Myeloma
Today Spring 2004
Volume 5
Number 10
A Publication of the International Myeloma Foundation
Dedicated to improving the quality of life of myeloma patients while working towards prevention and a cure.
Highlights
5
Bart Barlogie, MD, PhD
Message From IMF President
6
Dear Friends,
throughout the world for their myeloma
expertise and sophisticated data analysis.
Prof. Hervé Avet-Loiseau
On behalf of the International Myeloma
Foundation, I would like to thank you for your
We also are pleased to announce that Dr. Dalsu
support and update you on our progress with
Baris, a leading NCI-based epidemiologist, and
the IMF's research project, Bank On A Cure®.
ethicist Dr. Jeff Kahn, Professor of Medicine,
Center of Bioethics, University of Minnesota,
This past year has been very busy. There are
have joined our Bank On A Cure team.
two labs that process the DNA samples and
7
are doing the studies: one in the UK and the
All of the administrative paperwork is ready
other in the US. Our two Co-Chairs are Dr.
for final approval by the Institutional
Robert Orlowski, MD, PhD
Brian Van Ness, Head of the Department of
Review Board (IRB) at the University of
Genetics, Cell Biology, and Development,
Minnesota. This is an extremely important
whose lab is in Minneapolis, and Dr. Gareth
facet of this exciting project.
Morgan, Head of the Myeloma Group at the
Royal Marsden Hospital in London.
We
are
pleased
to
confirm
that
collaborations have been established with
All of the data-gathering and statistical
several important myeloma research groups.
analysis is being conducted by John
They are: SWOG (Southwest Oncology
9
Crowley's group, CRAB (Cancer Research
Group), ECOG (East Coast Oncology
Gary S. Jacob, PhD
and Biostatistics). CRAB is highly respected
PLEASE SEE NEXT PAGE.
This issue of Myeloma Today is supported by:
Celgene Corporation, CTI, Millennium Pharmaceuticals, Novartis Pharmaceuticals, and Ortho Biotech.

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Table of Contents
International Myeloma Foundation
Dedicated to improving the quality of life
Message From IMF President
1
of myeloma patients while working
toward prevention and a cure.
Why Bank On A Cure®
3
Founder
IMF Calendar
4
Brian D. Novis
Treating Multiple Myeloma: The Little Rock Approach
5
President
Susie Novis
The Genetics of Multiple Myeloma
6
Board of Directors
Drug Resistance
7
Chairman Dr. Brian G.M. Durie
Michael B. Bell
Education Initiative
8
Mark DiCicilia
Michael S. Katz
Atiprimod
9
Benson Klein
Dr. Robert A. Kyle
Cancer Research and Medicare
10
Isabelle Lousada
IMF Kicks Off 2004 Seminars with Florida Retreat
11
Dr. Edith Mitchell
Dr. Gregory R. Mundy
Los Angeles Area Support Group Salutes Leader
12
Charles Newman
Susie Novis
IMFers Pay Tribute To Janet Johnson
13
Richard H. Saletan
John L. Salter
IMF Member Fundraisers
14
E. Michael D. Scott
R. Michael Shaw
I'm Not Leavin'
15
Donald R. Woodward
News & Notes
16
IMF Headquarters
12650 Riverside Drive, Suite 206
Letters
17
North Hollywood, CA 91607-3421 U.S.A.
Tel: (800) 452-2873 or (818) 487-7455
Order Form
25
Fax: (818) 487-7454
E-mail: TheIMF@myeloma.org
Website: www.myeloma.org
IMF President -- continued
Kelly Cox, COO
kcox@myeloma.org
Group), Mayo Clinic, IFM (Intergroup
run tests on over 2,000 DNA samples
Suzanne Battaglia, Special Events
Français Myelome), University of
from
patients
who
have
already
sbattaglia@myeloma.org
Arkansas, the German Myeloma Study
consented to correlative analyses as part
Nancy Baxter, Hotline Coordinator
Group, The Japanese Myeloma Study
of ongoing clinical trials.
Initial
nbaxter@myeloma.org
Group, Central Europe Myeloma
observations include correlation between
Debbie Birns, Hotline Coordinator
Group, HOVAN (the Netherlands),
benefit with high-dose melphalan as part
dbirns@myeloma.org
the Nordic Myeloma Study Group,
of stem cell transplant and the gene-
JEM, Pethema (the Spanish Groups),
regulating
body
metabolism
of
Michele Cherney, Exec. Asst. to Ms. Novis
mcherney@myeloma.org
the Italian Group, the South American
melphalan. In addition, gene regulation
Study
Group,
Fundaleu
(the
of TNF-alpha production, a crucial
Spencer Howard, Meeting & Event Services
showard@myeloma.org
Argentinian Group), the Canadian
body cytokine (or hormone), correlates
Group at the Toronto General
with response to thalidomide treatment.
Marya Kazakova, Publications Editor
Hospital, and the National Canadian
The goal of identifying personal gene
mkazakova@myeloma.org
Cancer Group. Bringing these groups
expression patterns that correlate with
Kemo Lee, Subscriptions & Merchandise
together to work collaboratively is truly
treatment benefit is well within grasp!
klee@myeloma.org
a milestone in myeloma research and
Lisa Paik, Information Officer
shows the scope, breadth, and belief in
I look forward to keeping you posted
lpaik@myeloma.org
the importance of Bank On A Cure!
on the progress of Bank On A Cure. A
Stephen Robertson, Development Coordinator
truly heartfelt thank you from all of us
srobertson@myeloma.org
So, our research teams are in place and,
here at the IMF and from our Bank
thanks to your support, we have
On A Cure team. We couldn't do it
The information presented in Myeloma Today is not
intended to take the place of medical care or the advice
purchased a DNA extractor. This is the
without you!
of a physician. Your doctor should always be consulted
most critical (and a very expensive) piece
regarding diagnosis and treatment.
of equipment needed for this project.
Warmest regards,
We've also begun our research and have
Susie Novis
2
www.myeloma.org

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Why Bank On A Cure®?
EVERY MYELOMA PATIENT IS UNIQUE. TREATMENT SHOULD BE TOO.
What is the purpose of the Bank On A Cure study?
What is being tested?
Doctors and researchers around the world are united in the
Your DNA will be tested and analyzed to determine the
opinion that the potential cure for cancer lies somewhere in
characteristics of the behaviour of a number of specific genes that are
the better understanding of the genetic makeup of patients.
known to be implicated in the onset of myeloma and which may
The Bank On A Cure study aims to provide a unique
influence treatment outcome and performance in individual cases.
opportunity to develop genetic and clinical correlations that
will allow better treatment response and performance,
What are the alternatives?
improved treatment choices, and possibly future preventative
Due to the nature of this type of study and in the absence of
and curative strategies for patients with multiple myeloma.
a suitable similar or comparative study, there is no alternative.
However, this puts the patient at no disadvantage or harm
Who is organizing and funding Bank On A Cure?
whatsoever, and will not affect treatment in any way.
This project is being organized by the International Myeloma
Foundation.
The IMF is working
What are the disadvantages of
closely with two labs, one based in the
taking part?
USA and one based in the UK. The
There are no side effects at all
Bank On A Cure study is being
from taking part in this study and
funded through generous donations
there are no disadvantages that have
from IMF members and supporters.
come to light to date.
Who has reviewed this study?
What are the benefits of taking part?
This study was designed by a
As with most studies, results cannot
multi-disciplinary team of doctors,
be guaranteed. However, it is hoped
researchers, patients, and lay people.
that results from this study will allow
It has been reviewed and approved
doctors to tailor treatments specifically
by appropriate ethics committees.
to individual patients based on their
Dr. Brian Van Ness and grad student with the
dedicated robotic DNA processing machine.
genetic makeup.
This will help to
Who is taking part in this study?
maximize response and outcome and
Worldwide, up to 10,000 individual DNA samples will
to reduce side effects. It is also hoped that this study will lead to
be collected from persons diagnosed with multiple myeloma
preventative and curative strategies in the not-too-distant future.
who fit the entry criteria required to take part in this study.
What if new information becomes available?
Do I have to take part?
New information will only add value to this project and
No. The decision is entirely yours. If you choose not to take
will not affect DNA donors in any way.
part, this will not affect your current treatment and it will not
affect the relationship you have with your doctor. Even if you
What happens when the research stops?
decide to take part now, you are free to withdraw at any time
It is hard to predict when a research project like this will stop--
in the future without giving any reason and again, this will
if ever. DNA banks will provide a continual source of information
not affect the relationship you have with your medical team.
and it is likely that this type of research will become standard clinical
practice and will be integrated into everyday care of patients.
What will happen if I do take part?
After you have read all the information you need and have
Will my taking part in this study be kept confidential?
agreed to take part in this study, you will be required to
All information that is collected about you during the course
provide a DNA sample derived from a simple mouthwash. If
of the research will be kept strictly confidential. Any information
you have already provided a DNA sample as part of another
about you which is used or leaves the hospital will have your
clinical study, you will be required to give consent to allow
name and address removed so that you cannot be identified from
some of that DNA to be used in this study. Regardless of
it.
It is important to understand that specific results and
when you have given your DNA sample, you will be required
information about your own case will not be available.
to complete a simple patient questionnaire. You might be
asked to provide follow-up information when required. Your
What will happen to the results?
doctor will also receive a questionnaire regarding your
The results of this study will be published in scientific
medical history and current treatment.
journals and presented at scientific meetings. MT
800-452-CURE (2873)
3

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IMF Calendar
International Myeloma Foundation
Scientific Advisory Board
April 17-18
IMF Patient & Family Seminar in Vienna, Austria
Chairman Robert A. Kyle, USA
Raymond Alexanian, USA
April 19-20
IMF participates in OVAC in Washington, DC
Kenneth C. Anderson, USA
Hervé Avet-Loiseau, FRANCE
Bart Barlogie, USA
April 22-24
IMF participates in the Myeloma 2004 Conference
Régis Bataille, FRANCE
in Torino, Italy
Meral Beksac, TURKEY
William Bensinger, USA
James R. Berenson, USA
April 29-May 2
IMF participates in the ONS Conference in Anaheim, CA
Daniel Bergsagel, CANADA
Leif Bergsagel, USA
May 8
Robert A. Kyle Lifetime Achievement Award Dinner
Joan Bladé, SPAIN
Mario Boccadoro, ITALY
Honoring Dr. Bart Barlogie in Little Rock, AR
Y.C. Chen, REPUBLIC OF CHINA
J. Anthony Child, ENGLAND
May 14-16
IMF Scientific Advisors Retreat in Bermuda
Raymond L. Comenzo, USA
Franco Dammacco, ITALY
Meletios A. Dimopoulos, GREECE
June 5-7
IMF participates in the ASCO conference
Brian G.M. Durie, USA
in New Orleans, LA
Dorotea Fantl, ARGENTINA
Rafael Fonseca, USA
Ian Franklin, SCOTLAND
June 11
Multiple Musicians Against Myeloma, Sea Cliff, NY
Gösta Gahrton, SWEDEN
Morie A. Gertz, USA
John Gibson, AUSTRALIA
July 2-3
IMF Physician and Patient Seminar in Ankara, Turkey
Hartmut Goldschmidt, GERMANY
Jean-Luc Harousseau, FRANCE
July 9-11
IMF Annual Support Group Leaders Retreat in Durham, NC
Vania Hungria, BRAZIL
Douglas Joshua, AUSTRALIA
Tadamitsu Kishimoto, JAPAN
July 16-17
IMF Patient & Family Seminar in San Jose, CA
Henk M. Lokhorst, THE NETHERLANDS
Heinz Ludwig, AUSTRIA
Ian MacLennan, ENGLAND
September 20
IMF Patient & Family Seminar in Barcelona, Spain
James S. Malpas, ENGLAND
Jayesh Mehta, USA
September 24
IMF Patient & Family Seminar in Paris, France
Håkan Mellstedt, SWEDEN
Angelina Rodriguez Morales, VENEZUELA
Gareth Morgan, ENGLAND
October 1
IMF Patient & Family Seminar in Torino, Italy
Gregory R. Mundy, USA
Amara Nouel, VENEZUELA
Martin M. Oken, USA
October 8-9
IMF Patient & Family Seminar in Teaneck, NJ
Linda Pilarski, CANADA
Raymond Powles, ENGLAND
November 12-13
IMF Patient & Family Seminar in San Diego, CA
David Roodman, USA
Jesus San Miguel, SPAIN
Kazuyuki Shimizu, JAPAN
November 6
IMF 14th Anniversary Ribbon of Hope Gala
Seema Singhal, USA
in Los Angeles, CA
Bhawna Sirohi, ENGLAND
Alan Solomon, USA
Pieter Sonneveld, THE NETHERLANDS
December 3-6
IMF participates in the ASH Conference
Guido J. Tricot, USA
in San Diego, CA
Benjamin Van Camp, BELGIUM
Brian Van Ness, USA
Jan Westin, SWEDEN
IMF(Japan) and IMF(UK) events are not included above.
Collaborative Group meetings (i.e. ECOG and SWOG) are not included above.
4
www.myeloma.org

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Treating Multiple Myeloma
THE LITTLE ROCK APPROACH
Bart Barlogie, MD, PhD
stem cell-supported melphalan at 200 mg/m2 given within
two to four months of each other for a total melphalan dose
INTRODUCTION
of 400 mg/m2. Such tandem autotransplants have now been
shown, in a randomized clinical trial conducted by French
Peripheral blood stem cell (PBSC)-supported high-dose
investigators, to extend the duration of disease control and
melphalan 200 mg/m2 is now considered standard therapy
survival, while allowing mucous membrane recovery after the
for patients with symptomatic or progressive myeloma.
first transplant. With Total Therapy 1 performed at Arkansas
During the last five years, additional
in 231 patients, 40% achieved complete
new agents effecting salvage rates of
remission with an overall survival at 10
30% - 50% have been discovered and
years of 35%. The dominant adverse
patient outcomes improved.
prognostic feature was the presence of
cytogenetic abnormalities prior to
Standard Therapy for Myeloma
initiation of therapy, noted in one-third
Pursuit of dose intensity with
of patients. The two-thirds of patients
melphalan had markedly increased the
presenting
without
cytogenetic
frequency of complete remission and,
abnormalities enjoyed a 10-year survival
consequently, disease-free and overall
of 45%, compared to < 10% among
survival. The dose-limiting toxicity of
those with cytogenetic abnormalities.
melphalan as a hematopoietic stem cell-
damaging agent is irreversible bone
Salvage Treatment
marrow damage. A procedure commonly
At the time of disease progression, we
referred to as stem cell transplant can
distinguish between primary resistance
rescue patients from the harmful effects
(failure to respond to initial therapy)
of prolonged myelosuppression.
For
and relapse following at least partial
this purpose, patients' own peripheral
remission. In this latter setting, salvage
Bart Barlogie, MD, PhD
blood stem cells, collected upon
therapy may not have yet been
University of Arkansas for Medical Sciences
induction therapy with non-stem cell-
Myeloma Institute for Research and Therapy
performed (untested relapse), or may
toxic regimens such as VAD, are infused
Little Rock, AR
have been effective (sensitive relapse) or
back into the patient 24 hours after
ineffective (resistant relapse).
In
melphalan therapy, effecting rapid recovery of blood counts
planning salvage therapy, these issues have to be considered
with an average duration of neutropenia < 500/dL not
along with the duration of remission, the circumstances of
exceeding 7 days. As a consequence, treatment-related
relapse (whether or not it occurred during therapy), and the
mortality usually does not exceed 1% to 2%. In comparison
number of autotransplants the patient has received.
In
to standard-dose chemotherapy with melphalan
and
addition, marrow examination, especially for cytogenetics and
prednisone or combination therapies with additional
for evaluation of any normal marrow damage, and the
alkylating agents, a single melphalan 200 mg/m2-based
possibility of secondary myelodysplasia/early leukemia must
autotransplant has been shown to increase complete response
be considered. In anticipation of potential relapse after one
rates from < 5% to 25%, usually associated with extension of
or two autotransplants, there is a need for sufficient peripheral
event-free and overall survival by at least one year. Thus,
blood stem cell collection prior to the first transplant so that
despite similar total cumulative doses of melphalan with low-
all treatment options remain open for relapse management. In
dose chronic versus high-dose administration, the reduction
our case, we typically attempt to collect 20 million CD 34
of tumor burden is substantially lower with standard dosing
cells/kg body weight prior to first transplant.
due to ineffective cell kill, resulting in additional gene
mutations and further drug resistance.
Traditional salvage therapies include the VAD regimen,
dexamethasone pulsing, thalidomide alone or combined
While stem cell transplantation overcomes the harmful effects
with dexamethasone pulsing, or a highly effective regimen
of bone marrow damage inflicted by high-dose melphalan,
referred to as DT PACE, comprising dexamethasone,
other side effects have become dose-limiting, especially
thalidomide, and 4-day continuous infusions of cisplatin,
mucositis, or inflammation of mucous membranes such as the
adriamycin, cyclophosphamide, and etoposide.
lining of the mouth. In an effort to achieve further reduction
SEE LITTLE ROCK, PAGE 18
of myeloma tumor burden, we started applying two cycles of
800-452-CURE (2873)
5

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The Genetics of Multiple Myeloma
Prof. Hervé Avet-Loiseau
Finally, and probably most importantly, about half of the
patients present a loss of part or all of chromosome 13. This
Multiple myeloma is characterized by the abnormalityhasalsobeenrelatedtoapoorerprognosis,even
accumulation within the bone marrow of large
though the technique to use to identify it (classical
amounts of malignant plasma cells. This
cytogenetics or FISH) is still a matter of debate.
accumulation is responsible for the most common features of
the disease, like painful lytic bone lesions, or inhibition of the
What is the role of these specific chromosomal abnormalities in
normal hematopoiesis(1). However, despite these common
the occurrence and/or the evolution of multiple myeloma? This
characteristics, patients differ from each other in many
important question is so far unresolved, albeit some recent studies
aspects, including number of bone lesions, response to
have started to address this issue. The major related question is
treatment, or duration of response. These differences
whether multiple myeloma is a unique disease, or several diseases.
probably reflect heterogeneity(2) in the disease, heterogeneity
In other hematological malignancies, genetics have identified
that can also be recognized at the cellular or molecular levels.
novel entities, leading to adapted therapeutic strategies. Similar
implications can be envisaged for multiple myeloma. For
Extensive genetic lesions, both at the
instance,
the
two
major
14q32
chromosome and gene levels, characterize
translocations, t(4;14) and t(11;14), might
malignant plasma cells. Although most
identify two different forms of myeloma,
patients present with a large number of
possibly requiring different therapeutic
malignant plasma cells at diagnosis (up
approaches. The development of more
to 1,000 billion malignant cells),
global genomic analyses should enable
chromosomal analyses are still a difficult
investigators to further decrypt the disease.
art in multiple myeloma. Because
The recent use of microarray(7) technology
plasma cells are quiescent(3) rather than
has opened the door to a new
proliferant, and because cytogenetics(4)
understanding of diseases, based on the
requires the passage through mitosis(5),
definition of pathological entities on
chromosomes are difficult to obtain in
molecular signatures. The analysis of large
myeloma cells. Despite these difficulties,
numbers of patients presenting different
several studies have shown that several
Professor Hervé Avet-Loiseau
forms of multiple myeloma should modify
Laboratory of Hematology
chromosomal patterns can be identified,
our knowledge of myeloma, and possibly
University Hospital
mostly based upon the ploidy(6) mode
Nantes, France
should modify the way to manage patients.
(i.e., the modal number of chromosomes),
and on a few specific chromosomal abnormalities. The first
In conclusion, multiple myeloma is probably entering a novel era,
classification distinguishes myelomas on the basis of the
the genetic era. The systematic evaluation of the chromosomal
number of chromosomes, i.e., 46 chromosomes or less
and gene aberrations should modify our view of the disease,
(hypopseudodiploidy), and more than 47 chromosomes
leading to individual disease-adapted therapeutic management. MT
(hyperdiploidy). These two categories represent about half of
the patients each, and seem to differ by several parameters,
TERMS & DEFINITIONS
including other chromosomal changes and prognosis; those
patients with hyperdiploidy presenting a better outcome.
(1) The normal production of peripheral blood cells.
Other important chromosomal rearrangements involve the
(2) Diversity, nonuniformity.
14q32 region. Such rearrangements are observed in 50% to
(3) A resting cell, not dividing, but not dying.
70% of the patients with myeloma, depending on the studies
(4) Study that relates the appearance and behavior of
and the techniques used. Although a wide variety of
chromosomes to genetic phenomena.
chromosomal partners have been described, two specific
(5) Cell division in which the nucleus divides into
translocations involving the 14q32 region are observed with
nuclei containing the same number of chromosomes,
a higher frequency: the translocation t(11;14) and the
all of which are genetically identical to each other.
t(4;14). This latter translocation is invisible using classical
(6) The number of sets of chromosomes within a cell
cytogenetics and requires other techniques like FISH
or organism.
(fluorescence in situ hybridization) or molecular techniques.
(7) Sets of miniaturized chemical reaction areas that
The identification of these chromosomal changes is
may also be used to test DNA fragments, antibodies,
important in order to define the prognosis of the patients,
or proteins.
t(4;14) being associated with a poor prognosis, whereas
Note: Prof. Avet-Loiseau is the recipient of 2001 and 2002 IMF
t(11;14) is associated with a longer survival.
Senior Grant awards.
6
www.myeloma.org

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Drug Resistance
OVERCOMING MULTIPLE MYELOMA DRUG RESISTANCE BY INHIBITING THE PROTEASOME
Robert Orlowski, MD, PhD
which is expressed at higher levels than normal in plasma
cells from many patients with myeloma. This protein is usu-
Therearemanydifficulthurdlestoovercomeinthe allyfoundinthemembraneofmitochondria,whicharethe
treatment of multiple myeloma, but one of the most
energy-generating organelles of cells. One of the ways that
important is a phenomenon called drug resistance
chemotherapy and radiation kills cells is by damaging mito-
(recently reviewed in (1)). Myeloma cells that have this
chondria and inducing them to release a protein called
property can evade the effects of many chemotherapy drugs,
cytochrome c into the cytoplasm, which then activates a
allowing them to survive and even flourish in the face of such
process known as apoptosis, or programmed cell death. Bcl-
treatment. The impact that such drug resistance can have on
2 is found in the membrane of mitochondria, and is thought
the outcome of therapy may be seen in many different ways.
to work against apoptosis by preventing the release of
Some patients have disease that, when it
cytochrome c. Cells that overexpress
is first treated with chemotherapy, does
Bcl-2 are resistant to a variety of thera-
not respond well, and occasionally may
pies used in multiple myeloma, includ-
even progress, which is sometimes called
ing anthracyclines like doxorubicin,
primary refractory disease. If this
alkylating agents like melphalan, and
happens, patients are usually switched to
also steroids like dexamethasone. Such
a different chemotherapy regimen,
overexpression can account for the
which hopefully is more effective. Other
resistance of myeloma cells to the first
patients have disease that responds well
therapy that they receive.
and may even enter a complete
remission, but after some period of time
Acquired Chemoresistance
the disease relapses, and they need
Another mechanism of resistance can
additional therapy. This usually occurs
be called acquired chemoresistance,
because a small fraction of the original
because it is not present in every cell
myeloma cells were resistant to
from the beginning, but appears in cells
Robert Orlowski, MD, PhD
treatment, and once the majority that
only after therapy has begun. An exam-
Assistant Professor of Medicine, Division of
were
sensitive
were
killed
by
Hematology/Oncology
ple of this is the so-called P-glycopro-
chemotherapy, the remaining resistant
University of North Carolina at Chapel Hill,
tein, which is not often found in myelo-
cells had room and space to grow.
School of Medicine
ma cells initially, but after some types of
University of North Carolina,
Finally, many patients receive several
chemotherapy its expression increases,
Lineberger Comprehensive Cancer Center
different treatments for their disease,
and may be seen eventually in all plasma
Leukemia, Lymphoma, and Myeloma Program
and may find that each successive
cells. The P-glycoprotein has a useful
regimen results in a briefer, and less dramatic benefit. One
normal function, which is to recognize toxic chemicals in the
reason that this occurs is that some of the resistance pathways
cell and, from its position in the cell membrane, to pump
are active against several drugs, and therefore myeloma cells
them out, thereby saving the cell from damage.
may survive therapy with one agent because a previous
Unfortunately, many of the chemotherapy drugs used against
therapy activated a resistance mechanism that blocks the
multiple myeloma are also recognized as being toxins by this
action of both. Fortunately, there are new ways emerging to
pump. By removing them from myeloma cells, the P-glyco-
overcome such drug resistance that may improve the
protein reduces the chances that the drugs will have their
effectiveness of myeloma therapy, but first let's look at the
intended effect. Cells that overexpress P-glycoprotein are
molecular mechanisms by which this whole process occurs.
resistant to drugs such as doxorubicin and vincristine. Such
overexpression can account for the ability of myeloma cells to
Inherited Chemoresistance
resist treatments that they haven't previously been exposed to,
In thinking about the mechanisms of chemotherapy resist-
because the P-glycoprotein acts against many drug classes.
ance important in myeloma, it is convenient to divide them
up into several categories. The first is inherited chemoresis-
Inducible Chemoresistance
tance, which is something that is present right from the
One last mechanism can be called inducible chemoresis-
beginning in the very first myeloma cell, and is passed down
tance, and is one of the more recently described ways that
to all of the cells that arise later. Sometimes this genetic
this process of resistance can occur. Chemotherapy drugs are
change may even contribute to the process of cancer forma-
SEE DRUG RESISTANCE, PAGE 20
tion itself. An example of this is the so-called Bcl-2 protein,
800-452-CURE (2873)
7

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Education Initiative
COLLABORATION BETWEEN THE IMF AND MILLENNIUM PHARMACEUTICALS, INC.
BENEFITS NURSING AND OTHER HEALTHCARE PROFESSIONALS AND PATIENTS
TheInternationalMyelomaFoundation(IMF)and Frequently Asked Questions for health professionals and
Millennium Pharmaceuticals, Inc., of Cambridge,
patients in addition to programs for CE credit for nurses
MA, the developer of VELCADE® (bortezomib)
and pharmacists.
Some of the programs currently in
for Injection, are collaborating on a national medical
production include a Video Roundtable of oncology
education program designed for oncology nurses.
nurses discussing their experience with VELCADE and
VELCADE is a new and novel agent approved by the
outlining expectations for nurses and patients involved in
FDA in May 2003 for the treatment of relapsed and
treatment. Case Studies, approved for CE credit, will also
refractory multiple myeloma patients.
be available on the website and on CD ROM. Topics will
cover real life situations in which health professionals
Through an unrestricted educational grant provided by
have opportunities to address the concerns of patients
Millennium, the IMF is developing a multifaceted
suffering from multiple myeloma.
approach to reach as many health professionals as
possible. The initiative
The Speakers Bureau is made
includes
a
series
of
up of experienced oncology
The website, which will be accessed
accredited
Continuing
nurses who have received
Education (CE) programs.
special training to speak to
from the IMF website, www.myeloma.org,
These programs will include
professional and patient
will include a page of
roundtable discussions for
groups on the mechanism of
oncology nurses delaing
proteasome inhibition, the
Frequently Asked Questions
with their clinical experience
safe
administration
of
for health professionals and patients
in treating patients with
VELCADE, and the best
VELCADE, frequently
in addition to programs for CE credit
way to advise patients on the
asked questions about the
management of symptoms
for nurses and pharmacists.
therapy, and case studies
associated with VELCADE.
around nursing issues. In
To
date,
hundreds
of
addition, nurse speakers are available to speak at support
practicing oncology nurses have been reached during programs
group meetings, and there will be presentations by
throughout the United States.
oncology nurses from key trial centers on the VELCADE
mechanism of action, clinical and safety data, and
In addition, a VELCADE Nurse-on-Call program is
additional educational information regarding strategies
available within the U.S. in all time zones, Monday
for effective patient management. Facets of the program
through Friday, 9 a.m. to 4 p.m. Six nurses with
will be available through multiple venues including the
extensive experience using VELCADE are available
IMF website, CD-ROM, support group meetings, and
through this service to answer questions from other
Patient & Family Seminars.
nurses about their concerns in administering VELCADE
and to share their experiences in managing side effects.
A listing of these initiatives will be featured on a web-
Nurses calling outside the staffed hours may leave a
hosted portal accessible through the IMF website at
message; they will receive a call back as soon as possible.
www.myeloma.org. In addition to educating health care
professionals and patients about the risks and benefits of
This educational initiative is unusually comprehensive
proteasome inhibition therapy, this exciting initiative
and innovative. From one-on-one conversations between
will also introduce new prospects for treatment and
oncology nurses, to education programs, to a continually
symptom management.
updated website, health professionals and patients alike
will be able to learn about the latest developments in
The website, which will be accessed from the IMF
treatment options for multiple myeloma. MT
website, www.myeloma.org, will include a page of
8
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Atiprimod
A NEW DRUG CANDIDATE IN EARLY-STAGE DEVELOPMENT FOR MYELOMA
Gary S. Jacob, PhD
which were used to facilitate the September 2003 filing of an
Investigational New Drug (IND) Application for Atiprimod
Theseareencouragingtimesforpatientswithmultiple totreatmultiplemyelomapatients.
myeloma. After three decades of clinical trial research
involving thousands of patients with multiple
Initial animal model studies with Atiprimod by SmithKline
myeloma, the last few years have seen encouraging
scientists showed that the drug lowers serum levels of
advancements in new therapies to treat the disease. New drugs
interleukin 6 (IL-6) and tumor necrosis factor (TNF). Because
such as VELCADE® (Millennium Pharmaceuticals, Inc.), the
IL-6 is generally recognized as the primary growth factor in the
proteosome inhibitor recently approved by the FDA, and
bone marrow environment driving multiple myeloma (Figure
antiangiogenic agents such as Thalomid®
1), Callisto Pharmaceuticals began to
and Revlimid® (Celgene Corp.) are
further explore development of Atiprimod
providing doctors with additional ways to
for treatment of this disease. These recent
treat the disease. Additionally, advances
exploratory and preclinical studies on
in our understanding of the basic biology
Atiprimod have been conducted at Dana-
underlying the course of this disease are
Farber Cancer Institute (Laboratory of Dr.
creating new targets for research scientists
Kenneth C. Anderson), at the University
to explore as new potential treatments. A
of Texas M.D. Anderson Cancer Center
number of drug candidates at various
(Laboratory of Dr. Zeev Estrov), and at
stages of clinical development are
Callisto's research laboratory in Princeton,
currently being evaluated as both
New Jersey. These studies demonstrate
cytotoxic agents and as treatment for
that Atiprimod inhibits the growth of
bone pain associated with the disease.
human multiple myeloma cells.
One of these drug candidates, Atiprimod
(Callisto Pharmaceuticals, Inc.), is just
Atiprimod's actual mechanism for
about to enter the clinic.
Gary S. Jacob, PhD
inhibiting the growth of human multiple
CEO, CSO
myeloma cells is unknown, although
Atiprimod has a very interesting history,
Callisto Pharmaceuticals, Inc.
scientists have been able to show that the
New York, NY
providing yet another example of a drug
drug turns on programmed cellular
candidate that begins its story as a
death (apoptosis) within these cells.
potential treatment for a wholly different disease indication.
Scientists also know that tumors need to support their growth
Other examples of this phenomenon include Thalomid®,
by stimulating formation of new blood vessels, a process
approved for the treatment of leprosy; ViagraTM (Pfizer Inc.),
referred to as angiogenesis (see Figure ). In cellular assays
originally developed as a cardiovascular drug and approved
Atiprimod has been shown to inhibit secretion of the growth
for erectile dysfunction; and even further afield,
factor that promotes angiogenesis, referred to as VEGF, and to
NutrasweetTM (aspartame), originally developed at G.D.
directly inhibit angiogenesis in a developmental blood vessel
Searle as a potential cardiovascular candidate before finding
model performed in chicken eggs.
its present use as an artificial sweetener.
Finally, a separate set of experiments initially performed by
In the case of Atiprimod, the drug was originally developed
SmithKline research scientists provides an additional
by SmithKline Beecham as a treatment for rheumatoid
potential benefit of Atiprimod to treat multiple myeloma.
arthritis (RA) and successfully completed three Phase l
Atiprimod was found to inhibit the action of human
clinical trials(1) in RA patients. These trials included single-
osteoclasts (white blood cells that break down bone) from
dose studies, one-month multiple-dose studies and an open-
dissolving bone in in vitro cellular assays of bone resorption.
label(2) extension study in which patients were on the drug for
This effect of Atiprimod appears to be selective against
as long as one year. The results of these studies showed the
osteoclasts, with little or no effect on the bone marrow cells.
drug to be well-tolerated at the administered doses, with no
observed dose-limiting toxicity. These Phase l clinical trials,
Loss of bone mass due to the effects of multiple myeloma is
along with an extensive preclinical package of data, were a
a common occurrence in this disease, and despite the advent
significant benefit to Callisto Pharmaceuticals, Inc.,
of new treatments, such as more potent bisphosphonates and
providing considerable clinical and preclinical safety data
SEE ATIPRIMOD, PAGE 19
800-452-CURE (2873)
9

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Cancer Research and Medicare: Political Pork?
Greg Brozeit
Pork barrel spending sums up how members of Congress
prioritize much of their political decision making process. In
Anominousclimateisdevelopingaroundthecancer mostcasesittranscendstraditionalorideologicalaffiliations.
community and threatening to stick around. But
Critics of pork often ignore the fact that patrons usually have
unlike the weather, everyone can talk about it and do
very sound reasons for support and approval of their projects.
something to change it. And change it we must, otherwise
we will have denied our children a legacy free of death and
A project in the home district or state translates into
suffering due to cancer.
something tangible: a known number of people--
constituents--who care enough about it which, in turn,
The end of the last appropriations cycle--with the lone
makes it a priority for them too.
exception of funding for the Centers for Disease Control
cancer programs--and the passage of the Medicare reform
That highway bridge that needs to be built to ease congestion
bill, represented potentially momentous setbacks for all
and create safe bypass zones for families and children also
current and future cancer patients.
creates jobs. This after-school community program which
takes kids off the street and reduces
Congress
and
the
administration
truancy and vandalism can improve
approved the smallest increases in recent
their in-school performance. And those
memory for medical and cancer research
scientific research projects on marine
funding. In the long term, this will result
parasites actually help the seafood
in the loss of hundreds of research grants.
industry in your town to provide more
plentiful supplies to benefit fishermen,
The new Medicare laws have lowered
cooks, and restaurant goers alike.
reimbursements for oncology drugs and
promise to lower other reimbursement
Of course, if that highway is built in a
rates within a year. Recent reports call
sparsely populated area and is named
into question if and how many off-label
after a congressman, many may call it
drugs for cancer patients will be covered
pork. Should that after-school program
Greg Brozeit
under the new prescription drug benefit
focus on recruiting kids through the use
scheduled to take effect on January 1, 2006.
of midnight basketball leagues and rap
music, some might be skeptical about why the federal
All of this comes at a time when congressional critics on the
government should support it. And those far-out projects
left and right have deplored the extent of pork barrel projects
looking into the mating behavior of coastal jellyfish might
contained in the most recent omnibus appropriations bill--
just seem like some sort of payoff for a well connected
the same legislation with only minor increases for cancer
university. It depends on your perspective.
research; increase that will be wiped out by cost of living
adjustments and obligated funds. Moreover, these cuts and
In other words, political pork, like beauty, really is in the eye
policy changes are coming at a time of unprecedented progress
of the beholder--or, to stick with the theme of this piece: the
in the development of genetically targeted drugs--arguably
eye of the constituent. Pork barrel spending is not always as
the greatest development in the history of cancer research.
bad as it is made out to be. Individual projects, duly
considered on their own merit, can withstand the charge of
The failure of the cancer community to win big victories last
being frivolous or inappropriate.
Moreover, there are
year both in the appropriations process and in the Medicare
members of Congress who are willing to go to bat for
reform bill must be reversed. The silver lining may be that
programs and promote alliances to assure funding for them.
these actions will motivate the cancer advocacy community
to be more vocal and reverse these trends.
The questions remain: How can we apply the rules of pork to
the cancer patient and family community? Is it possible for
PORK BARREL SPENDING: THE LORD'S WORK?
a critical mass within Congress to identify with the National
Institutes of Health, the National Cancer Institute, and
A former colleague of mine who served as director of a
Medicare funding in the same way that they do for public
senator's state projects used to introduce himself by saying:
works projects in their states and districts? How do advocates
"Some people say what I do for a living is pork barrel
work together to form a collective vision of cancer issues as
spending, but I like to think I'm doing the Lord's work."
accountable political pork?
SEE POLITICAL PORK, PAGE 26
10
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IMF Kicks Off 2004 Seminars with Florida Retreat
Stephen Robertson
OnJanuary23-25,IattendedmyfirstIMFPatient&
Family Seminar at the Wyndham Bonaventure in the
city of Weston just outside Fort Lauderdale, Florida.
For weeks prior to this weekend, I'd had the pleasure of
speaking to myeloma patients, family members, caregivers,
and support group leaders, as well as local Florida nurses and
physicians. As a new addition to the IMF family, I approached
my first Patient & Family event with a tremendous feeling of
excitement and anticipation. I wasn't disappointed.
Friday morning, as attendees began arriving at the Registration
Desk, I had the pleasure of meeting our invaluable board
members Mike Katz and Don Woodward, and Don's lovely
wife Annette. There was a
Suzanne Saletan, Dr. Robert Kyle, Rich Saletan, and Susie Novis
real sense of community and
represented. At the donor Recognition Dinner on Saturday
excitement
as
everyone
evening, Susie expressly thanked support group leaders
assembled to hear IMF
Chuck and Pat Koval from Madison, WI, Andy and Cathy
president and founder Susie
Lebkuecher from Atlanta, GA, and Ken and Mary Makowka
Novis welcome all the
of Wilton, CT. Representing the many local Florida support
attendees and introduce the
groups were leaders Vicki Anderson of Miami, Terry
retreat's
distinguished
Nalband of Palm Beach, John and Dorothy Russell of
faculty of Myeloma experts:
Inverness, and Jean and Bill Brady of Broward County/Fort
Drs. Brian Durie, Robert
Lauderdale.
Kyle, Maurizio Zangari,
Mohamad Hussein, and
Besides working tirelessly as
Lewis Mehl-Madrona.
Terry Nalband and Susie Novis
support group leaders, many
of those mentioned above
The topics covered by this renowned group over the next few
have also been staunch
days included Myeloma Overview, Initial Therapy,
supporters of IMF programs.
Transplantation, Novel Therapies, Supportive Care,
Susie and I (with the help of
Combination Drug Therapies, and Alternative Healing.
little Marisa Vaccaro) were
pleased to pay tribute to
As participants continued to arrive throughout Friday and
these IMFers along with Dr.
Saturday, I was delighted to at last meet long-time IMF
Don Flatt, Jim Kilma,
supporters Kerri and Anthony Marioni, who successfully
Martin and Kim Rubin,
Mr. & Mrs. Francis Abel
launched the Hair Cares member fundraiser, as well as Terry
Melvin Bernhaut, Joseph and Frances Spaid, Beth Morgan and
and Howard Herman, who helped turn the Mail For A Cure
Barb Baxter, Bob, Cindy and Melanie Feltzin, Scheri Tamlyn
campaign into a resounding success.
(in absentia), and Wendy and
Barry Breslow. Speaking of
At Friday evening's Cocktail
Wendy Breslow, we're very
Reception
and Welcome
pleased that she has kindly
Dinner, I finally got to meet
agreed to be on the Steering
IMF board member Rich
Committee for IMF Gala in
Saletan and his wife Suzanne,
November. Again, we wish
as well as IMFers Joe and
to thank all our members,
Melissa Vaccaro and their
donors, and support group
adorable daughter Marisa.
leaders for their tremendous
generosity. Without you, the
Myeloma support groups
IMF would not be able to
from all over the country
Dr. Don Flatt attends his 8th
Dr. Mohamad Hussein
were
also
very
well
IMF Patient & Family Seminar!
SEE FLORIDA RETREAT, PAGE 24
800-452-CURE (2873)
11

---

Los Angeles Area Support Group Salutes Leader
Jackie Schwartz, PhD
gratitude, the tears of
appreciation rolled
Howcouldwedemonstrateourlove,admiration,and down her cheeks.
heartfelt appreciation for Janet, the founder of our
More gifts followed: a
group? This was the question that challenged our
big basket of fruit, spa
Support Group since Janet passed the baton in September after
gift certificates, plus a
the death of her dear husband, Art. By October we had
trip away for a deluxe
decided upon a plan. With the commitment of Dr. Brian
spa weekend.
Durie and Susie Novis to speak at our January meeting, we
expected that this would lure Janet to attend. When Janet said
It was only when six-
"yes" to my seemingly casual invitation to attend the January
year-old Dempsey came
meeting, way back in October, we could then shift into action.
forward with her own
special gift for her
Our emphasis was to honor Janet, in ways that she would feel
grandma, that Janet
appreciated. We knew, too, that she'd be most gratified if we also
seemed to be aware
Janet Johnson with her award
honored Art. We put out the word to all of the members of the
that members of her
Support Group, inviting them to contribute to gifts for Janet
family had come to see and participate in this ceremony to
and a donation to the IMF in memory of Art. With everyone's
honor her. Janet's daughter, Janine, had been a valuable, wise
cooperation and generosity, it all came together beautifully!
resource during the planning phase.
Never late for a meeting,
Characteristically gracious, Janet wanted to emphasize the
Janet entered quietly
members' qualities, and she asked how many had been with her
and sat at the rear of the
at that first meeting in Marta Schwartz's (no relation) living
room. The meeting
room back in 1998. Many hands went up, and Janet told those
started according to
in the audience that they are the real heroes, who keep on
plan. Susie Novis and
fighting the good fight and living their lives as fully as they're
Dr. Brian Durie spoke
capable. Why shouldn't they? They have had Janet and Art as
of the growth of the
models, and despite the decline in Art's health over that last year
IMF and the progress
and his almost daily doctors' appointments, Janet persistently
being made in the field
carried the weight of being an unparalleled group leader.
of myeloma, inspiring
hope in the 96 group
Of course, we couldn't have had a celebration without food,
Janet Johnson and Jackie Schwartz
members in attendance.
so then we enjoyed a luncheon catered by a local chef and
sponsored by Novartis Pharmaceuticals. That was capped off
When they had finished their presentations, I asked Sheila
with a huge decorated cake from a local bakery.
Wilson and Susie Novis to come forward. Sheila presented
Susie $1000 in checks collected from members of the group.
We miss you, Janet, and at the same time, we recognize that
By the end of Sheila's remarks, noting that this money was
your moving on to new involvements makes absolutely good
given in memory of Arthur Johnson, I again took the
sense. You've closed the MM chapter of your life, and you're
microphone and asked his caregiver, Janet, to come forward.
on to new discoveries. The words on your plaque will, I'm
sure, describe your participation in whatever you do:
Some people squealed, "Oh, is she here?" As Janet walked
forward, the excitement in the room was palpable. By the time
With sincere appreciation to Janet Johnson
Janet got up to the front of the room, everyone in the room was
We honor you for your vision, caring, and dedication,
on their feet, clapping and clapping and clapping. Honestly, it
as founder and leader of our group,
was the kind of fervor usually associated with a political
from the Los Angeles Multiple Myeloma Support Group,
January 17, 2004. MT
convention. Janet kept asking people to sit down, and everyone
continued to stand, and clap, clap, clap. She managed to keep the
moisture in her eyes from rolling down her cheeks just then, but
Note: Dr. Schwartz
clearly, she was very touched by people's enthusiastic reception.
is the new facilitator
of the L.A. Area
I brought up the first gift bag, from which Janet retrieved a
Multiple
Myeloma
beautiful plaque. When she read the words revealing our
Support Group.
12
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---

IMFers Pay Tribute To Janet Johnson
On January 17, 2004, the L.A. Area
Janet is boundless, and I know that I am
Multiple Myeloma Support Group
not alone in that admiration. She has
hosted a farewell bash for Janet Johnson,
our thanks and our very best wishes for
the first leader of the support group.
the next episodes of her life.
Janet initiated the group and has
-- Nancy Sorrenti
planned and led the meetings for over
six years. Her beloved husband and
We first met Janet and Art in 1998. They
partner Art, videotaped each meeting
had taken on the leadership of the L.A.
despite his worsening myeloma over the
MM support group since its inception.
years. Janet was Art's loving caregiver
Janet was a great leader: dedicated,
and upon his death this past August she
always encouraging and uplifting, and all
felt that she had completed her mission.
Nancy Sorrenti, Sheila Wilson, and Susie Novis
the while in full control of the meetings.
When Art was not feeling well, and I know they both would
Almost one hundred people,
have rather been at home, they always came anyway. Janet had
including members of her
many innovative ideas that raised funds for myeloma research
family, Dr. Brian Durie, and
and brought recognition to our support group. It was nice to
Susie Novis, gathered to
see Janet receive the recognition she truly deserves.
honor Janet. There were
-- Mike & Regina Conti
tears and there was laughter.
We thanked Janet for all of
Janet
deserved
all
the
the tremendous work she
appreciation
and
praise
did during the past six years.
given her by those of us who
She gave her heart to us
have benefited so much
unstintingly and left an
from the dedication to the
exemplary model for us to
support group. Each person
follow as we continue the
in attendance has been a
L.A. Area Multiple Myeloma
beneficiary of her kindness,
Janet Johnson with Dr. Brian Durie
Support Group.
support, and encouragement.
She and Art worked so hard
Sisters Olga Beale and Dora Polk
About 3l/2 years ago, I attended my first support group
and saw to it that every
meeting, having recently been diagnosed with myeloma. I was
meeting was a meaningful educational and supportive experience
a basket case, ready to cry at the drop of an eyelash. Janet's
for each one who came. Even as Art's health was failing, he held
adeptness at leading the group became apparent to me
the video camera steady to record each meeting to stock the
immediately, and my extreme
library for people that hadn't been able to attend. Janet was the
anxiety eased. As the years
ultimate caregiver, not only to her husband, but to the rest of our
passed, her leadership has
group. She is an encourager, always admonishing everyone to
remained
something
to
"Never give up!" We'll miss you Janet and wish you well as you
marvel at, especially since she
go forward and have time to be with your grandchildren.
was Art's caregiver. Janet and
-- Don & Althea Channell
Art had four grandchildren
and they took full advantage
The tribute to Janet was truly an uplifting experience! We all
of bonding with them. Two
embraced this well-deserved recognition. The look on
more
grandchildren
were
everyone's face was a wonderful thing to see... especially
added, and Art was able to see
Janet's! It showed what the human spirit really means. We are
them both to his great delight.
proud to be members of this courageous organization.
We certainly know that the
-- Fred & Sheila Wilson
demands of caregiving can be
relentless, yet Janet always had
I met Janet and Art Johnson in 1998 when I attended my
an ear for those of us who
first L. A. Area Multiple Myeloma Support Group meeting.
needed someone to talk with.
Milo and Deedee Sutton
Janet was an extremely caring and supportive spouse and
caregiver. She was well-informed on all aspects of myeloma
It is our hope to continue on the high plateau she has laid out
for us with her dedication and hard work. My admiration for
SEE TRIBUTE TO JANET JOHNSON, PAGE 25
800-452-CURE (2873)
13

---

IMF Member Fundraisers
Suzanne Battaglia
H igh
Walk-A-
Thon in Lake
For14years,theIMFhasbeensuccessfulinservingthe
Arr o whead
on
myeloma community thanks to people like you, people
August 14th, while
who realize that if we're going to beat myeloma, each
her sister Robin
and every one of us touched by this disease needs to get
hosts an event in
involved! And, over the years, that's what's been happending.
Huntington Beach.
Many of you have joined the fight to end this disease,
contributing to the cause in a variety of ways--grand and
Such tremendous
small--and making a world of difference.
enthusiasm is truly
inspirational, and
Myeloma Today has been recounting these efforts: You've read
has in fact inspired
about a little girl who collected pennies, children who baked
other IMFers to
cookies and sold them door to door, and IMF members who
get involved. Lisa
held gala benefits, walks in the park, bike rides, musical
Doyle's
effective
concerts, garage sales, and a host of other fundraisers too
grassroots approach
numerous to name.
We're forever grateful to all of our
has motivated Susan
members who have pitched in to help the IMF help others.
IMF's Suzanne Bataglia with event organizer
Rocchio of Staten
Lisa Doyle at the Mile High Walk-A-Thon
Island, New York.
Your support of the IMF helps us fund research that brings
registration desk.
Now
Susan
is
us all closer to a cure. But there is still a lot of work to be
organizing a similar event in memory of her mother-in-law,
done. And, while I'm thrilled to report that 2004 appears to
Donna Rocchio.
be a banner year for member fundraisers, I'd like to ask all of
you to join our efforts. We need your help.
You can get
The IMF's most successful 2003 member fundraiser, "Fiesta
involved by creating your own fundraiser or by drawing
for a Cure," was held by Jerry Pransky at the beautiful
inspiration from other IMF members who have put together
Mountaingate Country Club in Bel Air, California. Truly a
some terrific events.
fun fiesta, the event was complete with great Mexican food
and Margaritas, not to mention the appearance of the Laker
In the last issue of Myeloma Today, we reported on the
Girls! The silent auction featured fabulous items including
wonderfully successful fundraiser that Lisa Doyle and her
desirable sports and entertainment memorabilia. Also on
family held last September in Lake Arrowhead, California.
hand was auctionaire extraordinaire April Brown, who led
The IMF Mile High Walk-a-Thon honored Lisa's dad, Ed
the spirited cash prize raffle. What better way to spend a
Davenport,
whose
Sunday afternoon than to have a great time and raise over
myeloma is now in
$50,000 in support of Bank On A Cure®! Jerry Pransky is a
complete remission.
true champion and is planning to hold the next "Fiesta for
To ensure that this
A Cure" at Mountaingate Country Club on July 25th. We
special event offered
invite you to join us for a wonderful afternoon of great food,
"something
for
fun, and prizes.
everyone," Lisa came
up with the great idea
From Coast to Coast IMFers are organizing events, and these
of
selling
penny
are only two examples of the fun and creative ways to raise
suckers for a dollar.
awareness about myeloma and much needed funding for
This simple, fun, and
research. If you have an idea for a fundraiser or would like
original
concept,
to find out how you can get involved in one of the IMF
along with the walk
events in your area, we are here to help you get started.
itself, raised over
$8,000 for myeloma
Here's to making 2004 another banner year for the IMF! MT
research! Flush with
last years success, Lisa
Note: Please contact Suzanne Battaglia or Stephen Robertson at
will offer double the
800-452-CURE (2873). You can also contact Suzanne at
fun this year, by
sbattaglia@myeloma.org and Stephen at srobertson@myeloma.org.
To view a calendar of upcoming IMF events, please go to page 4
holding
the
2nd
or visit www.myeloma.org.
IMFers in Arowhead Lake, CA
Annual IMF Mile
14
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---

I'm Not Leavin'
Michael Tuohy
Excerpt from I'm Not Leavin'
Music and Lyrics by Michael Tuohy, ©2003
Likeallmultiplemyelomapatients,Iwasshockedand
devastated when diagnosed. It was September of 2000.
Well, the road that I've traveled is mighty uncertain
I was 36 years old, with a 7-year-old daughter and a
Some things in life aren't ever justified
2-1/2- year-old-son. My wife Robin had given up her career
If I could hide all my feelings simply believing
as a paralegal to stay home and raise our children. I was the
All of my sorrow would fade away
family's sole breadwinner. Would I be there for them? I
wanted to teach my son to play baseball and to walk my
Well, I've been faced with tough decisions
daughter down the aisle. And, when the anger and fear
But for the first time in my life
subsided a bit, I realized that I needed my family to know that
I'm looking at the future with my eyes open wide...
I will fight the beast known as myeloma with every ounce of
my energy and with a positive attitude that I will be there for
I'm not leavin' I have too much left to live for
them. And
that
I'm not leavin' gonna fight for my life
along the way I will
I can deal with it ­ I won't let it take me down
do all that I can to
Feeling that my heart will heed the call
help others facing
There are so many reasons for me to believe that
myeloma.
I can take anything that comes my way
Robin searched the
I have too much to live for ­ and nothing to die for
web for resources
All of my dreams will reach their destiny
and found the IMF.
If I could ever find a way to turn back time
When Susie Novis
Would I even realize to see the light?
called and asked if
In my heart I know, while my faith still grows
we would like to
Waiting for that silver lining to unfold
go to Washington,
D.C., with the IMF
Michael, Mikey, Allie, and Robin Tuohy
Now I'm looking for answers to so many questions
to represent young
Yearning to live, is this a test for me?
patients with myeloma, we were all fired up to raise awareness
And I know I'm inspired by a spirit that's higher
and ready to urge our representatives to support much-needed
All of my dreams will reach their destiny
funding for research. That was in 2001, the year of the blood
cancer hearings in which Geraldine Ferraro told of her
Well I'm turning back my change of fortune
diagnosis. While in D.C., we met other myeloma patients for
Ready for a long hard ride
the first time. We came home more inspired than ever to be
lookin' at the future with my eyes open wide...
proactive in fighting the beast. With the help of the IMF, we
started the first myeloma support group in Connecticut.
I'm not leavin' I have too much left to live for
I'm not leavin' gonna fight for my life
I wrote a song for our two young children to help them to deal
I can deal with it ­ I won't let it take me down
with what I going through. After writing the song, I decided to
Feeling that my heart will heed the call.
donate it to the IMF as a way to not only generate funding for
myeloma research and education but also to create awareness
about the disease. I hope that the song will inspire others to
Praise for I'm Not Leavin'
fight, to be positive, and to be proactive in their journey with
I received the CD a couple of hours ago. Thank you so much! As
myeloma.
We are donating all proceeds to the IMF, an
first I played it, I burst into tears: a mixture of emotions rushed to my
organization staffed by the most wonderful and caring people
heart. Bravo, Michael! Your lyrics are the words that every human
for myeloma patients and their families, to help support the
being comes to speak one day. Your song makes me feel the courage,
IMF in their continuous efforts to find a cure for myeloma. MT
the strength, the thirst for understanding and acceptance, and at the
same time the celebration of life with all its ups and downs. Thank
Note: The CD is available through the IMF. It is priced at $10 plus
you again for the precious gift of your music!
postage. In the U.S., shipping fee is $1.06 via First Class Mail. If
you are located outside the U.S., please contact Kemo Lee of the
Lots of love,
IMF at klee@myeloma.org or 800-452-CURE (2873) and he will
Meena Annovazzi-Catellani
quote the delivery cost for your destination.
Torino, Italy
800-452-CURE (2873)
15

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News & Notes
IMF Supports Senator Hutchison Initiative
IMF Educational Materials In Japanese
The announce-
A new Japanese version of the IMF Concise Review has
ment made on
been translated and published by the Tokyo Representative
March 24th by the
Office of the IMF. To obtain a copy of this publication,
office of Senator
please email Ms. Ikumi Okubo at okuboikumi@nifty.com,
Kay
B ailey
call her at +81(426)24-9848, or fax her at +81(426)24-9864.
Hutchison (R-TX)
The Japanese version of IMF Patient Handbook is not yet
regarding funding
completed. However, the MM Handbook, the 256-page pub-
for the Geraldine
lication of the IMF Tokyo Representative Office, can be
Ferraro
Blood
ordered from Ms. Okubo.
Cancer Education
(l-r) IMFer Carol Klein,
Program at the
2003 IMF Honor Roll Omissions
NCI Director Andrew von Eschenbach,
Centers for Disease
Geraldine Ferraro, Sen. Kay Bailey Hutchison,
Control
and
Our heartfelt appologies to the Los Angeles Area Multiple
and IMF's Michael Katz and Susie Novis
Prevention (CDC)
Myeloma Support Group for not listing their generous gift of
was met with tremendous support by the IMF. We are inspired
$1,001-$5,000 in the 2003 IMF Honor Roll.
by the courage of Geraldine Ferraro in raising the awareness of
multiple myeloma and the leadership of Senator Kay Bailey
Austrian Multiple Myeloma Support Group
Hutchison to secure the financial resources needed for the edu-
Ilse Hein, myeloma survivor since 1992, is the current
cation of all people fighting cancer. The important potential of
support group leader of the Austrian Multiple Myeloma
the Ferraro program is also underscored by the support of One
Support Group. The group welcomes your inquiries and
Voice Against Cancer (OVAC), a 50-plus member cancer fund-
participation:
ing coalition, and the National Patient Advocate Foundation.
Selbsthilfegruppe fuer Multiples Myelom Oesterreich
We believe this program will foster the creation of new part-
Buerglsteinstrasse 21-10
nerships and models of outreach. This will empower all blood
5020 Salzburg
cancer patients and provide them with increased knowledge.
Austria
Multiple Musicians Against Myeloma
+(43) 664 1318838
myelom.shg@aon.at
IMFer Naomi Margolin is organizing the 2004 Multiple
www.myelom-selbsthilfe.org
Musicians Against Myeloma event. Some of Long Island's
best-known musicians and performing artists will gather on
Talk About Cancer With Children of All Ages
Sunday, June 11, 2004, for an all-day celebration to help
CancerCare, in collaboration with the Lance Armstrong
defeat multiple myeloma. Please join us for an unforgettable
Foundation, the National Cancer Institute, the Intercultural
evening at Tupelo Honey restaurant in Sea Cliff, NY. For
Cancer Council, Living Beyond Breast Cancer, and the
more information, please contact Naomi at 516-487-6712.
National Coalition for Cancer Survivorship, is presenting
Recipes for a Cure, Volume 2
Cancer Survivorship: Living With, Through & Beyond Cancer,
the 2nd Annual Cancer Survivorship Telephone Education
Sharon Klein and her twin sister, myeloma survivor
Workshop. Talking About Cancer With Children of All Ages
Marilyn Alexander, were the driving force behind our very
workshop will take place on Wednesday, April 14, from 1-2
popular cookbook. The project was a huge success and all of
p.m. (Eastern Time). The faculty will be Wendy S. Harpham,
the copies have sold out. Sharon and Marilyn are now com-
MD, FACP, Attending Physician, Department of Internal
piling recipes for the second volume of the cookbook. We
Medicine, Presbyterian Hospital of Dallas; Melissa Hicks,
invite you to help us with this project by contributing your
MS, CCLS, LPC, RPT, Child Life Specialist, Program
favorite healthy food recipes to this upcoming publication.
Director Camp Sunshine, President, Child Life Council, Co-
Please send your submissions to Marilyn Alexander at
Founder, Wonders & Worries, Inc.; David K. Wellisch, PhD,
alex19115@aol.com or 8913 Alton Street, Philadelphia, PA
Professor in Residence, Chief Psychologist Adult Division,
19115. Please include your name, city, state, and e-mail
Department of Psychiatry, UCLA School of Medicine,
address, along with the category that your recipe would fit
Department of Psychiatry. The workshop is free ­ no phone
into (Appetizers, Beverages, Breads, Desserts, Entrees, Pasta,
charges apply. To register, go to www.cancercare.org and
Salads, Soup, and Vegetables).
click on the CancerCare Connect icon.
16
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Letters
Dallas P & F Seminar: An Open Letter To The IMF
ASH 2003: An Avalanche of New Information
Dear Peter,
Just wanted to say that I found Dr. Duries's remarks very
That was a great letter and expresses how we all felt after a
useful. His summaries are very helpful and I will be looking
weekend with Brian and Susie, Mike, Greg, and staff... We
up many of the abstracts in the literature. Many thanks!
are all encouraged by the IMF and their support. Yes, we like
Jim Mutch
to see the advances in treatment, but we need to be carried
through the process. That is what the IMF does for us.
IMF Hotline
Thank you again, Peter, for expressing it so well.
Ann Waldmann
Dear Debbie & Nancy:
Many thanks to both of you for your caring guidance and
Dear Peter,
counsel. Words cannot express what your being there to
Thank you for your beautifully writ-
answer my many questions means. You
ten letter. You expressed the sentiments
always answer in a cheerful, positive and
of many of us who have been the recipi-
caring manner. Again, thanks.
ents of TLC from the International
The IMF website is great and pro-
Myeloma Foundation. My feelings of
vides much needed information to both
aloneness with multiple myeloma ended
patients and family.
And, the
when I found the IMF and all of its won-
"Management Guidelines" you sent me
derful staff, members, and volunteers.
answers many questions and provides a
Deborah Eller
concise analysis of the complete picture.
I am sending you photos taken at
Dear Peter,
bike rides this year. One was taken at a
I can only say 'amen' to what you have
50 mile ride... The pictures put a face
written (and wish I had your talent for
on the voice you talk to.
putting thoughts and feelings into words).
Robert Reeves (center)
Robert Reeves
with friend and daughter
Thank you for sharing this with us!
Cathy Lebkuecher
Dear Debbie,
I reconcile to the fact that the IMF is a true friend at all times.
BRAVO!!!
Your attention, concern, and cooperation enhances all the good
Very well said, and I second it. We here in Philadelphia
virtues that the IMF is doing in regard to the myeloma patients,
feel the same way and can't thank all the efforts of the IMF
worldwide. The paradigm "Until There is a Cure... There is the
enough! You are our true heroes!
IMF" is VERY true. Many thanks for your efforts, and to the IMF.
Marilyn Alexander
V.K.Varma, India
Wow, Peter! Wish I'd said that. Very nicely done. And so
IMF InfoPack
very well deserved.
Debbie Exner
Thank you for the information pack I received today. I
think it is so generous of you to provide them to anyone,
Dear Peter,
anywhere in the world. Thanks again and all the best for
Your letter brought tears to my eyes. What can I say--the
2004... The Year of the Cure!!
seminars are profoundly felt on both sides. It was an honor
Barbara Stewart, Australia
to meet you and Lucy, Marcia, and Jerry, and all the won-
derful members of the North Texas Support Group. The
The Myeloma Minute Email Newsletter
courage of myeloma patients and their families--what some
smart soul defined as their "grace under pressure"--is what
Just a special thank you for the newsletter email. It gave us
gives those of us at the IMF inspiration to work harder and
more information about the disease than we had been able to
find anywhere else. We hope that 2004 will bring new and
be better, in our jobs and in our lives. Thank YOU.
bright hope to all MM patients.
Debbie Birns
Jack and Wanda Wahus
800-452-CURE (2873)
17

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Little Rock -- continued
ADVANCES IN MYELOMA TREATMENT:
the treatment of myeloma, known as proteasome inhibitors.
THE PAST 10 YEARS
We are currently testing a combination of VELCADE plus
thalidomide for patients relapsing after melphalan-based
Prognostic Factors
autotransplants. Nearly 70% of more than 60 patients with
Several clinical factors have been linked to a poor prognosis
sufficient follow-up achieved at least a partial response at the
in patients with multiple myeloma.
The presence of
end of the third cycle of therapy, including nearly 20% who
cytogenetic abnormalities represents the most powerful
achieved complete remission.
adverse prognostic factor, present in one-third of newly
Other Agents. Arsenic trioxide is another treatment under
diagnosed patients with symptomatic disease. The hazard of
investigation.
This compound targets mitochondria, the
relapse and death with such chromosome abnormalities
energy power houses in our cells, and thus may be able to
increases by two- to three-fold.
initiate programmed cell death of myeloma cells.
Other
compounds under investigation by ourselves and others
New Agents
include monoclonal antibodies to interleukin-6 receptor and
Thalomid®. Thalidomide was only the third compound,
CD20, farnesyl transferase inhibitors, and STI 571 (Gleevec®).
behind melphalan and dexamethasone, to be recognized as an
independently active treatment for myeloma. One hundred
Immunotherapy
and sixty-nine patients who were enrolled in a clinical trial and
Interferon was the first biologically-based treatment for
received up to 800 mg of the drug per day had a partial
myeloma.
Randomized trials have revealed that patients
response rate of nearly 33% and extended event-free and
receiving interferon as maintenance therapy had slightly
overall survival. Thousands of myeloma patients have since
improved event-free and overall survival compared with those
benefitted from thalidomide treatment, which can be
receiving no maintenance therapy. Trials are also underway to
combined with chemotherapy because thalidomide does not
determine whether vaccinations that have been developed from
interfere with the bone marrow production of blood cells and
patients' myeloma cells may be another means of treating the
platelets.
However, 50-80% of patients treated with
disease. We have begun an exciting trial employing cancer testis
thalidomide can suffer from peripheral neuropathy, a
antigen peptide vaccination. These tumor-specific antigens,
condition in which the nerves are affected, causing pain,
not present on normal tissue except testis, are expressed in over
numbness, or weakness of the extremities. In some patients,
one-half of patients with myeloma, especially at the time of
reducing the dose of thalidomide or stopping the treatment
relapse in the high-risk setting of cytogenetic abnormalities.
altogether will alleviate the symptoms.
In a randomized
clinical trial of Total Therapy II, the 4-year estimate of grade 3
Mini-Allogeneic Transplants
or greater sensory neuropathy was 16% among 263 patients
Allogeneic transplants use stem cells from a donor, usually
receiving thalidomide and 5% among 280 patients receiving
from a matched sibling. Only 1 of 7 patients potentially
no thalidomide.
The combination of thalidomide and
benefit from allogeneic sibling transplant.
Major
dexamethasone as both induction therapy (given prior to
complications include graft-versus-host disease and
autotransplant-supported melphalan therapy) and as
opportunistic infections, which cause high first-year
maintenance therapy (given after melphalan therapy) is now
treatment-related mortality of about 50%.
However,
being examined by the Southwest Oncology Group (SWOG).
survivors of allogeneic transplants may experience fewer late
Revimid®. The thalidomide derivative, Revimid or CC-
relapses than survivors of autotransplants. The "mini-allo"
5013, can beneficially alter the patient's immune system and
transplant differs from the standard myeloablative regimens
kill myeloma cells both directly and indirectly by altering the
in that lower doses of conditioning treatment are employed,
bone marrow microenvironment. One-third of patients with
such as total body irradiation at 2 Gy or melphalan at 100 to
advanced and refractory myeloma respond with at least a
140 mg/m2 with or without fludarabine. Mini-allogeneic
50% reduction in measurable myeloma protein, typically
transplants are much better tolerated because of a virtual
associated with marked improvement or normalization of
absence of mucositis and other toxicities, resulting in a
bone marrow. Revimid is essentially devoid of neurotoxic
marked drop in treatment-related mortality, from
side effects but produces myelosuppression that is readily
approximately 50% with standard allotransplants to the
reversible, unless there is major bone marrow compromise
10%-15% range. In view of the marked efficacy of donor
from extensive prior alkylating agent therapy.
lymphocytes in killing recipient myeloma cells, and in cases
VELCADE®.
VELCADE has been shown to have
of cytogenetic abnormalities, we are offering this approach to
remarkable activity in patients with myeloma that has not
high-risk patients following maximum disease control
responded to other regimens, including thalidomide. Also
achieved safely with a single autotransplant (tandem
referred to as PS 341, this is one of a new class of agents for
auto/mini-allotransplant).
18
www.myeloma.org

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Atiprimod -- continued
Targeting the Bone Marrow Microenvironment
Myeloma cell survival depends on interactions with the
bone marrow "neighborhood," the microenvironment.
Thus, researchers have demonstrated that with treatment
targeting the microenvironment by way of 1) osteoclast-
inactivating bisphosphonates (Aredia or Zometa); 2)
disrupting myeloma-stromal cell interaction (thalidomide,
Revimid, VELCADE); or 3) inhibiting angiogenesis;
myeloma cells die and bone is preserved.
SUMMARY
Myeloma researchers agree that, in order to control multiple
myeloma, achieving a high frequency of complete remission
early in the management is important for long-term benefit.
Because of its potential for inducing a complete remission in
other methods of controlling the bone disease, the effects are
nearly half of our patients, autotransplant-supported high-dose
not totally abated, particularly in patients who relapse or
melphalan, especially in the setting of tandem transplants, has
become refractory (resistant) to chemotherapy.
The
emerged as a safe platform of treatment upon which
capability of Atiprimod to control bone resorption could
improvements can be anticipated by introducing thalidomide,
potentially provide a significant additional benefit in the
Revimid and VELCADE for remission induction prior to, and
treatment of multiple myeloma patients.
for maintenance after, autotransplants. Reduced melphalan
doses at 100 to 140 mg/m2 with autologous hematopoietic
Atiprimod is about to enter a Phase l/lla(3) clinical trial in
stem cell support have recently been shown to be effective and
relapsed multiple myeloma patients in March 2004. These are
safe in patients presenting with renal failure or advanced age (>
patients who no longer respond to chemotherapy and are in
70 years), so that the majority of patients with myeloma can
advanced stages of the disease. The Phase l/lla trial will be
now be offered this highly effective therapy. We recommend
performed at two sites, Dana-Farber Cancer Institute (Boston)
that all patients with newly diagnosed myeloma be considered
and M.D. Anderson Cancer Center (Houston), with Principal
for appropriately dose-adjusted high-dose melphalan with stem
Investigators Dr. Nikhil Munshi (Dana-Farber) and Dr. Moshe
cell support.
The discovery of active new drugs, the
Talpaz (M.D. Anderson). The trial is an open label study, with
immunomodulatory agents thalidomide and Revimid, as well
the primary objective of assessing the safety of the drug, and
as the proteasome inhibitor VELCADE, has given hope to
the secondary objective of focusing on evaluating early
patients with refractory end-stage disease. MT
indicators of efficacy (any responses in multiple myeloma
patients). The duration of this clinical study will depend on
Note: The International Myeloma Foundation is proud to present its
how well the drug is tolerated and on drug response, with final
second Robert A. Kyle Lifetime Achievement Award to Bart Barlogie,
results not available until the end of 2004. MT
MD, PhD, Professor of Medicine and Pathology, and Director of the
Myeloma Institute for Research and Therapy in Little Rock, Arkansas.
Dr. Barlogie is being honored for his outstanding body of work, both
TERMS & DEFINITIONS
clinical and research, in the field of myeloma. The IMF is giving this
award to recognize his tireless work to significantly improve care,
(1) Phase I clinical studies generally involve a small
treatment, and prognosis for many myeloma patients.
group of people who take the same drug but via different
methods of delivery or different dosages. The purpose of
The IMF's Robert A. Kyle Lifetime Achievement Award was
the study is to measure safety and dosage of the drug.
established to honor an individual whose lifetime body of work
(2) An open label trial is a clinical study where each
furthers the ultimate goal of finding a cure for myeloma. The
accolade is named for Dr. Robert A. Kyle, noted physician and
patient and doctor knows what each patient is
founder of the Myeloma and Related Diseases Research Group at
receiving as the study drug.
the Mayo Clinic in Rochester, Minnesota.
(3) Phase l/IIa studies combine a Phase I study, testing
the safety and dosage of a drug, with an early
The award will be presented at a dinner at the Peabody Hotel in
indication of drug response (efficacy) that is otherwise
Little Rock on May 8, 2004. For information on participating in the
typically not explored until a classic Phase II study.
evening or placing an ad in the Tribute Book being assembled in
Dr. Barlogie's honor, please contact Stephen Robertson by email at
srobertson@myeloma.org or by calling 800-452-CURE (2873).
SEE ATIPRIMOD, PAGE 26
800-452-CURE (2873)
19

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Drug Resistance -- continued
typically thought of as only killing cancer cells, but in fact
both phosphorylation of this protein and also cleavage into
they have many effects, and sometimes can actually activate
small fragments (5). This reduces the Bcl-2 level in cells, and
signals that promote the survival of cells. This can be a
likely makes them more susceptible to chemotherapy, which
desired outcome, because it may decrease the toxicity of some
accounts in part for the ability of bortezomib to induce apop-
drugs against normal cells, thereby minimizing side effects to
tosis independent of Bcl-2 status. With regard to the P-gly-
the patient. However, it can also be harmful, because if it
coprotein pump, studies have shown that function of the
promotes the survival of cancer cells then the drugs have
proteasome is needed for normal P-glycoprotein to be made
actually decreased their own effectiveness against the tumor.
(6, 7). When the proteasome is inhibited, abnormal imma-
In multiple myeloma one of the most important of these
ture forms of this protein accumulate which cannot pump
mechanisms is the so-called nuclear factor kappa B (NF-B). chemotherapy drugs from the inside to the outside of cells.
When activated, NF-B opposes apoptosis in a number of Since this results in greater levels of these drugs inside cells,
ways, one of which is by inducing a family of proteins called
it could enhance the ability of these drugs to kill myeloma
IAPs, or inhibitors of apoptosis. These proteins are able to
cells. Finally, in terms of NF-B, proteasome inhibitors work
slow the process of cell death stimulated by chemotherapy
at several steps of this pathway, and block both the ability to
and radiation by binding to proteins called caspases, which
make some parts of the NF-B transcription factor (8), as
are the catalysts that carry out the cell death program. NF-
well as its ability to move into the nucleus, where it activates
B is activated in cells treated with drugs that are active in
proteins such as IAPs that block apoptosis. Based on just
multiple myeloma, such as doxorubicin and melphalan, and
these findings alone, there would be excitement about the
also by other treatments, such as radiation. Since NF-B is possibility that bortezomib could enhance the anti-tumor
found in all myeloma cells, it can contribute to resistance to
efficacy of standard chemotherapy drugs used in myeloma
chemotherapy at every stage of the disease process.
Drug Synergy
VELCADE®
Even more optimistic are laborato-
The approval in May of 2003 of
Chemotherapy drugs are
ry studies looking at the ability of
the drug bortezomib (VELCADE®;
typically thought of as only killing combinations of drugs including
formerly known as PS-341) by the
bortezomib to kill myeloma cells. In
Food and Drug Administration after
cancer cells, but in fact they have the first pioneering work that showed
positive results against multiple
the promise of bortezomib against
many effects, and sometimes can
myeloma in Phase-I (2) and ­II (3)
myeloma in the laboratory (9), inves-
clinical trials was an exciting devel-
actually activate signals that
tigators were able to show that the
opment. This drug works by inhibit-
addition of steroids caused more cell
promote the survival of cells.
ing the proteasome, which is a large
death than either of the two drugs by
complex in cells that is responsible
themselves. This is called drug syner-
for removing damaged proteins, and also proteins that have
gy, and is not always found between drugs, because some
already served their purpose for the cell and are no longer
combinations will actually antagonize each other and cause
needed (reviewed in (4)). Bortezomib, made by Millennium
less cell death, possibly compromising their clinical efficacy if
Pharmaceuticals, was approved for treatment of patients who
they were tried in patients. Also, cells that had previously
have had at least two prior therapies, with progression of that
been resistant to steroids were once again able to be killed by
disease on the last of these. Its ability to induce a complete
these drugs when they were added in combination with
remission in 10% of patients, and either a complete or par-
bortezomib. Other drugs that are used in patients with mul-
tial response in 27%, was very encouraging (3). In addition,
tiple myeloma have been tested with similar results (10-12),
the drug was able to double the time to disease progression
showing synergistic cell killing, and also the ability to kill
in patients with multiple myeloma compared to whatever
previously drug-resistant cells. These studies included agents
had been their previous therapy. This is different than the
such as melphalan, doxorubicin, and immunomodulatory
usual trend with additional chemotherapy regimens for
analogs of thalidomide, and strongly supported the testing of
briefer durations of benefit, as described above. Perhaps most
such combinations in patients with multiple myeloma.
exciting about this drug, however, are studies that show
bortezomib can help to overcome all of the mechanisms of
VELCADE® Plus Melphalan
chemotherapy resistance described above.
Based in part on the laboratory studies described above,
several drug combinations either are being tested, or already
How VELCADE® Counteracts Drug Resistance
have been, with a focus on myeloma, one of which is the
Laboratory studies of cells that overexpress the Bcl-2 sur-
combination of melphalan and bortezomib (13). Melphalan
vival protein showed that exposure to bortezomib resulted in
is also called Alkeran®, and is made by Celgene Corporation.
20
www.myeloma.org

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In the most recent update of these results, presented at the
of patients had a complete response, and 57% had either a
December meeting of the American Society of Hematology
complete or partial response. Such responses occurred even
(ASH), Yang and colleagues showed the outcome in the first
in patients whose myeloma had deletion of chromosome 13,
15 patients treated. From a side effect standpoint patients
which is usually a poor prognostic sign that predicts a worse
tolerated the drugs well, probably due in large part to the fact
response to most therapies than patients without this cytoge-
that the first dose level used melphalan at 0.025 mg/kg,
netic abnormality. Finally, the response rate was reported to
which is one-tenth the dose used in the melphalan/pred-
be the same in patients receiving bortezomib at 1.0
nisone combination, and bortezomib was used at 0.70
mg/m2/dose and the lowest dose of thalidomide, 50 mg per
mg/m2/dose, or about one-half of the approved dose of 1.30
day, compared with those receiving higher doses up to 200
mg/m2. Ten patients had responses, including five with par-
mg of thalidomide daily. This is important because it sug-
tial responses, meaning that there was a 50% decrease in
gests that it might be possible to reduce the doses of the
measurable disease burden, and some of these included
drugs given to patients with comparable, or maybe even
patients who had previously received melphalan.
enhanced efficacy, and such reductions will make the drugs
better tolerated.
VELCADE® Plus Thalidomide
Another combination that has been studied is that of
VELCADE® Plus DOXIL®
thalidomide and bortezomib (14). Thalidomide is also called
The last two-drug combination that was presented at
Thalomid®, and like melphalan is also made by Celgene
ASH used bortezomib and pegylated, liposomal doxorubicin
Corporation. At the ASH meeting last December results
(15). This drug, better known as DOXIL®, is made by
from the first 56 patients treated were
Tibotec Therapeutics, and is a differ-
presented, all of whom had relapsed
Thus, it may now be possible to
ent preparation of the standard drug
after transplantation, and 81% of
doxorubicin. Pegylated liposomes are
whom
had
previously
received
overcome the resistance of
lipid bilayers similar to cell mem-
thalidomide, to which their disease
branes, and the doxorubicin is con-
myeloma cells and recapture
had become resistant. Zangari and
tained inside these structures. There
colleagues noted that the combina-
drug sensitivity, allowing the
are several advantages to this formu-
tion was well-tolerated, and while
lation compared with regular dox-
beneficial reuse of agents which
peripheral neuropathy was a frequent
orubicin. One of these is that
event, it generally was mild to mod-
would previously have not been
because the drug is released very
erate, and not severe. This is impor-
slowly from the liposomes, it can be
considered options for patients
tant because peripheral neuropathy is
given intravenously over one hour,
a known complication of both
because of prior exposure.
but stays in the body over a long
thalidomide and bortezomib by
period of time, similar to the effect of
themselves, and one concern about combining them would
a continuous infusion of doxorubicin like many patients
be that patients would have even more of this problem.
receive with the standard "VAD" regimen. Because of this,
Neuropathy is caused by damage to the nerves and can pres-
patients do not need either a central line for these infusions
ent in many different ways, including numbness, tingling,
of doxorubicin or an infusion pump, and instead can receive
burning, and pain, especially in the extremities, and some-
DOXIL® through a regular peripheral intravenous line. Also,
times can cause weakness and even impair the ability to per-
the drug appears to be less toxic to the heart than standard
form activities of daily living. If such symptoms occur
doxorubicin which, if given at a cumulative dose in excess of
patients and their healthcare providers generally choose
550 mg/m2, can cause a so-called cardiomyopathy, with
either to decrease the doses of the responsible drugs, or in
decreased heart function that in severe forms causes conges-
more severe cases to stop the drugs altogether. There are also
tive heart failure. In this study, which was done at our insti-
supportive care measures that can be used, such as supple-
tution, bortezomib was given as an intravenous bolus dose on
mentation with vitamins like B-complex, including B6, vita-
days 1, 4, 8, and 11 of a 21-day cycle in a range of doses,
min E, and folic acid, and also some prescription medica-
though the final study recommendation will be to start with
tions, like gabapentin (Neurontin) and Elavil. Neuropathy
1.3 mg/m2/dose. DOXIL® was given on day 4 about one
can improve over time once the drugs causing it are stopped,
hour after the bortezomib at a fixed dose of 30 mg/m2.
but the time course can be very long, and may take weeks to
Patients tolerated the combination well, and the side effects
many months. Also, since nerve tissue does not regenerate or
were those that would be expected if either drug were used
heal well, some patients may be left with a residual, perma-
alone. Side effects that were seen in at least 25% of patients
nent neuropathy. In addition to these findings on neuropa-
thy from this study, more impressive was the fact that 22%
SEE DRUG RESISTANCE, PAGE 22
800-452-CURE (2873)
21

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Drug Resistance -- continued
included fatigue, thrombocytopenia (low platelet count),
the combination of this same agent and bortezomib. This
nausea, constipation, anemia, neutropenia (low white cell
supports the possibility that bortezomib is able to overcome
count), decreased appetite, diarrhea, neuropathy, and
drug resistance. Also, the fact that some of these responses
mucositis, or mouth sores. Responses with at least a 50%
occurred at doses that were less than what would be
reduction in disease burden were seen in 73% of patients,
considered standard is encouraging. If lower doses can be
with 36% having a complete response. Of particular interest
used, side effects will be decreased, and more people will
is that there were 13 myeloma patients on the study who had
hopefully benefit from therapy because fewer patients will
previously received either standard doxorubicin or DOXIL®
need to stop treatment due to drug-related toxicities.
itself, and whose disease had either progressed despite this
therapy, or at best not responded and remained stable. Out
What This Means to You
of these 13 there were complete responses in 5 and partial
What does all this mean for patients with myeloma, their
responses in 3, suggesting that bortezomib was indeed able to
families, and their health care providers? First of all, these
reverse resistance to doxorubicin in at least some of these
combination regimens will be tested in additional trials, and
patients. Also encouraging is the fact that of the two patients
by enrolling in these studies patients can have access to cut-
who went on to transplant after this treatment, both were
ting-edge medicine using drugs that are known to have ben-
able to have good numbers of stem cells collected, suggesting
efits against multiple myeloma. Only by doing such studies
that this combination does not damage stem cells and does
and collecting and analyzing the data will we be able to know
not close the door to later transplantation.
which combinations work best and, possibly, which regimen
is better for which type of myeloma patient. This may lead
Avenues for Further Research
ultimately to the ability to predict ahead of time which ther-
All of these studies have so far been done only at single
apy would be best for each patient as an individual. For those
institutions, and the number of patients treated has been
patients who do not have access to such trials, however, since
modest, so larger trials done at many centers will be needed
all of these drugs are FDA-approved, it is possible to receive
to confirm these preliminary results. Several such studies are
this therapy without enrolling on a clinical study. While
already being planned, and hopefully some of the results will
these regimens will probably not be the cure for multiple
be available soon. None of the combinations have yet been
myeloma, they may represent a new concept in the treatment
tested head-to-head in a randomized fashion, which is the
of this disease. In the older paradigm, patients were treated
best way to compare them directly, so it is not possible to
with certain drugs, but once their disease no longer respond-
know which is better, or if one is better for some patients
ed that drug was never reused, because the myeloma cells
while others may benefit from another. Other two-drug
retained their drug resistance to that agent by passing those
combinations based on bortezomib are being tested as well,
genetic characteristics on to their progeny. With the avail-
including one trial of the thalidomide analog CC-5013,
ability of drugs such as bortezomib, which seems able to
which is also known as RevlimidTM, and made by Celgene
overcome such resistance, this treatment paradigm may need
Corporation. Finally, some investigators are looking at three-
to be changed. Patients whose disease was resistant to
drug combinations, hoping that there would be a further
thalidomide or doxorubicin were able to have significant
improvement in efficacy. Thus, there certainly remains much
responses to these agents in combination with bortezomib, as
work to be done in this area. Also, it should be pointed out
noted above. Thus, it may now be possible to overcome the
that there are many other agents being studied that also may
resistance of myeloma cells and recapture drug sensitivity,
be able to overcome drug resistance in multiple myeloma.
allowing the beneficial reuse of agents which would previ-
One good example is oblimersen, or GenasenseTM, being
ously have not been considered options for patients because
developed by Genta Incorporated, which is an anti-sense
of prior exposure. As a result, the number of treatment
oligonucleotide that decreases levels of Bcl-2 protein.
options available to patients may be dramatically increased,
which is the next best thing to a cure. Furthermore, the
However, there are many encouraging results that have been
enhanced complete response rates suggests that such combi-
obtained so far from the bortezomib studies described above.
nations will improve survival, and ultimately may form part
The overall and complete response rates of some of the
of a multidisciplinary approach that will bring us closer to
bortezomib-based combinations appear to be higher than
the cure for this disease. MT
what would be expected with either bortezomib alone, or
with the standard chemotherapy agent alone. This supports
References
the possibility that the drugs are acting synergistically to kill
1. Yang, H. H., Ma, M. H., Vescio, R. A., and Berenson, J. R.
myeloma cells. Some patients with disease that was
Overcoming drug resistance in multiple myeloma: The emergence
previously resistant to the standard chemotherapy have had
of therapeutic approaches to induce apoptosis. J Clin Oncol, 21:
significant responses, including many complete responses, to
4239-4247, 2003.
22
www.myeloma.org

---

2. Orlowski, R. Z., Stinchcombe, T. E., Mitchell, B. S., Shea, T. C.,
10. Mitsiades, N., Mitsiades, C. S., Poulaki, V., Chauhan, D.,
Baldwin, A. S., Stahl, S., Adams, J., Esseltine, D. L., Elliott, P. J.,
Richardson, P. G., Hideshima, T., Munshi, N. C., Treon, S. P., and
Pien, C. S., Guerciolini, R., Anderson, J. K., Depcik-Smith, N. D.,
Anderson, K. C. Apoptotic signaling induced by immunomodulatory
Bhagat, R., Lehman, M. J., Novick, S. C., O'Connor, O. A., and
thalidomide analogs in human multiple myeloma cells: Therapeutic
Soignet, S. L. Phase I trial of the proteasome inhibitor PS-341 in
implications. Blood, 99: 4525-4530, 2002.
patients with refractory hematologic malignancies. J Clin Oncol,
20: 4420-4427, 2002.
11. Ma, M. H., Yang, H. H., Parker, K. M., Manyak, S., Friedman,
J. M., Altamirano, C. V., Wu, Z. Q., Borad, M. J., Frantzen, M.,
3. Richardson, P. G., Barlogie, B., Berenson, J., Singhal, S.,
Roussos, E., Neeser, J., Mikail, A., Adams, J., Sjak-Shie, N.,
Jagannath, S., Irwin, D., Rajkumar, S. V., Srkalovic, G., Alsina, M.,
Vescio, R. A., and Berenson, J. R. The proteasome inhibitor PS-341
Alexanian, R., Siegel, D., Orlowski, R. Z., Kuter, D., Limentani, S.
markedly enhances sensitivity of multiple myeloma tumor cells to
A., Lee, S., Hideshima, T., Esseltine, D.-L., Kauffman, M., Adams,
chemotherapeutic agents. Clin Cancer Res, 9: 1136-1144, 2003.
J., Schenkein, D. P., and Anderson, K. C. A phase 2 study of
bortezomib in relapsed, refractory myeloma. N Engl J Med, 348:
2609-2617, 2003.
12. Mitsiades, N., Mitsiades, C. S., Richardson, P. G., Poulaki, V.,
Tai, Y.-T., Chauhan, D., Fanourakis, G., Gu, X., Bailey, C., Joseph,
4. Voorhees, P. M., Dees, E. C., O'Neil, B., and Orlowski, R. Z. The
M., Libermann, T. A., Schlossman, R., Munshi, N. C., Hideshima,
proteasome as a target for cancer therapy. Clin Cancer Res, 9:
T., and Anderson, K. C. The proteasome inhibitor PS-341
6316-6325, 2003.
potentiates sensitivity of multiple myeloma cells to conventional
chemotherapeutic agents: Therapeutic applications. Blood, 101:
5. Ling, Y. H., Liebes, L., Ng, B., Buckley, M., Elliott, P. J., Adams,
2377-2380, 2003.
J., Jiang, J. D., Muggia, F. M., and Perez-Soler, R. PS-341, a novel
proteasome inhibitor, induces Bcl-2 phosphorylation and cleavage
13. Yang, H. H., Swift, R., Sadler, K., Vescio, R., Adams, J.,
in association with G2/M phase arrest and apoptosis. Mol Cancer
Schenkein, D., and Berenson, J. R. A phase I/II trial of VELCADE
Ther, 1: 841-849, 2002.
and melphalan combination therapy for patients with relapsed or
refractory multiple myeloma. Blood, 102: 235a, Abstract 826,
6. Loo, T. W. and Clarke, D. M. Superfolding of the partially
2003.
unfolded core-glycosylated intermediate of human P-glycoprotein
into the mature enzyme is promoted by substrate-induced
14. Zangari, M., Barlogie, B., Jacobson, J., Rasmussen, E., Burns,
transmembrane domain interactions. J Biol Chem, 273: 14671-
M., Kordsmeier, B., Shaughnessy, J. D., Anaissie, E. J., Thertulien,
14674, 1998.
R., Fassas, A., Lee, C.-K., Schenkein, D., Zeldis, J. B., and Tricot,
G. VTD regimen comprising Velcade (V) + thalidomide (T) and
7. Loo, T. W. and Clarke, D. M. The human multidrug resistance P-
added dex (D) for non-responders to V + T effects a 57% PR rate
glycoprotein is inactive when its maturation is inhibited: Potential for
among 56 patients with myeloma relapsing after autologous
a role in cancer chemotherapy. FASEB J, 13: 1724-1732, 1999.
transplant. Blood, 102: 236a, Abstract 830, 2003.
8. Palombella, V. J., Rando, O. J., Goldberg, A. L., and Maniatis,
15. Orlowski, R. Z., Voorhees, P. M., Garcia, R. A., Hall, M. D.,
T. The ubiquitin-proteasome pathway is required for processing the
Lehman, M. J., Johri, A., Humes, E., Adams, J., Esseltine, D. L.,
NF-kappa B1 precursor protein and the activation of NF-kappa B.
Gabriel, D. A., Shea, T. C., Van Deventer, H. W., Mitchell, B. S.,
Cell, 78: 773-785, 1994.
and Dees, C. Phase I study of the proteasome inhibitor bortezomib
in combination with pegylated liposomal doxorubicin in patients
9. Hideshima, T., Richardson, P., Chauhan, D., Palombella, V. J.,
with refractory hematologic malignancies. Blood, 102: 449a,
Elliott, P. J., Adams, J., and Anderson, K. C. The proteasome
Abstract 1639, 2003.
inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes
drug resistance in human multiple myeloma cells. Cancer Res, 61:
3071-3076, 2001.
Myeloma Today is available free of charge by subscription.
To subscribe to this quarterly publication,
please visit www.myeloma.org or call 800-452-CURE (2873).
800-452-CURE (2873)
23

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Florida Retreat -- continued
fulfill
its
mission
of
so many of this
education, research, advocacy,
event's participants
and support.
extended to me
and
the
entire
In talking with first-time
IMF team.
participants as well as those
who had attended IMF
On Sunday, many
seminars previously, it is
of
the
retreat's
very evident that no matter
attendees took the
how
many
of
these
opportunity
to
wonderful weekends one
participate in a
has been to, there is always
variety of special
Dr. Maurizio Zangari
new, pertinent information
activities:
yoga
Our littlest volunteer Marisa Vaccaro assists
available. But perhaps even more empowering than the
class,
nutrition
Susie Novis during award presention ceremony.
medical information you gain, is the knowledge that you are
class, and nature
not alone, that there are many, many others who share your
walk through the beautiful grounds. The weather was
experience
and
spectacular, truly Florida at its best, and these additional
who
understand
activities provided a really nice way to wind down the
what you're going
weekend.
The
through. We at the
group said their
IMF know this and
goodbyes
at
a
are committed to
farewell luncheon,
being there for you
having
tr uly
every step of the way.
benefited from
the memorable
I had heard what an
experience of the
opportunity these
retreat format of
seminars provide to
this particular IMF
The Feltzin Family
patients, caregivers,
Patient & Family
and health care professionals to interact and get the latest
seminar event.
information on myeloma in a supportive and empowering
setting. But actually seeing the invaluable benefits that
The appreciation
Ken and Mary Makowka with Susie Novis
individual patients derived from one-on-one consultations
and feedback that I
with our expert faculty members, as well as the extraordinary
continue to hear from everyone in attendance is phenomenal.
sense of community and support, is something I'll never
I have to admit, it touches me immeasurably to feel a part of a
forget. I truly was not prepared for the heartfelt gratitude that
foundation that provides a truly valuable service to those
affected by myeloma, and to be welcomed and acknowledged so
warmly by so many of those
at my first IMF event. I look
forward to attending many
more IMF events in the
future and look forward to
seeing familiar faces as well as
meeting more of our members.
Have a safe and healthy
2004 and remember:
"Until There is a Cure...
There is the IMF." MT
Note: Stephen Robertson has
joined the IMF staff as
patient and caregiver consult with Dr. Durie
Development Coordinator.
Joseph and Frances Spaid
24
www.myeloma.org

---

Tribute to Janet Johnson -- continued
and was a superbly well-
Few local support groups
organized leader of the
could possibly hope to
local chapter. Through the
have as a coordinator a
years, I became more and
person
such
as
Janet
more impressed with
Johnson. Her faithfulness,
Janet's leadership skills.
encyclopedic knowledge,
She worked hard to locate
common
sense,
and
a variety of speakers to
winsomness would be very
include doctors, nurses,
difficult to duplicate!
and myeloma patients.
-- Ralph D. Winter
Her constant strength and
her
positive
attitude
Janet and Art Johnson will
toward life while her
be greatly missed for all
husband was fighting
their tireless efforts to
cancer were admirable.
make the support group
Janet Johnson and Billy Ware
Janet and Art fought
what it is today.
Janet Johnson with Dempsey
together for as good a
-- Carrie Lacy
quality of life as was possible, regardless of the treatments Art
endured. She inspired us to do the same in our lives.
Thanks for the gift of Janet and Art,
-- Bob Brown
Stronger than granite in the heart.
-- Dora Polk
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25

---

Atiprimod -- continued
Political Pork -- continued
Note: Included in this article are "forward-looking" statements.
Newsweek columnist Robert Samuelson wrote an essay titled
Such statements are indicated by words such as "expect," "should,"
"Medicare as Pork Barrel" shortly after the Medicare reform
"anticipate" and similar words indicating uncertainty in facts and
bill was passed by Congress.
Rather than traditional
figures. Although Callisto believes that the expectations reflected in
definition
of
pork--highways,
bridges,
community
such forward-looking statements are reasonable, it can give no
programs, scientific research projects--Samuelson said the
assurance that such expectations reflected in such forward-looking
Medicare bill became a tool for satisfying a number of
statements will prove to be correct. Callisto's actual results could
constituencies with influence over lawmakers.
differ materially from those anticipated in the forward-looking
statements as a result of various factors.
The process behind the Medicare reform bill may
Callisto is a biopharmaceutical company primarily focused on the
provide a valuable lesson, but only if it can be linked to
development of drugs to treat multiple myeloma, other cancers, and
the real opportunities and probable outcomes of
osteolytic bone disease. Callisto's lead drug candidate, Atiprimod,
research. Policy makers must understand that unfulfilled
is a small-molecule, orally available drug with antiproliferative and
opportunities in research will literally cost tens--if not
antiangiogenic activity. In addition, Callisto has programs focused
hundreds--of thousands of lives over the course of the
on the development of an analog of the human intestinal hormone,
next couple of decades. MT
uroguanylin, to treat colon cancer, and drugs to protect against
staphylococcal and streptococcal bioweapons and as a protection
Note: For more information about how to become an effective
against the devastating effects of toxic shock syndrome.
advocate, please check regular updates in the IMF email newsletter,
The
Myeloma
Minute,
or
contact
Greg
Brozeit
at
Callisto has two operating subsidiaries, Callisto Research Labs, LLC
greg.brozeit@sbcglobal.net or 330-865-0046.
To subscribe to
and Synergy Pharmaceuticals Inc. For additional information, visit
The Myeloma Minute, please visit
the IMF's website at
www.callistopharma.com.
www.myeloma.org.

---

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