ANTHOLOGY II
Anthology of Articles of Continuing Interest
A PUBLICATION OF THE INTERNATIONAL MYELOMA FOUNDATION
Features
Introduction
Mechanisms of Drug Resistance
by Prof. Brian G.M. Durie
to show the complete remissions which can
in Myeloma: Why Does Therapy
sometimes be achieved in patients sensitive
Lose Its Efficacy?
Anthology II brings together a series
to melphalan therapy. In the early to mid
Page 2
of articles which continue to be of interest to
1980s, the group was also the first to show
Myeloma Today readers. In it, we profile four
that high dose melphalan therapy was not
Myeloma Today Profile:
IMF International Scientific Advisors as
curative, but can produce excellent quality
Prof. Heinz Ludwig
well as reprinting articles on six topics of
remissions.
Page 3
recurring interest.
· Dr. Meletios Dimopoulos
Myeloma Kidney:
PROFILES:
Alexandra Hospital
A Patient's Perspective
80 Vas. Sofias
Page 4
· Prof. Heinz Ludwig
Athens 11428 Greece
16, Monteleartstrasse 37
Dr. Dimopolous elected to return
Myeloma Today Profile:
Vienna 1171 Austria
to his native Greece to introduce newer
Prof. Ray Powles
Prof. Ludwig has been a pioneer in
concepts in the management of myeloma
Page 5
myeloma research in Europe. He has written
and related diseases. Dr. Dimopolous spent
a book on myeloma in German for central
many years working at M.D. Anderson
What Causes Myeloma?
European audiences and was the first to test
Cancer Center in Houston, Texas in the
Page 6
a series of biologic agents in the treatment of
group of Prof. Raymond Alexanian. He
myeloma. His paper in the New England
had a special interest in imaging tech-
Anti-Interlukin-6 Therapy in Myeloma
Journal of Medicine indicated the benefit of
niques, particularly the role of MRI in eval-
Page 6
erythropoietin (at the time a newly devel-
uating disease status in plasma cell disor-
oped genetically engineered body hormone;
ders. He has also had a particular interest
Myeloma Today Profile:
now commercially available as Procrit or
in Waldenstrom's Macroglobulinemia and
Dr. Melitios Dimopolous
Epogen) to trigger red cell production in the
was the first to introduce Fludarabine in a
Page 7
body. He showed this molecularly engi-
systematic fashion for the management of
neered compound to have dramatic benefit
this disease.
The Role of Adhesion Molecules
in improving the anemia of myeloma
in Myeloma
patients. Prof. Ludwig also pioneered the
· Prof. Douglas Joshua
Page 8
investigation of alpha-interferon as part of
Royal Prince Alfred Hospital
initial treatment as well as maintenance for
Missenden Road
A Randomized Trial of
myeloma, both as part of protocols involving
Camperdown NSW 2050 Australia
Maintenance Therapy with Intron-A
standard chemotherapy and, more recently,
Prof. Joshua is the most prominent
Following High Dose Melphalan
related to transplantation. These have been
myeloma researcher in the Asia/Pacific
and ABMT in Myeloma
among the best to show that alpha-interfer-
region. He trained with Prof. McClennan
Page 8
on can be helpful for a subset of patients
in the UK, then returned to Australia to
with myeloma, even at low dosage.
establish a research center for myeloma in
Myeloma Today Profile:
Sydney. As President of the Hematology
Dr. Douglass Joshua
· Prof. Ray Powles
Society for Australia, he has played an
Page 9
Royal Marsden Hospital
important role in education for myeloma
Downs Road, Sutton
and related diseases in the hematology-
Myeloma is Also a Bone Disease
Surrey SM2 5PT United Kingdom
oncology community. He has been active
Page 11
Prof. Powles has been a pioneer in
in promoting conferences for physicians
the use of high dose chemotherapy and
and has helped organize two IMF Patient &
transplantation in the management of
Family Seminars in Australia. It is very
myeloma. He worked with Prof. Tim
enlightening to hear Prof. Joshua's perspec-
McElwain in the development of the first
tive on the current and future trends in
studies using high dose melphalan as treat-
myeloma research and management.
ment for myeloma. This group was the first
Please see page 16

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MECHANISMS OF DRUG RESISTANCE IN MYELOMA:
The IMF
WHY DOES THERAPY LOSE ITS EFFICACY?
Founder
by Dr. Pieter Sonneveld
explanation for this observation is found in a
Brian D. Novis
protein present in the cell membrane. All
The hallmarks of myeloma treat-
cells in the human body have ways to elimi-
President
Susie Novis
ment are chemotherapy and radiotherapy.
nate toxic compounds, which are ingested
Over the last twenty-five years, many drug
with food. In the cellular membrane, a pro-
Vice President
regimens have been developed, varying from
tein is present to eliminate these molecules.
Amy Nielsen Palumbo
single agent oral therapy to intensive-combi-
This protein, named P-glycoprotein is also
Board of Directors
nation chemotherapy. Generally, patients
capable of pumping many cytostatic drugs
Chairman Dr. Brian G.M. Durie
with stage II or stage III multiple myeloma
out of the cell. In this way, the normal tis-
Dr. Kenneth Anderson
are initially treated with either oral melpha-
sues in the body protect themselves against
Michael B. Bell
lan plus corticosteroids, or a combination
drugs. In most myeloma cells P-glycoprotein
Brian Burns
regimen including doxorubicin, vincristine
can not be detected at diagnosis. However,
Mark DiCicilia
and steroids.
in myeloma, the amount of P-glycoprotein
Richard Funess
Michael S. Katz
With either regimen the chance to
in the cellular membrane has greatly
Dr. Robert A. Kyle
achieve a stable remission is approximately
increased in plasma cells isolated from the
Douglas M. Mancino
50%. Patients who fail initial therapy may
bone marrow at a stage of clinical refractori-
Dr. Gregory R. Mundy
respond to alternative regimens. The rea-
ness. Studies have shown that in such cells
John L. Salter
sons for refractoriness are poorly understood
the cytostatic drugs are eliminated much
E. Michael D. Scott
in most patients.
faster, even before the cellular functions are
R. Michael Shaw
Eventually, in all patients, signs of
interrupted. It has also been shown in the
Irv Skolnick
disease progression will occur, and therapy
treatment of other tumors, that increased P-
Donald B. Springer
should be reinstitut-
glycoprotein leads to
William Varnell
The reasons for refractoriness
ed. Although some
lower concentrations
Donald R. Woodward
are poorly understood
patients will respond
of many drugs.
Scientific Advisory Board
again to the initial
in most patients.
Therefore, this condi-
Chairman Robert A. Kyle, USA
treatment, this seems restricted to patients
tion has been named "Multidrug Resistance"
Raymond Alexanian, USA
with a long first remission. In many others,
(MDR).
Kenneth Anderson, USA
alternative regimens are more effective.
It should be emphasized however
Giuseppe Avvisati, ITALY
However, the proportion of responding
that MDR is not the only type of resistance.
Bart Barlogie, USA
Regis Bataille, FRANCE
patients is lower with each phase of disease
Using molecular techniques, other defects of
Meral Beksac, TURKEY
progression. The loss of responsiveness may
intracellular drug activation have been
James Berenson, USA
be the result of many variables, of which the
described and these may play a role in the
Daniel Bergsagel, CANADA
most relevant are a change of the disease
treatment of myeloma as well.
Joan Bladé, SPAIN
characteristics and the emergence of drug
Mario Boccadoro, ITALY
resistance.
MODULATION OF DRUG RESISTANCE
Y.C. Chen, REPUBLIC OFCHINA
Identifying drug resistance is now
J. Anthony Child, ENGLAND
DRUG RESISTANCE
an important tool in recognizing the pres-
Raymond Comenzo, USA
The mechanisms by which drugs
ence of therapy-resistant disease. Less effec-
Meletios A. Dimopoulos, GREECE
exert their cytotoxic activity to the myeloma
tive treatment and unnecessary toxicity may
Brian G.M. Durie, USA
cell may vary. The so-called alkylating
also be avoided, and a timely switch to alter-
Dorotea Fantl, ARGENTINA
Ian Franklin, SCOTLAND
agents like melphalan and cyclophos-
native regimens may be indicated. More
Gösta Gahrton, SWEDEN
phamide damage the DNA in the cell nucle-
recently, new ways to antagonize drug resis-
Jean-Luc Harousseau, FRANCE
us. Whether the cell survives depends on its
tance have been developed. In the case of
Vania Hungria, BRAZIL
ability to repair the DNA damage, which it
MDR, it has been shown that the action of
Douglas Joshua, AUSTRALIA
does with the help of several nuclear
P-glycoprotein can be blocked by several
Tadamitsu Kishimoto, JAPAN
enzymes. Other important drugs in myelo-
non-toxic drugs e.g., verapamil and
Heinz Ludwig, AUSTRIA
ma treatment are doxorubicin and vin-
cyclosporin. Through binding to P-glyco-
Ian MacLennan, ENGLAND
cristine. Doxorubicin is bound to DNA and
protein, these molecules render it ineffec-
James S. Malpas, ENGLAND
impairs its function. Vincristine inhibits
tive, and the sensitivity of the cells to dox-
Hakan Mellstedt, SWEDEN
cellular mitosis and duplication. All drugs
orubicin is restored. Presently, clinical trials
Angelina Rodriguez Morales, VENEZUELA
will lead to cell death, if sufficient concen-
are underway in several centers to investi-
Gregory R. Mundy, USA
Amara Nouel, VENEZUELA
trations are achieved. One would like to
gate if these agents can restore the initially
Martin Oken, USA
know why some cells react to either drug,
present sensitivity to chemotherapy in
Linda Pilarski, CANADA
while others do not. Recently one mecha-
patients who have become therapy-resistant.
Raymond Powles, ENGLAND
nism of drug resistance has been identified.
Other trials focus on the application of these
Jesus San Miguel, SPAIN
It has become clear that doxorubicin and
resistance modifiers at an early stage of the
Alan Solomon, USA
vincristine can be eliminated from drug
disease in order to avoid the emergence of
Pieter Sonneveld, THE NETHERLANDS
resistant cells at a higher rate than is
resistant cells. l
Benjamin Van Camp, BELGIUM
2
observed in sensitive myeloma cells. The

---

MYELOMA TODAY PROFILE: Prof. Heinz Ludwig
has the response been?
ease? Some physicians prefer that patients
Prof. Ludwig: The initial response has been
know it all while others feel less is best.
encouraging. Press releases were issued at the
Prof. Ludwig: This is a large responsibility that
time of the MRC's opening and I believe that
physicians have to deal with and the answer
they prompted myeloma patients to either tele-
depends on each individual patient. I feel it is
phone or to stop by for more information.
helpful if the patient can deal with all of the
information available and therefore be able to
MT: Do you feel there is a conflict of interest
work with his physician in deciding what treat-
in that patients are consulting with a physician,
ments are best for him. On the other hand, if a
other than their primary physician, concerning
patient is not able to cope with information
the treatment and management of their disease
then it is the physician's responsibility to make
at the MRC?
treatment decisions without the patient's input.
Prof. Ludwig: Yes, there is the potential for
Deciding how much a particular patient can
problems in that regard. In Europe it is some-
deal with is not accomplished by soley looking
thing like a
at laboratory results, but by
I feel it is helpful if the patient can
divorce for a
also trying to ascertain the
physician to lose a
deal with all of the information
patient's needs, thoughts,
patient to another available and therefore be able to work and general perceptions. It is
Prof. Ludwig
medical center. I
at this point that the physi-
Myeloma Today: What was it about multiple
with his physician in deciding what
am very careful at
cian's decision process
myeloma that intrigued you from the start of
this point, to keep
treatments are best for him.
becomes an art of sorts.
your career ?
my relationships with the patients who come to
Prof. Ludwig: Yes, I was very much interested
the MRC limited. I begin by providing them
MT: Have you ever worked in the U.S.?
in myeloma from the beginning. It is a disease
with basic information and advice. If a
Prof. Ludwig: Yes. I spent some time at the
of one of the most important cells of the
patient's disease seems to be being managed
Fred Hutchinson Cancer Center in Seattle,
immune system. My education began at the
well, if he has acheived remission, or if he is
Washington.
Institute of Immunology, (where?) therefore my
without symptoms and without complaints I
first experiences in medicine were in the area of
suggest that he stay with the physician and
MT: What was your main focus there?
immunology. I did my postgraduate work at
institution he is currently being treated at and
Prof. Ludwig: I worked in the bone marrow
the Institute of Immunology as well, and there-
to come back and see me in the case of any
transplant unit.
after studied at the Department of Medicine
problems.
where I was an internist. Of course, I had to
MT: What are your feelings on the subject of
run through all of the different departments,
MT: So, you are acting as a consulting myelo-
bone marrow transplantation?
which took time and distrated me from
ma specialist to patients who are already under
Prof. Ludwig: My feelings on allogeneic trans-
immunology. But, at the end of my formal edu-
the care of another physician?
plantation for myeloma have changed some-
cation I returned to work in hematology/oncol-
Prof. Ludwig: Yes. The goal of the MRC is not
what. Up until very recently there was hope
ogy and chose myeloma as my field of interest.
to draw patients away from their current physi-
that the malignant clone could be eradicated,
cians, but to provide the option for patients to
but we have learned that out of 162 patients
MT: How many years has it been now?
obtain additional
that have undergone allogeneic transplant only
Prof. Ludwig: It has
There was a time when I hoped that
information and
10 are without clinical signs of disease. Precise
been about 22 years. I
transplantation would be a great help to advice from physi-
methodology has been used on 6 of the 10
am presently the
cians who specialize
patients and has shown that half of them still
Director of the
myeloma patients, but the truth is that in the treatment
have malignant clones. However, even in light
Department of Medicine
at present the tools we have are not
and management of
of this new data, I am sure that there are some
and Medical Oncology
suffcient to obtain cures for patients.
multiple myeloma.
patients who benefit from an allogeneic trans-
at the
plant in terms of prolonged remissions. So the
Wilhelminenspital Der Stadt Wien in Austria.
MT: Patients in the U.S. are eager to become
real question is, who is the best candidate for an
We have several interests and are involved
as literate as possible about their disease. Do
allogeneic transplant? It is crucial that physi-
with a a number of trials focusing on the mono-
you find this to be true of European patients?
cians elect those, and only those, patients who
necrosis factor. We are also working with new
Prof. Ludwig: The American patient is much
will really benefit from this procedure. At the
hormonal agents, such as the new antiproges-
more informed and much more interested in
present there are no precise means available to
terone, RU46 (?), for use in treating breast can-
obtaining information about their disease and
do this. For other diseases, such as CML, allo-
cer. It is generally used by patients who have
the treatment centers that specialize in the
geneic transplant is still considered to be a good
responded to first line treatment.
treatment of that disease than the average
treatment approach, but it's effectivness for
European patient. This makes the American
myeloma is still open to question. Even if a
MT: Does RU46 hold any promise for the
patient more selective and always
We have to move to a higher
patient has a sibling
treatment of myeloma?
on the look out for the best treat-
donor it is a risky proce-
Prof. Ludwig: No, but one should keep in mind
level of research.
ments and treatment centers avail-
dure. If he decides to
that in the early fifties hormones were used to
able. The European patient is just beginning to
take his chances with the allogeneic transplant
treat myeloma and some myeloma's may
understand that mentality and it will take years
then he can hope to be in the small percentage
express hormonal receptors.
for it to fully develop. When that finally does
of patients who experience an extremely long
occur centers like the MRC will become
remission, what some call "cure", but he must
MT: The first Myeloma Reference Center
sought after by European patients.
know that there is the chance he could die
(MRC), a center with a special interest in the
from the procedure.
treatment and management of myeloma, was
MT: What do you feel is the amount of knowl-
opened in Vienna under your direction. What
Please see page 14
3
edge a patient can handle concerning his dis-

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The IMF is dedicated to improving the quality of
MYELOMA KIDNEY: A Patient's Perspective
life of myeloma patients while working toward
prevention and a cure.
by Ronald E. Merrill, PhD
of waste products produced by the body.
Creatinine should not exceed 1.1 mg/dL;
IMF Headquarters:
Kidney failure is one of the most
BUN not more than 19 (some labs use dif-
2129 Stanley Hills Drive
Los Angeles, CA 90046, USA
common complications of myeloma. About
ferent standards). Unfortunately, these tests
(800) 452-2873
50% of patients experience kidney problems
generally will not indicate trouble until sig-
Fax: (323) 656-1182
at some point in the course of the disease.
nificant kidney damage has occurred.
E-mail: TheIMF@myeloma.org
The kidneys excrete waste products
Healthy kidneys have a large safety
from the body into the urine. In the process,
factor; they are capable of processing about
IMF President:
they control the fluid balance of the body
ten times as much waste as the body normal-
Susie Novis
and maintain the proper levels of elec-
ly produces. So creatinine and BUN levels
trolytes in the blood. They also produce cer-
do not start to rise until the kidneys have
IMF Vice President:
tain hormones, including erythropoetin
been badly damaged and most of their func-
Amy Nielsen Palumbo
(EPO), which stimulates production of red
tion has been lost. Since kidney failure can
bleed cells.
appear rapidly ­ over a period of a few days ­
US Staff:
Suzanne Battaglia (slbattaglia@myeloma.org)
Researchers disagree about the
you can lose kidney function between blood
Romi Pfister (ripfister@myeloma.org)
cause of "myeloma kidney". It appears that
tests. However, usually there is at least some
Renee Rape (rlrape@myeloma.org)
the light chains of the myeloma M-protein
warning, except with rapidly progressive dis-
Ruth Lippmann
form complexes with other body proteins,
ease before myeloma is diagnosed or with
Carole Menacker
creating "casts" which clog up the tubules of
very aggressive relapse.
the kidneys. It has also been argued that the
Symptoms of kidney failure include
IMF (Philadelphia)
myeloma proteins are directly toxic to the
loss of appetite with nausea and vomiting,
2124 Mt. Vernon Street
kidneys. Hypercalcemia (high blood calci-
diarrhea, and lethargy and drowsiness.
Philadelphia, PA 19130
um level), which commonly occurs in
Obviously patients who are undergoing
(215) 236-0400
myeloma, may also damage the kidneys.
chemotherapy may expect these symptoms
Fax: 215-236-1400
The consequences of kidney failure
and not realize that they could indicate kid-
E-mail: anpalumbo@myeloma.org
are usually very serious. When the kidneys
ney problems! However, you should be alert
IMF (UK)
are not working, metabolic wastes build up
for problems with urination, and signs of
9 Gayfield Square
in the body very quickly. Moreover, the kid-
accumulation of fluids ­ especially swelling
Edinburgh EH1 3NT Scotland
neys are responsible for adjusting the level of
in the ankles or difficulty in breathing. If
(44) 0131-557-3332
potassium in the blood, and keeping it in a
you encounter such symptoms, get medical
Fax: (44) 0131-556-9720
narrow range. (The values 3.5-5.3 meq/L are
attention immediately. Hours count.
E-mail: myeloma@myeloma.org.uk
commonly used, but different clinical labs
Can myeloma kidney be prevented?
sometimes use slightly different standards).
There are some simple precautions the
IMF (UK) Executive Director:
Potassium plays a key role in maintaining a
myeloma patient can and should take. Most
Eric Low
regular heartbeat. When the kidneys fail,
important, beware of dehydration. Drink
potassium levels start to rise, until the heart
plenty of fluids ­ preferably around three
IMF (UK) Staff:
Christy Browne
simply stops. Thus kidney failure can result
liters per day. The kidneys, like a garbage
Susan Hamilton
in death within days.
disposal, are less likely to get clogged up if
Fortunately, kidney failure can be
the waste is washed down with plenty of
Myeloma Today is published quarterly by
treated. Hemodialysis, using an "artificial
water. You should also check that your med-
the International Myeloma Foundation.
kidney", can clean the blood and adjust
ications are not nephrotoxic (kidney-damag-
potassium levels. Nonetheless, kidney fail-
ing). Many antibiotics (e.g., gentamicin),
Editor:
ure is a major cause of death for myeloma
analgesics (especially non-steroidal anti-
Marya Kazakova
patients. Beyond the direct dangers, it can
inflammatories such as naproxen or ibupro-
interfere with treatment of multiple myelo-
fen), and contrast agents (used for X-rays or
The information presented in
ma. Many research protocols, especially for
MRI scans) are nephrotoxic. Sometimes use
Myeloma Today is not intended to
BMT, automatically exclude patients with
of nephrotoxic drugs is unavoidable, but you
take the place of medical care or the advice of
a physician. Your doctor should always be
kidney problems. Use of certain medica-
should at least be aware of the dangers.
consulted regarding diagnosis
tions, notably melphalan, may be limited
If prevention fails, you may still be
and treatment.
because the body can no longer excrete
able to recover some kidney function.
them. At minimum, kidney failure has a
Immediate use of a process called plasma-
WE WELCOME YOUR INPUT
major impact on quality of life. Commonly,
pheresis can remove much of the M-protein
Please send your comments and submissions
patients with severe kidney failure, who can-
from the blood, preventing or reducing fur-
for future issues of Myeloma Today to:
not make urine, are put on fluid restriction.
ther damage and giving the kidneys a chance
Your physician will track your kid-
to recover. Although myeloma kidney is
Marya Kazakova
ney function regularly using blood tests.
usually irreversible and there is no effective
The IMF
Normally the levels of creatinine and urea
treatment, in many cases the kidneys do heal
2129 Stanley Hills Drive
(blood urea nitrogen or BUN) are used to
by themselves, at least partially ­ sometimes
Los Angeles, CA 90046
judge kidney function. These compounds
in a few weeks, sometimes over several
E-mail: mkazakova@myeloma.org
are taken to represent the complex mixture
years. l
4

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MYELOMA TODAY PROFILE: Prof. Ray Powles
marrow transplant or peripheral blood stem
went into complete remission. And those
cell transplant has some sort of role to play.
results became the wonderful paper that Mac
Over the years, we have also entered data on
and I wrote. And what was lovely about
all these patients into our database. There
that was, I didn't know Mac was going to
are 10 million pieces of information in our
die. By the time we wrote that paper I said
database; high quality, prospectively gener-
to Mac, "don't let's have lots of authors on
ated, so we can always ask if we've got
this, just you and I write this." Send it in to
unusual situations occurring, if we have seen
Lancet. I just had a feel that it was going to
this before. The database is freely available
be pivotal. But of course it's something
to anybody who wants to use it. I get a lot
much more precious to me because Mac
of phone calls from people asking for second
died. I am so proud of that paper and it's
opinions and I frequently refer to the data-
very special. Mac died five years ago and it's
base. For example: someone might ask,
very sad. You can't take away from the bur-
"Have you ever seen bone marrow failure
den physicians carry, he was a wonderful car-
after a third transplant, or after such and
ing clinician, caring clinicians, you know,
Prof. Powles
such a treatment?" I can look at the data-
pay a price, and doctors have one of the
Myeloma Today: Please tell us a little about
base and I can say no, in 25 instances where
highest suicide rates of all professions. So
your background.
we've given that sort of program we've never
you always hear me talk about him. Mac was
Prof. Powles: I am a twin. My brother
seen bone marrow failure. So, it's a very use-
completely instrumental in designing, setting
Trevor and I were born in London. We
ful source of information.
up and organizing the interferon vs. no treat-
went to medical school in London and we
ment trial. The trial we are about to publish
both qualified in 1964. Then, we worked at
MT: We often hear Tim McElwain's name
is that after high dose treatment you give
St. Bartholomew's Hospital. We both
mentioned and I understand that you and he
interferon; see whether that has benefit.
became physicians, and Trevor became
worked together.
That was an entire year's program ­ a very
interested in endocrinology and I got inter-
Prof . Powles: Dear old Mac and I went up
imaginative, well organized controlled trial;
ested in immunology. That would be about
to medical school together; Trevor, Mac
actually it was Mac's trial.
the end of the sixties and then we sort of
and myself started the first Bart's bar, which
were looking, as you did in those days, for
has been in profit ever since and he was my
MT: What's been your experience in using
what areas would be interesting to work in.
oldest, oldest friend. I had a very large
high dose melphalan as a treatment?
Immunology was attractive from the point of
myeloma practice in the sixties; that was all
Prof . Powles: We've got a cohort of 195
view of cancer immunotherapy, and
to do with plasma exchange because we had
patients, who came in previously untreated
endocrinology was attractive, also from the
blood cell separators and all you were doing
under the age of 70 and we were able to first
point of view of cancer but in terms of bone
then was giving melphalan. People who had
of all look at their staging and we found they
disease, breast cancer and so on. So we both
hyperviscosity syndrome, you could sort of
were representative of what you'd expect
ended up working in cancer at the Royal
tide them over for a bit and within the twin-
demographically for the region. They are an
Marsden Hospital and with offices next to
kling of an eye I had one of the largest
ordinary group of patients, they're not select-
each other and now we even share a fax
myeloma practices in Europe. Then in
ed as they come to the Marsden. And with
machine. And if that's not enough, we look
about 1973/74 we began to be successful in
infusional chemotherapy (with C-VAMP
absolutely alike.
bone marrow transplantation in our
[similar to C-VAD]) what we found is that
leukemias, and I sort of gravitated more and
we were able to get a complete remission
MT: How do I know this is really you?
more to that. Then in 1981, I got a lot of
rate of about 20%. And it's creeping up.
Prof . Powles: The interesting thing is that
experience in the use of high dose melpha-
And we don't know whether it's creeping up
he dresses differently. He wears a white coat
lan as a single agent in hematological malig-
because we've got the cyclophosphamide in
and carries a stethoscope and you can't help
nancies. We had a great opportunity, which
there or whether you're getting better and
feeling that he might relate to the sort of
presents itself every so often, of a guy with a
harder and pushier at putting it in. But the
patient he's dealing with. We do, you see,
plasma cell leukemia. This patient's name
complete remission rate is now 20%, just
mold ourselves according to our patients'
was Ken. Ken came to me because of his
with five courses of C-VAMP, VAD, or call
images. And I tend to deal with younger
leukemia, (which turned out to be a plasma
it what you like. We now find that we can
people, particularly in leukemias, so I've sort
cell type) and it seemed that here was an
give some form of high dose treatment to
of molded that way.
opportunity to test using melphalan in a
over 70% of those 195 patients. So you are
myeloma type disease. We never had the
going to get the majority of the patients
MT: Please tell us about your bone marrow
opportunity before because we got people
through that first bit and 70%, the median,
transplant unit.
who lived three, four, five years. If you give
get some sort of high dose treatment. In
Prof . Powles: In fact, I'm actually head of
melphalan at the end of the disease, that's a
over 50% of them you can use high dose
myeloma and leukemia. We just happen to
disaster, and it takes a lot of courage to get
melphalan and you can also get an autograft
do bone marrow transplantation in there,
in there at the beginning, but plasma cell
(autologous) and the overall complete
but the basis of the unit is the disease, not
leukemia was that window of opportunity.
remission rate is better than 50%. Which of
the transplant. And so for every patient we
We treated that patient, and we treated him
course is astonishing, when you think of
transplant there are at least half as many
like a transplant, in isolation and so on.
comparison with acute myeloblastic
again that are not transplanted. I think
And he went into complete remission.
leukemias in 1980, that is a higher complete
that's pretty important because the disease
Then it was easy. We were able to treat
remission rate than we were seeing in acute
is, and has been for maybe 30 years, the basis
eight more myeloma patients, five of them
myeloblastic leukemia. Which was, of
of the running of the unit. At any rate, by
had never had any treatment before. We
course, in many respects the triumph of
having a large patient base, we can sort of
were able to show that we could get com-
hematology /oncology in the early 80's. The
decide whether a new treatment, like a bone
plete remissions. I think five of those nine
Please see page 10
5

---

WHAT CAUSES MYELOMA?
by Prof. Brian G.M. Durie
common (about half as common) in all
viduals working in and around nuclear facili-
Asian races, particularly Chinese. The
ties as well as radium dial factory workers.
Mostly we don't know what causes
genetic factors underlying the racial differ-
Other interesting associations include a past
myeloma. Occasional patients have a strong
ences are currently unknown. Likewise, for
history of allergies or treatment for allergies
history of radiation or chemical exposure or
the 104 cases of myeloma which has been
as well as a history of shingles prior to the
have a family history of myeloma. However,
reported in a total of 49 families, the cause is
onset of myeloma.
these situations are very rare. For the
unknown.
With such a diverse list of associa-
approximately 13,500 new myeloma patients
Despite our lack of knowledge
tions it is a truly daunting task to come up
each year in the United States there is no
about what causes myeloma in individual
with some theory that might link these vari-
obvious cause. Ignorance about the cause or
patients there have been a large number of
ous associations and identify a common fac-
causes of myeloma is not from lack of trying
studies looking at populations to see if any
tor that predisposes to the evolution of
to find clues about factors that may be
have an increased risk of myeloma. There
myeloma. Part of the problem is the identi-
involved. The most
have been 28 positive
fication of a specific chemical compound or
For the approximately 13,500
obvious factor is that,
associations between
group of compounds which are particularly
new myeloma patients each year
certainly until recently,
myeloma and various
dangerous. In many instances patients have
myeloma is predomi-
in the United States there is
agricultural occupations
been exposed to a variety of chemicals. For
nantly a disease of the
no obvious cause.
with a particular corre-
example, in evaluating the Vietnam experi-
elderly with an average age of approximately
lation with herbicide and insecticide expo-
ence and exposure to Agent Orange, there
65 years at the time of initial diagnosis.
sure. There have been 42 positive associa-
was indeed an association with the likeli-
This has suggested that as part of the aging
tions with non-agricultural exposures
hood of developing multiple myeloma.
process susceptibility increases, perhaps due
including a variety of chemicals such as
However, the association was primarily with
to a reduction in immune surveillance of
petroleum and petroleum derivatives, paints,
having been in Vietnam, rather that some of
evolving cancer or perhaps myeloma results
heavy metals, plastics, rubber industries, and
the specifics of exposure to Agent Orange
from an accumulation of toxic insults or
various dusts including asbestos. Patient
itself.
antigenic challenges over a lifelong expo-
occupations have included hair dressing and
We need to learn much more about
sure. Of interest, myeloma is approximately
cosmetology as well as individuals working
the processes or situations which result in
1.5 times more common in men as compared
in leather industries, industries involving
myeloma including co-factors or trigger fac-
with women. It is also approximately 2.5
wood products and also the textile indus-
tors such as emotional stress, immune stim-
times more common in blacks as compared
tries. There have, in addition, been associa-
ulation and viral infections. l
to non-blacks. Conversely, it is much less
tions with radiation exposure including indi-
ANTI-INTERLUKIN-6 (IL-6) THERAPY IN MYELOMA
treatment, 2 with evaluable data exhibited
for myeloma growth also in vivo.
by Drs. Bernard Klein & Regis Bataille
marked inhibition of plasmablast prolifera-
Suppression of CRP and worsening of
tion. Among the remaining six patients
thrombocytopenia both indicate that IL-6 is
Interleukin-6 (IL-6) is a critical
receiving anti-IL-6 for 11 to 45 days, com-
critically involved in acute phase responses
growth factor for human multiple myeloma
plete inhibition of C-reactive protein
and thrombopoiesis. Anti-IL-6 therapy is a
(MM) in vitro. There is excess production
(CRP) synthesis in three was associated with
novel therapeutic approach demonstrating
of IL-6 in vivo, and elevated serum levels are
objective antitumor effect in two patients
both cytostatic and cytotoxic antitumor
associated with high tumor proliferative
(decline in circulating plasmablasts by 86%,
effects even in terminal phases of MM.
activity and short survival. Preliminary
50% reduction in
Lack of sig-
good results in a patient with a plasma cell
...anti-IL-6 MAB, when administered in
myeloma cell mass).
nificant tox-
leukemia prompted us to perform a clinical
The three patients not
sufficient amounts to block IL-6-dependent icity and
trial with a murine anti-IL-6 monoclonal
achieving normaliza-
the associa-
antibody (MAB) in patients with advanced
production of CRP, can suppress the
tion of serum CRP lev-
tion of clin-
and rapidly progressive MM.
proliferation of myeloma cells...
els experienced rapid
ical antitu-
Nine patient with advanced and
disease progression. Anti-IL-6 was also asso-
mor effect with normalization of serum CRP
refractory MM, frequently with
ciated with resolution of low-grade fever in
levels justify clinical trials with anti-IL-6
extramedullary involvement (plasma cell
all the patients, but with aggravation of
MAB in patients with earlier disease stages.
leukemia, 5 patients; malignant pleural effu-
thrombocytopenia in 5 and mild neutrope-
Furthermore, there are now many
sion, 1; epidural involvement, 1), whose life
nia in 3 patients. Generation of human
new possibilities of neutralizing IL-6 which
expectancy was <1 month, were treated with
antibodies to murine anti-IL-6 MAB in one
could be investigated in MM, either alone
anti-IL-6 MAB, MAB were given intra-
patient was associated with dramatic relapse
or in combination. These include inhibitors
venously to 8 patients, on a daily basis for 4
from objective response.
of IL-6 production (i.e. steroids, other
to 45 days; the patient with malignant pleur-
These data demonstrate that anti-
cytokines like IL-4, IL-10, IL-13), inhibitors
al effusion received intrapleural therapy.
IL-6 MAB, when administered in sufficient
able to kill those cells expressing IL-6 recep-
Daily doses of MAB were chosen to provide
amounts to block IL-6-dependent produc-
tors (i.e. toxic IL-6) and inhibitors able to
high enough serum concentrations to inhibit
tion of CRP, can suppress the proliferation
compete with IL-6 for the binding of its
myeloma cell proliferation in vitro.
of myeloma cells and effect cytoreduction in
receptor (i.e. humanized anti-IL-6 or anti-
Of three patients succumbing to
vivo, underscoring the biological role of IL-6
IL-6 receptor MAB, mutated IL-6). l
progressive myeloma within one week of
6

---

MYELOMA TODAY PROFILE: Dr. Melitios Dimopolous
attending on the service at the same time. I
ment can be given during radiation treatment
became attracted to the disease mainly because
and we think that it may enhance even the
of my respect and admiration for his personality
effectiveness of radiation. Also it is probably
and achievement. So, in the next year of my
the single most active agent in the treatment of
fellowship, I had to decide where I was going to
myeloma since we have observed a 40%
work; where I was going to put my effort. I
response rate, which is even higher in patients
decided to join the myeloma section and work
with low tumor mass myeloma. The other very
with Dr. Alexanian.
interesting observation about high dose dexam-
ethasone therapy is that the majority of the
MT: What major myeloma projects were you
patients who are destined to respond, do so
involved in at MD Anderson?
within the first or at most the second course of
Dr. Dimoplous: At the beginning I focused on
treatment. So, after five or ten weeks at most,
salvage regimens for myeloma patients who had
we can separate the patient who will respond to
not responded or had progressed after VAD
that therapy and then give alternative therapies
based regimens. We evaluated the role of high
for patients who are not likely to respond.
dose glucocorticoids and VP-16 with growth
factor support and we obtained a 30 to 40%
MT: What do you mean by response?
response rate. Working with Dr. Alexanian, I
Dr. Dimopolous: At MD Anderson, we used
also evaluated the role of high dose dexametha-
slightly different response criteria. We consid-
sone as primary therapy in multiple myeloma
ered a response as 75% reduction of the
and we showed that this drug was very active in
immunoglobulin production and this should be
that setting. I was also interested in and
associated with almost complete disappearance
worked on further refinement and development
of the Bence Jones protein from the urine and
of high dose therapy with bone marrow or
with clearing of bone marrow plasma cells from
peripheral blood stem cell transplantation pre-
the marrow. But I think other response criteria
Dr. Dimopolous
ceding high dose chemotherapy for patients
are also valid as long as there is a consistency in
with myeloma in different phases of the disease.
the response criteria which each physician or
Myeloma Today: Please give us some back-
I helped Dr. Alexanian to illustrate from our
investigator uses for a particular patient or
ground information about yourself.
database the best category of disease and the
group of patients.
Dr. Dimopolous: I graduated from Athens
University Medical School in Greece in 1985
groups of patients that may benefit from such
high dose therapies. I also put a lot of effort
MT: And using this treatment regimen, what's
and subsequently completed an internship and
into defining prognostic factors for patients
the length of the response?
residency in internal medicine at the Royal
with sympto-
Dr. Dimopolous: We have shown
Victoria Hospital in Canada, McGill Medical
I believe that the answer,
matic myeloma
that the length of response and the
School. I moved to the MD Anderson Cancer
and also identify- and maybe the cure for myeloma, impact on overall survival is about the
Center in Houston, Texas in 1989, where I did
ing patients with
will not come from a singular
same as with more traditional thera-
a fellowship in hematology/oncology. In 1994,
asymptomatic or
pies such as melphalan and pred-
before I moved back to my native country,
therapeutic approach.
indolent myelo-
nisone. Most of the patients that were
Greece, I was appointed on staff as an Assistant
ma that were more likely to progress. We also
treated with high dose dexamethasone, when
Professor in the Department of Hematology.
focused on the assessment of magnetic reso-
they achieved a response, were maintained on
nance imaging (MRI), both in the staging and
low dose interferon. And although we have not
MT: Why did you select MD Anderson as the
the prognostic evaluation of patients with soli-
conducted a randomized study, we believe the
institution where to do your fellowship?
tary plasmacyromas and multiple myeloma.
remission duration and the overall survival for
Dr. Dimopolous: The MD Anderson Cancer
the dexamethasone treated patients is about the
Center is one of the major cancer centers in
MT: What was the dose regimen that you were
same as more conventional treatments.
the world. In 1989, when I had to make my
decision, I thought that MD Anderson would
using with dexamethasone?
Dr. Dimopolous: The dose regimen for dex-
MT: You were one of the first researchers to
give me more opportunities for clinical research
amethasone is 20 mg/ meters squared (typically
test Taxol in myeloma. Tell us about that.
because of the reputation of the researchers
30-40 mg. total) daily in the form of pills, day 1
Dr. Dimopolous: Taxol is an exciting agent
working there and the huge number of patients
through 4, and then we recommend that the
that over the last five years has shown signifi-
that were referred to that institution.
treatment is stopped for 4 days and then restart
cant activity in a variety of patients with solid
days 9 through 12 and then again after a 4 day
tumors, mainly ovarian cancer, breast cancer,
MT: How many myeloma patients do you
stop to repeat a final course days 17 through 20.
head and neck cancer. Thus in 1992, at MD
think are referred to MD Anderson?
These three, 4 day pulses of high dose dexam-
Anderson we asked permission from the
Dr. Dimopolous: It's hard to tell exactly, but I
ethasone are followed by a two week rest period
National Cancer Institute to design a study for
think probably more than 5,000 patients every
and then the same treatment is initiated again.
patients with early myeloma, essentially asymp-
year. As far as the myeloma clinic is con-
This treatment is usually well tolerated. We
tomatic myeloma, and to test the activity of a
cerned, we were seeing about 150 referrals of
recommend that patients take antacids, espe-
limited course of Taxol in those patients.
myeloma patients each year so it's probably one
cially if they have symptoms of gastritis.
Unfortunately, we were disappointed with
of the biggest myeloma clinics in the world.
Sometimes this treatment can be associated
Taxol because we observed a response of only
with some irritability and insomnia so we
15% in this good risk group of patients. This
MT: How did you first become interested in
administer a muscle relaxant or a mild sleeping
strengthened our belief that further new drugs
myeloma?
pill during that treatment. The beauty of this
should be tested in early phase myeloma
Dr. Dimopolous: During the first year of my
therapy is that it can be given to patients
patients in a setting where you can have a clear
fellowship there were rotations in different ser-
vices. During my rotation on the lymphoma-
regardless of their blood counts because it does
7
myeloma service, Dr. Raymond Alexanian was
not affect the bone marrow. Also this treat-
Please see page 12

---

THE ROLE OF ADHESION MOLECULES IN MYELOMA
by Prof. Benjamin Van Camp
ma cell as well as on the accessory cells in
(hyaluronate). Since fibronectin has been
the bone marrow. These signals are mole-
reported to be a strong cofactor of IL6, and
Although normal B cells circulate
cules with adhesive properties allowing the
malignant plasma cells synthesize
freely through the blood and lymphatic sys-
close cell-to-cell or cell-to-matrix protein
fibronectin themselves, a possible self-stimu-
tem, during the final differentiation towards
contact needed for specific cell homing or
latory loop might entertain continuous
becoming plas-
cytokine exchange.
growth. In contrast, the adhesion molecules
ma-cells they
This may be the reason why myeloma
The major adhesion
involved in the homing process of the pre-
"home" to the
cells remain confined to the bone mar- molecules can be sum-
cursor cell are not yet clearly defined. Most
bone marrow
marized in five groups
adhesion molecules described on malignant
row enviroment throughout the disease.
environment.
based on their molecu-
plasma cells are also present on normal or
Multiple myeloma (MM) represents a B cell
lar characteristics .
reactive BM plasma cells. This may be the
malignancy characterized by a monoclonal
Their binding counterparts (ligand)
reason why myeloma cells remain confined
proliferation of plasma cells. The striking
are often other adhesion molecules or an
to the bone marrow enviroment throughout
feature of MM is the property of the malig-
extracellular matrix protein. In essence,
the disease. In contrast, there is aberrant
nant plasma cells to reside and proliferate in
adhesion molecules are not cell specific and
expression of N-CAM (CD56) on malignant
the bone marrow. Therefore, MM can be
they function in synergy with cytokines or
plasma cells of most multiple myeloma
regarded as a model of nature to study the
other adhesion molecules.
patients. This adhesion molecule is known
final B cell maturation. On the one hand,
In our and other laboratories, the
to play a crucial role in neural development
circulating malignant precursor B cells will
adhesion molecule profile of myeloma cells,
and is not expected to be expressed on
home to the bone marrow, while on the
(the precursor cell as well as the malignant
haematopoietic cells. Analysis of N-CAM
other hand, functional interplay between
plasma cell) and BM stroma have been ana-
expression on a large number of patients has
the myeloma cells and the BM (bone mar-
lyzed. We are get-
frequent expression
row) stroma can enhance proliferation and
ting a clearer pic-
Future studies of adhesion molecules
of high density N-
plasma cell differentiation.
ture that shows us
CAM in myeloma,
in multiple myeloma may eventually
It has been shown that several fac-
that the anchoring
but not in MGUS
tors are involved in the homing process and
of the malignant
lead to novel therapeutic strategies.
(benign gammopa-
in growth support. A network of cytokines
plasma cell is
thy). In addition, the
(e.g, IL6, IL3, IL1b etc.) play a crucial role.
linked to its expression of VLA-4 (ligans):
loss of N-CAM expression in myeloma
However, their activity is guided by other
fibronectin and V-CAM-1), LFA-3 (CD-2),
signals present on the surface of the myelo-
syndecan (collagen) and CD44
Please see page 10
A RANDOMIZED TRIAL OF MAINTENANCE THERAPY WITH INTRON-A
FOLLOWING HIGH DOSE MELPHALAN AND ABMT IN MYELOMA
by Drs. D. Cunningham, R. Powles,
The patients have been followed up for a
remission and were randomized, beginning
J.S. Malpas, S. Milan, M. Meldrum,
median of 24 months and analysis is as of
in 1988 to receive or not receive alpha inter-
C. Viner, A. Montes, T. Hickish,
10/13/92. Overall, median progression-free
feron maintenance therapy.
M. Nicolson, P. Johnson, J. Mansi,
survival from HDM was 27 months in the
Even before the presentation itself,
J. Trolovan, J. Raymond, M.E. Gore
control group and 39 months in the Intron-
both CNN News and The Washington Post
A group (p<0.025). For the 62 patients who
carried reports indicating a major break-
High dose chemotherapy +/-ABMT
achieved CR with HDM, there was a signifi-
through in myeloma therapy. There was
produces a high response rate in multiple
cant prolongation of progression-free sur-
even more extensive press coverage in the
myeloma with up to 50% complete remis-
vival. Overall survival was also significantly
United Kingdom where the study was con-
sions. However, by and large, these remis-
longer for the Intron-A group, with one 1
ducted.
sions are not durable (median duration 18-
death vs. 6 deaths in the control group
The presentation was received
20 months). Recent data suggest a role for
(p<0.05). Toxicity from Intron-A consisted
favorably at the ASCO meeting and the
interferon-alpha in the maintenance of
mainly of flu-like symptoms, malaise and
study does represent the first randomized
plateau phase in multiple myeloma with a
skin problems. 11 patients stopped Intron-
study to show that alpha interferon mainte-
particularly marked effect in patients with
A, 5 of them because of toxicity which was
nance can prolong remission duration fol-
small volume residual disease. In view of
mainly malaise. Following intensive
lowing high dose chemotherapy with autolo-
this we have investigated the role of inter-
chemotherapy, Intron-A prolongs remission
gous bone marrow transplantation (ABMT)
feron-alpha as maintenance therapy follow-
and improves survival in myeloma. The
support. Although this was a relatively
ing high dose chemotherapy. 84 patients
effect is particularly marked in the group of
small study, it indicated the benefit of alpha
with myeloma were randomized to receive
patients who achieve complete remission.
interferon maintenance in the post marrow
maintenance Intron-A (Schering Plough), 3
transplant setting.
mu/m2 s.c. 3 times weekly or no treatment
COMMENTARY:
Dr. Cunningham indicated that, on
following induction therapy with C-VAMP
Above is the abstract of material
average, he was seeing an extra 18 months
(Cyclophosphamide, vincristine, adri-
presented by Dr. David Cunningham at a
added on to the remission period. Based
amycin, methyprednisolone), consolidated
meeting of the American Society of
upon the study, clinical practice at the Royal
with high dose melphalan (HDM)
Clinical Oncology (ASCO) in Orlando,
Marsden has changed with alpha interferon
200mg/m2 + ABMT. Prognostic factors
Florida. This study, initiated by the late
maintenance being routinely recommended
including previous chemotherapy (n=18)
Prof. Tim McElwain, former head of the
after high dose therapy and also being
response to C-VAMP/HDM, stage of dis-
Oncology Group at the Royal Marsden
strongly considered in all patients achieving
ease, isotype and median age, showed a bal-
Hospital in Surrey, England, enrolled 84
"good quality" remissions with standard
anced distribution between the two groups.
patients. 62 patients achieved complete
dose therapy. l
8

---

MYELOMA TODAY PROFILE: Dr. Douglas Joshua
until the last few years.
is recently diagnosed, who is in otherwise
good health, as to their treatment options?
MT: You mentioned that myeloma has
Dr. Joshua: In a relatively young patient,
been considered a disease of older people.
who has myeloma there are really two
Have you noticed an increase in patients
options; the standard combination therapy
over the last few years, and have you noticed
versus high dose therapy with perhaps a
an increase in younger patients?
bone marrow rescue. My own view is that it
Dr. Joshua: The answer to both questions is
is not clear which of these two options is the
yes. Certainly that's happened in our unit.
best. I have certainly no doubt that if the
It's hard to know whether this represents the
patient has an allogeneic donor I would sug-
fact that we now have an established unit
gest he have an allogeneic transplant. I
that attracts more referrals than it used to,
think it is unclear whether autologous trans-
and I suspect that is the answer. We've seen
plantation is any more effective than stan-
myeloma in patients in their 20s, and cer-
dard chemotherapy, and the main reason is
tainly when I was training that was an
that the patients who are selected for the
exceptional occurrence. We have seen quite
autologous transplant are often a very good
a number of patients in their 20s and clearly
risk group. They almost always have normal
Dr. Joshua
the therapy we want to give them is quite
renal function, otherwise it is very difficult
different than to patients in their 70s.
to transplant them. And of course renal
Dr. Joshua is the Senior Staff
function is a very important prognostic fac-
Specialist in Hematology at the Royal Prince
MT: At the Foundation we get calls from
tor. I think it is very important that this
Alfred Hospital in Sydney, Australia. He is
patients who live in a small towns and aren't
question be sorted out as soon as possible.
head of both the Myeloma Research Unit and
near a center that specializes in myeloma. It
the Bone Marrow Transplantation Unit. He is
must be the same in Australia. How do you
MT: Some feel that a transplant is the clos-
a past President of the Hematology Society of
handle this and what do you recommend to
est thing to a cure. Please address that.
Australia and is Associate Professor of Medicine
the patient for treatment options.
Dr. Joshua: I think the fact is that with
at the University of Sydney.
Dr. Joshua: In Australia, the medical care
autologous transplantation relapses unfortu-
outside Sydney is very good. We have a sys-
nately still occur and that the quest for a
Myeloma Today: Please tell us a little about
tem of base hospitals in the country which
cure may not be answered with our current
yourself.
we have established close connections with
technology. I'm certainly not arguing
Dr. Joshua: I grew up in Sydney and did all
and they have oncology physicians, but no
against aggressive therapy. However, I think
my training first in Sydney University, and
specialists in myeloma. We
it's a little bit early to be
then at Royal Alfred Hospital, which is the
I think it is unclear whether
generally have the patient
absolutely sure. Clearly
campus hospital at Sydney University. I
come to see us initially for
autologous transplantation bone marrow transplanta-
completed my clinical training in hematol-
workup, and treatment
is any more effective than tion needs to be explored
ogy in Sydney, so I was a committed hema-
planning. The patient may
and needs to be compared
tologist before I started any overseas train-
standard chemotherapy...
have to continue his
in a randomized fashion.
ing. My interest in myeloma essentially
chemo-therapy by traveling large distances
began when I went to Oxford and worked
to one of the major country base hospitals.
MT: What are your most notable achieve-
on murine plasmacytoma with Professor
We would love to have more facilities in the
ments thus far in your career in myeloma?
MacLennan. When I returned from Oxford
country, but the proper facilities are still city
Dr. Joshua: I guess my most notable
in 1977, I set up a myeloma research unit at
based.
achievement is establishing the myeloma
the Royal Alfred Hospital, and a clinical
unit and arousing an interest in myeloma
practice which is ongoing today.
MT: Does Australia have a national health
which wasn't evident in Australia. We've
care program?
managed to run two national trials, one on
MT: Do you spend more of your time in
Dr. Joshua: Yes, it's a universal health pro-
prognostic factors and one randomized trial
research or working with patients?
gram funded by taxation. Approximately
on alpha-interferon, which has never been
Dr. Joshua: Its about even. I spend perhaps
1/3 of the population take private insurance
done before in Australia. So I think the
40% of my time on research, 40% on clini-
in addition to the universal health offered.
establishment of an active unit, has been
cal work and the rest on compulsory admin-
quite a benefit to everyone. I think that it's
istrative duties.
MT: Do you feel that there are specific fac-
probably my most notable contribution to
tors linked to the cause of myeloma?
Australian hematology.
MT: Is there a feeling in Australia that
Dr. Joshua: The factors that I believe are
myeloma is still a relatively rare form of can-
associated are radiation and benzene. There
MT: What will you be focusing on in the
cer and that not much is known about it?
is always the intriguing occupational rela-
next few years?
Dr. Joshua: I think that that is still the per-
tionship to farm workers and people with
Dr. Joshua: Our current research programs
ception in Australia. It really doesn't hit the
industrial exposure to metals. But its not
are focused on mechanisms of disease escape.
press or have the human interest that say
really clear. I think it is very interesting
As you know many patients with myeloma
childhood leukemia has.
that the same factors involved in myeloma
enter a plateau phase, be that a plateau after
are the factors that are involved in
transplantation or a plateau after standard
MT: Why do you think that is?
leukemia. This may be one of the explana-
chemotherapy. We must understand why
Dr. Joshua: I'm not sure. I guess it's because
tions why a small percentage of myeloma
patients who are in this stable form of dis-
it's a disease that mostly strikes people in
patients have evidence of acute leukemia at
ease lose control, and escape from plateau.
late middle life and doesn't have the emo-
the time of diagnosis.
We are involved in a project which is fund-
tional associations with childhood illness.
There was little active interest in myeloma
MT: What do you suggest to a patient who
Please see page 10
9

---

Prof. Powles - continued
patients will not get to any sort of high dose
Dr. Joshua - continued
treatment. They won't be considered for it.
problem of course with myeloma is keeping
For example, we had 17 patients out of 195,
ed by our National Health and Medical
those remissions, and interferon prolongs
and half of those 17 had completely resistant
Research Council, which is looking at the
the remission but it doesn't appear at the
disease. The other half had complications of
mechanisms of escape. The things we are
moment to be producing a sub group that is
the VAMP, some of which died of infection.
concerned with are: the mutation of the
cured. Unlike acute leukemia where imme-
The death rate due to inductional infusional
immunoglobulin genes in myeloma; inter-
diately one was seeing 20, 25 or even 30%
chemotherapy is about 3%. We haven't had
leukin-6 receptor status; interleukin-6 recep-
with autografting who were cured. So our
a death from the group who had an autolo-
tor dysregulation; and changes in nucleoside
current studies are looking at how we can
gous bone marrow transplantation using
transporter status when the proliferation of
prolong complete remission.
melphalan alone and stem cell rescue. So
myeloma cells changes. We must understand
that's very low; certainly lower than 3%. It
why, patients leave plateau and enter an
MT: You were the first to use alpha interfer-
was running at 8% initially. Now it's com-
active disease state, the disease then
on. Would you tell us more about that?
ing down and down and down. And it looks
becomes very difficult to treat.
Prof. Powles: That's not strictly true,
like there's going to be a very low transplant
although we were among the first to use
related mortality rate, indeed.
MT: What do you see as the most promising
interferon in the maintenance of patients
treatment in the future?
post-BMT. In fact interferon had been used
MT: What are your thoughts on double
Dr. Joshua: I think the interferons will have
by the Swedish and the Italians; they used it
transplant versus what you're doing at your
a role to play, perhaps a role in selective
for patients who had responded or were still
center?
types of myeloma like IgA, specifically. I
responding to treatment. A control trial was
Prof. Powles: Well, we're not doing double
think high dose therapy will have a role to
done on patients who have had a BMT and
transplants. First of all because we don't use
play which might be restricted to younger
are either in very good plateau stage or in
TBI (total body irradiation). We could, in
patients. And I think more advances will
complete remission. Our control trial shows
theory at least, easily do double transplants.
really come when we understand more about
that interferon has marked benefit in pro-
We don't think there's a place for TBI, cer-
the biology of the disease. We need to
longing the duration of those remissions and
tainly not in our current program. Also,
understand where the cell of origin comes
it translates into a survival benefit, but it's
we're not very keen on a double transplant.
from and I think that will give us a much
only in the patients who are in complete
What we're doing now is after patients have
better understanding of the clonogeneic cell
remission. The 25% of patients who haven't
had their first transplant, all patients go
and that may allow us to actually do autolo-
responded to the high dose treatment, and
onto interferon. We've got a randomized
gous transplantation and eradicate that cell
have still got detectable disease, aren't bene-
trial where one half then get chemotherapy,
from the marrow.
fited by interferon. This is contrary to
but it's the sort of chemotherapy you use in
what's seen if you don't give high dose treat-
acute lymphoblastic leukemia. It's directed
MT: How do you feel about working with
ment. If you don't give high dose treatment,
at pre-B-lymphocytes . This additional
such a difficult disease as myeloma?
patients will respond to interferon during
chemotherapy is given two to four months
Dr. Joshua: I think myeloma is probably one
induction or during further chemotherapy
after the autologous transplant, with half the
of the most difficult diseases to work with.
and maintenance. So we sort of turned it on
patients not getting this additional
But I think what has happened in the last
its head and we haven't got an explanation
chemotherapy. That's the randomized trial
few years is that there have been tremendous
for that at the moment.
we're locked into. That's not to say that
advances in management of the disease,
some patients shouldn't get double trans-
such as the introduction of VAD
MT: What's your current policy for treat-
plants. I think that patients who have had
chemotherapy, plus associated things like
ment for those patients under the age of 70?
their first transplant, particularly the ones
better treatment for nausea and tremendous
Prof. Powles: We feel quite strongly that
that go into complete remission, are not
advances in the management of pain. Pain
some form of chemotherapy without a trans-
going to be cured. And I think the more
in myeloma has always been one of the
plant must initially be done, as with
studies we've got going, particularly in the
major problems, especially back pain, and I
leukemias and all other hematological
form of controlled trials, looking at different
think realization that there is a proper way
malignancies, to get the disease under some
treatment methods, immunotherapy, pre-B-
to use analgesics, a proper way to use nar-
sort of control. Our experience on the last
lymphocyte chemotherapy, second trans-
cotics if they're required, has really made a
200 patients we've had is there is no reason
plants, other agents, other growth factors
major difference to a lot of patients. I think
for patients under the age of 70 not to be
etc., the more we can learn about what
it is very difficult every time you see patients
able to tolerate infusional chemotherapy,
works. I think there's plenty of room now
who escape from the stable phase of their
such as VAD or VAMP every three weeks.
for a lot of work to be done in that area.
disease. You know that they are going to
So our policy is first of all, up front, every
have a very rough time and it does impact
patient is a candidate and should get infu-
MT: You have been a faculty member at
upon you. You obviously get involved with
sional chemotherapy in our institution. The
IMF Patient and Family Seminars. What
your patients and I think it's a very difficult
median number of courses is five. So that
did you think?
process and very difficult to deal with.
we're talking about something like four
Prof. Powles: Well I was deeply moved. To
months. We then have a policy that all of
be honest, I couldn't believe it. I saw truly
MT: Has the progress you've seen made you
those patients will be planned for some sort
something being done in myeloma by the
more optimistic about finding a cure?
of autologous transplant. And we have
patients for the patients. If nothing else, it
Dr. Joshua: I think patients are vastly better
found that 70% of the patients will be able
can make people like me remain relevant.
managed now compared to 10 years ago
to have high dose treatment and at least
My research can be focused, it can be per-
when there were no specialty myeloma unit.
50% of those or more will have some sort of
sonal, it can be relevant. And I would like
In Sydney almost all myeloma cases now
autologous rescue with bone peripheral stem
to take that message into Europe. What has
come to special units. There are a lot of sup-
cells. But our policy is that all patients, after
happened here in the States has been really
port facilities now available to these
they've had infusional chemotherapy would
quite remarkable and I think that British
patients, and this has been a tremendous
be candidates for autologous transplant.
and European patients are not only ready for
change. In terms of whether we are closer to
During the induction chemotherapy there is
it, I think they need it. l
Please see page 12
10
a resistant disease component. About 8% of

---

MYELOMA IS ALSO A BONE DISEASE
by Francesca M. Thompson, MD
shuts down osteoblasts. As if that isn't
patients are bedridden; this immobilization
enough, activated osteoclasts themselves
speeds the resorption of bone even more.
Patients suffer greatly from bone
produce more IL-6. On top of that, the
Although much of the marrow
disease in myeloma; in general hematologists
malignant plasma cell is stimulated by IL-6
exists in the axial skeleton (i.e. the spine,
and oncologists concentrate on the treat-
to pump up and produce more IL-6, which in
the skull, the pelvis, and the ribs), and we
ment of the malignant cells and are unaware
turn revs up the osteoclasts--a vicious circle.
see much myeloma bone disease in the axial
of the concept of protecting your bones, in
Thus the malignant plasma cell is affected by
skeleton, the long bones can be afflicted
other words, doing all that can be done to
IL-6 from two sources: an autocrine source
also. Because the limbs are appendages off
keep the bone you have.
(the IL-6 it makes itself) and a paracrine
the trunk, their bones are called the appen-
source (the IL-6 made next door by the
dicular skeleton. The thigh bone, or femur,
NORMAL BONE
osteoclasts).
has a fair amount of marrow, and is subject
Let's start with normal, healthy
The first result is osteopenia, which
to much stress in weight-bearing. Pathologic
bone. This is a living tissue that is continu-
means loss of mineralized bone in general,
fractures can be expected when lytic lesions
ally engaged in deconstruction and rebuild-
but this particularly occurs in bone where
occur in the hard outer core of the long
ing activity in a balance that we call bone
there is more marrow, because that is where
bone, the cortical diameter. When 50% or
turnover. The deconstructors are cells
most of the plasma cells live. Osteopenia, a
more of the cortical bone is lost, or when
called osteoclasts, which burrow into bone
more generalized term than osteoporosis, is
there is an "open-section" effect in which
like little termites, dissolving the mineral-
impossible to detect on regular x-rays in its
less than 50% of the diameter of the bone is
ized bone (the hard
early stages. The rule
eroded along a length that exceeds 75% of
stuff). This is good in
...most patients suffer pain and
of thumb is that half of
the diameter of the bone, a stress-riser, or
normal bone because
the mineral content of
weak point, is created. This decreases the
decreased mobility caused by
you have to get rid of
bone (the hard stuff)
torsional strength of the bone by more than
myeloma bone disease.
old bone to have some-
has to be lost before it
90%, leading to pathologic fracture from a
place to put the new bone. The new bone is
is noticeable on x-ray. (More sensitive tests
seemingly minor postural adjustment.
laid down by the
are now available which I will discuss later.)
When the osteoclasts chew up
rebuilders, cells called osteoblasts. Actually,
Because this occurs in bone with more mar-
bone, calcium is released into the blood-
they do not make the hard stuff, mineralized
row, the second result often is vertebral
stream. Eventually a point can be reached
bone, rather they elaborate protein material
compression fractures and rib fractures as the
when the kidneys cannot excrete enough,
called osteoid on the scaffolding of the bone
first sign of something gone awry with the
and the blood level, or serum level, of calci-
already there which later petrifies because of
bone. Many myeloma patients are first diag-
um rises above normal. This is called hyper-
the chemical environment in which it lives;
nosed at this juncture.
calcemia, or too
in other words, it becomes mineralized.
The third result
It makes sense to do everything
much calcium in the
In young adults the deconstruction
is called lytic bone dis-
possible to avoid as many of these
blood. This is a
and rebuilding are in perfect balance so that
ease, and is the stage from
lethal condition,
complications as possible.
no bone is lost; after age 25 or 30 years, a lit-
which multiple myeloma
and if it cannot be
tle more is lost than is put back, and this
derives its name, in that it involves many lit-
corrected, can cause death quite rapidly.
trend continues through the decades. In
tle holes in the bone. How does this hap-
postmenopausal women this tendency is
pen? The process is the same as described
TREATMENT POSSIBILITIES
exaggerated and they wind up at the end of
above, namely uncoupling of osteoclasts and
The occurrence of myeloma bone
normal life with less bone than men. Older
osteoblasts, the slowing down of osteoblasts,
disease does not "just happen". By the time
men generally lose bone at the same rate as
and the extreme speed-up of osteoclasts, all
the patient is aware of a bone problem,
elderly women, but they start this loss later
puddled in the same area of bone, excavat-
much bone has been lost forever. It makes
and with more bone than women.
ing a big hole in the bone which fills up with
sense to do everything possible to avoid as
The synchrony of matching the
blood and millions of plasma cells. When
many of these complications as possible.
amount of rebuilding with the amount of
this hole gets very big, say the size of an
While there is no evidence at all that con-
deconstruction is called coupling, or team-
orange, it is called a plasmacytoma, or tumor
trolling bone disease will prolong overall sur-
ing up of osteoclasts with osteoblasts in what
of plasma cells. This can happen all over
vival, there are also no long term studies
are essentially work crews, or bone remodel-
the skeleton, but some favorite places are
that show that it won't. Nevertheless, most
ing units. The exact ways in
the skull, the spine,
patients suffer pain and decreased mobility
The bone part of the disease
which this occurs is the subject
and the pelvis. The
caused by myeloma bone disease. There can
needs aggressive medical
of much intense research activi-
skull can show many
be no doubt that spending one's remaining
ty.
management.
so-called "punched
years without painful rib fractures, without
out" lesions, as if someone had dotted the
the loss of several inches of spine from verte-
BONE DISEASE IN MYELOMA
skull with a hole puncher. The vertebral
bral crush fractures, without a long bone
There is a natural progression of
bodies can have major holes in the structural
fracture and the radiation and surgery that
untreated myeloma associated bone disease.
parts, and wind up collapsing in a lopsided or
may be required is better than suffering these
It starts with an uncoupling of the bone
major way, much more than the little squish
complications of an already harsh disease.
remodeling units, so that the osteoclasts
of the more routine vertebral stress fracture
I am now going to review things
show up for the work crew but their cohorts,
caused by osteopenia discussed above.
you can do yourself or discuss with your doc-
the osteoblasts, are on strike. The malig-
Sometimes the collapse distorts the shape of
tor as possible medical management for you.
nant plasma cell of myeloma is probably the
the spinal canal enough to cause pressure or
culprit here because it produces a protein
blockage on the spinal cord or nerves, lead-
· Imagine Studies
called interleukin-6 (IL-6) which turns
ing to paralysis as well as pain. Another
The first thing is to find out where
osteoclasts into a frenzy of bone destruction,
problem caused by the pain of vertebral frac-
i.e. they become activated; some think IL-6
tures is that it hurts so much to move that
Please see page 12
11

---

Thus, none of the nucleoside analogs are active
with myeloma. I would like to see that effort
Dr. Joshua - continued
in myeloma. Actually we did a small study
continued and expanded to patients in other
curing myeloma than we were 5 years ago ­
with 2-CDA in myeloma and it was completely
countries. I will try to help establish a role for
I think we're not. But I think we are about
negative. On the other hand, high dose dex-
the IMF in the Mediterranean area. Through a
to be. I think we are getting much closer to
amethasone, which is quite active in myeloma,
combined effort of physicians, families and
understanding the myeloma stem cell. If we
does not seem to have significant activity in
patients, there will be improvement in the care
know where the stem cell is, we can pheno-
macroglobulemia. We view macroglobulemia
of patients with myeloma. I am optimistic that
type it and perhaps isolate it and perhaps
as a disease related more to chronic lymphocyt-
in a few years there will be more effective thera-
even purge it from the marrow. We have
ic leukemia than to myeloma as far as treat-
pies and I can foresee that even a curative treat-
mechanisms to support bone marrow trans-
ment response is concerned.
ment may become available. l
plantation which didn't exist a few years ago
which we can now use. So I am really hope-
MT: What are your plans and what direction
Adhesion Molecules - continued
ful that things will improve over the next
will your research take you?
few years. l
Dr. Dimopolous: As soon as I went back to
patients seems to be linked to the develop-
Greece I became active in the Greek myeloma
ment of drug resistance.
Dr. Dimopolous - continued
study group which is chaired by Dr. Alice
Future studies of adhesion mole-
cules in myeloma may eventually lead to
answer about the activity of a medication with
Maniatis, Professor of Hematology at the
novel therapeutic strategies. The blocking
a small number of patients.
University of Patras. We activated several pro-
tocols for patients with high risk disease that
of homing receptors or inhibition of func-
tional cell contact might prevent settling of
MT: Could you explain your research in the
will compare standard chemotherapy to autolo-
precursor cells and arrest myeloma growth.
use of 2-CDA in Waldenstrom's?
gous bone marrow or peripheral stem cell trans-
In order to test the hypothesis, studies using
Dr. Dimopolous: 2-CDA or 2 chloro deoxy
plantation. We have a protocol for peripheral
blocking antibodies against several key
adenosine, is a new nucleoside analog similar to
blood stem cell allogeneic transplantation for
adhesion molecules are currently being
fludarabine and pentostatin. Although it is
selected younger patients with myeloma. We
undertaken in mouse myeloma models. l
unknown how 2-CDA works, in a variety of
also have a protocol to investigate the role of
patients with indolent low grade B-cell malig-
interferon during induction therapy in patients
nancies such as hairy cell leukemia, low grade
with low risk myeloma. We have a protocol for
Myeloma is Also a Bone
lymphomas and Waldenstrom's macroglobu-
improving the staging of patients with solitary
Disease - continued
linemia we believe that this nucleoside analog
bone plasmacytoma with MRI and flow cytom-
forms strong bonds with DNA and eventually
etry. On the other hand, at my own hospital
you are in terms of bone disease. There are
induces programmed cell death, or apoptosis as
we have initiated a screening effort to identify
many radiological techniques for looking at
we call it. We initially investigated fludara-
patients with monoclonal gammapathy of
bones. You have probably already had a
bine in the treatment of patients with
undetermined significance (MGUS) and we
skeletal survey which involves plain films of
Waldenstrom's who were resistant to alkylating
plan to investigate these patients extensively
your whole body except maybe your hands
agents and we observed a 30 to 40% response
including molecular studies and evaluation of
and feet. Regular x-rays do not show early
rate. Subsequently, we administered a limited
several anti-oncogenes or tumor suppressors.
osteopenia but will reveal lytic bone disease,
course of treatment with 2-CDA, only 2 cours-
i.e. holes in your bone that indicate tumor
es 4 weeks apart, in a similar category of
MT: As a researcher, what do you think holds
erosion of bone or healed fractures of the
patients with disease resistant to alkylating
the most promise for myeloma patients?
ribs or vertebral bodies. Lytic bone disease
agents and we observed a 40% response rate.
Dr. Dimopolous: I believe that the answer,
in weightbearing bones such as the femur
We were highly encouraged by this activity in
and maybe the cure for myeloma, will not come
should be looked for, because it is better to
previously treated patients and subsequently we
from a singular therapeutic approach. I strong-
fix what we call an "impending" fracture
used 2-CDA as primary therapy in previously
ly believe that all the phases of basic and clini-
with planned surgery than sustain the trau-
untreated patients with Waldenstrom's. And
cal research should continue. High dose thera-
ma of a fall and a fracture and undergo emer-
again by using a limited schedule of treatment
pies with the refinement and improvement of
gency surgery. If you haven't had a skeletal
that included only two courses. We observed
supportive care may lead to long term disease
survey and your disease is active even if you
an 80% response rate, and this work was pub-
free survival and even cure for a subset of
have no symptoms.
lished recently in the Journal of Clinical
patients. Better understanding of the side
Computer-assisted tomography
Oncology . Furthermore, by limiting the courses
effects and complications of allogeneic bone
(CAT) scans are x-rays that are taken and
of treatment, we avoided most of the side
marrow transplantation will provide better
analyzed by computer so that vertical or hor-
effects that other investigators have observed
treatment for selected patients. On the other
izontal slices can be seen much more clearly,
when they use 2-CDA in a repetitive manner
hand, I believe that improvements in molecu-
without the shadow of stronger overlying
for patients with other malignancies. Also,
lar biology will enable us to conduct studies
bone. Particularly in the area of the spine,
after a response to 2-CDA we observed patients
that will incorporate gene therapy in the treat-
analysis of the bony elements of the verte-
with no treatment and we have seen that if the
ment of myeloma and I know that such studies
bral column is improved with CAT scan
disease recurs, they are likely to respond again
have been initiated in animal models and will
compared to regular x-ray. It is also a good
to 2-CDA. Although we don't have data yet as
be soon available for patients with myeloma.
way to look at an area that looks "suspicious"
to whether 2-CDA will change the natural
Thus I believe that both new drug develop-
on the regular x-ray anywhere in the skele-
course of macroglobulemia, we're very encour-
ment efforts targeting gene therapy in myelo-
ton.
aged by the high response rate and believe that
ma, and further refinement of high dose thera-
Magnetic resonance imaging (MRI)
this is a very promising agent in this disease.
pies will give improved results in a subset of
creates computer generated images on the
patients.
basis of a strong magnetic field rather than
MT: Why isn't it equally effective in myeloma?
x-ray. It is sensitive to changes in the bone
Dr. Dimopolous: This is something that has
MT: As an IMF Scientific Advisor, what role
marrow in multiple myeloma, but it is some-
puzzled us. Despite the fact that the phenotype
do you feel is important for you?
what difficult to quantitate precisely the
of macroglobulemia and myeloma are quite
Dr. Dimopolous: The IMF is playing a very sig-
amount of bone lost with this technique.
similar, from a therapeutic point of view, this
nificant role in helping patients with myeloma
disease behaves in a completely different way.
cope with their disease by educating patients
Please see next page
12
and creating an interaction among patients

---

Soft tissues are especially well visualized by
which is why it is so often used when women
activated Vitamin D called calcifediol (25-
MRI. It is thus an invaluable technique
have the type of breast cancer that is stimu-
hydroxyvitamin D) (40 micrograms/day oral-
when there is question of whether tumor
lated by estrogen. There have been some
ly) plus calcium also counters the effect of
from a vertebral body is spilling into the
suggestions that tamoxifen may have an
steroid on the intestine with less associated
spinal canal putting the spinal cord at risk.
estrogen-like positive effect on bone reten-
hypercalcemia risk. It is also simple to mon-
Quantification of osteopenia is
tion and formation. A longer term study of
itor the blood to avoid this complication. If
possible with dual energy x-ray absorptiome-
women at high risk of breast cancer treated
your serum calcium level goes up, your dose
try (DEXA), a highly specific technique for
with tamoxifen currently under way may
of activated vitamin D can be stopped and
measuring bone mass which may be useful in
yield some useful data with respect to its
restarted later at a lower level.
assessing the effectiveness of treatment of
effect on bone. Tamoxifen is a maybe for
patients with various bone diseases, particu-
the future; for today, I believe estrogen
What Steroids Do to Bone
larly myeloma. In a French study involving
replacement therapy is a must, and if you are
Many patients with myeloma are
10 myeloma patients before and after autolo-
post-menopausal you should discuss this with
treated cyclically with prednisone or high
gous bone marrow transplant, DEXA showed
your oncologist and your gynecologist.
dose dexamethasone, which accelerates bone
changes not seen with radiographs, CT, and
loss via several mechanisms: 1) somehow
MRI; the result of treatment was an average
· Calcium and Vitamin D
osteoblasts are turned off, 2) osteoclast bone
16.4% increase in lumbar bone density
Your body cannot hold onto bone if
resorption is stimulated and 3) there is
(Mariette et al). Weinstein noted that
it doesn't get enough calcium in the diet.
decreased calcium absorption from the
DEXA could be useful in patients with mul-
Women with myeloma are typically post-
intestines as a direct effect of the steroids.
tiple myeloma in prognosis and evaluation of
menopausal, or become so after high dose
In addition to the direct effect, a ripple
therapy. At my hospital, a DEXA scan is
chemotherapy and are thus at risk of osteo-
effect of this loss of intestinal absorption can
also less expensive than an MRI.
porosis even without the tumor effect on the
occur in another hormonal system, the
If you want to know how your
bone. As paradoxical as it sounds in a dis-
parathyroid system, which overcompensates
bones are with respect to osteopenia, get a
ease with a terminal phase noted for hyper-
in the form of making too much parathyroid
DEXA scan. If you have no bone loss com-
calcemia, calcium supplementation should
hormone (secondary hyperparathyroidism).
pared to normal people your age, that's great.
be standard treatment for women, and prob-
This is bad because parathyroid hormone
But if you do have osteopenia, you may want
ably men as well. A New Zealand study has
(PTH) causes increased bone resorption.
to do something to help hold on to what's
shown that a higher dose (1000 mg daily po)
Using vitamin D in some form counteracts
left.
calcium supplement slows bone loss in post-
the steroid effect on the intestinal cells and
menopausal women (Reid 1993).
may also turn on osteoblasts (Meunier).
· Walking
Urinary calcium can be followed in both
Walking has been recommended to
male and female patients to make sure their
Osteoclast Inhibitors
myeloma patients for years. Recent data has
dietary intake of calcium is enough by main-
So far we have seen that bone loss
shown that menopausal women retain more
taining a ratio of 250 mg calcium/gr creati-
occurs when osteoclasts are activated, and
bone if they engage in weightbearing activi-
nine.
start chewing on the bone. Various drugs
ty, i.e. walking as opposed to a non-weight-
In addition to getting adequate cal-
have been used to stop this activity.
bearing activity such as swimming.
cium in your diet, the calcium must be
Calcitonin, mentioned briefly
Obviously, if you have a painful healing frac-
absorbed into the bloodstream from the gut.
above, is a hormone which is produced natu-
ture, you can't start till you get the go-ahead
Vitamin D is very crucial in this process. If
rally in the body as one of the brakes on
from your doctor, and you probably wouldn't
you are lacking Vitamin D the calcium
osteoclasts. Calcitonin hormone derived
want to anyway. If you have been doing
won't be absorbed in sufficient quantity to
from salmon has the same effect as human
some walking and want to do more, be judi-
make up for what you lose every day.
calcitonin, and was used for many years in
cious about how to increase your distance,
Vitamin D is added to milk so that children
subcutaneous injections for people with
speed, or time spent walking. A good rule is
don't develop rickets. Many older people
another bone disease. More recently human
to increase one parameter, such as distance,
don't drink milk, and have a borderline or
calcitonin has been manufactured in the lab-
by no more than 10% a week. That means
deficient Vitamin D status. Several calcium
oratory, and is said to have fewer allergic
that if you are walking a mile, or 20 New
supplements have Vitamin D added to make
reactions than salmon calcitonin. Another
York City short blocks, when you increase
up for this.
new development is that calcitonin can be
you only go up to 22 blocks; after a week at
Some people have a Vitamin D
administered as a nasal spray which is easier
22, go up to 24 blocks, and so on. If you are
resistance in that Vitamin D cannot be effi-
than giving yourself shots. Some studies
a total couch potato right now, start with a
ciently absorbed from the body to be activat-
have indicated that calcitonin decreases
very wimpy distance, like a few blocks.
ed in the liver and kidney as is normal.
osteoclast activity. Calcitonin and calcium
Don't add too much too soon because your
Steroids can cause this. This can be over-
yielded significant increases in lumbar,
bones, muscles, ligaments, and tendons need
come by increasing the dose of Vitamin D so
femoral, and radial bone density in patients
gentle nudging to increase their strength; if
that enough will make it through the
being treated with steroids (Ringe). Longer
you overuse them, you can injure them. It
intestines to the bloodstream, or by taking a
term studies have cast some doubt on the
will take awhile to get up to a level most
special prescribed form of Vitamin D which
continued effectiveness ofcalcitonin. The
exercisers consider aerobic, but that's OK,
is already activated. The most
thinking now is that turning off the osteo-
it's much safer.
active Vitamin D is calcitriol. A dose of 0.5
clasts with the hormoneis compensated for
to 1.0 microgram/day orally and calcium
after a number of months so the effective-
· Estrogen Replacement Therapy
1000 milligrams/day orally, used as a preven-
ness of the treatment in myeloma is lost.
Estrogen replacement therapy
tive intervention with or without the hor-
Calcitonin enjoyed popularity in Italy as a
reduces bone resorption in post-menopausal
mone calcitonin (400 IU/d intranasally), did
treatment of myeloma bone disease, but cur-
women. Some have suggested that estrogens
prevent bone loss in the lumbar spine in
rently the Italian national free health system
can even increase bone formation, but this
non-cancer patients treated with steroids
will not pay for calcitonin, an indication
has not been clearly substantiated as a long
(Sambrook et al). Meunier noted that 25%
that they don't think it works. Patients may,
term effect. Tamoxifen is a drug that is anti-
of calcitriol treated patients developed
estrogenic in its effect on breast tissue,
hypercalcemia. He further noted that a less
13
Please see page 14

---

Myeloma is Also a Bone
these are very responsive to treatment with
ment therapy for postmenopausal women,
Disease - continued
acetaminophen. Pamidronate has been
adequate dietary intake of calcium and
shown to maintain axial and appendicular
Vitamin D analogues, and osteoclast
however, but it at their own expense.
bone in a 2 year study on non-cancer
inhibitor treatment before the bone melts
Bisphosphonates, potent osteoclast
patients receiving steroid therapy. Studies
away. l
inhibitors, have been studied extensively in
are currently under way in the United States
recent years, primarily in Europe. The only
utilizing pamidronate in multiple myeloma
Prof. Ludwig - continued
preparation available in the United States
(Berenson), but the imaging techniques used
are not the most sensitive available, in my
MT: In other words, there is high up front
which is worthwhile taking is pamidronate.
judgment, so we may not have information
mortality?
First though, I will tell you about the others
about subtle differences in osteopenia that
Prof. Ludwig: Yes, in a certain percentage of
as background information and because the
might be available if DEXA scans were part
patients who undergo an allogeneic transplant
clinical studies in myeloma are more exten-
of the study.
there is the risk of mortality within the first
sive.
three months after the procedure has been per-
Etidronate, the first bisphosphonate
Can We Make Bone Form Faster?
formed. Another option for the patient inter-
introduced for clinical use, was an effective
Normal bone metabolism is a bal-
ested in an aggresive approach is, if eligible, to
osteoclast inhibitor but was found to pro-
ance of bone formation and bone resorption.
undergo an autologous transplant. This is a rel-
duce poor bone mineralization, whereas later
Although we have drugs to block the exces-
atively safe procedure, but the chances of eradi-
preparations, clodronate and pamidronate,
sive resorption in myeloma bone disease,
cating the maligant clone is even smaller than
do not have that drawback (Hosking). The
there is little or nothing to offer patients to
with the allogeneic transplant.
effectiveness of bisphosphonates in control-
ling lytic bone disease has been amply
increase bone formation. It was thought
that sodium fluoride had a long lasting abili-
MT: You don't seem to be a big fan of bone
demonstrated. Siris et al. were the first to
ty to form new bone, but then it has been
marrow transplantation.
demonstrate effectiveness of clodronate at a
found that the new bone produced was too
Prof. Ludwig: No, not anymore. There was a
dose of 3200 milligrams/day by mouth in
brittle to do much good.
time when I hoped that transplantation would
decreasing osteoclast-mediated bone resorp-
Bone formation can be quantified
be a great help to myeloma patients, but the
tion in myeloma. A smaller dose (1600 mil-
by testing for a protein called serum osteo-
truth is that at present the tools we have are
ligrams/day by mouth was used by Delmas et
calcin which is produced only by osteoblasts
not suffcient to obtain cures for patients. And
al. in an 18 month, double blind study com-
when they are building bone. This is thus a
the newer tools, such as interferon, haven't
paring clodronate to placebo. They found
measure of how much bone formation is
changed enough to do that either.
that clodronate reduced bone pain and
appeared to halt bone disease progression in
building bone. This is thus a measure of how
much bone formation is going on in the
MT: Stem cell transplantation is a treatment
most patients, although two patients eventu-
body. This has significant prognostic impli-
option we are hearing more and more about, do
ally sustained severe relapses which the
cations for myeloma disease activity. It was
you think it holds any real promise?
authors interpreted as an indication for the
found that serum osteocalcin is inversely
Prof. Ludwig: Maybe, I am not sure, nobody is.
higher 3200 milligram dose used by Siris.
correlated with severity of myeloma disease;
Peripheral stem cells are nothing new, they
Furthermore, their study showed a reduced
the more active the disease, the lower the
have always been used in autologous tranplants.
number of osteoclasts in iliac crest bone
level of serum osteocalcin. What is really
The real question is whether or not we can suc-
biopsies of clodronate patients. In a Finnish
interesting is that indolent myeloma (the
ceed in selecting pure, normal stem cells that
study on women with metastatic breast can-
type that does not progress for years even
are not contaminated by myeloma cells.
cer lytic bone disease, clodronate seemed to
prevent the hypercalcemia of metastatic
with no treatment) has higher levels of
serum osteocalcin than even normal subjects
MT: Isn't this the problem when purging bone
bone disease and delay the formation of new
(Bataille, et al.). It would be great to find
marrow for transplantations as well?
bone metastases and the progression of old
out how this more desirable state could be
Prof. Ludwig: Yes. If you are lucky a "pure"
ones (Eloma et al.). More recently, Italian
initiated in those with more active disease,
stem cell population can be obtained, but there
researchers (Ascari, Merlini) conducted a
but we are not there yet.
is always the danger that that population has
long-term trial of clodronate comparing
Mundy has suggested a novel use for
been contaminated by myeloma cells and/or by
chemotherapy alone to chemotherapy plus
parathyroid hormone (PTH) in that it may
pre-myeloma cells. On top of this, there is still
clodronate. Clodronate yielded significantly
have bone growth potential if given in
the problem of getting rid of the malignant
(p < 0.001) less bone pain, and fewer new
bursts, i.e. by intermittent injection, without
clone in the patient which is extremely hard to
lytic lesions and pathological fractures. No
affecting bone resorption but the optimal
do with the standard types of treatment avail-
toxic or side effects were noted. The main
dosage schedule for best response is not
able to us today.
conclusion of these studies is that supportive
long-term treatment with clodronate can
known, so this is another maybe-in-the-
future idea.
MT: It seems that there is a missing link.
contribute significantly to controlling the
Prof. Ludwig: Yes, I agree. We have to move
progression of myeloma bone disease.
Summary
to a higher level of research. I'm not sure
Clodronate is not available in the
Myeloma bone disease is a major
exactly what that level is, maybe gene therapy.
United States but another bisphosphonate,
source of morbidity in multiple myeloma
There is hope that gene therapy could be a
pamidronate, has recently gained acceptance
patients. It may be significantly reduced by
solution to myeloma as well as other types of
and is widely employed to treat breast cancer
drug therapy currently available but not
cancers. Cancer is a disease of the genes and if
patients with lytic bone disease and appears
often considered. We should no longer
we are able to correct the defect in the gene
to have the same effect on osteoclasts as clo-
remain comfortable with the notion that if
then we should be able to correct the disease
dronate. The dose for myeloma (60 mg or,
myeloma is treated with watchful waiting in
and in turn cure the patient. Investigating
preferably, 90 mg IV in 500 cc D5W)
the indolent phase and chemoradiotherapy
gene therapy where myeloma is concerned
requires intravenous administration, but for-
in the active phase, the bone disease will
marks the first time we have focused on finding
tunately the dose only has to be given every
take care of itself. The bone part of the dis-
the specific location of the malignant transfor-
3 to 4 weeks, not daily. Pamidronate can
ease needs aggressive medical management:
mation. Up until now we have focused on
have side effects (fever, flu-like symptoms)
which were not noted with clodronate, but
DEXA scan at diagnosis, estrogen replace-
Please see next page
14

---

influencing epiphenomenon, but now we are
for the resistance. There is much debate over
between a European patient and his physician
trying to identify the molecular basis of the
the high cost of this drug, but this shouldn't
is not technical. Conversations are focused on
malignant transformation. Once we identify
prevent us from studying all aspects of this ther-
how to increase the patient's self-esteem, help
this we will know which genes are expressed,
apy because I am convinced that patients that
him feel better, stronger, and him bear the bur-
are missing, are rearranged, or translocated in
undergo this treatment and respond, benefit
den which has been heaped on his shoulders.
myeloma and we will be able to correct that
immensely. They are more active, are less fear-
As a physician it feels good to know you can
and cure the patient.
ful, and experience less anxiety than they did
help the patient by providing essential emo-
MT: Interferon therapy has been garnering its
before treatment. The patient's quality of life is
tional support. Even if I can't prolong a
share of attention, do you think it is warranted?
improved, and that is remarkable. Sooner or
patient's life expectancy, I can enhance his
Prof. Ludwig: The most promising data on
later the economic questions won't be as press-
quality of life through the use of various thera-
interferon has come from patients who have
ing as they are today and hopefully this product
pies and by communicating with him.
undergone a bone marrow transplant. I feel
will be more readily available at a reasonable
MT: You attend numerous scientific and clini-
that these patients do benefit from interferon
price. Presently, it is very difficult to obtain
cal conferences on myeloma where your time is
therapy, in terms of prolongation of remission
EPO in certain countries. In my country,
spent on the technicnal aspects of the disease.
durations as well as overall survival rates.
Austria, there is not a problem obtaining it
Would you like to see lectures focused not only
because it has been "registered" and therefore
on the technical aspects but on the human
MT: Do you recommend interferon as a main-
the National Health Service pays for it.
aspects of the disease as well? Do you feel there
tenence therapy after transplantation?
are some physicians who forget about this
Prof. Ludwig: Yes. The most recent data sug-
MT: Do you think changes in the American
aspect of the disease when treating a patient?
gests this. As far as using interferon in a con-
health care system will have an impact on the
Prof. Ludwig: Yes, to both questions It is much
ventional treatment situation, I am convinced
accessibility and cost of drugs?
easier for a physician to limit oneself to just the
that it depends on the patient population being
Prof. Ludwig: Oh yes. I am watching very
technical aspects of the disease, and that is
cared for as to whether or not interferon will be
closely to what happens in regard to changes in
commonly all that is expected of a physician
of any benefit.
the American health care system. I am very
when providing "good medicine". Personally, I
interested in how America solves the problem
try to seperate what it means to provide "good
MT: Is interferon ever substituted for conven-
of providing health care for all.
medicine" and what it means to be a doctor to
tional chemotherapy?
an individual patient.
Prof. Ludwig: This was done in the early 80's
MT: Should a patient seeking the best care
when the first promising news about interferon
become involved in a clinical trial?
MT: Do you see research in the area of myelo-
was published. More recently, we have
Prof. Ludwig: I agree that a patient may feel
ma gaining momentum?
assumed a ban on doing so because the response
better if involved in a clinical trial and that
Prof. Ludwig: Although we are gaining new
rate using interferon as a mono-treatment was
may be due to the fact that participants are
theoretical information on myeloma, there is
not what was hoped for. The efficacy of
closely monitored, and supported. However,
stagnation in gaining new information to help
chemotherapy as a mono-treatment is better.
the degree of monitoring and support is directly
us improve the outcome of treatments.
This finding led us to experiment with combin-
related to the organization of the health service
Regrettably, I think the solutions we are look-
ing interferon and chemotherapy treatments.
in the individual countries that are sponsoring
ing for are going to be a long time in coming. I
clinical trials. In other words, patients should
think it is realistic to say that the break-
MT: How did that pan out?
be aware that there are differences. But, in fact,
throughs we are hoping for won't happen for
Prof. Ludwig: Our data and the data from
my group has made the observation that in our
one or two more decades.
Sweden show that a certain proportion of
EPO trials involving myeloma patients, even
patients who underwent the treatment did ben-
those patients who did not achieve an objec-
MT: In your opinion, after 20 or so years you
efit somewhat. But, there is data from other tri-
tive response felt better during the trial. One of
have been engaged in myeloma treatment and
als that does not support either my group's or
our explanations for this occurence is that the
research and considering the available treat-
Sweden's findings. One has to be very careful
intensive support and care each patient
ment modalities, what holds the most promise?
when interpreting the outcomes from such data
received while involved in the trial contributed
Prof. Ludwig: We touched on the subject of
because there is considerable diversity between
to their sense of well being.
gene therapy very briefly earlier in the inter-
the treatment schedules, regimens, patient pop-
view and I feel that this is the most promising
ulations, i.e. age, and stage of disease, of the dif-
MT: Your finding is very interesting. Maybe
approach to finding a cure for myeloma. To be
ferent trials.
the European patient may welcome the fact
able to correct the principal defect which is
that an aggressive stance has been taken
responsible for transforming normal cells into
MT: It seems difficult to ascertain a definitive
towards the treatment of his disease, i.e.
malignant cells, or to at least establish method-
answer on this subject because there are so
involvement in a clinical trial.
olgy which can neutralize and/or contain the
many variables.
Prof. Ludwig: I agree, and directly related to
defect would be optimal. We have to kill the
Prof. Ludwig: I agree, but we can conclude
the topic of the differences and similarities
pathogen. In order to cure cancer we have to
from what we know that that interferon thera-
between European and American patients is a
correct the defective gene, the defective gene
py can have a positive impact on certain
very striking difference; the European patients
machinery, or the defective regulation of the
patient populations.
stronger desire for an intense doctor patient
gene machinery Gene therapy has been evolv-
relationship. European patients still put an
ing very rapidly over the last few years and I
MT: What is the current focus of your
enormous amount of faith in their doctors.
think it will really explode within the next year
research?
or so. Everybody will begin to focus on it.
Prof. Ludwig: My group started working with
MT: Wouldn't be nice if the patient's desire
erythropoietin (EPO), which is used to control
for knowledge of their affliction and a strong,
MT: It sounds like we have come full circle.
the symptoms of anemia in myeloma patients,
trusting relationship with their physician could
There are a variety of treatments available and
rather early on and this is where our focus con-
be brought to the same level?
there will continue to be newer and better
tinues to be. Our research is focused on why
Prof. Ludwig: I think if I could change one
ones, but these will not be the answer. We
certain patients respond to EPO treatment and
thing in the American health care system that
have to learn how to stop it before it starts.
others do not, why they remain or become
would be it, but I am not sure it would work
Prof. Ludwig: Yes, this will be the solution
unresponsive and which mechanisms account
well with European patients. Conversation
we have been seeking. l
15

---

ARTICLES:
· The Role of Adhesion Molecules
Though further studies have shown that
One of the most characteristic
apparently not all patients benefit from
· Mechanisms of Drug Resistance
aspects of myeloma is the fact that it grows
interferon, it is clear that a subset of patients
Peter Sonneveld concisely summa-
almost exclusively in the bone marrow.
do clearly derive benefit with prolongation
rizes the role of resistance of myeloma cells
Why do myeloma cells grow in the marrow
of remission. The pioneering work from
to conventional drug treatment. Develop-
and rarely anywhere else? For several years,
the UK group has helped clarify the current
ment of drug resistance is the most crucial
Prof. Van Camp and his colleagues in
and future role of interferon in myeloma
problem in the chemotherapy management
Belgium have been studying adhesion mole-
management.
of myeloma. Ways to circumvent this prob-
cules on the surface of myeloma cells in an
lem are a focal area of continuing research.
effort to understand why myeloma cells track
· What Causes Myeloma
The pioneering work of Peter Sonneveld
to the marrow and grow preferentially in
One of the first questions that
and his colleagues is a great benefit to the
that environment. This research is impor-
comes to mind for patients diagnosed with
myeloma community.
tant to the understanding of the disease and
myeloma is what has caused the disease.
to the possible development of new treat-
We are learning more about the predisposi-
· Myeloma Kidney
ment strategies to block this preferential
tion and suceptibility factors as well as the
Ron Merrill, a doctor and a patient,
growth of myeloma in the bone marrow.
different exposures that can trigger or cause
concisely summarizes the impact of myeloma
myeloma. This is an area of ongoing
on kidneys. Kidney disease is a critical com-
· Maintenance Therapy with Intron-A
research and we hope that new information
plication of active myeloma and so the pre-
Following High Dose Melphalan and ABMT
will expand our knowledge and lead to
vention of kidney damage is crucial for day
This study from the UK was the
prevention strategies. l
to day management.
first to establish a potential role of alpha
interferon as a maintenance strategy.
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