ANTHOLOGY I
ANTHOLOGY
A PUBLICATION OF THE INTERNATIONAL MYELOMA FOUNDATION
Dear Reader,
The International Myeloma Foundation
BONE MARROW &STEM CELL
was established by Brian D. Novis in 1990.
Diagnosed with myeloma at age 33, it was Brian
T
who set the goals of the IMF: Education,
RANSPLANTATION
Treatment, Research.
The IMF has provided a broad spectrum of
Myeloma Today asked leading myeloma physicians to give their considered opinions
on the controversial topic of bone marrow and stem cell transplantation in the treatment of
services for physicians, patients, family members,
myeloma. We hope that these articles will help you in your decision-making process. We
and other concerned individuals regarding myelo
asked myeloma specialists to address the following questions:
ma treatment and management. The IMF is
governed by a Board of Directors and guided
· When to transplant?
by an expert Scientific Advisory Board.
· Who is a transplant candidate?
Myeloma Today is a quarterly publication
· Why transplantation?
· Transplant vs. standard treatment, what are today's statistics?
of the IMF. It provides up-to-the-moment infor
mation about treatment and management of
myeloma, as wel as current research, and
human interest stories. It is geared to both physi
Transplantation for MM in the 1990s Page 1
cians and laypersons. In publication since 1992,
What is Multiple Myeloma? Page 2
Myeloma Today has covered a broad range of
Transplantation for Myeloma: The Mayo Clinic Philosophy Page 3
topics. The scientific articles are contributed by
High Dose Therapy: University of Arkansas Approach Page 4
the leading specialists and researchers in the field.
Autologous Hematopoietic Stem Cell Transplantation in MM Page 5
Myeloma Today is an excellent chronicle of the
Bone Marrow & Peripheral Blood Stem Cell Transplantation in MM Page 6
specialized aspects of myeloma.
Role of Hematopoietic Transplantation in Multiple Myeloma Page 7
This Anthology is a first in a series. It
Role of Stem Cell Transplantation in Multiple Myeloma Page 8
focuses on one approach in the treatment of
Bone Marrow Transplantation in Multiple Myeloma Page 9
myeloma, compiling previously published articles
One Patient's Experience Page15
which continue to be current and of interest.
We hope that you wil find this anthology
informative and wil consider becoming a
Transplantation for Multiple Myeloma in the 1990's
Myeloma Today subscriber.
by Prof. Brian G. M. Durie
Allogeneic transplant utilizing stem
Susie Novis, President
cells or bone marrow from a matched broth-
The role of transplantation in the
er or sister or non-related donor introduced
management of multiple myeloma
the possibility of replacing marrow with
The IMF is dedicated to improving the
has evolved considerably during the past
absolutely no contamination and in addition
quality of life of myeloma patients while
decade. When high dose therapy
providing a graft versus myeloma effect.
working toward prevention and a cure.
with stem cell rescue was first introduced
This, too, has proved to rarely induce very
over 10 years ago, there was a hope for fre-
long term remission. Thus it has become
International Myeloma Foundation
quent cure of myeloma. When Prof. Tim
clear that the preparative regimens used
2129 Stanley Hills Drive
McElwain reported his first patients treated
along with high dose therapy are still inade
Los Angeles, CA 90046, USA
with high dose melphalan in the Lancet in
quate to remove residual drug resistant cells.
(800) 452-2873
1983, there was a sense of euphoria that
The critical point addressed in a
(323) 654-3023
finally this type of high dose therapy had
variety of ways by the authors over the past
TheIMF@myeloma.org
overcome the typical drug resistance seen in
decade has therefore become: In the
www.myeloma.org
patients with myeloma. However, by the
absence of cure, what is the role for high
late 80s and early 90s this initial enthusiasm
dose therapy with stem cell rescue in
The information presented in
was tempered with the realization that cure
patients with multiple myeloma? What are
Myeloma Today is not intended to
was rarely if ever accomplished and that,
the complications, the down sides to the
take the place of medical care or
although excellent quality remissions can be
high dose therapy approach? What are the
the advice of a physician.
achieved with high dose therapy, there is
short and long term benefits? Does the high
Always consult a doctor regarding
both a price to pay and unfortunately a high
likelihood of good quality remission justify
diagnosis and treatment.
likelihood of relapse after anywhere from 2
to 5 years.
Please see page 10

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The IMF
WHAT IS MYELOMA?
Multiple myeloma is a form of bone
Who is Affected?
Founder
marrow cancer involving plasma cells.
Multiple myeloma used to be con-
Brian D. Novis
Under normal circumstances, plas-
sidered an uncommon disease that typically
ma cells produce antibodies in response to
affected the elderly. However, recent evi
President
infection or other antigen challenges. This
dence suggests that myeloma is increasing in
Susie Novis
antibody production is usually short lived
incidence and occurring at a younger age.
Vice President
and there is no permanent build-up of plas-
There are currently about 4/100,000 new
Amy Nielsen Palumbo
ma cells in the bone marrow.
cases of multiple myeloma each year. This
Board of Directors
However, in multiple myeloma, for
means that in the U. S., there are approxi
Chairman Dr. Brian G.M. Durie
reasons which are currently unknown, the
mately 13,500 new cases each calendar year.
Dr. Kenneth Anderson
plasma cells which have "Myeloma differs from other types In comparative terms,
Michael B. Bell
accumulated in response
Brian Burns
of bone marrow cancer in that, this is similar in inci
to some, as yet unknown
dence to several types of
Mark DiCicilia
instead of spreading into the blood
antigen challenge, per
acute and chronic
Richard Funess
sist and grow in the
stream as the number of cells
leukemia as well as
Michael S. Katz
Dr. Robert A. Kyle
marrow and give rise to
build up in the bone marrow,
lymph node cancers. In
Douglas M. Mancino
the disease which we
the myeloma spreads outwards comparison to patients
Dr. Gregory R. Mundy
call multiple myeloma.
directly into the adjacent bone
requiring dialysis, it rep-
John L. Salter
The mechanisms
and results in destruction and
resents approximately
E. Michael D. Scott
responsible for this
50% of the number of
R. Michael Shaw
expansion and growth
invasion of the surrounding bone." new patients requiring
Irv Skolnick
in the marrow of these abnormal plasma
dialysis each year.
Donald B. Springer
cells is the focal point for current research
Since the average survival of
William Varnell
efforts.
myeloma patients is about four years, this
Donald R. Woodward
Unfortunately, the myeloma cells
means that at any given time there are about
Scientific Advisory Board
normally spread relatively quickly to involve
50,000 patients with myeloma in the U. S.
Chairman Robert A. Kyle, USA
multiple areas of the bone marrow through-
receiving medical care. Myeloma is more
Raymond Alexanian, USA
out the body and this is why the disease is
common in men than women and slightly
Kenneth Anderson, USA
called multiple myeloma.
more common in people of Jewish heritage.
Giuseppe Avvisati, ITALY
Myeloma differs from other types of
It is the most common type of lymphatic
Bart Barlogie, USA
bone marrow cancer in that, instead of
malignancy in African Americans.
Regis Bataille, FRANCE
Meral Beksac, TURKEY
spreading into the blood stream as the num
Myeloma is virtually unheard of in children,
James Berenson, USA
ber of cells build up in the bone marrow, the
although, as noted above, it is becoming
Daniel Bergsagel, CANADA
myeloma spreads outwards directly into the
more frequent in younger adults with almost
Joan Bladé, SPAIN
adjacent bone and results in destruction and
half of the cases in the U.S. now occurring
Mario Boccadoro, ITALY
invasion of the surrounding bone. This is
under the age of 55.
Y.C. Chen, REPUBLIC OFCHINA
responsible for the typical complications of
J. Anthony Child, ENGLAND
the disease including often severe bone pain.
Symptoms
Raymond Comenzo, USA
Among the most common early
Meletios A. Dimopoulos, GREECE
What Causes Multiple Myeloma?
symptoms are tiredness and weakness caused
Brian G.M. Durie, USA
The exact cause or causes of multi
by anemia. As the myeloma starts to spread
Dorotea Fantl, ARGENTINA
ple myeloma are as yet unknown. In general
deeper into the bone, the associated bone
Ian Franklin, SCOTLAND
Gösta Gahrton, SWEDEN
terms, it is believed that multiple myeloma
pain is a characteristic feature. Often, the
Jean-Luc Harousseau, FRANCE
results from a combination of the following:
spine and pelvic areas are affected first.
Vania Hungria, BRAZIL
1. An underlying immune susceptibility;
Persistent bone pain is frequently the reason
Douglas Joshua, AUSTRALIA
2. Plasma cell damage resulting from expo-
why patients seek medical help. As the dis
Tadamitsu Kishimoto, JAPAN
sure to one or several environmental toxic
ease continues to spread within the bone
Heinz Ludwig, AUSTRIA
factors or substances, including chemicals
marrow, the normal blood cells are reduced
Ian MacLennan, ENGLAND
and/or radiation. Chemicals suspected to be
and patients become prone to infection
James S. Malpas, ENGLAND
involved include those used in the agricul
and/or bleeding. As calcium released from
Hakan Mellstedt, SWEDEN
tural and wood industries, benzene, hair dyes
the bone and protein released from the
Angelina Rodriguez Morales, VENEZUELA
and other chemicals used in the cosmetics
myeloma cells build up, there can be pro
Gregory R. Mundy, USA
industry. Other toxic substances such as
gressive kidney damage. This can become a
Amara Nouel, VENEZUELA
Martin Oken, USA
heavy metals may also be involved. Both
major medical complication of the disease.
Linda Pilarski, CANADA
conventional dose radiation and higher dose
Raymond Powles, ENGLAND
atomic radiation have been associated with
Prognosis
Jesus San Miguel, SPAIN
this disease. More recent interest focuses on
Myeloma is a very variable disease.
Alan Solomon, USA
the role of a cancer causing virus as a trigger
In the early benign stages of the disease,
Pieter Sonneveld, THE NETHERLANDS
factor; however, this remains controversial.
Benjamin Van Camp, BELGIUM
Please see page 10
2

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TRANSPLANTATION FOR MYELOMA: THE MAYO CLINIC PHILOSOPHY
By Morie A. Gertz, MD and Martha Q. Lacy, MD
The outlook for patients with multiple
there is no absolute threshold. We have
that there are patients who are destined to do
myeloma continues to improve. Better prog-
transplanted patients up to age 74 if his/her
well no matter what form of therapy they
nostic factors help individualize therapy for
clinical condition permits. A patient age 50
receive. Patients who are below age 65, who
each patient. Of all
is likely to recover from
have a low beta 2 microglobulin (low tumor
of the new interven-
"It is our hope that with
intense treatment much
burden) and low percent plasma cells synthe
tions, however, none
sequential chemotherapy fol-
faster than someone age 70.
sizing DNA (low labeling index; slow growing
has appeared to have
Patients who have signifi
cells) have a very favorable outcome. It is not
such an impact on
lowed by transplant the course cant impairment in heart
clear that these patients benefit from early
management as blood of the disease can be extended." or in lung function are not
intensive therapy. Currently, we have been
stem cell and bone
good candidates because
trying to enroll patients on the national study
marrow transplantation. This article hopes
their risks are increased and could negate any
to answer the question regarding the timing
to deal with issues confronting patients with
benefit of the procedure. Good kidney func
of transplant. However, for those patients
multiple myeloma facing the decision about
tion is important. This is not to say that kid
who are not eligible or who do not wish to
treatment options, including transplant.
ney function needs to be normal. The kidney
participate in a randomized study, we have
may be functioning at 30% of normal and still
been treating with standard VAD
What are the principles of a transplant?
be adequate for transplant.
(Vincristine, Adriamycin, Dexamethasone).
Many believe that the transplant
We then collect their stem cells (seed cells)
itself is responsible for improved outcomes in
When is the optimal time to transplant?
from the blood and store them. If patients
patients with myeloma. This is not quite
The timing of transplant is currently
have shown an inadequate response at that
true. In myeloma higher doses of chemother
the subject of a national study. In this proto
point, immediate transplantation is recom
apy produce greater destruction of myeloma
col comparisons will be made between
mended. The risk of transplant is justified
cells. How much chemotherapy can be safely
patients who are transplanted immediately
because the failure to respond to chemothera
administered is limited by permanent damage
after diagnosis (within 6 months) and those
py is an adverse predictor of outcome. In
to the normal bone marrow cells. Should a
where transplant will be performed at the
patients who are chemotherapy-responsive,
very high dose of chemotherapy be adminis
time of first relapse of the disease. Until the
the stem cells are stored. Bone marrow trans-
tered with no special precautions, the
results of this study become
chemotherapy would irreversibly destroy the
Although the average patient plant will
available, what is a patient to
remain an
bone marrow.
do? The facts are: 1) In the
survived about a year longer, option. We
In bone marrow and stem cell transplanta
study looking at bone mar-
place these
tion the "seeds" that grow into bone marrow
this does not mean that every
row transplant versus stan-
patients on
are collected and stored frozen. High doses of
dard chemotherapy there was patient with MM who received conventional
chemotherapy are administered to destroy as
a benefit for those patients
chemotherapy
a transplant lived longer than
many myeloma cells as possible. After the
undergoing bone marrow
and transplant
chemotherapy leaves the body, these "seeds"
transplant. Bone marrow or
every patient with MM who did at the first sign
are returned to the patient to restore bone
stem cell transplantation
not receive a transplant.
of progression.
marrow function. The transplant does not
(using seeds from the blood
We have
kill any myeloma, but it overcomes the limi
stream rather than the bone marrow) should
patients who have done well for four years
tation to high dose chemotherapy, that being
be considered in every newly diagnosed
and still have stem cells frozen. It is our hope
permanent bone marrow damage.
myeloma patient under age 70. This is not to
that with sequential chemotherapy followed
say this is the correct strategy for every
by transplant the course of the disease can be
Who are candidates for a transplant?
patient, but every patient needs to know this
extended.
Bone marrow transplantation is rela
option exists. 2) When a transplant is per-
Although in one study transplant has been
tively safe. However, it is impossible to
formed after multiple relapses, the overall
shown to be superior to standard treatment,
administer high dose chemotherapy com
duration of response appears to be shorter
this does not mean it is a choice for everyone.
pletely risk free. After the "seeds" are thawed
than patients who are transplanted in the
The collection of the seeds, the transplant
and returned to the
early phase. This
and the post-transplant recovery come to
patient, there is a lag of The patient may decide what is addresses only
approximately six months during which
8-15 days before white
patients are too fatigued to work. For some
in their best interest when
response duration
cells reappear. During
and not overall out-
this is too much of a disruption and they may
this period of low white
given accurate information on come from diagno
elect conventional chemotherapy. Another
cell count there is risk
study suggests that patients who would have
expectations for response, sur- sis. 3) Prior expo-
of serious infection. A
sure to certain
been eligible for a transplant but were treated
careful assessment must
vival and quality of life.
chemotherapy, par-
with standard therapy had exceptionally good
be made as to which
ticularly Alkeran
results. Questions that persist include: Are
patients benefit the most from a transplant
(Melphalan) significantly impairs the ability
two transplants better than one? If two trans-
and which would be better served with a con
to collect healthy seeds from the bone mar-
plants are performed should they be done
servative approach.
row or blood stream. The decision regarding
back to back or the second one at the time of
Who represents a good transplant candi
transplant should be made prior to the initia
disease recurrence? Does it help to filter the
date? The patient's activity level is impor
tion of chemotherapy and not one year later.
seeds to eliminate myeloma cells?
tant. Patients who are incapable of being up
The average cost of a transplant is
and about most of the day are at higher risk
What is Mayo's current treatment philosophy
$75,000.00. This includes the collection of
for complications. Patients should be fully
for myeloma patients?
seed cells. These costs also cover hospitaliza-
active or have only minimal impairment from
Studies performed by Dr. Philip
their normal routine. Age is a factor, but
Greipp of our Institution have demonstrated
Please see page 10
3

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HIGH DOSE THERAPY: UNIVERSITY OF ARKANSAS APPROACH
by Bart Barlogie, MD
Despite three decades of
FIGURE 1: SOUTHWEST ONCOLOGY GROUP MYELOMA TRIALS
has surged as a result of the
clinical trial research with
reduction in morbidity and
standard dose chemotherapy
mortality associated with
and involving thousands of
the use of PBSC (Table 1).
patients with multiple
Collectively, these trials
myeloma (MM), still fewer
demonstrate that treatment
than 5% achieve true com-
related mortality can be
plete remission (CR), and
reduced to well below 5%,
median survival typically
CR rates of 30% to 40%
does not exceed 30-36
were routinely achieved,
months, depending upon
and median durations of
tumor stage and other prog-
event-free and overall sur
nostic variables present at
vival exceeded three and
diagnosis (Figure 1).
five years, respectively,
Combination chemo-thera-
depending on patient selec
py with addition of other
tion and treatment regimens
alkylating agents such as
employed.
cyclophosphamide or
Recognizing the notori
nitrosoureas and anthracy-
ously poor outcome of MM
clines has not improved the
patients treated with stan
prognosis of patients with MM beyond results
London explored high dose melphalan (140
dard dose chemotherapy and the promising
obtained with standard melphalan-prednisone
mg/m2) in nine patients with high risk newly
results of pilot autotransplant trials (see Table
(MP). This lack of progress with standard ther
diagnosed or advanced and refractory MM in
1), most physician were hesitant to conduct for
apy is perhaps not surprising considering that
1983. True CRs were observed following this
mal randomized trials. The French Myeloma
low doses of individual agents with mild anti-
risky procedure, which used no growth factor or
Intergroup (IFM) recently reported superior CR
tumor activity were combined so that, by
stem cell support. This advance prompted us to
rates and event-free and overall survival dura
design, the overall bone marrow toxicity was
introduce autologous bone marrow transplanta
tions among 100 newly diagnosed patients ran
not substantially different from that seen with
tion in the mid-80's, using patients' bone mar-
domized to either an autotransplant with mel
MP. In this fashion, MM physicians sought to
row that sometimes contained up to 30% plas
phalan (140 mg/m2) and total body irradiation
avoid excessive morbidity and mortality in typi
ma cells. The underlying hypothesis was that
(TBI, 800 cGY) after four cycles of standard
cally immunosuppressed elderly patients.
reinfusion of tumor cells with low proliferative
therapy with VMCP/VBAP or a continuation
High dose therapy (HDT) for MM was not
activity would not contribute significantly to
of the standard therapy (Figure 2). Our group
considered until Fefer and colleagues at the
disease recurrence and would not compete with
recently reported on a pair-mate analysis of 116
Fred Hutchinson Cancer Center performed
hematologic recovery. The introduction of
previously untreated patients receiving "Total
identical twin transplants in a few patients in
peripheral blood stem cells (PBSC) collected
Therapy" (remission induction with mutually
the early 1980's, some of whom have survived
after high dose chemotherapy with cyclophos
non-cross resistant regimens and double trans-
for more than 15 years with minimal disease
phamide or with a hematopoietic growth factor
plants) who were matched for age, beta-2-
activity. The rarity of identical twins and the
alone such as G-CSF was a major advance by
microglobulin and renal function with 116
morbidity and mortality associated with allo
shortening the duration of severe bone marrow
patients receiving mainly VAD as part of
geneic bone marrow transplantation prevented
suppression to only a few days from two weeks
Southwest Oncology Group trials. As in the
the systematic evaluation of dose-intensive
or longer in the case of autologous bone marrow
IFM randomized trial, this pair-mate analysis
therapy until the late Tim McElwain and col
transplantation. National and international
revealed superior remission rates and prolonged
leagues from the Royal Marsden Hospital in
interest in HDT trials for various stages of MM
event-free and overall survival durations among
T
the transplanted patients (intent-to-treat).
ABLE 1: PHASE II STUDIES FOR MULTIPLE MYELOMA
Results of standard SWOG treatment were
superior to the IFM standard treatment arm.
Likewise, probably due to greater dose intensity
with tandem transplants, our CR rate of 40%
was almost twice the IFM rate of 22% after a
single transplant; median event-free survival of
49 months with "Total Therapy" exceeded the
27 months median of the French study. The
apparently greater cytoreduction effected by two
versus one transplant has prompted the current
IFM randomized trial of one versus two trans-
plants, which is also comparing PBSC versus
autologous bone marrow as a source of stem
cells.
Investigators in the U.S. and Canada are
currently participating in a North American
Intergroup trial (INT 141, SWOG 9321) that
compares high dose chemoradiotherapy (mel
phalan [140 mg/m2] plus TBI [1200 cGY] with
Please see page 11
4

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AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION IN MM
by Prof. Jean-Luc Harousseau
Centre Hospitalier Regional et Universitaire de Nantes, Hotel Dieu, France
In the absence of any significant improve
diagnosed patients, the toxic death rate is
ing age, performance status and response to
ment of conventional dose chemotherapy,
less than 2%, which is not superior to the
initial chemotherapy. Historical compar
high dose therapy has been widely ex-plored
toxic death rate observed with conventional
isons have suggested that survival of patients
in multiple myeloma during the last 10
chemotherapy regimens like VAD.
less than 65 years of age responding to initial
years. High doses of melphalan, up to 140
Although autologous transplantation has
chemotherapy and receiving only standard
mg/m2 intravenously (HDM), yield high
been offered to patients aged 60-70 years,
therapy was similar to that reported in select
remission rates (including apparent com
and occasionally over 70, the feasibility of
ed series of patients given early high-dose
plete remissions) but at
the procedure is reduced
"Most importantly, autologous
therapy. Therefore, prospective randomized
the expense of severe
in patients over 60. In
trials were needed to compare standard
and durable myelosup-
transplantation has become a the recently published
chemotherapy with high-dose therapy. In
pression. Autologous
safe procedure with reduced multicentric French trial
1990, the Intergroupe Français due Myéloma
transplantation of
IFM90, autologous trans
(IFM) began a trial designed to address this
hematopoietic stem
morbidity and mortality."
plantation was actually
issue. The results of this trial have recently
cells, collected in the marrow or in the
less frequently performed in patients over
been published. Patients less than 65 years of
peripheral blood reduces the hematological
60: 58% of the patients randomly assigned
age with Durie-Salmon stage II or III multiple
toxicity of HDM and allows the use of mye
to undergo transplantation as compared to
myeloma were eligible and were randomly
loablative regimens with total body irradia
82% of patients aged 60 or less. The issue of
assigned at the time of diagnosis to receive
tion or higher doses of melphalan (200
age is critical since the median age of
either conventional chemotherapy or high-
mg/m2). As compared to autologous trans-
patients with multiple myeloma is approxi
dose therapy.
Conventional chemotherapy
plantation, allogeneic bone marrow trans-
mately 65 years. Furthermore, although
consisted of alternating cycles of VMCP and
plantation offers two important advantages:
HDM can be administered relatively safely
VBAP administered at 3-week intervals for 12
the absence of graft contaminant by the
to patients with renal failure, most physi
months for a total of 18 cycles. High-dose
malignant clone and the potential graft vs.
cians remain reluctant regarding high-dose
therapy was to be administered after 4 to 6
myeloma effect induced by the donor's
therapy in patients with severe renal failure.
cycles of VMCP/VBAP and consisted of
immune system. However, allogeneic bone
Finally, autologous transplantation is gener
HDM (140 mg/m2) and total body irradiation
marrow transplantation is restricted to
ally restricted to patients with a good perfor
followed by autologous unmanipulated bone
patients having an HLA-identical sibling
mance status and with no severe organ dys
marrow transplantation. Maintenance thera
and because of a high risk of severe toxicity,
function. As a conse
py with alpha-Interferon
to patients under the age of 50-55. In spite
quence of these limits, a
"...as there is no plateau of the was administered in
of a high toxic death rate, allogeneic bone
large proportion of
survival curves in published series both arms until relapse.
marrow transplantation yields encouraging
patients are currently
Between October
with adequate follow-up, some
results when applied early in the course of
not candidates for high-
1990 and May 1993,
the disease. A recent case-matched analysis
dose therapy with
form of maintenance therapy
200 patients (100 per
of data compiled in the European Blood and
autologous transplanta-
appears necessary."
arm) from 33 centers
Marrow Transplant Registry has shown no
tion. Preparative regi-
were evaluable. None
survival advantage of allogeneic as compared
mens without total body irradiation (high-
of the initial characteristics differed signifi
to autologous transplantation.
dose Melphalan 200 mg/m2) could be better
cantly between the treatment groups. The
tolerated and offered to more patients.
response to initial chemotherapy and the
WHO IS A CANDIDATE FOR AUTOLOGOUS
compliance to Interferon treatment were
TRANSPLANTATION?
WHAT ARE THE CURRENT RESULTS OF
also comparable.
AUTOLOGOUS TRANSPLANTATION?
Seventy four out of the 100 patients
Peripheral blood progenitors collected
assigned to high-dose therapy did actually
after moderately intensive chemotherapy
A number of monocentric or cooperative
undergo transplantation. Twenty-two of
(high dose cyclophosphamide) plus G-CSF
studies have been published reporting the
them (30%) achieved complete remission,
or GM-CSF, or after priming with G-CSF
results of high-dose therapy followed by
16 (22%) had a very good partial remission
alone are currently preferred to bone mar-
autologous transplantation. Results of all
(90% reduction of the M component) and
row, mainly because of more rapid
these uncontrolled studies have shown that
32 (43%) had a partial remission. The prob
hematopoietic reconstitution. The use of
autologous transplantation is a useful salvage
ability of event-free survival (EFS) and of
hemopoietic growth-factors after transplant
therapy for primary refractory patients and
overall survival (OS) five years after diagno
(G-CSF or GM-CSF) and of peripheral
for patients with chemosensitive relapses,
sis were 39% and 68%.
blood instead of bone marrow progenitors
although of limited value in patients with
The comparison of the two therapeutic
has dramatically reduced the duration of
resistant relapses. In some of these studies,
modalities was made on an intention-to-
myelosupression induced by high-dose thera
complete remission rates of 30 to 50% have
treat basis, all patients being studied in their
py. As a consequence the duration of hospi
been reported in newly diagnosed patients
assigned treatment groups. High-dose thera
talization and hopefully the costs of inten
and this more important tumor burden
py significantly improved the response rate
sive treatment have been significantly
reduction was apparently converted into a
since 38% of the high-dose therapy arm had
reduced.
prolongation of remission and survival.
a complete or very good partial remission as
Most importantly, autologous transplan
However, all these pilot studies are difficult
compared to 14% of the patients assigned to
tation has become a safe procedure with
to analyze because the recruitment of
the conventional chemotherapy arm.
reduced morbidity and mortality. In newly
patients was subject to selection bias regard-
Please see page 13
5

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BONE MARROW & PERIPHERAL BLOOD STEM CELL TRANSPLANTATION IN MM
by Prof. Gösta Gahrton
Department of Medicine, Huddinge Hospital, Sweden
The number of myeloma patients that are
chemotherapy intermittently, peripheral white
in multiple myeloma. The difficulty is to select
treated with bone marrow (BMT) or peripheral
blood cells containing stem cells are harvested
patients for this treatment option. For patients
blood stem cell transplantation (PBSCT) has
through leukapheresis. The cells are stored and
who do not respond to initial treatment by com
increased excessively over the last ten years.
frozen, and during this time the patient is con
bination chemotherapy, the early death rate with
Despite this increase the chances for long-term
ditioned for transplantation. Bone marrow
autologous and allogeneic transplants are about
survival or cure have not been dramatically
ablative therapy with total body irradiation
the same. Because of the lower relapse rate, allo
changed. I will discuss mainly the option of
and/or high-dose chemotherapy, usually mel
geneic transplantation may be an option for these
using BMT or PBSCT, but would like to point
phalan or cyclophosphamide or both, is given
patients. Also, in relapses following autologous
out that these treatment modalities, because of
and the patient is thereafter rescued by return
transplantation, allogeneic transplantation could
a biological age limit around 65 years, are indi
transfusion of his/her stored stem cells. There
be a possibility. There are now research protocols
cations for only about 25%-30% of the patients.
are obvious difficulties to understand how this
that try to diminish transplant-related mortality
The following options are at hand for a
method could work unless the peripheral blood
in allogeneic transplantation by decreasing the
patient with the disease: no treatment, moder
white cells are void of malignant plasma cells.
number of T-cells either by direct T-cell deple-
ate-dose conventional chemotherapy with mel
So far, it is not clear to what extent myeloma
tion or by selecting CD34-positive stem cells.
phalan + prednisone, combination chemothera
cells among the infused cells participate in the
Since graft-versus host disease induced by T-cells
py using several drugs without stem-cell support,
relapses that occur more frequently than when
is one of the important causes of early death in
autologous BMT or PBSCT, allogeneic BMT or
allogeneic cells are used. However, whether
allogeneic transplantations, such treatment pro
PBSCT. Already in the pipeline are transplan
they do or not, a randomized study performed
tocols may prove to be superior in the long run
tation with selected CD34-positive or CD 34-
by the Intergroup France has shown that autol
because of a lower relapse rate. Another possibili
positive/CD38-negative stem cells and cord-
ogous transplantation is superior to treatment
ty now being attempted is to select both T-cells
blood cells. Thus, it is getting more and more
with the VMCP-VBAP combination of drugs.
and CD34-positive cells from the donor. CD34-
difficult to advise patients concerning treatment
This study was made at the time when bone
positive cells are used to rescue the patient direct
options, because the advice is dependent on a
marrow was used for stem-cell support, but it
ly after conditioning, while T-cells are given later
number of factors, such as age, sex, type of pre
has repeatedly been shown in the registry of the
if there is disease progression or relapse following
vious treatment, response to previous treatment,
European Group for Blood and Marrow
the transplantation. T-cells may then induce a
B2-microglobulin in serum,
Transplantation
T-cell-versus-myeloma effect that may induce a
chromosomal aberrations, and "Many older patients can live a rela- (EBMT) that periph
remission. Thus, although allogeneic transplan
availability of the treatment
tively normal life for quite some time eral blood stem cell
tation must now be rated as a second choice after
option at a reasonable cost.
autologous transplantation for most patients, the
without cytotoxic drugs or irradiation." support is as good as
bone marrow support.
new research protocols may eventually change
NON-TRANSPLANT OPTIONS
Thus, one can conclude that high-dose mye
this view.
For patients with very moderate signs of
multiple myeloma without symptoms, so-called
loablative therapy followed by autologous bone
FUTURE POSSIBILITIES
Stage IA patients, there is frequently no need
marrow or stem cell transplantation in patients
As described above, current research proto
for early treatment. Many older patients can
below 65 years of age is superior to combination
cols for allogeneic transplantation include the
live a relatively normal life for quite some time
chemotherapy in treatment-requiring disease.
use of more selective peripheral stem cells, more
without cytotoxic drugs or irradiation. If symp
However, it has to be pointed out that in the
effective T-cell depletion and later T-cell infu
toms or skeletal changes appear or if there are
French study, the difference in survival
sions. Hopefully, there will be better antiviral
signs of progression, such therapy should be
between chemotherapy and autologous trans-
treatment options that could decrease the death
instituted. Many studies have been made to
plantation could not be seen until 30 months
rate in interstitial pneumonitis. Gene transfer
compare the original conventional treatment
from the start of
therapy may be used in
with melphalan+prednisone instituted by Dr.
treatment, although
"...current research protocols for allogeneic attempts to perform
Alexanian in Houston, Texas, to treatment
it appeared already 15 transplantation include the use of more selec- vaccination that
using a combination of drugs. In some of these
months after start of
studies, it has been claimed that the multi-drug
treatment in patients
tive peripheral stem cells, more effective T- would elicit a better
immune response to
regimen was superior to melphalan + pred
under 60 years of age.
cel depletion and later T-cell infusions."
the disease, or in so-
nisone, but in others the difference has not
ALLOGENEIC TRANSPLANTATION
called suicide gene therapy, a method to
been documented. For older patients, the mel
Allogeneic bone marrow transplantation is
increase the susceptibility of the myeloma cells
phalan+prednisone regimen is frequently easier
used less frequently than autologous transplanta
to specific drugs. Gene transfer therapy can also
to carry out and is therefore preferred.
tion. The reason is that allogeneic transplanta
be used to modulate the T-cell response and
Combinations of drugs without melphalan, like
tion is still hampered by a high transplant-related
thus the graft-versus-host disease.
the VMCP-VBAP regimen (vincristine, mel
mortality. Overall, about 40% of the patients
In autologous transplantation higher purifi
phalan, cyclophosphamide, prednisone; vin
will die in such complications. In a comparison
cation of the stem cells may be an important
cristine, BCNU, adriamycin (doxorubicin),
made by the EBMT, transplant-related mortality
option, either by fishing out the CD34-positive
prednisone) or the less toxic VAD (vincristine,
was about 40% in allogeneic transplantation, but
stem cells or by cleaning the infusate from
adriamycin [doxorubicin], dexamethasone) reg
only 14% with autologous transplantation.
myeloma cells using immunological methods.
imen are preferable for the pretreatment period
During the last five years, the transplant-related
Attempts are also being made using autologous
before autologous or allogeneic transplantation.
mortality has decreased even more for autologous
transplantation in two sequences, i.e.. with
A
transplants to about 7%, while it has not clearly
myeloablative therapy twice with a few months
UTOLOGOUS TRANSPLANTATION
Autologous bone marrow transplantation
changed for allogeneic transplants. However, the
interval, each time followed by autologous
has for safety and practical reasons been substi
relapse rate is significantly higher with autologous
stem-cell transplants. Hopefully, these mea
tuted for autologous peripheral blood stem cell
transplants than with allogeneic transplants.
sures will eventually cure more patients with
transplantation. After a period of some months
Thus, with the goal to cure the disease, it appears
multiple myeloma.
when the patient is treated with combination
that there is stil a place for allogeneic transplants
6

---

ROLE OF HEMATOPOIETIC TRANSPLANTATION IN MULTIPLE MYELOMA
by Dr. Kenneth C. Anderson
Dana Farber Cancer Institute, Boston, Massachusetts, USA
There were an estimated 14,400 new
MM, low serum B2 microglobulin, stage I
strated donor CD4+ T cells in the patient
cases of multiple myeloma (MM) in 1996,
disease at diagnosis, having received one
transiently after transplantation which pro
with a mean age of affected individuals for
line of previous treatment, and being in CR
liferated specifically in response to the MM
men of 62 years (75% <age 70) and women
prior to BMT. In the EBMT experience,
protein. Efforts are ongoing to determine
of 61 years (79% <age 70). Although multi
transplant related mortality overall is 40%
whether these strategies can result in allo
ple studies have documented the sensitivity
(50% in males). In a recent update of the
geneic immunity to MM.
of MM cells to radiotherapy and chemother
allografting experience in Seattle, actuarial
High dose chemoradiotherapy followed
apy, durable complete responses (CR) are
probabilities of
by transplan
"A most encouraging lead for new treatment
rare, and this disease remains uniformly
overall survival
tation of
fatal. Oral administration of melphalan and
(OS) and event
approaches for MM stems from reports of CRs either autol
prednisone (MP) produces objective
free survival (EFS)
after the administration of alkylating agents ogous BM or
responses in 50-60% patients; although some
for the 36%
(i.e., melphalan, cyclophosphamide, busulfan) PBPCs has
combination chemotherapy programs have
patients achieving
in higher-than conventional doses..."
more com-
been reported to be superior to MP, prospec
CR were 50 + 0.21
monly been
tive randomized trials of MP vs various drug
and 43 + 17, respectively at 4.5 years.
utilized to treat patients with MM.
combinations have failed to clearly show
Adverse prognostic factors included: trans-
Although CR and PR rates are each approx
that combination chemotherapy is better
plantation > 1 year from diagnosis; serum B2
imately 40%, the median duration of these
than MP. Studies from Scandinavia, Italy
microglo-bulin >2.5 at transplant; female
responses has unfortunately been only 24-36
and Canada suggest that a prolongation of
patients transplanted from male donors; hav
months. Patients with sensitive disease and
response to conventional therapy can be
ing received > eight cycles of chemotherapy;
who are less heavily pretreated have the
obtained by the use of maintenance recom
and Durie Salmon Stage III disease at the
most favorable outcomes. For example,
binant alpha interferon (IFN) therapy, i.e.
time of BMT. Thirty-five (44%) patients
Attal and colleagues treated 35 patients
in patients with near CR to chemotherapy
died of transplant-related causes within 100
with newly diagnosed MM with combina
or those with IgA or Bence Jones MM. In
days of BMT. In the United States multi-
tion chemotherapy (vincristine, doxorubicin
contrast, studies from Germany and the
group randomized trial of high dose versus
and dexamethasone) or VMCP (vincristine,
Southwest Oncology Group have not con-
conventional therapy in MM, there were 15
melphalan, cyclophosphamide and pred
firmed a benefit for IFN therapy and its role
deaths among 36 patients registered to the
nisone) followed by high dose melphalan,
is under evaluation in several ongoing
allogeneic transplant arm. As a result of this
autologous BMT, and maintenance IFN:
randomized trials. Thus, to date, conven
excessive toxicity, the allografting arm has
53% patients achieved CR and 40% PR; and
tional therapy has not resulted in either long
been closed and strategies encouraged to
PFS at 33 months was 85% and 24% for
term disease free survival or cure in MM.
avoid transplant-related morbidity and mor
patients with CR and PR, respectively.
A most encouraging lead for new treat
tality. At our Center, we have carried out
More recently, Cunningham and coworkers
ment approaches for MM stems from reports
T (CD6) depleted allografing using histo
have treated 84 patients with C-VAMP
of CRs after the administration of alkylating
compatible sibling donors in 37 MM
(cyclophosphamide, vincristine, methyl
agents (i.e., melphalan, cyclophosphamide,
patients, with only 4 (11%) transplant relat
prednisolone) followed by melphalan and
busulfan) in higher-than conventional doses
ed deaths; therefore transplantation of T cell
autologous BMT; patients were then ran
with or without total body irradiation (TBI),
depleted allogeneic bone marrow in this
domized to either receive or not receive
followed by transplantation of syngeneic
patient population has acceptable toxicity.
IFN. Progression free survival for patients
(identical twin), allogeneic, or autologous
Recent exciting data has shown that in-
randomized to IFN was 39 months versus 27
bone marrow (BM), or of autologous periph
fusions of lymphocytes collected from the
months (p<0.025) for those in the control
eral blood progenitor cells (PBPCs). Reduc
marrow donor (DLI) can achieve marked
group. Most importantly, a recently com
tion in tumor mass in some cases has been
responses when administered to treat re-
pleted national French trial of 200 patients
dramatic, with CR rates commonly in the
lapsed MM after allografting, providing for
with MM who received two courses of
40% range and a similar number of partial
the first time direct evidence of graft versus
VMCP alternating with VBAP (vincristine,
responses (PRs). Syngeneic BMT has been
MM affect. Studies at our Institute have
BCNU, adria-mycin, prednisone) and then
done infrequently, but patients reported
shown that CD8 depleted DLI resulted in
were randomized to receive either conven
from Seattle remain disease free at long
responses in the majority of cases, in some
tional chemotherapy (8 additional courses of
intervals post BMT. The European Bone
patients in the absence of graft-versus host
VMCP/VBAP) or high dose therapy (mel
Marrow Transplant Group (EBMT) has
disease (GVHD). Given the high rate of
phalan and TBI) followed by autologous
recently reported on allografting in 162
relapse after allografting noted in all series to
BMT has demonstrated significantly higher
patients with MM: overall actuarial survival
date, we are currently using CD8 depleted
response rates, PFS and OS for those
was 32% at 4 years and 28% at 7 years for
DLI at 6 months post allografting, when
patients treated with high dose compared to
the 72 (44%) patients who achieved CR
donor hematopoiesis is achieved, in an
those receiving conventional therapy.
after BMT. However, overall progression
attempt to prevent relapse in patients who
Response rate in the high dose and conven
free survival (PFS) was 34% at 6 years, and
have achieved CR and to treat residual dis
tional arms were 81% versus 57%, respec
only 9 patients remain in continuing CR at
ease in patients with PRs after allografting.
tively. The 5 year probability of EFS and
>4 years post allografting. Favorable pre-
Finally, Kwak et al have recently immunized
OS was 28% and 52%, respectively, in recip-
BMT prognostic factors for both response to
the allogeneic marrow donor to the patient's
and survival after BMT were female sex, IgA
MM protein before transplant and demon-
Please see page 13
7

---

ROLE OF STEM CELL TRANSPLANTATION IN MULTIPLE MYELOMA
by Prof. Jesus F. San Miguel
Hospital Universitario de Salamanca, Salamanca, Spain
The use of high dose chemotherapy fol
both a graft-versus-host disease (GVHD) and
with tandem transplants results in a higher CR
lowed by stem cell support has become one of
possibly a graft-versus-myeloma effect (GVM).
rate (40%) and EFS (49 mos.). Whether this
the most attractive therapeutic approaches in
The former results in high morbidity and mor
will eventually translate into longer overall sur
MM since, in relation to conventional
tality (around 40% in some series) while the
vival needs to be confirmed. Several random
chemotherapy, it increases the number of com
GVM effect may contribute to the eradication
ized trials in different countries are underway.
plete remissions (CR), duration of event free
of the residual disease, reducing the risk of
Regarding the positive benefits of double vs sin
survival (EFS) and probably, overall survival
relapse. Due to the high toxicity of allogeneic
gle transplant suggested by the Arkansas and
(OS). However, there are still many questions
transplants, our policy is first to offer an auto-
Karolinska studies, appropriate randomized tri
surrounding the transplant itself, as well as the
graft and to reserve allografting for patients that
als, such as the one by the French group (IFM),
selection of candidates:
relapse (providing that the patient is <55 years
will help to clarify this.
· Autologous of allogeneic transplant?
and has a histocompatible sibling donor - two
4. What does transplantation hope to achieve?
· What is the best source of stem cells?
prerequisites for allografting). However, it is
The final goal of transplantation is to pro-
· What is the optimal conditioning regimen?
probable that the toxicity of this procedure will
vide stem cell support for myeloablative
· Is purging cost-effective?
be substantially reduced with the new protocols
chemotherapy/ radiotherapy specifically
· Should CR be a primary goal?
to abrogate GVHD, and the use of peripheral
designed to reduce the tumor load, ideally up to
· Who are the best candidates?
blood stem cells to shorten the duration of bone
its eradication. However, eradication of the
· When to transplant?
marrow suppression.
myeloma clone is difficult to achieve because
The answers to these questions will be found
residual disease usually persists. At present, the
through some of the well designed clinical trials
2. Source of stem cells:
main goals are to increase the rate of complete
that are currently being undertaken. These
There are two major sources of stem cells:
remissions, to prolong EFS and subsequently
will lead to the design of predictive models for
the bone marrow (BM) or the peripheral blood
OS, and to provide a better quality of life for
the identification of patients most likely to
(PB). Most available data shows that PB stem
our patients.
benefit from transplant, thereby avoiding the
cells (PBSC), collected after stimulation with
An important inconvenience of conven
financial and emotional burden on those
hematopoietic growth factors with or without
tional chemotherapy is that the patient is ther
unlikely to benefit. Patients should be aware
high dose chemotherapy, accelerates recovery
apy-dependent for at least one year, and then
that myeloma is a heterogeneous disease and
from aplasia, which results in a significant re
again as soon as relapse occurs. Transplant
each patient has individual biological features
duction in mortality, particularly when due to
ation should provide a durable control of the
that affect response to therapy and prognosis.
infections. In the experience of the Spanish
disease making the patient therapy-indepen
For this reason, in patients with multiple
myeloma transplant group that includes over
dent for a long time. The major tumor reduc
myeloma, the optimal therapeutic option
400 patients, transplant related mortality was
tion after transplant should result in a decrease
might not be the specific type of treatment
only 4%. This experience with autografting
in complications and an improvement in quali
given, but the referral to a specialized center
has stimulated the use of PBSC also for allo
ty of life. Studies especially designed to evalu
involved in such trials, which will assure the
grafting. The initial reluctance about a possible
ate these items will clarify the overall benefit of
best disease control with good alternatives if
increase in acute GVHD has apparently not
autografting. On the other hand, in the case of
the treatment fails.
been confirmed and it is possible that PBSC
may result in a reduction in the mortality of
allogeneic transplantation, the clinical prob
1. Autologous or allogeneic?
allografting, making this type of transplant
lems derived from GVHD may lead to an
When comparing these two types of trans-
more feasible. The use of cord blood as an
impairment in quality of life at least during the
plants, one should keep in mind that allograft
alternative source of stem cells is still at an early
early post-transplant period.
ing is usually restricted to patients under 55
experimental level.
5. Who's a transplant candidate?
years with an histocompatible donor, while
Autotransplants can be offered to sympto
these restrictions do not apply to autografting.
3. Transplant vs. standard chemotherapy:
matic myeloma patients up to 70 years, or even
In both types of transplants the chemotherapy
The French Myeloma Intergroup (IFM) has
older if the patient is in a very good clinical
used to eradicate the malignant (myelomatous)
recently shown, through a randomized study,
condition. The best candidates are probably
cells is basically the same, the differences lying
that autotransplant (melphalan + TBI) was
those patients who have responded to initial
in the source of stem cells used to rescue the
superior to conventional chemotherapy
chemotherapy or have primary resistant disease
patient from the myeloablative therapy: cells
(VMCP/VBAP) in terms of CR (22% vs 5%),
or an early relapse, while transplants appear to
from a donor in allogeneic transplants and cells
EFS (27 vs 18 months) and OS (60+ vs 37
months). The major criticism of this study is
be less useful during later phases of disease.
harvested from the same patient and then
the poor results obtained with standard therapy
Candidates for allogeneic transplants are
frozen in autologous transplantation. There-
in a relative low risk group of patients (<65
patients <55 years of age with a histocompati
fore, in allogeneic transplants there is no risk of
years old and good performance). Upon analyz
ble sibling donor or patients <40 years with an
re-infusing myeloma cells, but this will proba
ing the data of a similar cohort of patients treat
unrelated donor. Never-theless, to be a candi
bly not result in a major difference in disease
ed with conventional chemotherapy in the
date for a transplant option doesn't mean that
outcome since theoretically we can also select-
Spanish PETHEMA study group, the OS (60
is the best choice, and each case must be con
purge normal stem cells within autografts by
months) is clearly superior (Bladé, et al, Journal
sidered individually, particularly upon con-
negative depletion of contaminating MM cells
Clinical). Nevertheless, the results obtained by
fronting the pros and cons of auto vs allograft
or positive selection of CD34 cells. In fact, one
the Arkansas group with double transplants,
ing or auto vs conventional chemotherapy. For
of the most relevant differences between allo
compared to a pair-matched historical control
this purpose, information on prognostic factors
grafting and autografting derives from the
population obtained from the SWOG trials,
could help both patients and physicians in clin
immune response generated when foreign cells
confirms the superiority of transplants, and sug
ical decision making. We already know which
are infused into an individual, which produces
gests that further treatment intensifications
Please see page 14
8

---

BONE MARROW TRANSPLANTATION IN MULTIPLE MYELOMA
by Dr. Mohamad Hussein
The Cleveland Clinic, Cleveland, Ohio
Over the past several months, we
acute leukemia, studies reinfusing purged
tion has not been as popular as autologous
have read the thoughts and opinions of
bone marrow did not appear to improve the
transplant.
leading myeloma physicians on the contro
outcome of autologous bone marrow trans-
If an appropriate donor is available,
versial topic of bone marrow and/or stem
plantation, and T-cell depletion in allo
several pretransplant prognostic factors
cell transplantation in the management of
geneic bone marrow transplantation to
could define the group of patients that
the disease. With all the available data, the
acute leukemia is plagued by the decreased
would do better. Favorable pretransplant
jury is still out relative to the role of high-
graft versus leukemia effect, the disease biol
prognostic factors for survival are female sex,
dose chemotherapy salvaged by bone
ogy might be different, and benefits might
Stage I disease at diagnosis, one line of pre
marrow or stem cell transplantation. The
be elicited in multiple myeloma. The results
vious treatment and being in remission
approaches to therapy of multiple myeloma
of these studies are eagerly awaited.
before transplantation. The subtype
has varied from a conservative to a more
immunoglobulin A "IgA" and a low b2
Why is High Dose Therapy and Bone
aggressive one. The Mayo Clinic's approach
microglobulin level also tend to have a
Marrow Transplantation Considered in
is one of avoiding aggressive therapy in
Multiple Myeloma?
favorable prognostic impact.
patients with good prognostic factors i.e. age
For the last 30 years, conventional
At this stage, however, there are no
below 65, low b2 microglobulin and low
dose melphalan and prednisone or cortico
randomized trials available to justify the 30-
plasma cell labeling
Although complete remission rates
40% transplant related deaths associated
steroids alone at vari
index. Even though
with this procedure.
range from 25 to 80%, the median ous dose levels have
this is a favorable
· Autologous Bone Marrow (ABMT) or
approach, the selec-
duration of these responses,
been the mainstay of
treatment for patients
Peripheral Stem Cell Transplant (APSCT)
tivity could bias cur-
unfortunately, has been only
with multiple myelo
The low complication profile, as
rent trials evaluating
24 to 36 months, at best.
ma. Complete remis
well as the potential of performing the pro
the role of aggressive
sions are unusual, and few if any are cured
cedure safely up to the age of 70 years, make
therapy versus standard therapy. This
with conventional therapy.
this a very attractive treatment method and,
is probably balanced by the more aggressive
This has prompted the interest in
hence, heavily studied. Unfortunately, only
direction taken at the University of
studying high dose therapy, which has
one prospective randomized trial by the
Arkansas where the investigators at this
demonstrated a higher incidence of com
French Group has been reported in the liter
institution are studying the role of single and
plete remissions. The use of stem cell or
ature.
double high dose chemotherapy followed by
bone marrow salvage does allow the admin
Transplantation of APSC alone or
stem cell and/or bone marrow transplanta
istration of high doses of chemotherapy in a
as a supplement to ABM has been reported.
tion. The group at the University of
relatively safe fashion. Although complete
Engraftment of all lineages is more rapidly
Arkansas feels that higher CR rates might
remission rates range from 25 to 80%, the
achieved with APSCT than after autologous
translate into longer durations of event free
median duration of these responses, unfortu
bone marrow grafting. Also, a theoretical
and overall survival. The French Myeloma
nately, has been only 24 to 36 months, at
advantage of APSCT is less contamination
Intergroup recently reported in a randomized
best.
with myeloma cells compared with ABMT.
trial superior CR event free and overall
What are the different types of bone marrow
Who Should Receive Autologous
survival among the patients who received
transplantation? What are the pros and cons
Transplantation?
autologous bone marrow transplantation
for different types of transplant and
Autologous PSC or bone marrow
versus standard chemotherapy. This study
conventional therapy:
transplantation are more likely to be associ
involved a large number of newly diagnosed
ated with adverse outcomes if patients have
multiple myeloma patients. Those results
· Syngeneic (identical twin) or Allogeneic
b2 microglobulin levels more than 2.5
have been questioned on both methodologi
(related or unrelated) Bone Marrow Transplant
mg/ml, received more than two regimens of
cal and statistical grounds, however. In an
The advantage of this procedure is
prior therapy, time to transplant longer that
attempt to define the role of decreasing the
the use of uncontaminated bone marrow to
3 years from diagnosis, and prior radiation
number of malignant cells, and/or graft
salvage the recipient. Moreover, the use of
therapy.
versus host following stem cell or bone mar-
allogeneic bone marrow transplants may be
The criteria to choose the patient
row transplantation, respectively, the inves
associated with a graft-versus-myeloma
who could potentially benefit from ABMT
tigators at the Dana Farber are evaluating
effect, but there have not been enough syn
or APSCT are far from clear. In a recent
the utility of in vitro manipulation of bone
geneic transplants reported in patients with
publication, the outcome of patients with
marrow. The group is studying the utility of
multiple myeloma to make meaningful com
multiple myeloma who were potential candi
in vitro treatment with monoclonal anti-
parisons of relapse rates to clarify this issue.
dates for early high dose therapy followed by
bodies to rid autologous bone marrow from
The median age at diagnosis for
APSCT or ABMT was evaluated. The
residual multiple myeloma cells prior to
patients with multiple myeloma is 70 years,
median survival time of patients who were
reinfusion into the patient. The utility of
while 55 is the usual upper age limit for allo
less than 65 years of age and who responded
depleting allogeneic bone marrow from
geneic bone marrow transplantation in most
to initial chemotherapy was 5 years. This
T-cells that are responsible for the graft
transplant centers. In addition, most
survival duration is similar to that reported
versus host activity is also being studied in
patients do not have syngeneic or suitable
in selected series of patients given early high
an attempt to reduce the complications that
allogeneic donors. For these reasons, syn
accompany the procedure. Even though, in
geneic/allogeneic bone marrow transplanta-
Please see page 14
9

---

Transplantation in the 1990s -
What is Myeloma - continued
the technique is appropriate. The patient can
continued
then acquire the information necessary to
known as smoldering/indolent myeloma, the
make an informed decision.
the other negative aspects of aggressive ther
number of plasma cells rise but no treatment
apy, supportive care needs, and the like?
is required. It can then either progress slow
How should one treat a patient who suffers
It will be seen from the diverse
ly and require treatment over a period of
from multiple myeloma?
We are asked this question on a
opinions expressed in this anthology that
many years or be much more aggressive
daily basis. Our primary value is that the
anything from double or tandem transplant
needing extensive chemotherapy and/or
needs of the patient come first. Although
up front as a primary approach to treatment
radiation even within the first 1 or 2 years.
randomized studies can help us decipher
for all patients to transplant, predominantly
which therapies on average provide the
for patients who have failed with primary
Treatment
longest overall survival, they don't address
therapy, can be the recommended strategy of
There are three treatment stages of myeloma:
the fact that all patients with multiple
individual specialists.
1. Induction ­ intial treatment to achieve
myeloma are different in one way or anoth
Clearly, it is a decision involving
response;
er. It is critical that the patient be presented
both the physician and the individual
2. Maintenance ­ treatment used to sus
the data needed to make the final decision
patient involved. We still do not know the
tain remission and delay or prevent relapse;
as to what therapy is appropriate for them
relative benefit of high dose therapy with
3. Relapse ­ treatment for patients whose
guided by a knowledgeable physician pre
senting the facts in the most understandable
stem cell rescue in patients with different
disease progresses after an initial response to
fashion. This should be done preferably
types of myeloma. Is transplant particularly
therapy.
with a physician knowledgeable in various
helpful for patients with aggressive disease?
aspects of the biology of multiple myeloma
with an initial high tumor burden of myelo
Two major types of therapy are used to con
and bone marrow transplantation.
ma? with a very high growth rate of the
trol myeloma:
myeloma with an elevated myeloma cell
1. Radiation ­ to treat local areas of bone
So what is the data?
labeling index? with many initial complica
destruction and to relieve pain or prevent
The prospective randomized study
tions from the disease including bone dam-
fracture from weakness;
done by Attal, et al., demonstrates a survival
age and the like? Is high dose therapy with
2. Chemotherapy ­ to gain more general
benefit for patients who are transplanted
transplant more important for patients with
control of the disease.
compared to those that receive systemic
early disease in an effort to preserve the
The majority of myeloma patients
chemotherapy. Although the average
patient survived about a year longer, this
maximum remission for the longest period of
benefit from chemotherapy with or without
does not mean that every patient with MM
time? These questions remain to be
local radiation. The extent to which high
who received a transplant lived longer than
answered. Thus far, only one randomized
dose therapy with transplant rescue can
every patient with MM who did not receive
study comparing high dose therapy with tra
result in better survival is the focus of the
a transplant. Unfortunately, no patient is
ditional therapy has been published. There
current anthology. The majority of patients
average and all patients bring to the deci
is only one preliminary study evaluating the
relapse and suffer new bone disease with
sion-making process religious beliefs, philo
role of 2 transplants up front versus just 1
pain, fractures and potential hypercalcemia.
sophical tenets and general feelings about
transplant which showed no clear cut bene
These are uncomfortable and costly compli
quality of life versus quantity of life. Trans-
fit for the double transplant approach.
cations and can result in irreversible damage
plant does not offer a cure. It does not even
Therefore, for the next few years,
to organs such as the kidneys.
offer what some may consider a major pro
the various opinions expressed in this
Progress thus far has been slow in
longation of life. It does require a significant
initial investment of time and effort and yes,
anthology need to be considered in evaluat
conquering this disease, however the future
some sufferng. So, intelligent and knowl
ing what may be best for an individual
holds much promise.
edgeable patients when faced with the same
patient. It is hoped that it will be helpful to
facts can come up with vastly different deci
see the different perspectives of different
Mayo Clinic - continued
sions that are right for them and their partic
centers and different physicians in evaluat
ular situation but diametrically opposed to
ing what might be best.
tion in a specialized unit staffed by a team of
each other. In 1997, we performed 18 trans-
One option which has not been
transplant physicians and nurses. Many
plants for MM and we obtained peripheral
fully discussed until very recently is the role
insurers and Medicare consider transplanta
blood stem cells on an additional 96 for use
of harvesting stem cells at the time of first
tion experimental. With privately insured
if they should fail therapy.
complete remission for use not immediately
patients there is specific information that
We currently discuss bone marrow
needs to be filed with the insurance company
but at some future time when additional
transplant with every patient that we see
before approval. Approval may require a spe
under the age of 70 who would be a suitable
therapy may be required to induce an excel-
cific protocol for transplant. A system has to
candidate based on cardiac and hepatic
lent remission. This concept of harvesting
be in place for analysis so the insurance com
function. All patients should be aware of
and freezing is definitely better appreciated
pany can be certain that the center can do a
this procedure and its potential role in the
now and is an option which needs to be dis
good job. The transplant center should have
overall management of myeloma. If patients
cussed in detail at the time of the initial
experience with myeloma. Between one-
are candidates and wish to consider partici
decision process.
third and one-half of patients are denied by
pation in a clinical trial, our first priority is
Upcoming issues of Myeloma Today
insurance carriers.
to try to answer the important questions
will continue to address new questions con
raised by the National Intergroup Myeloma
cerning the role of high dose transplant, but
What should the patient be aware of?
Transplant Study that compares early trans-
the perspective over the past decade may be
First, transplant can play an impor
plant with late transplant. This is a study
tant role in management. This is not to say it
helpful in evaluating these new perspectives
that will provide important answers.
is required for every patient. Patients should
However, for patients who are not interested
as they emerge.
be aware that transplant is an option.
Consultation with a specialist that performs
Please see next page
10

---

Mayo Clinic - continued
of optimal timing of myeloablative therapy,
especially in the presence of low beta-2-
i.e., early following remission induction or sal-
microglobulin levels, in line with our current
in participating in this protocol, or who do
vage after standard VBMCP fails.
practice of a scheduled tandem transplants
not satisfy the eligibility criteria, we chose
Many investigators have limited HDT trials
within six months. If only a single autotrans
the arm in that protocol that assigns patients
to patients aged 60 or 65 years with relatively
plant is planned, we recommend that sufficient
to late transplantation and follow a schedule
normal renal function (creatinine < 2mg/dL).
PBSC be obtained prior to the first transplant
of four cycles of VAD followed by mobiliza
Based on our recent demonstration that mel-
to allow a subsequent transplant procedure, if
tion and collection of stem cells followed by
phalan pharmacology is not affected by rental
needed. Selected patients who relapse after two
VBMCP with transplant at first progression.
function, we have performed HDT trials with
transplants also deserve further therapeutic con-
Whether this will be in any way inferior or
high dose melphalan (200 mg/m2) in 23
sideration, especially if pre-transplant beta-2-
superior to early transplant is not known and
patients with creatinine levels >2 mg/dL, in-
microglobulin was low and relapse occurred
will not be known for a number of years.
cluding 7 patients on hemodialysis. Compared
more than 12 months after two transplants.
Based on a retrospective analysis of the 82
with 46 patients with creatinine levels <2
MM tumor cells exhibit complex genetic
Mayo Clinic patients who have come to
mg/dL who were matched for C-reactive pro-
abnormalities which may explain their marked
transplant thus far, our experience suggests
tein, immunoglobulin isotype, duration of prior
resistance to currently available treatment
that the use of late transplant does not result
therapy, and sensitivity to standard therapy, the
modalities. Clinical trials using randomized
in inferior overall survival and avoids the
renal failure group had an early mortality of 0%
concurrent or historical controls both demon-
early morbidities and possible mortalities
versus 2% in patients without renal compro-
strate that "more is better" even to the point of
that can be seen from time to time with stem
mise; the amount of CD34+/kg collected as
tandem transplants that can be performed
cell transplantation.
well as marrow recovery post-transplantation
safely in patients older than 70 years or those
In patients with good prognostic
was identical among the two groups. Thus,
with renal failure (when using melphalan +
factors our colleague, Philip Greipp, and his
melphalan 200 mg/m2, one of the most active
TBI) with a transplant-related mortality of well
associaties, have demonstrated there are sub-
regimens for MM, should no longer be withheld
under 5%. Work in progress will shed light on
sets of patients with median survivals that
from patients who have renal failure, which is
the importance of early versus delayed trans-
will exceed six years. This particularly is
usually the result of high tumor burden with
plantation (SWOG 9321), double versus a sin
true for patients with low beta 2 microglobu
hypercalcemia, dehydration and excessive
gle transplant (IFM study ongoing in France),
lin, low labeling index, low LDH and low
Bence Jones proteinuria. In fact, improvement
and on the use of CD34 selection as a means of
serum IL6 receptor levels. This is a very spe
in renal function (creatinine < 1.2 mg/dL) was
reducing the likelihood of tumor cell reinfusion
cialized subset of patients with MM who
observed among 43% of the 23 patients in renal
in the autologous transplantation process.
obviously will do well with conventional
failure who were treated with PBSC-supported
With the above in mind, I try to answer
therapy. This is not to say they won't do
HDT with melphalan 200 mg/m2.
some of the specific questions raised by
even better with dose-intensive chemothera
Another critical variable in MM therapy
Myeloma Today.
py and stem cell transplant but, when the
pertains to patients' frequently advanced age,
survival of the "control" group is that long, it
which has been one of the main obstacles, his-
When to Transplant
would be nearly impossible to demonstrate a
torically, to investigating dose intensification.
The history of HDT for MM clearly shows
survival benefit with transplant unless many
Examination of survival revealed no difference
that superior results are obtained when trans-
hundreds were entered into a study limited
as a function of age by decade. In fact, we have
plants are performed relatively early in the dis
to patients with favorable prognostic factors.
now applied HDT to 23 patients over the age of
ease course, before additional resistance has
Thus, we fear the ultimate answer will not be
70, including one at age 82.
developed as a result of further mutations
answered with clarity for some time to come
An important concern for both patients and
caused by long term administration of low dose
but it would be incorrect to surmise that
referring physicians is life after relapse post-
alkylating agents, such as melphalan and
transplant would be indicated for all of these
transplant. Our data, using a regimen of high
nitrosoureas. In an analysis of 542 patients
patients or none of these patients. The
dose dexamethasone combination chemothera-
enrolled in double transplant trials at the
patient may decide what is in their best
py with DCEP, or further transplant, indicate
Arkansas Cancer Research Center, we identi
interest when given accurate information on
that post-transplant relapse should not be con-
fied that > 12 months of prior standard therapy
expectations for response, survival and quali
sidered an ultimate treatment failure. Patients
was an important unfavorable feature for both
ty of life.
with only one prior transplant definitely benefit
event-free and overall survival, in addition to
We commend the IMF for the out-
from timely administration of further HDT,
standing service they have performed in
Please see page 12
keeping the public informed of new develop
FIGURE 2: COMPARTIVE TRIALS OF STANDARD VS. HIGH DOSE THERAPY:
ments in the management of multiple
myeloma, as well as the realities, difficulties
and daily frustrations that occur in dealing
with this disease.
Dr. Barlogie ­ continued
PBSC support) with VBMCP standard
chemotherapy (M2 protocol) in a randomized
fashion. A mandatory PBSC collection is also
included in the standard treatment arm and the
plan for salvage transplantation upon relapse
after VBMCP assures that all patients are candi
dates for HDT, an important ethical considera
tion in light of the improved prognosis with
HDT suggested by several Phase II autotrans
plant trials and, more recently, by the IFM ran
domized trial and our pair-mate analysis.
INT141/SWOG 9321 will answer the question
11

---

Dr. Barlogie ­ continued
transplantation while the treatment-related
Prof. Harousseau - continued
mortality is not higher than with standard dose
cytogenetics and pre-transplant beta-2-
chemotherapy.
In the conventional chemotherapy arm,
microglobulin level. The question of HDT
the median EFS was 18 months and the
timing will be formally answered by the ongo
Transplant vs. Standard Treatment
median OS 37 months. The probability of
ing Intergroup trial (INT141/SWOG 9321)
Fig. 2 details the results of the IFM random
EFS and OS for 5 years after the diagnosis
that compares timely transplant after remission
ized trial and the Arkansas double transplant
were respectively 10% to 12%. In the high-
induction with transplant as a salvage strategy
results compared to a pair-mated historical con
dose therapy arm, the median EFS was 27
for patients who relapse on standard VBMCP.
trol population. For the transplant arm, both
months and the median OS has not been
Thus, while this trial will resolve the issue of
studies included all patients in whom a trans-
reached. The probability of EFS and OS for
early versus delayed transplantation, the sal
plant was intended and not just those in whom
5 years after the diagnosis were respectively
vage transplant approach, in all likelihood, will
a transplant was actually performed (intent-to-
28% and 52%.
not be a late intervention applied after multiple
treat approach). Regimen-related mortality
The IFM 90 trial was designed to avoid
salvage strategies have been exhausted. The
was low and improved outcome is apparent.
the selection bias issue since patients were
trial also takes into account our knowledge that
In closing, I would like to stress that, in
standard alkylating agents inflict damage to
randomized at diagnosis and were analyzed
order to advance the prognosis of patients
hematopoietic stem cells; thus, PBSC collec
in their assigned treatment group even if
afflicted with MM, referral to a specialized cen
tion is performed after 4 cycles of stem cell-
treatment was not actually administered.
ter is strongly recommended both for disease
sparing induction with VAD for all patients,
confirmation and examination of prognostical
This analysis showed a significant superiority
regardless of early versus delayed transplanta
ly relevant base line parameters. Patients
of high-dose therapy over standard therapy
tion. It will be interesting to see if there are dif
should be made aware of clinical trials designed
regarding the response rate, the 5 year EFS
ferences in incidence of secondary MDS/AML
to advance understanding of myeloma biology
and OS, although 26% of the patients did
in the two arms.
and to improve long term prognosis. The
not undergo the planned autologous trans-
reproducibly dismal outcome with standard
plantation. As the conventional chemothera
Who is a transplant candidate?
therapy in the majority of patients should alert
py arm of this trial was a commonly used regi
All patients with symptomatic or progressive
physicians and patients alike to the notion that
men and yielded results comparable to those
multiple myeloma requiring initiation of thera
participation in a well-designed clinical
published in the literature, this trial demon
py should be considered candidates for what
research trial should become the "standard
strates that high-dose therapy represents a sig
currently appears to be the most effective treat
approach" as it assures progress in therapy.
nificant improvement and should be proposed
ment strategy, i.e., high dose therapy with stem
Given the efficacy and safety of PBSC-support
as part of front line therapy in younger patients
cell support. If we heed the lessons from acute
ed high dose therapy, this approach should be
(up to the age of 65).
leukemia research, it should be clear that
available to all patients with symptomatic
durable disease control and cure will not be
myeloma who have adequate cardiac and pul
accomplished unless there is a high incidence
FUTUREDEVELOPMENTS
monary functions. Patients in a more fragile
of true complete remission, perhaps even at the
condition, because of significant co-morbidity
However, a number of issues remain to be
molecular level. Given the nature of the
or advanced age, can be managed with intense
addressed:
genetic diversity of myeloma cells and the
glucocorticoid pulsing (high dose dexametha
1. When to transplant? The optimal timing
inherent resistance to currently employed stan
sone) plus bisphosphonates. In cases of failure
of autologous transplantation can be discussed
dard agents at standard doses, marked dose
to respond and worsening condition, PBSC
since autologous transplantation has also been
escalation requiring stem cell support has been
collection should be considered in support of
considered as an effective salvage therapy in
shown to overcome drug resistance, resulting in
intermediate melphalan doses (100-140
primary refractory multiple myeloma and in
CR rates of 40% to 50% with tandem trans-
mg/m2), which are likely to bring about
chemosensitive relapses. Whether delayed
plants and, in both randomized and historically
marked tumor cytoreduction in the majority of
controlled trials, significant prolongation of
transplants, given at the time of a progression
patients with predictably short myelosuppres
event-free and overall survival. Depending on
of diseased after conventional chemotherapy,
sion and limited extramedullary toxicity.
the high dose therapy regimen employed, eligi
could give similar results will be clarified in
New agents must be evaluated as well. An
ble patients should have adequate heart and
ongoing trials.
ideal setting for evaluation is disease recurrence
lung functions, whereas kidney failure and
2. Which source of hematopoietic stem cells?
or primary failure to respond to optimal strate
advanced age should not be considered as
Contamination of the autologous support by
gies currently available. Thus, upon relapse
exclusion criteria.
the malignant clone remains a critical concern
from PBSC-supported high dose therapy,
even with blood progenitors. Sensitive meth
What Transplantation Hopes to Achieve
patients' hematopoietic stem cell function is
ods including amplification of a patient's
The word "transplantation" carries with it
usually well preserved so that potentially bone
rearranged gene allow detection of myeloma
an unnecessary connotation of a life-threaten
marrow-toxic agents can also be evaluated.
cells in blood and apheresis products.
ing intervention while, certainly with autolo
Biological agents are best tested in the setting
Attempts to purge marrow with cyclophos
gous PBSC support, we are actually offering
of markedly reduced tumor burden, as is the
phamide derivates or with monoclonal anti-
modern supportive care so that more effective
case after intensive therapy with persistence of
bodies have proven feasible although inducing
therapy can be administered more safely. With
measurable disease.
prolonged myelosuppression. Selection of
high dose melphalan and PBSC support, more
Progress in myeloma therapy can be antici
CD34 positive progenitors appears to be a
than one-half of patients can be treated in the
pated by substantially increasing accrual of
promising alternative. Tumor depletion up to
outpatient setting. The short term treatment
patients into clinical research trials from the
4.5 logs can be obtained with this technique
goal should be maximum tumor cell kill and a
current level of < 5% in the United States.
but sophisticated assays for detection of mini
high incidence of complete remission, allowing
Such clinical trials must ask sufficiently radical
mal residual disease show the persistence of
pursuit of the long term goal of durable disease
questions to yield biologically and clinically
control and cure. Unless cure is an objective of
meaningful answers. Specialized centers with
myeloma cells in the CD34 positive cell frac
our therapeutic efforts, it is unlikely to be
comprehensive laboratory and therapeutic
tion. Thus, an additional purging step might
achieved. Results with autologous transplants
research programs are ideally suited to develop
be necessary to obtain tumor-free grafts. The
in well over 1,000 patients would indicate that
more rational therapies that correct the under-
clinical impact of these cumbersome and
a better quality of life is obtained with auto-
lying dysregulation of cytokines and
immune response in MM.
Please see next page
12

---

Prof. Harousseau - continued
ventional therapy. Attempts to improve
ic graft. There were 61 men and 28 women
upon this outcome include the use of autolo
with a median age of 46 (31-65) years. The
expensive procedures has not yet been fully
gous BM either depleted of tumor cells or
interval from diagnosis to BM transplanta
evaluated.
processed to select normal hematopoietic
tion was a median of 20 (4-162) months.
3. How to improve current results? In the
progenitor cells, as well as the use of multi
Patients had received a median of 3 (1-7)
IFM trial, the 5-years EFS was only 28% in the
ple autologous transplants. However, it
prior chemotherapy regimens. Over-all 35
high-dose therapy group. Strategies to
(39%) patients achieved CR and 43 (48%)
improve this result are clearly warranted.
remains unclear at present whether anyone
PR; 4 patients did not respond (NR), and
Since achievement of complete response or
with MM is cured using autografting based
there were five toxic deaths (TD). This
very good partial response resulted in a signifi
treatments. As noted above, relapses after
included 21 (40%) CR, 28 (54%) PR, 1 NR
cant prolongation of survival, the aim of future
allografting for MM are also common and
studies should be to increase the complete
treatment of minimal residual disease post
and 1 TD in patients who received autolo
response rate. One possibility to attain the
BMT with DLI is under evaluation. Efforts
gous BM; and 14 (38%) CR, 15 (41%) PR, 3
objective could be to repeat intensive treat
to improve the outcome after autologous
NR and 4 TD in patients in the allogeneic
ments. This strategy appears to be well tolerat
transplantation for MM by enhancing autol
BM group. Overall progression free survival
ed thanks to peripheral blood progenitors,
ogous immunity to tumor cells are also
is a median of 23.5 (2-103) months and 30
autologous transplantation, and to hematopoi
underway.
(3-77) months for autograft and allograft
etic growth factors. A recent analysis of 496
Transplantation of autologous PBPCs
recipients, respectively. Disease free survival
patients enrolled by the Little Rock Group in
alone or as a supplement to autologous BM
is a median of 42 (3-102) months and 39.5
clinical trials of tandem transplants confirms
has also been reported in patients with MM.
(7-77) months for autologous and allogeneic
the feasibility of this approach and demon
As is true in other settings engraftment of all
BM patients, respectively. At present, we
strates that the second transplant can increase
hematopoietic lineages, including platelets,
have treated 6 patients with the same abla
the complete response rate. However the
is more rapidly achieved than after autolo
tive regimen followed by transplantation of
impact of such an aggressive strategy on OS
gous BM grafting. Early reports included
autologous PBPC purged with the same
warrants further evaluation. In 1994, the IFM
only patients with refractory disease; more
MoAb cocktail. Although all patients to
group initiated a randomized study comparing
recently PBPC transplantation has facilitat
date have engrafted, purging of PBPC using
one and two courses of high-dose therapy in
ed treatment up front with single or double
MoAB and complement will not be pursued
patients up to the age of 60.
high dose therapies. Ade-quate numbers of
on a larger scale due to the large amounts of
4. Is cure possible with autologous transplanta
PBPCs can be collected in the majority of
reagents and time required to purge several
tion? Finally, as there is no plateau of the sur
patients with <1 year exposure to chemo
apheresis collections for each patient treat
vival curves in published series with adequate
therapy. Response rates have in most series
ed. We have also entered 22 patients in a
follow-up, some form of maintenance therapy
been similar to those observed in allogeneic
recently completed randomized multicenter
appears necessary. Several randomized studies
series, with approximately 40% patients
trial comparing transplantation of unseparat
have shown that, in patients responding to
achieving CR and a similar number PR. A
ed autologous PBPC versus CD 34+ selected
conventional chemotherapy, Alpha-Interferon
theoretical advantage of PBPCs is less conta
autologous PBPC transplantation after high
maintenance prolongs remission duration by 5
mination than marrow with MM cells.
dose cyclophosphamide and busulfan thera
to 12 months as compared to observation.
However, minimal residual disease in MM
py in 193 patients with MM. Study end-
Alpha-Interferon has also been used after high-
can be detected in both PB and BM using
points were hematologic engraftment and
dose therapy with the hypothesis that it could
sensitive techniques (polymerase chain reac
evidence of residual tumor in the two study
be more effective in patients with minimal
tion); although tumor cells can be depleted
arms. This study has not yet been fully ana
residual disease. In the only randomized study
from BM or PBPCs, it is not yet clear
lyzed; however, there have been no failures
completed until now, the Royal Marsden
whether this improves outcome.
to engraft in either arm, and a marked reduc
Group in London has reported that the medi
At Dana-Farber, we have utilized autolo
tion in BM and PB evidence of MM noted
an progression-free survival was significantly
gous BMT for patients with MM in sensitive
out to 180 days post transplant.
longer in the Interferon arm. Further studies
relapse: T cells have been depleted from
In conclusion, it remains unclear whether
are needed to confirm these preliminary
allografts and tumor cells have been depleted
anyone with MM is cured with high dose
results. However, although Alpha-Interferon
from autografts using in vitro MoAb and
approaches. Relapses after allografting for
was to be administered to all patients after
complement lysis methodology. MM cells
MM are common, but treatment of minimal
high-dose therapy in the IFM90 trials, there is
within autografts were depleted with MoAbs
residual disease post BMT with DLI is under
no plateau of the EFS curve. Therefore, the
directed at CALLA (CD10); B1 (CD20);
evaluation. Attal and coworkers have
cure of myeloma patients with a single course
and PCA-1 Ags, targeting the malignant
already demonstrated in a randomized trial
of high-dose therapy followed by Alpha-
clone from the pre-B cell to plasma cell
that high dose therapy followed by autograft
Interferon is unlikely. New strategies to con
stage. Post purging phenotypic analysis
ing is superior to conventional therapy, and
trol minimal residual disease after autologous
revealed no MM cells, but PCR for CDR3
are currently comparing single versus double
transplantation are necessary.
confirmed MM within autografts from 17 of
transplantation approaches. In the US,
28 patients pre-lysis and 10 post lysis.
Scandinavia and Spain, there are ongoing
Dr. Anderson ­ continued
As of October 1996, 89 patients have
randomized trials comparing high dose ther
ients of high dose therapy and only 10% and
received high dose chemoradiotherapy with
apy with conventional therapy in order to
12%, respectively, in patients treated with
either melphalan or cyclophosphamide fol
confirm the French experience. Finally, a
conventional therapy; treatment-related
lowed by TBI; cyclophosphamide and busul
recently completed and not yet analyzed
mortality was comparable between the two
fan was used in 2 patients in whom prior
randomized trial has compared CD 34+
groups. Ongoing trials in England, Spain,
radiotherapy precluded TBI. Fifty-two
selected versus unselected PBSC transplan
Scandinavia, and the US are also examining
patients received MoAb purged autografts,
tation in MM. These and similar studies
the efficacy of high dose compared with con
36 T cell depleted allografts and 1 a syngene
Please see page 14
13

---

Dr. Anderson ­ continued
Prof. San Miguel - continued
Dr. Hussein - continued
will determine how many patients with
are the most important prognostic factors in
dose therapy. To confound matters further,
newly diagnosed MM benefit from high dose
patients under conventional chemotherapy
a study from MD Anderson suggested that
strategies. They will evaluate IFN mainte
(B2micro-globulin levels, proliferative activity
the subpopulation of patients with primary
nance therapy and provide a setting for eval
of plasma cells, cytogenetic abnormalities, C-
resistant myeloma is the most likely to bene
uation of innovative methods for the identi
reactive protein, etc). Preliminary data suggest
fit from transplantation.
fication and treatment of minimal residual
that these factors are also important in high
The only published trial that has
disease. Finally, these studies will determine
dose chemotherapy programs, but appropriate
randomized patients between conventional
whether responses achieved after high dose
studies in uniform cohorts of transplanted
chemotherapy and high dose therapy fol
therapies translate into improved quality of
patients, in which the most relevant biological
lowed by ABMT has shown that the con
life. At present, therefore, patients <70
disease characteristics are evaluated, are still
ventional therapy group achieved a median
years of age who have MM, which is stable
needed. This will help to identify risk groups
event-free survival of 18 months with a
or has responded to conventional therapy,
for which a particular therapeutic option is
median overall survival of 37.4 months. In
should consider high dose therapy followed
more appropriate.
the high dose group, the median event-free
by hematopoietic stem cell transplantation.
6. When to transplant?
survival was 27 months and the median sur
Patients <age 55 years who have histocom
Most available data from myeloma trans-
vival was not reached at the time of the pub
patible sibling donors should consider allo
plant registries show that results are poorer
lication. When prognostic factors for over-
geneic bone marrow transplantation which
when transplants are performed late in the
all survival were analyzed with multivariant
may have the benefit of the graft (donor
course of the disease. In the study of the
analysis, only b2-microglobulin level stood
bone marrow) versus MM effect. Patients <
Spanish Registry (A. Alegre, submitted for pub
out as a statistically significant factor.
age 70 years should consider high dose thera
lication) patients that had received two or
The estimated (not actual) proba
py followed by autologous hematopoietic
more lines of chemotherapy previous to PBSC
bilities of event-free survival and overall sur
stem cell transplantation. Since the French
transplantation had a significantly lower sur
vival after the diagnosis in the conventional
randomized trial has shown a significant
vival than those transplanted after only one
dose group was 10% and 12%, respectively,
benefit of high dose therapy and transplanta
line of therapy. This general statement applies
both to autografting and allografting and is
versus 28% and 52% in the high dose thera
tion in terms of both patient response and
probably due to the emergence of resistant cell
py group. These results are encouraging, but
survival, there is no basis for denial on the
clones, with disease evolution, in patients that
need to be confirmed by other studies.
part of insurers to cover such therapy.
have been previously heavily treated.
In summary, bone marrow trans-
Finally and most importantly, patients
Accordingly, transplants should be performed
plantation appears to be a promising proce
should utilize the International Myeloma
at an early phase of the disease. But, how early
dure, however, at this time, it should not be
Foundation and speak with other patients
should this be done? It is obvious that all
recommended outside of study boundaries.
when considering treatment options and
patients should first receive a cytoreductive
It would be reasonable to consider harvest
be treated at a Center with experience in
treatment -- three to four courses of conven
ing stem cells from responding patients for
treating MM using high dose therapy
tional chemotherapy -- and if the patient fails
future use, especially given that repeated
approaches.
to respond, we recommend immediate trans-
regimens or large dosages of melphalan
plantation, since continuing with chemothera
could impair future stem cell collection.
py will only contribute to select resistant
In conclusion, at the Cleveland
clones. However, this is an unlikely situation
IMF President:
Clinic Multiple Myeloma Program we do
since most patients will respond to initial
Susie Novis
believe that the therapy of multiple myelo
chemotherapy; for these cases it is still debat
ma should be divided into two phases; a) an
able whether transplant should be immediately
IMF Vice President:
induction phase to reduce the tumor burden,
performed as a consolidation/intensification
Amy Nielsen Palumbo
and b) a maintenance phase to maintain the
treatment or whether conventional
remission status achieved by the first phase.
chemotherapy should be continued up to 12
US Staff:
cycles and transplant reserved for relapse.
The induction phase usually consists of some
Suzanne Battaglia
Several trials already underway will help to
form of chemotherapy, where the standard
Romi Pfister
answer this question. In any case, if the patient
for the maintenance phase is currently no
Renee Rape
receives chemotherapy, it is important to
therapy. Trials at the Cleveland Clinic are
Ruth Lippmann
restrict the use of certain drugs, such as melpha
focusing on the role of biologics, and more
Carole Menacker
lan, that damages the hematopoietic stem cells
recently bisphosphonates and/or monoclonal
and may impair the quality of the harvest.
antibodies to prolong the duration of the
IMF (UK) Executive Director:
Now that clinicians have a wide range of
plateau phase, or improve on the rate of
Eric Low
therapeutic options at their disposal, a new era
remission. The latter should hopefully trans-
has begun for patients with multiple myeloma.
late into a better disease free and overall sur
It would be desirable that, as occurs in other
IMF (UK) Staff:
vival. We believe that all patients with mul
disorders such as acute leukemias and non-
Christy Browne
tiple myeloma, newly diagnosed or relapsed,
Hodgkin lymphoma, treatment should be
Susan Hamilton
should be part of a clinical trial attempting
adapted to specific subsets of risk (patients dis
to find a new drug therapy or advance the
playing common biological characteristics). In
Myeloma Today Editor:
results of current approaches to manage
any case, the participation in a well-designed
ment.
Marya Kazakova
clinical trial is the best guarantee to assure a
patient that he is receiving the optimal thera
peutic control for his disease.
14

---

STEM CELL TRANSPLANTATION:
ONE PATIENT'S EXPERIENCE
by Joseph Lerner, PhD
After having smoldering myeloma for at
Diflucan. The energy gradually began to flow
checked for vital signs by the oncology nurses.
least eleven years, I became anemic and devel-
from my body. Day 2, etoposide (chemothera
Each day at 4AM, blood was drawn, and by
oped a fracture in my spine. Consequently, in
py) was begun and continued for three days. I
6AM my blood counts were prominently dis
August 1996, I told my hematologist/oncolo-
grew weaker, but could not sleep even with
played on a wall chart. By 7AM my oncolo
gist that I chose to have high-dose therapy
added Valium.
gist, his two residents, and an oncology nurse
with stem cell transplantation as opposed to
The following week my blood counts began
lined up to take my vital signs.
standard therapy, primarily because I was
to drop; I felt faint and extremely fatigued. In
Since I had no appetite to eat in Dec
impressed by what I read in the literature
a day, my white count dropped from 5800 to
ember or January, I lost weight. In total, I
about potential life expectancy, and I was still
800. I could no longer stand, and was hospi
dropped from 215 to 189 pounds. The smell
young enough for the procedure at age 54.
talized as my marrow was being destroyed.
of food made me nauseated. I couldn't eat or
Stem cells are "seeds" that replenish the bone
Daily injections of Neupogen were given to
drink. The closest I came to nourishment was
marrow with blood cells, and their removal
grow the marrow back. I required two transfu
to suck on popsicles or to eat Jell-O. The
before high-dose melphalan chemotherapy
sions of red blood cells and two of platelets.
diarrhea was as bad as the nausea. Neither
would protect them from the damages of treat-
When your hematocrit (red cells) falls below
could be controlled. Day after day my intesti
ment, as opposed to conventional therapy. In
24-25, you begin to really lose your energy,
nal track would not cooperate. I continued to
principle, the procedure seemed to be the cor-
and even standing to use the urinal required
brush my teeth with a sponge toothbrush and
rect choice for me.
assistance. At that point I was on oxygen. I
swish salt and baking soda in my mouth to
So after taking a variety of chemotherapeu-
barely recognized people sitting beyond the air
prevent sores. My belly started to swell, and I
tic agents, e.g., dexamethasone (also an anti-
barrier, which was present to prevent infec
complained that I was receiving too much IV
inflammatory agent) every other week, along
tions. There were no hugs; no touching of
fluid. I succeeded in having the flow rate of
with one treatment of vincristine, Adriamycin
loved ones.
IV fluid reduced.
and dexamethasone (VAD), I was ready to
Strangely, the myeloma discomfort disap
During each hospitalization, I never devel
undergo the process designed to grow and har-
peared. But, I had no appetite, no interest in
oped a fever above 100.5, or an infection, or a
vest the blood "seed" cells. Since VAD and
reading, or in watching television, or even in
condition called mucositis in my bowel. I did
Aredia (to strengthen my bones) required
talking to loved ones. Each day merged into
require two more transfusions of red blood
intravenous infusions, I had surgery to place a
the next, and I lost track of time completely.
cells and one of platelets. After thirteen days,
catheter in my chest. The surgery was only a
Through my irrationality, I had one thought:
I left the hospital entirely weakened, short of
minor inconvenience.
I didn't want to go through this process with-
breath, and in need of Zofran and Immodium
During the first week of December, I had
out someone staying in the hospital room with
to control the gastrointestinal problems. I
all organ systems checked for their ability to
me all night. A loved one had to be with me,
remember getting "hot flashes" alternating
withstand the rigorous treatment. I had
should I suddenly die. Arrangements were
with shivering. Skin rashes came and went. I
endoscopy to check my esophagus and stom-
subsequently made to have my mother's sister
finally was able to get out of bed, and to eat
ach for ulcers and inflammation; I had sigmoi-
who had about 50 years of experience as a
more than just very small amounts of food and
doscopy to check my rectum and colon. The
nurse assume this function.
drink grape juice, but only after several weeks
lung tests were uneventful, but the blood gas
After about a week, I was sent to surgery to
at home. Gradually, I was able to get around
test involved drawing blood from an artery in
implant a second catheter. This one was
the house and finally to start walking short
my wrist--a painful process. My heart was
much larger and would be used to circulate my
distances outdoors.
checked thoroughly and a battery of blood
blood through a machine to collect the seed
I'm still fatigued and have back discomfort,
tests was done for liver and kidney function, as
cells. For several days I couldn't raise my arm
but my blood counts have increased into the
well as a bone marrow aspirate. I felt like an
due to the discomfort of the surgery. I was lay-
acceptable range and my IgG (tumor protein)
airplane undergoing a ground check before
ered with blankets and connected to the
has dropped significantly. I don't know what
takeoff into a storm. Once you're into it,
"leukopheresis" machine each morning for
the future will bring; there are no guarantees.
there is no turning back, or no means of usual
several hours over a period of three days, while
I'm being watched closely for changes in the
medical intervention I thought, except what
my blood flowed in and out of my body.
myeloma, taking Aredia, and contemplating
could be administered through a vein (IV) or
During this process, I received yet another
the possibility of a second transplant.
given as a pill. My anxiety increased with
drug--a blood thinner. The seed cells were
Naturally, patients and their physicians have
each "what if" thought.
collected, then frozen, and I went home weak
difficulty in deciding what's best for them in
My oncologist was pleased with the test
and fatigued.
management of this disease.
results, so my wife, sister and I rented an
On January 7, after several days on an
A friend (aged 60) took a year to overcome
apartment near the hospital and I vowed that
antibiotic to prevent a deadly form of pneu-
the fatigue of her transplant, but she is
I would now get even with the myeloma.
monia, I was again hydrated with salt solution,
presently doing well. Another (aged 50), died
Day 1 of the seed mobilization process
and received by IV two small bags of high-
from complications of an infection following
seemed uneventful after all the testing. The
dose melphalan administered as a fast drip.
her transplant. There are those friends who
first activity was the administration of an IV
The same ingredients as before were added to
have made it over 15 years on standard thera
bag of salt water, the second bag, however,
lessen the shock to the body. The next day
py, or 7 years after eleven melphalan/pred
contained high-dose Cytoxan (chemotherapy
was a rest day in which I was given liters of
nisone treatments followed by alpha-interfer
and an agent to get the seed cells into the
salt solution. The seed cells were then given
on therapy.
blood); and to make it palatable to the body,
to me intravenously to grow the marrow back
Ultimately, we are not data points on a
Benadryl (antihistamine), Zofran (anti-nau-
after the high-dose chemotherapy. I lay in my
graph; nor is there a "magic bullet" for us. But
sea), Ativan (anti-nausea and tranquilizer)
hospital bed day after day waiting for my
there is hope as long as our bodies can accept
and dexamethasone were also included.
blood counts to bottom out. Neupogen was
the presence of a disease that remains
Antibiotics were given too: Floxin and
again given, and every four hours I was
under control.
15

---

NEW BMT BROCHURE
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"So You're Considering an Autologous Bone Marrow Transplant:
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able free of charge upon request. The topics discussed are:
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· Am I a Candidate fo an Autologous Transplant?;
by Dr. Pieter Sonneveld;
·Myeloma Today Profile: Prof. Heinz Ludwig;
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·"What Causes Myeloma?"
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·"Anti-IL-6 Therapy in Myeloma"
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· Glossary.
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·"Myeloma is Also a Bone Disease"
Made possible by a grant from Nexell Therapeutics Inc.
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