain reactions (PCRs) following myeloablative allo-
hematopoietic stem-cell transplant (HSCT) had 0%
In an effort to determine the prevalence of MGUS,
actuarial risk of relapse at 5 years, whereas all 13 with
we identified 28,063 residents of Olmsted County
persistently positive PCRs had 100% actuarial risks
who were 50 years of age or older. Serum samples
of relapse at 5 years.
were obtained from 76% of the population. MGUS
was identified in 3% of patients. The prevalence was
Dr. Robert Kyle (Mayo Clinic, USA) opened the
4-fold higher in patients 80 years of age or older
session on prognosis with a presentation on
than in those 50 to 59 years of age. The prevalence
MGUS.1 MGUS is characterized by the presence of
was 3-fold higher than reported in the literature in
an M protein less than 3 g/dL, bone marrow (BM)
patients 50 years of age or older and almost twice
containing less than 10% plasma cells, no evidence
that previously reported in persons older than 70
of related organ or tissue impairment (ROTI) (end
years of age. We concluded that MGUS is one of the
organ damage), and no other plasma cell disorder.
most common premalignant disorders in the general
There is no evidence of hypercalcemia (C), renal
population.
insufficiency
(R),
anemia
(A),
or
skeletal
involvement (B) (CRAB). SMM (asymptomatic) is
Dr. Enrica Morra (Niguarda Ca' Granda Hospital,
characterized by an M protein 3 g/dL or greater
Italy) evaluated the natural history of 384
11
asymptomatic patients with IgM MGUS diagnosed
IgM to less than 30 mg/dL to be indicators of a
from 1975 to 2001.2 The cumulative probability of
shortened TTP. Multivariate analysis was limited to
evolution to lymphoid malignancy at 5 and 10 years
the 72 patients who had complete information for
was 8% and 25%, respectively. In the median
all 5 variables. The low-risk patients (33 patients)
follow-up of 45 months, 11.7% evolved to
were characterized by normal MRIs and serum M
symptomatic WM. On univariate analysis BM
protein less than 3 g/dL and had a median TTP of
lymphoplasmacytic infiltration, high erythrocyte
79 months. The intermediate-risk group (27
sedimentation rate (ESR), IgM size, lymphocytosis,
patients) had abnormal MRIs or M protein greater
and hemoglobin level correlated with evolution. The
than 3 g/dL and had median TTP of 30 months.
multivariate analysis confirmed IgM size and
The high-risk group (12 patients) had abnormal
lymphocytosis as independently predictive of
MRIs and M protein greater than 3 g/dL and
malignant evolution as well as the hemoglobin level.
median TTP of 18 months. The impact of MRI in
The patients were divided into 3 risk groups based
72 patients revealed that those with abnormal
on laboratory findings. The low-risk subgroup had
patterns were more likely to have shorter TTP. They
an event-free survival of 89% at 10 years, whereas
also performed multivariate analysis without the
the high-risk subgroup had an event-free survival of
MRI results but included Bence Jones proteinuria.
44% at 10 years. A total of 172 patients had BM
In the 109 patients, the serum M-protein levels and
aspirates and biopsies and were divided into IgM
IgA were significant prognostic features. The
MGUS or smoldering WM (SWM). The 2
patients were divided into a low-risk group (49
subgroups differed in terms of IgM size, hemoglobin
patients) characterized by a serum M protein less
level, ESR level, and degree of BM infiltration.
than 3 g/dL and IgG type. The median TTP was 57
Fourteen patients with IgM MGUS (10.1%)
months. The intermediate-risk group (52 patients)
evolved to malignant lymphoproliferative processes,
had M protein greater than 3 g/dL and IgA type.
whereas 13 patients with SWM (38%) evolved to
The median TTP was 26 months. The high-risk
overt WM. Overall survival did not differ
group (8 patients) was characterized by M protein
significantly between the 2 subgroups.
greater than 3 g/dL and IgA type and had median
TTP of 9 months.
Dr. Thierry Façon and colleagues (CHU Lille and
Nantes, France) reported that the incidence of
Dr. Brian Durie and colleagues (Cedars-Sinai
14q32 rearrangement was 48% in 181 patients with
Medical Center, USA) reported that 84 patients
MGUS or SMM compared with 73% of 669
underwent 122 FDG/PET scans between 1996 and
patients with MM.3 Translocation of t(4;14) or
2001.5 Of the 84 patients, 21 had untreated active
t(14;16) was rarely present in MGUS/MM. The
MM, 16 had MGUS, 13 had MM in remission,
frequency of t(11;14) was the same in all plasma cell
and 34 had relapsing MM. All 16 patients with
disorders (about 15%). Del(13) was noted in 23%
MGUS had normal FDG/PET scans. All 21
of patients with MGUS/SMM and in 43% of
patients with untreated active MM had positive
patients with MM.
scans; 5 of the 21 had negative radiographic
surveys. Another 5 of 21 patients with MM had
Dr. Donna Weber and associates (University of
focal extramedullary disease. Extramedullary
Texas, M. D. Anderson Cancer Center, USA)
uptake was noted in 23% of 34 patients in relapse.
presented the prognostic features of 135 patients
Thirteen of 16 (81%) relapsing patients had new
with asymptomatic SMM.4 Univariate analysis
sites of disease on PET scan. The authors concluded
revealed abnormal MRI, M protein greater than 3
that the whole-body FDG/PET scan provided
g/dL, b2m greater than 2.5 mg/L, BM plasmacytosis
important staging and prognostic information.
greater than 25%, and suppression of uninvolved
12
Dr. Marco Ladetto (University of Turin, Italy) and
4. Weber DM, Wang LM, Delasalle KB, Smith T,
colleagues assessed 102 samples from 86 patients for
Alexanian R.
Prognostic features of asymptomatic
COX-2 expression.6 COX-2 expression was not
multiple myeloma. In: Boccadoro M, Pileri A, eds.
observed in 15 normal BM samples. It was found in
Multiple Myeloma 2004. Turin, Italy; 2004:71-72.
16% of MGUS, 35% of MM at diagnosis, and 47%
of MM at relapse. All patients in clinical remission
5. Durie BGM, Waxman AD, D'Agnolo A, Williams
CM. Advances in the diagnosis and staging of multiple
appeared to be COX-2 negative. COX-2 expression
myeloma. In: Boccadoro M, Pileri A, eds. Multiple
appeared to be prognostically important.
Myeloma 2004. Turin, Italy; 2004:75-77.
Dr. Paolo Corradini (University of Milan, Italy) and
6.
Ladetto M, Vallet S, Dell'Aquila M, et al.
colleagues used a nested PCR technique to monitor
Cyclooxygenase-2 (COX-2) in multiple myeloma. In:
minimal residual disease in 48 patients with MM
Boccadoro M, Pileri A, eds. Multiple Myeloma 2004.
receiving myeloablative allo-HSCT.7 Sixteen of 48
Turin, Italy; 2004:78-79.
patients (33%) remained persistently negative
during follow-up and had a 0% actuarial risk of
7. Corradini P, Carrabba M, Ladetto M, Montefusco V,
relapse at 5 years. Thirteen of 48 patients (27%)
Gahrton G, Majolino I. Role of molecular monitoring
were persistently positive and had a 100% actuarial
after allogeneic transplantation in multiple myeloma.
risk of relapse at 5 years. The intermediate group (19
In: Boccadoro M, Pileri A, eds. Multiple Myeloma
patients) had alternatively positive or negative PCR
2004. Turin, Italy; 2004:83-85.
results during follow-up and had actuarial risk of
relapse of 33% at 5 years. Seven other patients had a
nonmyeloablative allo-HSCT.
All 7 were in
complete clinical remission, but all had persistently
positive PCR results. The authors are now studying
real-time quantitative PCR (TaqMan PCR) and
suggest that this approach is feasible for patient
monitoring.
References
1. Kyle RA. Monoclonal gammopathy of undetermined
significance (MGUS) and the plasma cell disorders. In:
Boccadoro M, Pileri A, eds. Multiple Myeloma 2004.
Turin, Italy; 2004:69-70.
2. Morra E, Cesana C, Barbarano L, Lazzarino M.
Predictive variables for malignant transformation in
asymptomatic IGM monoclonal gammopathies. In:
Boccadoro M, Pileri A, eds. Multiple Myeloma 2004.
Turin, Italy; 2004:80-82.
3.
Façon T, Avet-Loiseau H, Leleu X, Bataille R.
Cytogenetic changes in the evolution of monoclonal
gammopathy of undetermined significance (MGUS) to
multiple myeloma (MM). In: Boccadoro M, Pileri A,
eds. Multiple Myeloma 2004. Turin, Italy; 2004:73-74.
13
Session 6:
Supportive Therapy
Heinz Ludwig
Clinical symptoms depend on the type of organs
Vienna, Austria
affected by amyloid deposits. Involvement of
kidneys results in renal impairment and deposits in
Amyloidosis
cardiac tissue cause restrictive cardiomyopathy with
insufficient cardiac output and characteristic
Dr. Giampaolo Merlini (University of Pavia, Italy),
peripheral low voltage in the electrocardiogram
one of the world's leading experts in amyloidosis,
(ECG). In severe forms, cardiac decompensation
presented an overview on this disorder. Amyloidosis
may ensue. Profound postural hypotension can
is a disease in which misfolding of extracellular
occur without concomitant tachycardia because of
proteins (of various origins such as immunoglobulin
cardiac dysautonomia and failure to respond with
light chains) leads to insoluable toxic protein
appropriate increase in heart rate. Patients may
aggregates, which are deposited in various tissues
present with an enlarged tongue, periorbital
(Fig. 1). The prevalence of amyloidosis is one fifth of
that of multiple myeloma (MM) and less than 1 case
ecchymoses, carpal tunnel syndrome, malabsorption
per 100,000 persons. The most common form of
in
case
of
intestinal
amyloid
deposits,
systemic amyloidosis is light chain amyloidosis (AL),
hepatosplenomegaly, and peripheral and autonomic
with lambda light chains (80%) more prevalent than
neuropathy. Amyloidosis may occur as primary
kappa light chains (1).
disease or secondary in conjunction with MM or,
rarely, with other monoclonal plasma cell disorders.
Patients with amyloidosis have a mean survival of
18 to 24 months on conventional therapy, but
prognosis can substantially be improved with more
aggressive treatment. High levels of cardiac
troponin T predicted poor prognoses and increased
levels of N-terminal probrain natriuretic peptide
predicted good prognoses (median survival 26 and
66 months, respectively) in patients treated with
autologous transplantation.
Treatment aims at elimination of the pathogenic
light chains. Hence, elimination of the monoclonal
Figure 1. Schematic diagram of generation of
plasma cells is the main treatment goal. High-dose
amyloid fibrils and their deposition in kidneys
chemotherapy followed by autologous stem cell
Diagnosis is established by fine-needle aspiration of
transplantation is the preferred treatment, provided
abdominal fat and by bone marrow (BM) biopsy.
the patient is fit enough to tolerate the associated
Staining of the affected tissue with Congo red yields
toxicities.
Treatment-related
mortality
is
a typical apple green birefringence under polarized
significantly higher in patients with amyloidosis
light microscopy (2).
than with MM. Patients with involvement of the
The mechanisms underlying specific organ targeting
intestine are at particular risk. Melphalan is often
by amyloidogenic light chains remain elusive, but
used for conditioning, but a lower dose (100 to 140
significant correlations among different genes of the
mg/m2) than commonly used for patients with
variable segment of lambda light chains and renal or
MM is recommended. Patients who achieve
cardiac involvement have been reported. AL
complete remission show significant dissolution of
amyloidosis frequently affects cardiac tissue, kidneys,
amyloid deposits and marked clinical improvement.
liver, spleen, and the intestinal tract.
In patients not suitable for an aggressive approach,
14
"conventional" treatments may be considered.
with IgM, marginal zone lymphoma with IgM
Vincristine, doxorubicin, and dexamethasone
paraprotein, and rare cases of chronic lymphocytic
(VAD); high-dose dexamethasone; melphalan-
leukemia (CLL) with IgM paraprotein.
dexamethasone; and thalidomide are reasonable
treatment choices, although poor tolerance is
Clinical symptoms usually stem from consequences
frequently encountered (3). Thalidomide should
of the abnormal IgM paraprotein. Binding of IgM
to myelin sheets of peripheral nerves can lead to
only be given to patients without significant cardiac
sensorimotor neuropathy, and coating of platelets
involvement and without overt neuropathy, as it
with the paraprotein can interfere with platelet
may
aggravate
neuropathy
and
aggravate
function, resulting in increased tendency for
impairment of heart conduction and arrhythmias.
bleeding. High concentrations of IgM and
Novel therapies, such as bortezomib and CC-5013
aggregation of paraprotein molecules lead to the
await clinical testing. Attempts to mobilize amyloid
hyperviscosity syndrome with fatigue, dizziness,
deposits with 4'-iodo-4'deoxydoxorubicine have not
confusion visual disturbances, and even stroke as
rendered clinical meaningful results. Monoclonal
clinical
sequelae.
BM
infiltration
with
antibodies against amyloid fibrils were shown to
lymphoplasmacytoid tumor cells may impair
dissolve amyloid deposits in experimental animals
hematopoiesis; anemia and thrombocytopenia are
but have not been tested in humans.
frequent complications.
Treatment Strategies in Waldenström's
Prognosis varies according to individual features(4).
Patients with low B2m, low IgM, and normal
Macroglobulinemia
hemoglobin have excellent prognoses and may
remain stable for years. The same applies to patients
Dr. Meletios-Athanassios Dimopoulos (University of
with normal hemoglobin and young age. These
Athens School of Medicine, Greece) discussed
treatment strategies in patients with Waldenström's
parameters were used by Dr. Dimopoulos for a
macroglobulinemia (WM). The peculiar features of
scoring system that distinguishes among patients
this disease are BM infiltration by lymphoplasmacytic
with marked differences in survival (Table 1).
cells and presence of a monoclonal IgM paraprotein.
In contrast to MM, patients with WM do not present
Treatment should only be initiated in case of
with osteolytic lesions. WM must also be
presence of symptoms or of rapidly progressive
distinguished from lymphoplasmacytic lymphoma
disease. Alkylator-based regimens (chlorambucil,
Median
Percentage of
Risk
Characteristics
Survival
P Value
Patients
(months)
Low
Hb 10 g/dL and age
23
172
< 65 years
Intermediate
Hb < 10 g/dL or age

45
107
< 0.0001
65 years
High
Hb < 10 g/dL and age

32
46
65 years
Table 1. Scoring System According to Hemoglobin
15
prednisolone;
cyclophosphamide,
vincristine,
Is There Still a Role for Conventional
prednisone [COP]; cyclophosphamide, doxorubicin,
Chemotherapy in Multiple Myeloma?
vincristine, prednisone [CHOP]) have been
extended by the introduction of purine nucleosides
The important question of whether there is still a
(fludarabine and cladribine) and by the monoclonal
role for conventional chemotherapy in MM was
antibody against CD20 (rituximab). In a recent
addressed by Jan Westin (University of Lund,
Southwest Oncology Group (SWOG) trial, single-
Sweden), one of the founders of the European
agent fludarabine therapy yielded remissions in 38%
Myeloma Network. Dr. Westin noted that the
of patients and an overall survival of 88 months (5).
median age of patients with MM is approximately
The published experience with single-agent
65 years in the United States and close to 70 years in
cladribine is more limited, and objective responses
Europe. In many of these patients, high chronologic
have been documented in 44% to 86% of patients.
age and/or poor physical condition hinders
In most studies with nucleosides, the median time to
treatment with high-dose chemotherapy and stem-
response was shorter than with chlorambucil.
cell transplantation. For these patients, conventional
chemotherapy is still the preferred treatment (8).
Rituximab is active both as single agent and
particularly in combination with nucleosides and
Since the introduction of melphalan in 1957,
alkylating agents. Small phase 2 trials with rituximab
virtually dozens of different regimens have been
combinations yielded long durations of response
proposed. Melphalan/prednisone (MP) is a simple,
(>24 months). At present, several trials are ongoing,
easy-to-administer oral treatment given in intervals
of 4 to 6 weeks. Dosing should be appropriate to
and some test the clinical value of rituximab for
achieve a mid-cycle nadir (drop of leukocytes
remission maintenance treatment (6).
<1500/_L). Usually, MP is given until best response
and thereafter continued for 2 to 4 cycles.
High-dose chemotherapy with autologous stem cell
Treatment is continued for at least 6 to 8 months;
transplantation can be safely used in younger
about 40% to 60% of patients achieve remissions,
patients (<65 years) with WM and has been shown
but complete remissions are rare. MP has been
to result in high response rates and in some complete
tested against several combination chemotherapy
remissions. It is likely to improve survival but it will
protocols aimed to duplicate the success of
be difficult to prove this in randomized trials, given
polychemotherapy
in
Hodgkin's
disease.
the low incidence of WM.
Unfortunately, these attempts failed to show an
improvement in survival (9). Polychemotherapy
There is limited experience with thalidomide/dex-
yields a slightly higher response rate (mean increase
amethasone/clarithromycin in pretreated patients
of 6%) than MP and is the preferred therapy in
(7). Newer options are alemtuzumab, a monoclonal
patients with need for rapid tumor reduction, such
antibody against CD52; bortezomib, antisense bcl-
as patients with imminent renal failure or other
2, and radioimmunoconjugates.
myeloma-associated complications. One of the most
effective and widely used polychemotherapy
In summary, important advances have been
regimens is VAD. VAD induces responses in up to
accomplished in the understanding of the biology,
70% of newly diagnosed patients and in about 30%
prognosis, and treatment of WM. Patients now
to 40% of pretreated patients. For patients with
can more readily be assigned to subgroups with
slowly progressive disease and without imminent
different prognoses, and treatment has improved
severe complications, MP is generally considered the
with the introduction of nucleosides and
standard treatment. Melphalan is toxic to MM stem
monoclonal antibodies
cells and should be withheld in patients planned to
undergo a stem-cell collection.
16
At present, several groups are evaluating whether
The incidence rate in patients who were nonanemic
they can enhance the efficacy of standard
at enrollment and were followed up for 6 months
chemotherapy regimens by adding 1 or more of the
under chemotherapy was 56%.
newer drugs such as thalidomide. Preliminary data
with MP and thalidomide indicate an improved
Anemia usually normalizes in patients who achieve
response rate but also increased toxicity (10). A
complete remission after chemotherapy, but persists
combination of bortezomib, doxorubicin, and
in patients who are unresponsive and recurs in those
dexamethasone has shown responses in more than
with relapsing disease. Anemia is more frequent in
90% of newly diagnosed patients (11).
patients with long-standing disease, when toxicity of
long-term treatment, impairment of renal function,
Dr. Westin concluded that oral intermittent MP is
and heavy tumor load contribute to its induction
still standard therapy for elderly patients with MM
and aggravation.
and encouraged clinicians to enroll patients into new
protocols that test the new drugs either as single-
The cause of anemia in MM often is multifactorial.
agent treatment or in combination with established
Inadequate erythropoietin production, decreased
treatments, such as MP, or in regimens that
numbers of erythroid precursors, and reduced
substitute one of the old drugs with a new substance.
responsiveness of the erythron to erythropoietin,
impaired iron utilization, and shortened life span of
Pathogenesis and Treatment of Anemia in
red blood cells are the most important pathogenetic
Multiple Myeloma
factors. In addition, dilutional anemia due to
paraprotein-induced expansion of the plasma
Dr. Heinz Ludwig (Wilhelminenhospital, Vienna,
volume and a direct proapoptotic effect of aggressive
Austria) stressed the high prevalence and the
MM cells on erythroid precursors (12) as well as
negative consequences of anemia in patients with
MM specific tumor treatment may contribute to
MM. In previous studies, anemia with hemoglobin
and/or aggravate anemia.
less than 12.0 g/dL was
found in 40% to 60% of
patients at diagnosis. In one
Hemoglobin (g/dL)
of his studies in elderly
patients
with
MM
prevalence of mild anemia
(Hb £ 12.0 g/dL) was 72%
and that of severe anemia
(hemoglobin 8g/dl) 21%
(Fig. 2).This high prevalence
is explained by the high age
of patients (median age: 68
years) enrolled into this trial.
In a recent large European
cancer
anemia
survey
(ECAS),
prevalence
of
anemia (Hb <12.0 g/dL) was
Figure 2. Distribution of hemoglobin levels in 292 newly diagnosed
53%
in
patients
with
patients with high median age (68 years) at presentation. Seventy-two
myeloma and lymphomas.
percent of patients presented with hemoglobin 12g/dl and 21% with
hemoglobin 8g/dl. (Ludwig et al., unpublished)
17
Anemia may cause various symptoms such as fatigue,
Erythropoietin is the most active stimulator of
weakness, drowsiness, depression, decreased cognitive
erythropoiesis and active in MM yielding responses
function, and reduced exercise capacity. Moderate to
(increase in Hb level >2.0 g/dL) in 60% to 80% of
severe anemia leads to peripheral hypoxia and
patients. Treatment should be started with 30 to
vasodilatation, with consecutive hyperactive heart
40,000 IU erythropoietin per week or with 2.25
syndrome manifested as tachycardia, left ventricular
mcg/kg darbopoetin per week. In the case of no
hypertrophy,
and­in
case
of
severe
response after 4 weeks (increase in Hb < 1g/dL),
anemia­congestive heart failure with pulmonary
the dose of erythropoietic agents should be
edema, which, in extreme cases, may be fatal.
increased by 50%. If this does not result in
significant improvement after 8 weeks, treatment
The negative impact of low hematocrit values is
should be discontinued.
often underestimated, probably because patients
have a remarkable capacity to adapt to adverse life
Parenteral or oral iron supplementation must be
circumstances such as the cumbering symptoms of
administered to patients with concomitant iron
anemia and therefore, do not report them frequently.
deficiency and should be considered for patients
These patients, however, are often surprised of the
with the "chronic inflammation" type of anemia.
magnitude of improvement that is induced by the
The superiority of parental over oral iron
correction of anemia with erythropoietin treatment.
supplementation has recently been demonstrated in
a randomized study (14).
Many elderly patients with multiple myeloma
present with comorbidities. These fact and the
Patients with stable or responding disease and
possible impairment of organ function by MM
without severe infections or a very recent episode of
and/or by amyloidosis and the side effects of MM
anesthesia and surgery are most likely to respond.
treatment make patients with MM particularly
Response rates are higher in patients with low
vulnerable to suffer from even mild anemia. Hence,
endogenous erythropoietin levels (< 100mU/ml)
the indication for treatment should mainly be based
and in those with preserved BM function (platelet
on the individual patient's anemia-related symptoms
counts >100.000/µL), whereas patients with heavy
and less on the actual hemoglobin level, as
transfusion dependence (more than 2 transfusions
sometimes is recommended in guidelines for
per month) are less likely to respond. Treatment
treatment of anemia.
should be continued until optimal improvement of
symptoms, and hemoglobin levels should be
Blood transfusions are still the mainstay of treatment
maintained at the level needed to alleviate the
for severe anemia and for the need for rapid
sequelae of anemia. The treatment may be
improvement (13). They also constitute the treatment
continued for several months and even for years if
of choice in patients who are unresponsive to
required. Often, dose reductions or an increase in
erythropoietin. Red-cell transfusions, unfortunately,
the treatment interval are necessary to prevent
can be associated with some risks such as the
overshooting of hemoglobin levels.
transmission of infectious agents and the induction
of acute or delayed hemolytic reactions, fever, post-
transfusion purpura, graft-versus-host disease, and in
Erythropoietin is very well tolerated in MM. So far,
cases of heavy transfusion needs, iron overload.
more than 900 patients have been enrolled into
Although multiple testing for infectious pathogens
prospective
randomized
trials
comparing
and
depletion
of
leukocytes
from
red-cell
erythropoietin or darbopoetin with placebo or with
transfusions have made transfusion much safer, there
an untreated control group. None of these showed a
is still a small risk for transmission of known and of
significant increase in adverse effects. There were no
hitherto unknown pathogens.
18
significant increases in hypertensive episodes or
high-dose dexamethasone is effective and well
thromboembolic complications, which are slightly
tolerated in patients with AL (primary) amyloidosis
increased in anemic patients with other malignant
who are ineligible for stem cell transplantation.
diseases during erythropoietin treatment. Analysis of
Blood. 2004 Apr 15;103(8):2936-8.
survival in treated and untreated groups did not
reveal a survival benefit for erythropoietin.
4. Dimopoulos MA, Hamilos G, Zervas K,
Symeonidis A, Kouvatseas G, Roussou P, Gika D,
The most important benefits of erythropoietin
Karmiris T, Bourantas K, Zomas A, Mitsouli C,
treatment comprise a significant improvement in
Xilouri I, Vervessou E, Matsis K, Anagnostopoulos
overall quality of life, exercise capacity, increase in
N, Economopoulos T; Greek Myeloma Study
hemoglobin levels, and reduction in transfusion
Group. Survival and prognostic factors after
needs. Most trials, however, have analyzed only the
initiation
of
treatment
in
Waldenstrom's
macroglobulinemia.
Ann
Oncol.
2003
functional aspects of quality of life: for instance, the
Aug;14(8):1299-305.
performance status. Despite this limitation, it is
noteworthy that practically all published reports on
5. Dhodapkar MV, Jacobson JL, Gertz MA,
erythropoietin treatment in anemic patients with
Crowley JJ, Barlogie B. Prognostic factors and
cancer showed a positive relationship between the
response to fludarabine therapy in Waldenstrom's
erythropoietin-induced correction of anemia and
macroglobulinemia: an update of a US intergroup
quality-of-life related parameters (15).
trial (SW0G S9003). Semin Oncol. 2003
Apr;30(2):220-5.
Dr. Ludwig concluded that anemia is the most
frequent hematologic complication in patients with
6. Dimopoulos MA, Zervas C, Zomas A, Hamilos
MM and needs careful assessment of possible clinical
G, Gika D, Efstathiou E, Panayiotidis P, Vervessou
symptoms. For treatment of significant anemia-
E, Anagnostopoulos N, Christakis J. Extended
related side effects, erythropoietic agents (and, in
rituximab therapy for previously untreated patients
certain situations, red cell transfusions) should be
with Waldenstrom's macroglobulinemia. Clin
considered.
Lymphoma. 2002 Dec;3(3):163-6.
References:
7. Coleman M, Leonard J, Lyons L, Pekle K,
Nahum K, Pearse R, Niesvizky R, Michaeli J. BLT-
1. Merlini G, Bellotti V. Molecular mechanisms of
D (clarithromycin [Biaxin], low-dose thalidomide,
amyloidosis.
N
Engl
J
Med.
2003
Aug
and dexamethasone) for the treatment of myeloma
7;349(6):583-96.
and Waldenstrom's macroglobulinemia. Leuk
Lymphoma. 2002 Sep;43(9):1777-82.
2. Guidelines Working Group of UK Myeloma
Forum; British Commitee for Standards in
8. Westin J. Conventional chemotherapy in
Haematology, British Society for Haematology.
multiple myeloma. Pathol Biol (Paris). 1999
Guidelines on the diagnosis and management of
Feb;47(2):169-71.
AL
amyloidosis.
Br
J
Haematol.
2004
9. Myeloma Trialist's Collaborative Group.
Jun;125(6):681-700
Combination chemotherapy versus melphalan plus
prednisone as treatment for multiple myeloma: an
3. Palladini G, Perfetti V, Obici L, Caccialanza R,
overview of 6,633 patients from 27 randomized
Semino A, Adami F, Cavallero G, Rustichelli R,
trials. Myeloma Trialists' Collaborative Group. J
Virga G, Merlini G. Association of melphalan and
Clin Oncol 1998 (12):3832-42.
19
10. Palumbo, A and Boccadoro M et al.
Thalidomide and Melphalan/Prednisone versus
Melphalan/Prednisone in previously untreated
patients with multiple myeloma International
Meeting on Multiple Myeloma, Torino, Italy, April
2004.
11. Richardson PG, Hideshima T, Mitsiades C,
Anderson K. Proteasome inhibition in hematologic
malignancies. Ann Med. 2004;36(4):304-14.
12. Silvestris F, Tucci M, Quatraro C, Dammacco
F.
Recent
advances
in
understanding
the
pathogenesis of anemia in multiple myeloma. Int J
Hematol. 2003 Aug;78(2):121-5.
13.
Ludwig
H.
Anemia
of
hematologic
malignancies: what are the treatment options? Semin
Oncol. 2002 Jun;29(3 Suppl 8):45-54. Review.
14. Auerbach M, Ballard H, Trout JR, McIlwain
M, Ackerman A, Bahrain H, Balan S, Barker L,
Rana J. Intravenous iron optimizes the response to
recombinant human erythropoietin in cancer
patients with chemotherapy-related anemia: a
multicenter, open-label, randomized trial. J Clin
Oncol. 2004 Apr 1;22(7):1301-7.
15. Littlewood TJ, Nortier J, Rapoport B, Pawlicki
M, de Wasch G, Vercammen E, Schuette W, Wils
J, Freund M; Epoetin Alfa Study Group. Epoetin
alfa corrects anemia and improves quality of life in
patients with hematologic malignancies receiving
non-platinum chemotherapy. Hematol Oncol.
2003 Dec;21(4):169-80
20
Session 7: Round Table on
Autologous Transplantation
Joan Bladé
Autologous Transplantation as
Barcelona, Spain
Intensification Therapy in Responding
Patients
This Round Table was chaired by Professors Sante
In the randomized Spanish PETHEMA trial, 164
Tura and Jean-Luc Harousseau. The following
patients with MM sensitive to the initial
speakers presented the trials of their respective
chemotherapy were randomized to receive 8 addi-
groups and actively participated in the Round Table
tional cycles of alternating vincristine, carmustine
discussion: Joan Bladé (Spanish PETHEMA trial), J.
(BCNU), melphalan, cyclophosphamide, pred-
Anthony Child (MRC British experience), Michel
nisone/vincristine, carmustine (BCNU), doxoru-
Attal (French IFM results), Michele Cavo (Italian
bicin,
dexamethasone
(VBMCP/VBAD)
Bologna 96 trial), Jean-Paul Fermand (French
chemotherapy (83) or HDT intensification (81). It
Group
of
"Myélome-Autogreffe"),
Hartmut
was found that the CR rate was significantly higher
Goldschmidt (German GMMG experience), Pieter
with HDT (30% vs 11%). However, the event-free
Sonneveld (Dutch-Belgian HOVON results), Mario
survival (EFS) (median, 42 vs 34 months) and over-
Boccadoro (Italian Multiple Myeloma Study
all survival (OS) (median, 65 vs 67 months) were
Group), John Crowley (US Intergroup results), Bart
not significantly different in both arms. As deliv-
Barlogie (University of Arkansas, Little Rock
ered in that trial, it seems that HDT intensification
experience), and Jean-Luc Harousseau (IFM results
does not offer significant benefit over the continua-
plus overall summary of all presentations).
tion of combination chemotherapy in responding
patients with good prognosis MM.
Summary
The importance of the achievement of CR as the
crucial step for a long-lasting response and
There was a general agreement that high-dose
prolonged survival in patients with MM was
therapy (HDT) followed by autologous stem-cell
highlighted.
Two
single-institution
studies
rescue should be considered in the front-line
performed at the M. D. Anderson Cancer Center in
therapy of younger patients with multiple myeloma
the United States and at the Hospital Clinic in
(MM). Tandem transplant seems to be superior to
Barcelona showed that patients with disease
single transplant in patients who do not achieve a
responsive to the initial chemotherapy and who
very good response after 1 HDT regimen. However,
achieved
CR
after
transplant
(negative
tandem transplant in MM should still be considered
immunofixation) had EFS and OS significantly
investigational until the definitive results of the
longer than those who achieved only partial
trials currently in progress are available. For all
response. Furthermore, patients who did not
patients, an attempt to collect enough stem cells for
achieve CR with HDT had similar EFS and OS
2 transplants was encouraged; the second transplant
rates compared with patients who met the eligibility
could be performed after relapse, particularly in
criteria for HDT and who did not receive HDT but
those patients having achieved complete remission
were continued on standard therapy. A small group
(CR) or a very good partial response (VGPR) after
of patients from the Alexanian series who had
the first transplant. It appears that the introduction
achieved CR with conventional chemotherapy had
of new agents (thalidomide, IMiDsTM, bortezomib)
the same EFS and OS as patients achieving CR after
into our current approaches (ie, induction,
transplantation. The meaningful difference between
maintenance) will constitute an important step
conventional therapy and HDT is that although
forward in improving the long-term outcome of
CR is only achieved in approximately 10% of
patients with MM.
patients treated conventionally, HDT increases the
rate of CR in an additional 25% to 30% of patients.
21
Consequently, the identification of factors that can
above-mentioned studies. He concluded that this
predict the patients who may achieve CR is
therapeutic approach should not be discussed any
important as these patients are more likely to benefit
longer as part of front-line therapy in younger
from the HDT procedure. The sensitivity to initial
patients with MM. The participants in the Round
therapy as measured by the M-protein size at the
Table agreed that HDT constitutes an important
time of transplant seems to be the most important
step forward in the treatment of MM.
predictor of CR after autologous transplant.
Single versus Double (Tandem)
High-Dose Therapy versus Single Transplantation
Autologous Transplant
Several randomized trials have compared conven-
The IFM group presented the mature results of the
tional therapy with HDT. The Intergroupe
first randomized trial comparing single vs tandem
Francophone du Myélome (IFM) in its IFM 90 trial
transplant in 399 patients with MM younger than
found that HDT was significantly superior to vin-
60. Forty-two percent of patients achieved CR or
cristine, cyclophosphamide, melphalan, pred-
VGPR in the single-transplant arm vs 50% with
nisone/vincristine, carmustine (BCNU), doxoru-
tandem transplant (P=ns). The probability of EFS
bicin, prednisone (VCMP/VBAP) chemotherapy in
at 7 years was 10% with single transplant vs 20%
terms of CR, EFS, and OS in 200 patients with
with double transplant (P=0.03). The OS at 7 years
stage II and III MM who were younger than 65.
was significantly higher with tandem than with
Similarly, the British Medical Research Council
single transplant (21% vs 42%, P=0.01). The most
reported that HDT was better than the convention-
interesting finding of this trial was that patients
al doxorubicin, carmustine (BCNU), cyclophos-
failing to achieve CR or VGPR within 3 months
phamide, melphalan (ABCM) regimen in terms of
after 1 transplant had a 7-year survival probability
CR rate, progression-free survival (PFS), and OS in
of 11% with single transplant vs 43% with tandem
their series of 401 patients. In both studies, the
transplant (P<0.001). From the results of this trial,
importance of upgrading the response from mini-
the authors concluded that double transplant
mal to partial to complete was recognized and high-
should be recommended for patients failing to
lighted. In contrast with these results, the US
achieve at least VGPR after 1 transplant.
Intergroup was not successful in increasing the
response rate with HDT compared with conven-
The results of the Bologna 96 trial on the first 220
tional vincristine, doxorubicin, and dexamethasone
patients included in the study were presented. The
(VAD) followed by VBMCP chemotherapy. In this
response rate (CR plus near CR) between single and
large trial, the EFS was significantly longer with
tandem transplant was not significantly different
HDT (25 vs 21 months, P=0.05) with no signifi-
(31% vs 43%). Tandem transplant was associated
with a significantly longer EFS (21 vs 31 months,
cant impact on OS (58 vs 53 months). Although
P=0.02) and time to progression (TTP) (23 vs 39
not presented at the Turin Multiple Myeloma 2004
months, P=0.002). As in the IFM trial, double
meeting, other randomized trials from the French
autologous transplantation was of particular clinical
Group of Myélome-Autogreffe failed to show any
benefit in patients who failed to respond to first-
advantage in response rate, EFS, and OS of HDT
line conventional chemotherapy and/or in those
over conventional chemotherapy in patients aged
who did not achieve CR or near-CR after the first
55 to 65. Dr. Harousseau, chair of the session, sum-
transplant. At present, no significant difference in
marized the results of all the trials comparing
OS was found between single and tandem
HDT/autologous transplantation and conventional
transplant, but the median follow-up of the series is
chemotherapy, highlighting that HDT resulted in a
still less than 4 years.
low (<3%) toxic death and that it significantly
increased the median EFS and OS in several of the
22
The French Group of Myélome-Autogreffe also
Total Therapy 2 (TT2) versus Total
reported the results of single vs tandem transplant
Therapy 1 (TT1)
in a series of 232 patients who were younger than
Dr. Barlogie extensively presented the design of
56. The response rate (CR plus near-CR) was
TT2 and compared its results with those achieved
similar in both arms (37% vs 39%). After a median
with TT1. In short, TT2 consisted of an intensified
follow-up of 53 months, no significant differences
induction, tandem autologous transplant with
in EFS and OS were observed between arms.
MEL-200, consolidation chemotherapy plus inter-
feron/dexamethasone maintenance. In addition,
The German group presented the preliminary results
thalidomide was introduced in a randomized trial
of the GMMG-HD2 trial. A total of 261 patients
design in both induction and maintenance, but the
were available for the analysis. Patients allocated to
results of thalidomide-related outcomes were still
double transplant had significantly longer EFS than
blinded. The outcomes of 476 patients included in
those who received a single transplant (median 23
TT2 were compared with those of 231 included in
months vs not reached, P=0.03).
the TT1 program. The 4-year EFS was increased
from 35% with TT1 to 58% with TT2. Despite a
The HOVON group randomized 303 patients who
significantly higher proportion of patients older
were younger than 65 to intensive vs double
than 65 enrolled in TT2, the 3-year treatment-
intensive therapy. The response rate, EFS, and PFS
related mortality decreased from 10% to 2%, and
were better with double intensive therapy. However,
the cumulative incidence of PFS decreased from
no significant difference was observed in OS.
52% to 24%. With gene-expression profiling data
available in 220 patients, 3 genes identified 25% of
In the discussion it was concluded that tandem
patients at high risk of relapse/progression (60% at
transplant is feasible in younger patients with MM
2 years compared with less than 10% in the remain-
and that it seems to be particularly beneficial for
der). Finally, Dr. Barlogie outlined the TT3 pro-
patients who do not achieve CR or VGPR with the
gram in which the tandem transplant approach
first transplant. However, its definitive role must
with 2 courses of MEL-200 is complemented with
await the final results of the trials currently in
bortezomib and dexamethasone, thalidomide-cis-
progress. At present, tandem transplant remains an
platin, doxorubicin, cyclophosphamide, etoposide
investigational procedure.
(DT-PACE) in the induction; thalidomide/dexam-
ethasone after the first and second transplant; con-
Intermediate-Dose Melphalan in Elderly
solidation with bortezomib, dexamethasone,
Patients With MM
thalidomide-cisplatin, doxorubicin, cyclophos-
The Italian group reported the results of a multicenter
phamide, etoposide (VDT-PACE); and intensive
clinical trial including 195 newly diagnosed elderly
maintenance
with
VTD
followed
by
patients with MM who were randomized to receive
thalidomide/dexamethasone.
either 6 cycles of melphalan and prednisone (MP) or
2 courses of intermediate-dose melphalan (100
In the General Discussion it was agreed that it
mg/m2) followed by stem-cell rescue. The frequency
seems difficult to improve significantly the results
of
near-CR
was
significantly
higher
with
that we are currently achieving using only
intermediate-dose melphalan (26% vs 7%). The
combinations of "classic" cytotoxic agents plus
median EFS was significantly higher with 2 courses of
HDT. The introduction of new drugs with different
MEL-100 (28 vs 16 months). The median OS was
mechanisms of action to our current treatment
also significantly longer with the more intensive
approaches will likely result in a significant
therapy (43 vs 58+ months). Thus, the conclusion of
improvement in response rate, EFS, and OS and
this trial was that intermediate-dose melphalan is a
the hope for long-lasting control of disease for
more effective first-line regimen than standard MP,
patients with MM.
improving response rate, EFS, and OS.
23
References
1. Alexanian R, Weber D, Giralt S, et al. Impact of
complete remission with intensive therapy in
patients with responsive multiple myeloma. Bone
Marrow Transplant. 2001;27:1037-1043.
2. Attal M, Harousseau JL, Façon T, et al. A
prospective, randomized trial of single versus double
autologous stem cell transplantation in multiple
myeloma. N Engl J Med. 2003;349:2495-2502.
3. Attal M, Harousseau JL, Stoppa AM, et al.
Autologous bone marrow transplantation versus
conventional chemotherapy in multiple myeloma.
N Engl J Med. 1996;335:91-97.
4. Bladé J, Vesole DH, Gertz MA. Transplantation
in multiple myeloma: who, when, how often?
Blood. 2003;102:3469-3477.
5. Child JA, Morgan GJ, Davies FE, et al. Medical
Research Council Adult Leukemia Working Party.
High-dose chemotherapy with hematopoietic stem-
cell rescue for multiple myeloma. N Engl J Med.
2003;348:1875-1883.
24
Session 8: Round Table on
Allogeneic Transplantation
Gösta Gahrton
eradicate most of the myeloma cells, sparing the
Stockholm, Sweden
normal cells and thus diminishing transplant-related
mortality. It is also assumed that the GVM can be
Summary
enhanced by adding donor lymphocytes later on to
prevent or to treat threatening relapse. At the Round
Results of allogeneic transplantation following high-
Table, both myeloablative and nonmyeloablative
dose myeloablative conditioning regimens have
conditioning methods were discussed.
improved during the last 10 years, but high
treatment-related mortality is still a problem. Recently
Allogeneic Transplantation Using
introduced nonmyeloablative conditioning regimens
Conventional Myeloablative Conditioning
result in reduced transplant-related complications,
The Bologna group1 reported on 84 patients who
but the impact on relapse rate is still unclear.
had received allogeneic transplants between 1990
and 2003. Most patients had received sibling donor
Introduction
grafts and were conditioned with total body
irradiation + cyclophosphamide, but some patients
Allogeneic transplantation in multiple myeloma
had received total body irradiation + busulfan +
(MM) has been performed since the early 1980s. It
cyclophosphamide. The patients were divided into
has the potential to cure patients with many
2 groups: those who were transplanted between
hematologic disorders, including MM. However, it is
1990 and 1995 and those who were transplanted
hampered by significant transplant-related mortality.
from 1996 to 2003. The complete remission (CR)
Allogeneic transplantation involves 3 main steps:
rate was similar: 38% during the earlier time period
conditioning with high-dose chemotherapeutic
and 43% during the later one. However, there was
agents with or without total body irradiation; the
a dramatic difference in the predicted 5-year overall
actual transplant procedure when hematopoietic
survival, which was only 27% in the earlier
stem cells from the donor are transfused into the
transplants but 60% in the later ones. Progression-
patient; post-transplant procedures to prevent graft-
free 5-year survival was predicted to be 18% in the
versus-host disease (GVHD), other transplant-
earlier transplants and 39% in the later ones. The
related complications, and relapse.
improvement in results was due to a lower
transplant-related mortality during the later period.
Conventional conditioning treatment usually
The relapse rate was mainly unchanged during
consists of total body irradiation in a dose of about
these 2 periods.
10 Gy, fractionated or nonfractionated, and
combined with high-dose cyclophosphamide. This
The Bologna group also made investigations of
method is myeloablative, which means that both
molecular remission in those patients who obtained
normal cells and tumor cells are killed. However,
complete hematologic remissions. Seventy-five
despite the high-dose treatment, precursors that can
percent of the patients who were analyzed remained
give rise to relapse seem to persist in most patients.
persistently polymerase chain reaction (PCR)
Thus, one would think that even higher-intensity
negative for a median of 3 years, with some patients
treatment would be needed, but this would involve
still being PCR negative 4 to10 years after
increased transplant-related mortality and is
transplantation. This corroborates data presented in
therefore not possible. In fact, lately attempts have
another session by Corradini and colleagues,2
been made to reduce the dose instead of increasing
showing that those patients with hematologic
it. Several clinical trials have shown that engraftment
remissions who were also in molecular remission
can be obtained, and the idea is that a graft-versus-
continuously had no predicted measurable risk of
myeloma (GVM) effect should be enough to
relapsing, whereas those who were intermittently
25
PCR positive or PCR negative had a high risk of
plantation (84 patients).4 The predicted 4-year sur-
relapsing. All those who did not enter molecular
vival in these groups of patients was 40%, 35%, and
remission would eventually relapse.
70%, respectively. The nonrelapse mortality rate was
2% at day 100 post-transplant and 17% overall.
Allogeneic
transplantation
with
a
full-dose
GVHD was significant in these patients and partic-
conditioning was also reported by the European
ularly in those who received the graft from unrelat-
Group for Blood and Marrow Transplantation
ed donors (18 patients). Sixty-one percent of these
(EBMT).3 They too had investigated patients during
patients had GVHD grade 2, and 11% had grade 3.
2 periods: from 1983 to 1993 and 1994 to 1998. A
Thus, although the long-term relapse rate or long-
dramatic improvement in overall survival was
term overall survival is not yet known, the results
shown. As in the Bologna study, this improvement
seemed very promising, particularly considering that
was due to reduced transplant-related mortality but,
the patients belonged to a high-risk group.
unfortunately, with no significant improvement in
relapse rate.
The Italian GITMO group also presented data on
nonmyeloablative allogeneic transplants.5 This
Allogeneic Transplantation Using
group had used the same regimen as originally used
Nonmyeloablative Conditioning Treatment
by the Seattle group: 200 cGy total body irradiation.
Nonmyeloablative
conditioning,
or
reduced-
The allotransplant was preceded by an autologous
intensity conditioning, was based on experimental
transplantation. The nonmyeloablative transplant
evidence by the Seattle group that engraftment could
was performed 2 to 4 months following the
be obtained even if the conditioning was not
autologous transplantation. Eighty-two patients
myeloablative. Similar results have been obtained in
entered the study, and 69 had completed both
various hematologic malignancies by the Slavin
transplant procedures at the time of presentation.
group in Israel. The Seattle group used very low-dose
After a median follow-up of 13 months, 83% of the
conditioning--that is, 200 cGy total body
patients responded. Sixty-two percent of them
irradiation--which did result in engraftment of
entered CR and 21% partial remission (PR). Overall
about 90%. In later trials, the group used a
treatment-related mortality was 13%. Twenty-eight
combination of total body irradiation 200 cGy and
percent of the patients had grade 2 acute GVHD,
fludarabine, particularly in transplants using
and 12% grades 3 to 4. Chronic GVHD was seen in
unrelated donors.
48% of the patients. Although the follow-up is
short, and little is known about the relapse rate, the
The idea of using nonmyeloablative regimens is that
study
indicates
the
feasibility
of
using
the conditioning treatment is not primarily used for
nonmyeloablative transplants. The transplant-
treatment of the disease but for ensuring engraft-
related mortality was low compared with high-dose
ment. It is well known that nonmyeloablation will
conventional conditioning.
not kill the last MM cells. Instead, the hope is that
the GVM effect, which is now well documented,
The Little Rock group presented less encouraging
will be responsible for killing MM cells. Dr. Rainer
results in 45 consecutive patients with either
Storb (Fred Hutchinson Cancer Research Center,
relapsed or high-risk MM.6 The patients received
USA) reported on results in 3 groups of patients
nonmyeloablative
allotransplant
conditioning
with MM: relapsed patients who had failed auto-
regimens of melphalan 100 mg/m2. Although 29
transplantation (14 patients), relapsed patients who
patients achieved CR or near-CR, the transplant-
had not received the previous autologous transplan-
related mortality was high. Twenty-five patients have
tation (19 patients), and patients who were candi-
died: 17 of transplant-related mortality, 7 of
dates for both autotransplantation and allotrans-
progressive disease, and 1 of nontransplant-related
26
cause. However, the patient number is small, and
lack of allogeneic HLA-identical sibling donors and
these patients constituted a very high-risk group.
66 to the trial group, with 31 patients pending allo-
cation (typing is ongoing). Forty patients have
Dr. Nicolaus Kröger (University Hospital Hamburg-
received the nonmyeloablative allogeneic transplants.
Eppendorf, Germany) used a nonmyeloablative
Only safety analyses are made in this study until
regimen in 24 related and 23 unrelated transplants.7
complete recruitment and until the patients have
The conditioning regimen consisted of fludarabine
received grafts (260 patients should be included).
90 to 150 mg/m2 + melphalan 100 to 140 mg/m2
Three patients of 40 have died of transplant-related
with an option to add antithymocyte globulin. The
complications following the nonmyeloablative trans-
remission rate was 53% in related and 55% in
plantation. One other patient has died in the allo-
unrelated transplants. The 3-year overall survival was
geneic arm, before the nonmyeloablative transplant
60% and 83%, and the event-free survival 47% and
was performed but after autologous transplant. Thus,
66%, respectively. Most important was the low
it was concluded that the trial is feasible.
treatment-related mortality, which was 10% and
Recruitment is planned to be complete in 2004. It is
13%, respectively. The relapse rate at 2 years was
hoped that the results of the trial will yield informa-
34% in unrelated transplants and 46% in related
tion on the role of nonmyeloablative conditioning
ones. Acute GVHD grades 2 to 4 were 39% in
for allotransplantation in MM.
unrelated transplants and 29% in related ones. The
authors concluded that this regimen provides
Source of Cells for Transplantation
sustained engraftment with durable complete
The source of stem cells for transplantation may be
chimerism and low 1-year treatment-related
of some importance. In studies performed between
mortality. Also, transplantation with unrelated
1983 and 1993, bone marrow (BM) was the only
donors did not lead to a significantly higher
source reported by the EBMT group.3 From 1994,
treatment-related mortality or significantly poorer
peripheral blood stem cells were increasingly used.
overall event-free survival. Although the results are
The retrospective EBMT registry analysis indicated
encouraging, the number of patients in this study is
that peripheral blood stem cells were not superior
also small, and the follow-up time is relatively short,
to BM for transplantation. A total of 297 patients
particularly with respect to assessing the long-term
who had received BM had borderline significantly
relapse rate.
superior overall survival compared with 224
patients who had received peripheral blood stem
From these studies it can be concluded that nonmye-
cells. However, relapse rate and transplant-related
loablative regimens are associated with relatively low
mortality did not differ significantly, although
early transplant-related mortality compared with
there was a small tendency for a higher transplant-
myeloablative conditioning regimens, but it is too
related mortality with peripheral blood stem cells.
early to judge relapse rate. Thus the place of nonmye-
Also, chronic GVHD was more prevalent with
loablative transplantation in MM is still far from
peripheral blood stem cells than with BM, which
clear. Therefore, the EBMT has started a study based
could contribute to a slightly higher transplant-
on genetic randomization.3 Patients with HLA-iden-
related mortality.
tical sibling donors are offered nonmyeloablative
allotransplants (conditioning with total body irradia-
The HOVON group used
T-cell­depleted
tion 200 cGy + fludarabine 30 mg/m2 x 3 days) after
allogeneic
transplantation
in
63
patients.8
a previous autotransplant, whereas those who lack
Transplant-related mortality was high, and the
compatible siblings are offered 1 or 2 autotransplants
conclusion was that T-cell depletion cannot be
in tandem. To date, 227 patients have been included,
recommended in allogeneic transplantation. Donor
130 have been allocated to the control group by the
lymphocytes were given later as part of the
27
procedure to 54 patients (see below). Although this
2. Corradini P, Carrabba M, Ladetto M, Montefusco
treatment induced both CR and PR in a significant
V, Gahrton G, Majolino I. Role of molecular
number of patients, it could not obliviate the
monitoring after allogeneic transplantation in
detrimental effect of the T-cell depletion.
multiple myeloma. In: Boccadoro M, Pileri A, eds.
Multiple Myeloma 2004. Turin, Italy; 2004:83-85.
The quantity of stem cells given is of importance for
outcome. Most studies have shown that at least 2 x
3. Gahrton G, Iacobelli S, Apperley J, et al.
106 CD34+ cells (hematopoietic stem cells)/kg
Myeloablative allografting in myeloma: analysis of the
body weight should be given to ensure good
EBMT registry. In: Boccadoro M, Pileri A, eds.
engraftment. If possible, the aim should be to give
Multiple Myeloma 2004. Turin, Italy; 2004:146-147.
as much as 4 to 5 x 106 CD34+ cells/kg. This seems
to improve engraftment efficacy and reduce
4. Storb R. From myeloablative to nonmyeloablative
transplant-related complications.
conditioning regimens in multiple myeloma: the
Seattle experience. In: Boccadoro M, Pileri A, eds.
Post-Transplant Treatment: Donor
Multiple Myeloma 2004. Turin, Italy; 2004:148.
Lymphocyte Transfusions
Post-transplant treatment consists of prevention of
5. Bruno B, Rotta M, Omedè P, et al.
GVHD, supportive treatment, and could also
Nonmyeloablative
conditioning:
the
GITMO
include donor lymphocyte transfusions (DLIs). At
experience. In: Boccadoro M, Pileri A, eds. Multiple
the Round Table, Dr. Henk Lokhorst and the Dutch
Myeloma 2004. Turin, Italy; 2004:144-145.
HOVON group presented results on DLI in 54
patients who had relapsed after partially T-
6. Tricot G. Allogenic transplantation. In: Boccadoro
cell­depleted allogeneic transplantation.8 Twenty-
M, Pileri A, eds. Multiple Myeloma 2004. Turin, Italy;
eight (52%) patients responded: 19 (35%) with PR
2004:143.
and 9 (17%) with CR. The median overall and
progression-free survival was 23 months and 19
7. Kröger N, Sayer HG, Schwerdtfeger R, et al.
months, respectively. Six patients were in sustained
Update of autologous-allogeneic tandem stem cell
CR more than 2 years following DLI. The most
transplantation in patients with newly diagnosed
important predictors for response were the presence
multiple myeloma with emphasis on unrelated
of acute (57%) or chronic (47%) GVHD. The
donors. In: Boccadoro M, Pileri A, eds. Multiple
authors concluded that minor histocompatibility
Myeloma 2004. Turin, Italy; 2004:140-141.
antigens, present on both myeloma and normal cells,
may be targets for the cytotoxic donor T cells.
8. Lokhorst HM, van der Holt B, Sonneveld P. T cells
However, despite these somewhat promising results
and the graft versus myeloma effect. In: Boccadoro M,
of DLI for prevention and treatment of relapse post-
Pileri A, eds. Multiple Myeloma 2004. Turin, Italy;
transplant, the procedure is insufficient and should
2004:137-139.
probably be combined with other treatments such as
thalidomide, interferon, or bortezomib.
References
1. Tosi P, Cellini C, Bonifazi F, et al. Related and
unrelated allografting after myeloablative conditioning:
the Bologna experience. In: Boccadoro M, Pileri A, eds.
Multiple Myeloma 2004. Turin, Italy; 2004:135-136.
28
Session 9: New Drugs
Sundar Jagannath
cells and the action of IL-6 trigger a signaling
New York, New York, USA
cascade via JAK, STAT3, BCL-XL, and myeloid
cell factor (MCL)-1, resulting in drug resistance.5
Since the successful introduction of thalidomide
In
addition,
cell-adhesion­mediated
drug
for the treatment of refractory multiple myeloma
resistance is associated with induction of KIP1 and
(MM) in 1998, a number of new drugs have been
G1 growth arrest.6 Cytokines also signal via the
studied in clinical trials. Recently, bortezomib, a
PI3K and AKT pathway, with downstream
proteasome inhibitor, has been approved for the
activation of BAD and NF- B that prevent
treatment of refractory MM. CC-5013, a
apoptosis of MM cells. PI3K kinase signaling
thalidomide-derived immune modulator, has
induces protein kinase C (PKC) activity and MM
shown significant activity in this disease and is
cell migration.7
being evaluated for approval. The activity of such
drugs as thalidomide has shown that there can be
Dr. Anderson reviewed the current understanding
successful treatment by interrupting the tumor
of the mechanism of action for several new drugs
cell­stromal cell interaction. Such drugs as
that are currently in clinical practice.1 Drug
bortezomib have shown that targeted therapy­that
therapy for MM induces cell death by 2
is,
interrupting
important
cell-signaling
mechanisms. The first pathway is called the
pathways­could
also
be
effective.
New
extrinsic pathway or the death receptor pathway
developments
in
preclinical
models,
better
and is mediated by caspase-8. Radiation therapy
understanding of the tumor cell­stromal cell
and
traditional
chemotherapy,
as
well
as
interaction and cell-signaling pathways, and
thalidomide
and
its
immunomodulatory
increasing ease of monitoring antitumor responses
derivatives, activate this pathway. The second
in patients has provided a new paradigm for
pathway is called the intrinsic pathway or the
development of drugs for the treatment of MM.
mitochondrial intrinsic pathway and is mediated
by caspase-9. Dexamethasone and arsenic trioxide
Dr. Kenneth C. Anderson (Dana-Farber Cancer
(As2O3) activate this pathway. Dexamethasone
Institute, USA) reviewed the impact of biology on
activates the related adhesion focal tyrosine kinase
the treatment of MM.1 Homing of the MM cells to
(RAFTK), causing the release of a second
the bone marrow is guided by chemokines and
mitochondrial activator of caspase (SMAC), but
their
receptors
and
adhesion
molecules.2
not of cytochrome c, from mitochondria. Drugs
Chemokine SDF-1 and its receptor play a role in
such as the proteasome inhibitor PS-341 activate
the homing of plasma cells to the bone marrow,
both pathways. Downstream death signaling is
where they bind to the stromal cells and
then mediated by activation of caspase-3 and the
extracellular matrix via the adhesion molecules
cleavage of poly-(ADP-ribose) polymerase (PARP).
CD38, VLA-4, and VLA-5 expressed on their
surface. Adhesion triggers signal transduction, gene
Thalidomide and its derivative, CC-5013, target
transcription, and elaboration of cytokines by both
both the tumor cell and the microenvironment.
the MM cell and in the stromal cell. Cytokines,
Although CC-5013 can inhibit cell growth and
such as interleukin (IL)-6, tumor necrosis factor
directly induce apoptosis in MM cells, thalidomide
(TNF)- , insulin-like growth factor (IGF)-1, IL-
is unable to do so even in micromolar
21, and vascular endothelial growth factor
concentrations, establishing the paradigm that
(VEGF), play an important role in the growth and
tumor cell growth can be inhibited by a drug's
survival of MM cells.3 Signaling through Ras,
effect on the surrounding stromal cells and
MEK, and the p42/44 MAPK pathway leads to cell
immune cells.8 Both CC-5013 and thalidomide
proliferation.4 Adhesion of MM cells to stromal
inhibit TNF-
and other inflammatory cytokine
29
production;
upregulate
IL-10
production;
in MM cells is a potential target for treatment.
downmodulate cell-adhesion molecule expression
Tumors with t(4;14) have aberrant fibroblast
such as I-CAM1; and inhibit VEGF and basic
growth factor receptor 3 (FGFR3) expression that
fibroblast growth factor (b-FGF).9 CC-5013 and
could be targeted by FGFR3 inhibitors. High
thalidomide stimulate natural killer (NK) cell
expression of the ubiquitin-proteasome pathway
activity against autologous tumor cells in patients.10
lends itself to treatment with bortezomib; potential
resistance due to hsp90 expression may need to be
Bortezomib is a boron-containing dipeptide that
countered with geldanamycin.
specifically
and
reversibly
inhibits
the
chymotryptic site of the enzyme proteasome.11 The
The role of thalidomide in newly diagnosed MM
ubiquitin-proteasome pathway accounts for 90%
was presented by Dr. S. Vincent Rajkumar (Mayo
of the protein turnover within cells. The ubiquitin
Clinic, USA), Dr. Donna Weber (M. D. Anderson
system of regulated protein degradation pathway is
Cancer Center, USA), and Dr. Antonio Palumbo
a fundamental process that influences vital cellular
(University of Turin, Italy). Dr. Rajkumar presented
events
including
cell
cycle,
malignant
the Mayo Clinic results on the 50 newly diagnosed
transformation, and the response to inflammation
patients with MM treated with thalidomide and
and immunity.12 In preclinical models, bortezomib
dexamethasone.15 Thirty-two (64%) had achieved a
induced apoptosis through caspase-8 and caspase-9
partial response (PR) or greater. There were 3
activation in drug-resistant MM cell lines and in
treatment-related deaths: 1 each from pancreatitis,
patients' cells.1 It downregulates NF- B-dependent
pulmonary embolism, and infection. This has led to
cytokine secretion in bone marrow stromal cells
a randomized trial by the Eastern Cooperative
and inhibits angiogenesis. Gene microarray
Oncology Group (ECOG) comparing thalidomide-
profiling shows that bortezomib downregulates the
dexamethasone
combination
therapy
with
transcription of genes that encode growth factors,
dexamethasone alone. The study has been closed
with an associated induction of apoptotic,
early, with the interim analysis report to be
ubiquitin-proteasome, and stress-response gene
presented at the American Society of Clinical
transcription in MM cells.13 Thus, addition of heat
Oncology (ASCO) 2004 meeting. Dr. Rajkumar
shock protein (hsp) 90 inhibitor, geldanamycin,
also presented the Mayo Clinic data on the use of
enhances the cell kill triggered by bortezomib in
thalidomide in asymptomatic MM.16 Thirty-one
cell lines known to be resistant and points to the
patients were treated with thalidomide alone; overall
direction of future drug development in MM.
response was 34%. At 2 years, almost 64% had no
progression of disease. Dr. Weber reported the M.
Comparison of the gene expression profile of
D. Anderson experience with thalidomide and
CD138+ MM cells from a patient with CD138+
thalidomide-dexamethasone combination in newly
plasma cells and from a genetically identical twin
diagnosed patients with MM.17 Patients with early-
revealed novel targets for drug development.14
stage disease (28 patients) were treated with
There was high expression of: Mcl-1, telomerase,
thalidomide alone; their response rate was 36%.
XBP-1, ubiquitin-proteasome pathway, stress-
Patients with advanced disease were treated with
response gene hsp90 and hsp70, IGF-1, and FLIP
thalidomide and dexamethasone; of the 40 patients
that inhibits caspase 8. An antiapoptotic member of
treated, 5 patients achieved complete response (CR)
the Bcl-2 family, Mcl-1 has been identified as an
(16%), and 24 patients (56%) achieved PR.
important survival factor in MM cells. Blockade
Emphasis was made on the need to fully
using antisense oligonucleotides has shown that
anticoagulate patients receiving thalidomide and
Mcl-1, and not Bcl-2 or Bcl-xL, is an essential anti-
dexamethasone pulse therapy.
apoptotic gene in MM. Elevated telomerase activity
30
Dr. Palumbo presented the results of the
diagnosed MM. Bortezomib was administered at 1.3
combination of melphalan, prednisone, and
mg/m2 twice weekly for 2 weeks followed by 1 week
thalidomide in patients older than 65 years or
of rest. A total of 6 cycles were administered. At the
younger patients who refused stem-cell transplant.
end of each 2 cycles, patients were monitored for
Melphalan 4 mg/m2 with prednisone 40 mg/m2
tumor response. Dexamethasone 40 mg on the day
daily for 7 days at monthly intervals for 6 cycles was
of and the day following administration of
administered to 49 patients. There was a high CR
bortezomib was permitted following 2 cycles for
rate of 25% and an overall response rate (CR+PR) of
patients not in PR and at the end of fourth cycle for
80%. Thalidomide was allowed to be continued for
those not in CR. The preliminary results in the first
a year unless discontinued earlier for toxicity or
12 patients indicated a near CR of 33% and PR in
progression of disease. Most common side effects
42%, for an overall response rate of 75%. In some of
were infection (29%) and thromboembolism in
the published articles on transplant results, negative
20% of patients. Most of the thromboembolism
immunofixation was not mandated for definition of
events occurred during the first 4 months of
CR.21 Thus, for the first time, Drs. Palumbo and
treatment, infections during the first 6 cycles of MP,
Jagannath were able to report CR rates greater than
whereas neuropathy was seen throughout the course
25% with standard treatments incorporating novel
of administration of thalidomide.18
agents in newly diagnosed patients with MM.22
Dr. Paul Richardson (Dana-Farber Cancer Institute,
Dr. Maurizio Zangari (University of Arkansas for
USA) presented phase 1 trial results of CC-5013 in
Medical Sciences, USA) reported on the novel
refractory or recurrent MM.19 CC-5013 dose
combination of thalidomide, bortezomib, and
escalation was 5, 10, 20, and 50 mg daily; there was
dexamethasone in relapsed and refractory MM.23
no dose-limiting toxicity within the first 28 days.
Bortezomib was administered to the first group of
Beyond 28 days, the major dose-limiting toxicity
patients at 1 mg/m2 while escalating the dose of
was myelosuppression. Maximum tolerated dose was
thalidomide by 50 mg from 50 mg daily to 200 mg
25 mg. Minor responses or better were noted in 72%
daily in cohorts of 10 patients each. In the second
of patients. Two-thirds of these patients had been
group, bortezomib was given at 1.3 mg/m2, and
treated previously with thalidomide. This was
the dose escalation with thalidomide was repeated.
followed by a phase 2 clinical trial of CC-5013 alone
Dr. Zangari reported on the results on 73 patients
at 30 mg daily for 3 weeks on and 1 week off
treated with these regimens; half of the patients
conducted in patients with relapsed and/or
were able to receive 4 of the planned 8 cycles, and
refractory MM.20 The study initially randomly
29 patients completed all 8 cycles. Overall response
assigned patients to 2 dosing schedules: 15 mg twice
rate was 58%, including 21% CR or near CR.
daily or 30 mg once daily. Because of increased
hematologic toxicity, the twice-daily dosing was
In summary, during the session on new drugs for
abandoned. Among the 91 evaluable patients, 9
the treatment of MM, the results of thalidomide
patients (10%) achieved CR, and 11 (12%) achieved
and bortezomib in newly diagnosed patients with
PR with CC-5013 alone; an additional 15 patients
MM and in novel combinations in relapsed
(16%)
achieved
PR
upon
addition
of
patients were reported. The promising results from
dexamethasone 40 mg daily for 4 days every other
phase 2 studies of CC-5013 were shown,
week. Another immunomodulatory drug, CC-4047,
indicating that this new agent may have value in
has shown efficacy in a phase 1­2 trial in England.
the treatment of MM. Progress in understanding
Dr.
Sundar
Jagannath
(Saint
Vincent's
the biology of the disease and robust preclinical
Comprehensive Cancer Center, USA) reported the
models have paved the way for rapid development
preliminary results on bortezomib in newly
of new agents for the treatment of MM.
31
References
10.
Davies FE, Raje N, Hideshima T, et al.
Thalidomide and immunomodulatory derivatives
1. Hideshima T, Anderson KC. Molecular
augment natural killer cell cytotoxicity in multiple
mechanisms of novel therapeutic approaches for
myeloma. Blood. 2001;98:210-216.
multiple
myeloma.
Natl
Rev
Cancer.
2002;2:927937.
11. Adams J, Palombella VJ, Sausville EA, et al.
Proteasome inhibitors: a novel class of potent and
2. Teoh G, Anderson KC. Interaction of tumor
effective
antitumor
agents.
Cancer
Res.
and host cells with adhesion and extracellular
1999;59:2615-2622.
matrix molecules in the development of multiple
myeloma. Hematol Oncol Clin North Am.
1997;11:27-42.
12. Ciechanover A, Schwartz AL. The ubiquitin-
proteasome pathway: the complexity and myriad
3.
Anderson KC, Lust JA. Role of cytokines in
functions of proteins death. Proc Natl Acad Sci U
multiple myeloma. Semin Hematol. 1999;36:14-20.
S A. 1998;95:2727-2730.
4.
Ogata A, Chauhan D, Teoh G, et al. IL-6
13. Mitsiades N, Mitsiades CS, Poulaki V, et al.
triggers cell growth via the Ras-dependent
Molecular sequelae of proteasome inhibition in
mitogen-activated protein kinase cascade. J
human multiple myeloma cells. Proc Natl Acad Sci
Immunol. 1997;159:2212-2221.
U S A. 2002;99:14374-14379.
5. Damiano JS, Cress AE, Hazlehurst LA, Shtil AA,
14. Munshi NC, Hideshima T, Carrasco D, et al.
Dalton WS. Cell adhesion-mediated drug resistance
Identification of genes modulated in multiple
(CAM-DR): role of integrins and resistance to
myeloma using genetically identical twin samples.
apoptosis in human myeloma cell lines. Blood.
1999;93:1658-1667.
Blood. 2004;103:1799-1806.
6. Hazlehurst LA, Damiano JS, Buyuksal I, Pledger
15. Rajkumar SV, Hayman S, Gertz MA, et al.
WJ, Dalton WS. Adhesion to fibronectin via beta1
Combination therapy with thalidomide plus
integrins regulates p27kip1 levels and contributes to
dexamethasone for newly diagnosed myeloma. J
cell adhesion-mediated drug resistance (CAM-DR).
Clin Oncol. 2002;20:4319-4323.
Oncogene. 2000;19:4319-4327.
16. Rajkumar SV, Dispenzieri A, Fonseca R, et al.
7.
Hideshima T, Nakamura N, Chauhan D,
Thalidomide for previously untreated indolent or
Anderson KC. Biologic sequelae of interleukin-6
smoldering
multiple
myeloma.
Leukemia.
induced PI3-K/Akt signaling in multiple myeloma.
2001;15:1274-1276.
Oncogene. 2001;20:5991-6000.
17. Weber D, Rankin K, Gavino M, Delasalle K,
8.
Hideshima T, Chauhan D, Shima Y, et al.
Thalidomide and its analogs overcome drug
Alexanian
R. Thalidomide
alone
or
with
resistance of human multiple myeloma cells to
dexamethasone for previously untreated multiple
conventional therapy. Blood. 2000;96:2943-2950.
myeloma. J Clin Oncol. 2003;21:16-19.
9. D'Amato RJ, Lentzsch S, Anderson KC, Rogers
18. Palumbo A, Bertola A, Musto M, et al. Oral
MS. Mechanism of action of thalidomide and 3-
melphalan, prednisone and thalidomide for newly
aminothalidomide in multiple myeloma. Semin
diagnosed myeloma patients. (2004 ASCO Annual
Oncol. 2001;28:597-601.
Meeting Proceedings, Post-Meeting Edition) J Clin
Oncol. 2004;22 (14S) (July 15 suppl):abstr 6549.
32
19. Richardson PG, Schlossman RL, Weller E, et
al. Immunomodulatory drug CC-5013 overcomes
drug resistance and is well tolerated in patients
with
relapsed
multiple
myeloma.
Blood.
2002;100:3063-3067.
20. Richardson PG, Jagannath S, Schlossman R, et
al. A multi-center, randomized, phase 2 study to
evaluate the efficacy and safety of 2 CDC-5013
dose regimens when used alone or in combination
with dexamethasone (dex) for the treatment of
relapsed or refractory multiple myeloma (MM).
Blood. 2003;102(11): abstr 825..
21. Attal M, Harousseau JL, Facon T, et al. Single
versus double autologous stem-cell transplantation
for
multiple
myeloma.
N
Engl
J
Med.
2003;349:2495-2502.
22. Jagannath S, Durie B, Wolf J, et al. First-line
therapy with bortezomib (formerly PS-341) in
patients with multiple myeloma (MM). (2004
ASCO Annual Meeting Proceedings, Post-Meeting
Edition). J Clin Oncol. 2004; 22(14S) (July 15
suppl): abstr 6551.
23. Zangari M, Barlogie B, Jacobson J, et al. VTD
regimen comprising Velcade (V) + thalidomide (T)
and added dex (D) for non-responders to V + T
effects a 57% PR rate among 56 patients wtih
myeloma (M) relapsing after autologous transplant.
Blood. 2003;102(11): abstr 830.
33
Session 9: New Drugs
Antonio Palumbo
Dr. Paul Richardson (Dana-Farber Cancer Institute,
Torino, Italy
USA) showed some of the clinical results achieved
with a number of the new drugs. The efficacy of
The international meeting "Multiple Myeloma
thalidomide and combination thalidomide plus
2004" was held in Turin, Italy, April 22 to 24, 2004.
dexamethasone in refractory/relapsed or newly
This workshop brought together the best myeloma
diagnosed patients was reported and confirmed by
investigators from the United States and Europe.
several independent studies.2 In newly diagnosed
Important updates of the more recent research find-
patients,
combination
thalidomide
and
ings were discussed. In the "New Drugs" section,
dexamethasone induced a response rate of 60% to
several new therapeutic approaches were presented.
70%. The thalidomide analog CC-5013 was
After 40 years from the introduction of melphalan
evaluated in patients with refractory/relapsed MM.
and 15 years from the beginning of autologous
Most common toxicities were neutropenia and
transplant, the discovery of new drugs might change
thrombocytopenia; the incidence of neuropathy and
and significantly improve treatment of multiple
deep-vein thrombosis (DVT) was low. Significant
myeloma (MM).
constipation, somnolence, and neuropathy were not
observed. Myelosuppression was observed, and a
Dr. Kenneth Anderson (Dana-Farber Cancer
maximal tolerated dose of 25 mg/d was defined. In
Institute, USA) showed the impressive results gener-
these patients with progressive MM despite
ated at the Dana-Farber Cancer Institute in Boston.
conventional therapy, remarkable activity, evidenced
He explained how research must be conducted from
by a 25% decrease or better in myeloma serum
the laboratory bench to the bedside of the patients
paraprotein, was achieved in 63% of patients.
and how the discoveries of the biology of MM can
Stabilization, or a decrease in MM paraprotein, was
lead to the selection of specific compounds that
evident in 79% of patients, including 46% of
inhibit myeloma cell growth and survival. The group
patients who had received previous treatment with
developed several in vitro systems and in vivo animal
thalidomide. The median time to best response was
models to characterize the mechanism of MM
2 months.
growth, survival, and drug resistance.1 They tested
several promising therapies that can target both MM
Dr. Sundar Jagannath (St. Vincent's Comprehensive
cell growth and bone marrow (BM) microenviron-
Cancer Center, New York) showed preliminary
ment such as thalidomide and thalidomide analogs
results achieved by bortezomib as first-line therapy
(IMiDs) including CC-5013, bortezomib, vascular
in patients with MM. 3 Bortezomib has been
endothelial growth factor receptor kinase inhibitor
extensively studied in refractory/relapsed patients,
PTK787, and histone deacetylase inhibitor SAHA-
who showed 45% response rates associated with
LAQ824. Other compounds only target MM cells
clinical benefits. A phase 3 trial comparing
such as heat shock protein 90 inhibitor 17-AAG,
dexamethasone vs bortezomib in patients with
statins, and insulin growth factor receptor inhibitor.
refractory/relapsed MM induced the FDA to
Others target only the BM microenvironment: IKK
accelerate the approval of this drug as salvage
inhibitor and p38MAPK inhibitors. These agents
treatment for MM. The primary objective of this
are active in vitro and significantly prolong survival
study was to determine the response rate after
of mice affected by MM, whereas others inhibit the
bortezomib alone or in combination with
diffusion of MM lesions. The association of drugs of
dexamethasone in newly diagnosed patients and to
these classes might induce the complete eradication
assess the tolerability and toxicity. The secondary
of the MM clone. They also showed that low-dose
goal was to establish if stem-cell harvest can be
bortezomib significantly enhances the sensitivity of
reduced by previous treatment with bortezomib.
DNA to the damage induced by chemotherapy.
This approach induces a 33% response rate of
These results represent the preclinical rationale for
immunofixation-positive complete remission (CR)
clinical trials combining the old chemotherapy with
and an overall response rate of 75%. This ongoing
the new agents.
study is based on a small patient population, but no
34
major drug-related side effects have been observed.
cause myelosuppression. Intravenous chemotherapy
The spectrum of adverse events is similar to those
may require an intravenous central catheter, which
observed in previous larger phase 2 clinical trials.
can induce sepsis and thrombosis. At Mayo Clinic,
These data suggest that bortezomib is clearly
50 patients with newly diagnosed MM were treated
effective and well tolerated as front-line therapy;
with combination thalidomide plus dexamethasone.
combination with dexamethasone improves clinical
Results were impressive: 64% of patients achieved
benefit. Stem-cell harvest after bortezomib was
PR without any chemotherapy regimen. When
feasible and not significantly reduced. A larger
minimal response and PR were combined, response
accrual is required to better define the toxicity
was observed in 92% of patients. Toxicity profile of
profile and the clinical efficacy of this approach.
this approach included 6% treatment-related
mortality. The incidence of DVT was 12%. At
Dr. Maurizio Zangari (Arkansas Cancer Center,
present, data are insufficient to determine whether
USA) reported experience on the combination of
prophylactic anticoagulation is required in patients
bortezomib, thalidomide, and dexamethasone.4
treated with thalidomide plus dexamethasone as
This combination represents one of the most
front-line therapy. A prophylactic dose of low-
exciting new approaches. The synergy among these
molecular-weight heparin for the first months of
agents, observed in preclinical studies, was evaluated
therapy is a reasonable approach. Because the
in a clinical phase 1 and 2 study. A total of 73
rapidity of response may play a role, gradual
patients
with
refractory/relapsed
MM
after
escalation of thalidomide dose may be considered as
autologous transplant were treated; 95% of patients
an alternative. Neurologic toxicity, such as
had received previous autotransplants, and 71% had
constipation, fatigue, sedation, and peripheral
previous treatment with thalidomide. In this study, 2
neuropathy, were the major side effects: mainly
doses of bortezomib were used; 4 different
WHO grade 1 to 2. These results were confirmed by
thalidomide doses were used for each single
a parallel independent study conducted at the M. D.
bortezomib dose. The trial is still ongoing. Dr.
Anderson Cancer Center. Thalidomide has been
Zangari presented the data of the entire population
also evaluated in patients with asymptomatic
of patients. In these heavily pretreated myelomas,
smoldering MM (SMM) in an attempt to delay
the response rate was very high. For patients
progression of disease. This approach induced a
receiving 8 courses of therapy, partial response (PR)
34% PR rate. In SMM, thalidomide treatment
was achieved in 90% of patients and CR in 10%. PR
should be suggested in the frame of investigational
with reduction of tumor mass greater than 90% was
control trials, actually ongoing. They will determine
achieved in almost 60% of patients. Major adverse
whether thalidomide reduces the rate of progression
events were fatigue, sensory neuropathy, diarrhea,
from asymptomatic to overt MM.
nausea, and constipation, but WHO grade 3 to 4
toxicities were limited. The time required to achieve
a PR was 3 months in the majority of patients. Even
Dr. Donna Weber (M. D. Anderson Cancer Center,
if bortezomib can overcome drug resistance to
USA) presented experience on thalidomide and
thalidomide, clinical outcome was significantly
dexamethasone as primary treatment for MM and
lower
for
patients
who
received
previous
illustrated the role of bortezomib added to this
thalidomide treatment compared with those who
combination. This group, together with the Mayo
were not previously exposed to thalidomide.
Clinic team, pioneered clinical trials with
thalidomide and dexamethasone for untreated
Dr. Robert Kyle (Mayo Clinic Rochester, USA)
MM.6 More than 200 patients were treated; PR
showed results obtained using thalidomide in newly
rates were 65% to 70%, including 10% CR. They
diagnosed and asymptomatic MM.5 Thalidomide in
tested the combination bortezomib, thalidomide,
combination
with
dexamethasone
has
clear
and dexamethasone as first-line treatment for newly
advantages
over
intravenous
chemotherapy.
diagnosed patients. Several cohorts of patients with
Thalidomide can be administered orally and does not
increasing doses of bortezomib were analyzed, but
35
results were shown for the entire group. Severe
effective agents are available for clinicians and
adverse events were limited to 1 patient with DVT,
patients. The next challenge is how to use these new
1 infection, and 1 severe case of myelosuppression.
agents: together to achieve the best response at
The response rate was approximately 80% with a
diagnosis and therefore the best prolonged duration
CR rate of 20%. When they compared historical
of remission, or in a sequential mode ­ some at
control groups treated with other combined
diagnosis, some at relapse ­ to ensure the best tumor
approaches, the best response rate was achieved by
control for a long period. These questions will soon
bortezomib, thalidomide, dexamethasone followed
be addressed and answered. Laboratory activity is
by the combination thalidomide, dexamethasone,
producing an impressive series of new compounds
and then by the chemotherapy regimen vincristine,
ready to move from the bench to the bedside. Which
doxorubicin, dexamethasone (VAD) followed by
of them will change the outcome of patients with
melphalan plus dexamethasone.
MM is the important question we are facing today.
Finally, Dr. Antonio Palumbo (University of Turin,
References
Italy) showed the feasibility and efficacy of the
combination
melphalan,
prednisone,
and
1. Hideshima T, Anderson KC. Molecular mecha-
thalidomide. This combination was evaluated in 49
nisms of novel therapeutic approaches for multiple
patients newly diagnosed with MM.7 According to
myeloma. Natl Rev Cancer. 2002; 2: 927-937.
the European Group for Blood and Marrow
Transplantation
(EBMT)/International
Bone
2. Richardson P, Hideshima T, Anderson KC.
Marrow Transplant Registry (IBMTR) criteria, 29%
Thalidomide: emerging role in cancer medicine.
of patients achieved immunofixation-negative CR,
Annu Rev Med. 2002; 53:629-657.
15% immunofixation-positive near-CR, 9% very
good partial response (VGPR), 35% PR, and 12%
3. Jagannath S, Durie G, Wolf J, et al. Bortezomib
no response. The time to maximal response was 3
(VelcadeTM, formerly PS-341) as first-line therapy
months in 80% of patients. After a median follow-
in patients with multiple myeloma (MM). Blood.
up of 13 months, 5 patients relapsed.
2003;102(11): 452 (abstr 1650).
The major acute adverse events included DVT
4. Zangari M, Barlogie B, Jacobson J, et al. VTD
(20%), infections (12%), constipation (6%), and
regimen comprising VelcadeTM (V), thalidomide
hematologic (22%) and neurologic (8%) toxicities.
(T) and added dexamethasone for non-responders
Hospitalization for intravenous antibiotic therapy
to V + T effects a 57% PR rate among 56 patients
was required in 5 patients. One patient died of
with myeloma relapsing after autologus transplant.
pulmonary thromboembolism and 1 of pneumonia.
Blood. 2003;102(11): 236a (abstr 830).
These data suggest that the combination of
melphalan, prednisone, and thalidomide induces a
5. Rajkumar SV, Gertz MA, Lacy MQ, et al.
fast tumor response with a CR rate similar to that
Thalidomide as initial therapy for early-stage
observed after transplant. A regimen of prophylactic
myeloma. Leukemia. 2003;17: 775-779.
anticoagulation should be adopted to prevent DVT.
6. Dimopoulos MA, Anagnostopoulos A, Weber D.
In conclusion, the meeting showed the promising
Treatment
of
plasma
cell
dyscrasias
with
activities of several new drugs such as thalidomide
thalidomide and its derivatives. J Clin Oncol. 2003;
CC-5013 and bortezomib. These new agents are
21(23): 4444-4454.
definitely increasing the response rate usually
achieved by conventional chemotherapy. Whether
7. Palumbo A, Bertola A, Musto P, et al. Oral
these increased response rates will also improve
melphalan, prednisone and thalidomide for newly
clinical outcome will be defined in the near future. A
diagnosed myeloma. Blood. 2003;102:509.
new era is emerging. After almost 40 years, new and
36
Session 10:
Immunotherapy
Nikhil C. Munshi
response­have been investigated. Based on data
Boston, Massachusetts, USA
that cultured DCs from patients with MM can
efficiently and rapidly endocytose different classes
Myeloablative therapies requiring hematopoietic
of myeloma proteins, as well as support generation
stem-cell support can induce complete remissions in
of anti-myeloma immune response, the clinical
up to 40% of patients with multiple myeloma
trials have investigated vaccination with DCs
(MM). However, patients ultimately experience
pulsed with idiotype protein. Two clinical studies
progression of disease because of the emergence of
involving 25 patients confirmed the feasibility of a
chemotherapy-resistant disease, and there is no cure.
DC-based vaccination, development of Id-specific
Novel therapeutic interventions specifically targeting
immune responses, and even occasional clinical
the myeloma cell are under intense investigation.
responses.5 However, robust clinical responses
One such focus of investigation has been the use of
have not been observed, and the strategy targeting
immune-based
therapies.
The
potential
single known tumor-associated antigens is subject
susceptibility of MM cells to immune-based therapy
to
development
of
tumor
cell
resistance.
has been demonstrated in the setting of allogeneic
Approaches being explored to circumvent this
transplantation, where the graft-versus-myeloma
limitation are DC pulsing with whole MM cell
effect is thought to be responsible for the decreased
lysate or fusing MM cells with DCs. Preclinical
risk of relapse and potential curative outcomes.
results both in a murine model and with human
However, morbidity and mortality associated with
cells have confirmed the feasibility of presenting a
this mode of therapy have limited its use and have
wide array of myeloma-related antigens through
prompted a search for effective autologous,
DC-myeloma cell fusions and the development of
immune-based therapy. This session was focused on
CTLs able to lyse primary myeloma cells.6
A
discussing
the
recent
developments
in
clinical study of MM-DC fusion vaccination based
immunotherapy directed at MM.
on this is ongoing at the Dana-Farber Cancer
Institute. This study is also providing an
Dr. Nikhil Munshi (Dana-Farber Cancer Institute,
opportunity to identify novel myeloma-associated
USA) opened the session on immunotherapy with a
antigens for eventual development of an antigen
presentation
on
dendritic
cell
(DC)-based
cocktail. Also, novel immunomodulatory agents
vaccination strategies. Although MM is associated
are being evaluated to provide T-cell costimulation
with
both
humoral
and
cellular
immune
to improve immune response post-vaccination.7 In
dysfunction, immune responses have been observed
conclusion, these stepwise improvements in
against both viral and tumor antigens. The
immunotherapeutic strategies directed at MM are
development of an anti-keyhole limpet hemocyanin
likely
to
lead
to
immune
and­more
(KLH) response and induction of Id-specific
importantly­clinical responses that will eventually
immune responses, including generation of cytolytic
help achieve a cure in MM.
T lymphocytes (CTLs) specifically able to lyse MM
cells, has confirmed immune competence in a
Dr. Qing Yi (University of Arkansas for Medical
clinical study in 49 patients vaccinated with patient-
Sciences, USA) evaluated the efficacy of Id-pulsed
specific Id protein coupled with KLH.
mature DCs administered subcutaneously in a pilot
study of 5 patients. Four of 5 patients developed Id-
To improve on these results, DCs­the most potent
specific T-cell responses (4 by ELISPOT assay and 2
antigen-presenting cells (APCs), equipped with the
by proliferation assay), and all 5 patients developed
necessary costimulatory and major histocompatibility
Id-specific B-cell responses. The cytokine secretion
complex (MHC) molecules effective in presenting
profile of activated T cells demonstrated a type 1
MM-associated antigens to induce specific immune
response. One patient achieved more than a 50%
37
reduction in myeloma protein, and 3 patients
CD4+ T-cell response that may be more meaningful
remained stable. These promising results emphasize
for induction of clinical response. The variable
the need to optimize DC-based immunotherapy. In
region (V) genes encoding the Id determinants are
this direction, CTLs induced by tumor-lysate­pulsed
assembled as a single-chain Fv (scFv) and fused with
DCs have been shown to specifically kill autologous
an immunoenhancing sequence that is derived from
tumor cells, but not normal cells, and provide a
the Fragment C (FrC) of tetanus toxin. Based on
rationale for vaccination with tumor-pulsed DCs in
success in mice, a patient post-autologous
MM. These CTLs have also demonstrated activity in a
transplantation has been treated; this patient
murine model of human MM. Also, further
demonstrated induction of significant long-term T-
modification in DC vaccine administration was
cell responses against both the Id protein and FrC. A
considered to make it more effective. As DCs, upon
larger trial is now planned.
injection, have to travel to lymph nodes to interact
with T lymphocytes, their direct injection into the
To improve upon current results, vector designs are
lymph node would increase the chance of interaction
being modified to induce high-level cytotoxic T-cell
and subsequent antigen presentation. This has now led
responses. The initial fusion gene design was aimed
to a phase 2 study to evaluate the efficacy of intranodal
to induce CD4+ T-cell responses against idiotypic
DC vaccination in patients with MM. Two groups of
antigen. However, to attack the large number of
patients are being vaccinated: Group A consists of
tumor-specific
or
tumor-associated
proteins
patients with indolent or smoldering MM who receive
expressed in the intracellular compartment of the
Id-pulsed, CD40L-matured DC vaccine; group B
tumor cell, induction of MHC Class I-restricted
consists of patients with advanced MM who receive
CD8+ CTL cells will be required. A modified DNA
tumor lysate-pulsed, CD40L-matured DC vaccine.
vaccine that incorporates a minimized domain from
KLH pulsing is used as adjuvant, and low-dose
FrC upstream of a sequence encoding a defined
interleukin-2
is
administered
following
each
CTL epitope was designed and has been successfully
vaccination. To date, 14 patients have been enrolled­9
tested in animal models (6/6 candidate epitopes).
in group A and 5 in group B­with evidence of
The effector CTLs are focused only on a single
development of immune response post-vaccination.
peptide epitope but can kill tumor cells in vitro and
in vivo. Strategies being evaluated to improve
Dr. Freda Stevenson (Southampton University
vaccine delivery have included "primeboost"
Hospital, UK) further discussed novel methods to
approaches, whereby priming with naked DNA is
administer myeloma-specific antigens. One of the
followed by boosting with the same gene delivered
major challenges in tumor immunology is to develop
in a viral vector, and electroporation of the muscle
vaccines able to induce specific immunity from a
following intramuscular injection. These approaches
compromised
repertoire.
To
overcome
this
have shown promise in initial preclinical studies.
challenge, a DNA-based vaccine that encodes tumor
antigens fused to immunoenhancing sequences has
Finally, Dr. Roberto Lemoli (University of Bologna)
been successfully tested in an animal model. These
discussed the results of vaccination using DCs
DNA-based vaccines are designed to induce selected
pulsed with tumor idiotype-derived class I-restricted
effector mechanisms from tolerized repertoires and
peptides. Based on their previous demonstration
to maintain long-term immunologic memory. By
that positively selected peripheral blood CD14+
manipulating designs, immune effectors are able to
monocytes from patients with MM can be induced
attack target antigens expressed in different
to differentiate into fully functional, mature CD83+
molecular forms on cancer cells. Dr. Stevenson has
DCs that are efficient in priming autologous T cells,
also used idiotype secreted by tumor cells as a tumor-
a phase 1/2 study is now evaluating Id-pulsed DC
specific antigen target and focused on inducing a
vaccination in MM. Thirteen patients with MM
38
after high-dose therapy have been entered in the
4. Butch AW, Kelly KA, Munshi NC. Dendritic cells
study. Adequate DCs were generated from
derived from multiple myeloma patients efficiently
peripheral blood monocytes, with a high degree of
internalize different classes of myeloma protein. Exp
Hematol. 2001;29:85-92.
purity in all patients. Ten patients have received Id-
pulsed DC vaccinations: 3 subcutaneous and 2
5. LeBlanc, HideshimaT, Catley S.
intravenous. DCs from 4 patients were pulsed with
Immunomodulatory drug costimulates T cells via
whole Id protein, while in 6 patients DCs were
the B7-CD28 pathway.
charged with Id-derived HLA class I-restricted
Blood. 2004; 103(5):1787-1790
peptide. No toxicity was observed in 6 evaluable
6. Yi Q, Desikan KR, Barlogie BB, Munshi NC.
patients; 5 patients developed anti-KLH humoral
Optimizing dendritic cell-based immunotherapy in
and T-cell responses; all 6 developed anti-Id T-cell
multiple myeloma.
responses, but none of them developed anti-Id B-cell
Br J Haematol. 2002;117:297-305.
responses. Six and 2 of 8 patients developed anti-
KLH and anti-Id delayed-type hypersensitivity
7. Wen YJ, Barlogie B, Yi Q. Idiotype-specific
responses, respectively.
These results provide a
cytotoxic T lymphocytes in multiple myeloma:
evidence for their capacity to lyse autologous
preliminary basis for larger study of peptide-pulsed
primary tumor cells.
DC vaccination in MM.
Blood. 2001;97:1750-1755.
In conclusion, dendritic-based and DNA-based
8. Wen YJ, Min R, Tricot G, Barlogie B, Yi Q.
vaccines have demonstrated induction of protective
Tumor lysate-specific cytotoxic T lymphocytes in
immunity in the clinic. Further improvements in
multiple myeloma: promising effector cells for
immunotherapy.
dose, schedule, and injection strategies will lead to
Blood. 2002;99:3280-3285.
optimization based on relevant data emerging from
the current clinical trials. Although Id is an
9. Forconi F, King CA, Sahota SS, Kenaway CK,
important target, many other candidate antigens are
Russell NH, Stevenson FK.
Insight into the
becoming available. Vaccination strategies, including
potential for DNA idiotype fusion vaccines designed
combination of these antigens and adjuvant
for patients by analysing xenogeneic anti-idiotypic
antibody responses.
immunostimulatory agents, will eventually lead to
Immunology. 2002;107:39-45.
long-term success in the treatment of MM.
10. Rice J, Buchan S, Stevenson FK. Critical
References
components of a DNA fusion vaccine able to induce
protective cytotoxic T cells against a single epitope of
1. Munshi NC. Immunoregulatory mechanisms in
a tumor antigen.
multiple myeloma.
J Immunol. 2002;169:3908-3913.
Hematol Oncol Clin North Am. 1997;11:51-69.
2. Maecker B, Anderson KS, von Bergwelt-Baidon
MS, et al. Viral antigen-specifc CD8+ T-cell
responses are impaired in multiple myeloma.
Br J Haematol. 2003;121(6):842-848.
3. Raje N, Gong J, Chauhan D, et al. Bone marrow
and peripheral blood dendritic cells from patients
with multiple myeloma are phenotypically and
functionally normal despite the detection of Kaposi's
sarcoma herpesvirus gene sequences.
Blood. 1999;93:1487-1495.
39
Intentionally Left Blank
A Comprehensive Guide to Torino
Multiple Myeloma 2004
Registration for Credit
Please mail or fax this form to
Institute for Continuing Healthcare Education
210 West Washington Square
Philadelphia, PA 19106
Fax: 215-592-9085
Forms must be submitted by September 30, 2005 to receive credit.
Please print clearly.
First Name
Middle Initial
Last Name
Degree (Check the appropriate box.)
US-licensed physician
Non­US-licensed physician
Other
Specialty
Affiliation (University or Hospital)
Address (to mail certificate)
City
State
ZIP/Postal Code
Telephone
Fax
E-Mail Address
Number of hours claimed
I certify that I have participated in the above-named continuing medical education activity.
Signature
Date
Certificates will be mailed in approximately 3 to 4 weeks of receipt of form.
Post-Test Answer Sheet
Please circle one answer per question. A score of at least 70% is required to receive a certificate.
1.
a
b
c
d
6.
a
b
c
d
2.
a
b
c
d
7.
a
b
c
d
3.
a
b
c
d
8.
a
b
c
d
4.
ab
c
d
9.
ab
c
d
5.
a
b
c
d
10.
a
b
c
d
Intentionally Left Blank
A Comprehensive Guide to Torino
Multiple Myeloma 2004
Activity Evaluation
Please indicate the extent to which you agree or disagree with the following statements.
(1=Strongly disagree, 5=Strongly agree).
1.
The learning objectives were appropriate for the activity.
1
2
3
4
5
2.
The monograph was examined with scientific rigor
1
2
3
4
5
and was up to date.
3.
This activity was presented in a fair and balanced
1
2
3
4
5
manner.
4.
The information presented was pertinent to my
1
2
3
4
5
educational needs.
5.
The activity was well organized and of high quality.
1
2
3
4
5
6.
I successfully met the goals of this educational activity.
1
2
3
4
5
Based on your previous knowledge and experience, the level of this activity was (please check one):
Too basic
Appropriate
Too complex
What questions do you still have regarding the treatment of patients with multiple myeloma?
What major challenges or obstacles do you face in your daily practice when treating patients with multiple myeloma? Please be
inclusive.
Management of newly diagnosed patients
Management of transplant patients
Management of relapsed patients
Other:
Which emergent therapies for the treatment of multiple myeloma are you most interested in learning about?
Thalidomide/dexamethasone
Bortezomib
New agents in clinical trials
Other:
General comments, suggestions, and future topics of interest:
Intentionally Left Blank
A Comprehensive Guide to Torino
Multiple Myeloma 2004
Torino Proceedings Post-Test
Session 1:
In the study of the molecular pathogenesis of MM, which genetic event/marker is related to progression of
disease and outcome?
A. BAFF/APRIL receptor function in the peripheral blood
B. A 4-gene model predicting early mortality: RAN, ZHX-2, CHC1L, and p53
C. Translocations involving cyclin D genes
D. Hyperdiploidy with high del(13) and t(14q32) predicting shorter survival
Session 2:
A possible result of the phenotypic differences and increased antigen-presenting capability of plasma cells
found in patients with MGUS compared with plasma cells from patients with MM is the inability of T
cells to control tumor proliferation. True or false?
A. True
B. False
Session 3:
Which of the following have been implicated as part of a complex interactive network between tumor cells
and the bone marrow microenvironment in patients with MM?
A. IL-2, IGF-1, CD3, VEGF receptor
B. IL-6, IGF-1, VEGF receptor, Akt/PI-3K, hsp90
C. FDG/PET, IL-6, hsp90, IGF-1
D. IL-6, IL-2, hsp30, VEGF receptor
Session 4:
Clinical observations in patients with MM reveal that expanded CD4-positive clones of T cells are
associated with a more favorable prognostic outcome, suggesting that these CD4-positive T cells can
maintain the malignant B-cell clone in MM in a nonprogressive state. True or false?
A. True
B. False
Session 5:
Which of the following are important prognostic features supporting a diagnosis of smoldering MM or
MGUS compared to a diagnosis of MM?
A. Smaller M-protein spike
B. Normal FDG/PET scan
C. Low(er) incidence of COX-2 expression in bone marrow samples
D. All the above
Session 6:
Waldenström's macroglobulinemia (WM) has a number of peculiar features including bone marrow
infiltration by lymphoplasmacytic cells and the presence of a monoclonal IgM paraprotein. By contrast to
MM, patients with WM do not present with osteolytic lesions. At diagnosis, WM must be distinguished
from what other conditions?
A. MM, acute and chronic lymphocytic leukemia (ALL and CLL)
B. MM, lymphoblastic lymphoma, follicular non-Hodgkin's lymphoma, and amyloidosis
C. MM and general hyperviscosity syndrome
D. MM, lymphoplasmacytic lymphoma or marginal zone lymphoma with IgM, and rare cases of
C. LL with IgM
Session 7:
The Round Table on Autologous Transplantation ended in general agreement that High-dose therapy
(HDT) followed by autologous stem-cell rescue should be considered a front-line therapy in younger
patients with MM and that tandem transplants seem superior to single transplants in patients who do not
achieve a very good response after one HDT regimen (warning, however, that tandem transplantation in
MM is still investigational).True or false?
A. True
B. False
Session 8:
Allogeneic transplantation in MM using nonmyeloablative conditioning seeks to take advantage of what
principle(s) to achieve clinical effectiveness?
A. Seeks to achieve full ablation of normal cells and tumor cells
B. Graft-versus-host disease (GVHD)
C. Reduced tumor load and graft-versus-myeloma (GVM) effect
D. Incomplete killing of precursor cells
Session 9:
Promising activities in MM were demonstrated for several new/reemergent drugs, especially thalidomide,
CC-5013, and bortezomib. Next steps include combining these agents or using them sequentially at initial
diagnosis and/or at relapse. The drugs in question have shown no significant side effects in trials to date.
True or false?
A. True
B. False
Session 10:
MM is associated with both humoral and cellular dysfunction. Evidence to date suggests that patients with
MM do not mount antikeyhole limpet hemocyanin (KLH) responses or idiotype-specific immune
responses when vaccinated with patient-specific idiotype protein coupled with KLH, suggesting that
vaccination strategies in MM are not likely to succeed. True or false?
A. True
B. False
Release Date: September 20, 2004
Expiration Date: September 30, 2005
This activity is jointly sponsored by the
Institute for Continuing
Healthcare Education
and the
International Myeloma Foundation.
A Comprehensive
Guide to Torino
International Myeloma Foundation
International Headquarters
12650 Riverside Drive, Suite 206
North Hollywood, California 91607
Multiple Myeloma
800 452 CURE (2873) Fax: 818 487 7454
TheIMF@myeloma.org
www.myeloma.org
2004 Conference
A Publication of the International Myeloma Foundation
Dedicated to improving the quality of life of myeloma patients while working toward prevention and a cure.
© 2004 International Myeloma Foundation
Proceedings from the live conference in Torino, Italy: April 22-24, 2004.