Document 9374D69abwxzpRGMJO2okL31L
CONCISE
REPORT
High-Dose
Chemoradiotherapy
and Autologous
for Resistant
Multiple
Bone Marrow Myeloma
Transplantation
By Bail Barlogie,
Raymond Alexanian, Karel A. Dicke, Gunar Zagars, Gary Spitzer, Sundar Jagannath, and Leonard Horwitz
Seven patients with advanced
multiple myeloma.
refrac-
tory to therapy
with alkylating
agent-VAD
(vincristine-
adriamycin-dexamethasone).
received
a regimen
com-
bining high-dose
melphalan
with total body irradiation
supported
by autologous
bone marrow
transplantation.
Very rapid. usually >90% tumor mass reduction
was
achieved in six patients. regardless
of prior chemotherapy
responsiveness
and marrow
plasmacytosis
up to 30%.
Despite signs of early relapse in three patients
(median
F OR NEARLY
20 years, the combination
of melphalan
and prednisone (MP) has been the standard therapy for
multiple myeloma. Once resistance
to treatment
develops,
other agents have been ineffective,
and survival has been
short. Using a program that combines a continuous
infusion
of vincnistine and adriamycin
with dexamethasone
(VAD),
about 50% of patients resistant to MP responded, but for a
median duration of only 9 months."2 Despite encouraging
results with high-dose
melphalan
(HDM)
in untreated
myeloma,"4
the median duration of remission in patients
resistant to VAD was only 3 months.' Since autologous bone
marrow transplantation
(BMT) improved the tolerance to
HDM,5 we added total body irradiation
(TB!) to the cytore-
ductive programsa in an attempt to achieve more frequent
and durable remissions in a tumor generally acknowledged
to
be radiosensitive.
While there is only limited experience with
TB! alone in myeloma,6 extramedullary
plasmacytomas
are
dependably
eradicated
with total doses of 4500 cGy,7 and
local manifestations
of advanced myeloma are effectively
palliated even with single doses of 700 to 1000 cGy.8'9
We now report our initial experience with TB! and HDM
in conjunction
with autologous
BMT in seven consecutive
patients with VAD-refractory
myeloma. Six patients have
responded with >75% tumor mass reduction for a median of
1 5 months; and five patients remain alive from 2 to 21
months. Incidence and duration of remission were indepen-
dent of prior chemotherapy
resistance and not influenced by
the degree of plasmacytosis
in the marrow autografts.
MATERIALS
AND METHODS
Seven consecutive patients with advanced multiple myeloma
resistant to prior standard treatments
and VAD form the basis of
this report (Table 1). Their ages ranged from 45 to 63 years
(median, 50 years). Written informed consent was obtained from all
patients prior to therapy, indicating its potential benefits and risks,
in keeping with institutional policy. Three patients were unnespon-
sive to initial alkylating
agent and VAD therapy, and one patient
(ES) had not even responded to HDM at a dose of 70 mg/M2; four were relapsing despite VAD. Tumor mass was high in four patients
and intermediate in two; myeloma protein type was IgA in three and
IgG in three; one patient had nonsecretory myeloma with 27%
plasmacytosis (patient iH). Four patients were moderately disabled
from painful lumbar spine compression fractures, and one patient
was bedridden from fractures of femur and humerus, with hypercal-
cemia and progressive skull plasmacytomas
,(Table 1 patient BL).
remission
duration of all patients,
1 5 months).
five remain
alive and well without further cytotoxic
therapy
21 months (median.
9+ months).
Two patients
from 2 to died, one
from surgical complications
after transplantation
and a
second due to persistent
neutropenia
with fatal pneumo-
nia. This treatment
provides meaningful
disease control for
selected patients with resistant myeloma and a poor prog-
nosis.
S 1987 by Grune & Stratton,
Inc.
Except for the one bedridden patient who required intensive
nursing, treatment
was given in a protected environment
unit and
consisted of TBI in a dose of 850 cGy in five fractions over 2'/2 days,
preceded (two patients, FS and GR, Table 1), or followed one day
later by melphalan 140 mg/M' intravenously (IV) oven 30 minutes
(remaining
five patients). Bone marrow was infused on the following
day in a dose of at least 2 x 10 nucleated cells per kilogram body
weight. Autologous marrow had been harvested during a previous
VAD-induced remission in three patients (marrow plasmacytosis of
6%, 6%, and I 1%) and after resistance to initial on salvage alkylating
agent-VAD treatment in four patients (6%, 10%, 27%, and 30%
plasmacytosis).
Antibiotic prophylaxis was performed with tn-
methopnim sulfamethoxazole
and ketoconazole.
Additional
support-
ive cane was given as needed, including blood products and IV broad
spectrum antibiotics.
Frequent measurements
of myeloma protein
level were conducted, and clinical response was defined by a greaten
than 75% reduction
in calculated
tumor mass.' Bone marrow
aspirates and biopsies were examined monphologically and by flow
cytometny
to determine
abnormalities
in DNA and RNA content
and to monitor the proportion of cells with monoclonal cytoplasmic
immunoglobulin
light chain
sistently detected < 1% monoclonal
This technique plasma cells.
has con-
RESULTS
All six patients
with measurable
myeloma
protein
responded rapidly to treatment with a median tumor halving
time of 1 2 days, and 90% tumor mass reduction
was
achieved in four patients (Table 1 , Fig 1). Marrow plasmacy-
tosis cleared
in all seven patients,
including
two whose
From the Department
of Hematology,
The University of Texas
System Cancer Center, M.D. Anderson Hospital and Tumor Insti-
tute, Houston.
Submitted
March 30, 1987; accepted May 15, /987.
Supported
in part by Grants No. CA 37/61 and CA23077 from
the National
Institutes
of Health and the Cullen Trust Founda-
tion.
Address reprint requests to Bart Barlogie. MD. M.D. Anderson
Hospital and Tumor Institute,
Department
of Hematology,
15/5
Holcombe Blvd. Box 55, Houston, TX 77030.
The publication costs ofthis article were defrayed in part by page
charge payment. This article must therefore be hereby marked
"advertisement"
in accordance
with 18 U.S.C. 1734 solely to
indicate this fact.
I 987 by Grune & Stratton, Inc.
0006-497//87/7003-0033$3.00/0
Blood, Vol 70, No 3 (September),
1987: pp 869-872
869
870
BARLOGIE
ET AL
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HIGH-DOSE
CHEMORADIOTHERAPY
AND AUTOLOGOUS
BMT
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02 S S
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5 10 15 20 95 100 105 110 115 120 Months From Diagnosis
Fig 1 . Tumor mass reduction in refractory myeloma following
high-dose melphalan (HDM)/TBI
and autologous bone marrow
support. (A) Primary refractory disease. A 46-year-old
patient
failed to respond to initial VAD plus cyclophosphamide
but
responded
to HDM/TBI
despite marked plasmacytosis
of 30% in
the marrow autograft. (B) Third relapse. This 50-year-old patient
had responded previously but achieved even greater cytorereduc-
tion after HDM/TBI.
autografts contained 27% and 30% plasma cells. One of these
patients (JH) died from pneumonia
2'/2 months after treat-
ment with poor marrow engraftment.
A second patient (BL)
with >90% cytoreduction
died after 3 months (with early
signs of relapse)
from uncontrolled
osteomyelitis,
which had
developed following surgical reduction of a femoral fracture.
Three patients remain in remission without further therapy
at 2, 1 1, and 21 months after chemoradiotherapy;
the other
two patients have developed signs of early relapse at 6 and 15
months, but currently do not require cytotoxic treatment.
Five patients were discharged
from the hospital within 2
months and have resumed normal activities.
Despite extensive prior therapy (including HDM alone in
a 63-year-old
patient, ES) and varying degree of marrow
plasmacytosis,
the hematologic
recovery
was prompt in six of
seven patients treated. The median recovery time of granulo-
cytes to 500/jzL was 25 days (range, 19 to 62 days) and of
platelets to 50,000/tL
was 41 days (range, 20 to 99+ days).
Within 3 months after treatment,
granulocytes
exceeded
1500/giL and platelets
100,000/.tL
in five of the seven
patients; these five patients eventually
achieved normal
hemograms
with average values for hemoglobin
of 1 2.9g%,
for granulocytes
of 3,200/jL
and for platelets of 250,000/
zL. In addition, their marrow biopsies and aspirates showed
normal cellularity and differential counts, respectively,
with-
out detectable
monoclonal
plasmacytosis
on flow cytometry.
One patient (BL) remained thrombocytopenic
at a level of
50,000/L
until his death, 3 months after therapy, from
osteomyelitis
and sepsis after surgical
reduction
of femoral
fracture. A second patient (JH) with 27% plasma cells in the
autograft had only partial engraftment
with persistent neu-
tropenia
of <750/zL
and severe
thrombocytopenia
< 10,000/zL.
Four patients had fever without documented
infection
during the seven to ten days of agranulocytosis,
prompting
empiric administration
of intravenous
antibiotics.
Three
patients required ventilator
support for pneumonia,
two
short-term (BL and ES), whereas the third patient (JH) with
slow marrow engraftment
died from interstitial pneumonitis,
with marked pulmonary fibrosis and no evidence of myeloma
at autopsy.
DISCUSSION
While the prognosis of individual patients is often uncer-
tam, none of our patients was expected to live more than 8
months without disease control. Only 1 5 of 37 comparable
patients had responded previously to HDM alone at doses
ranging from 50 to 140 mg/M2 (90 and 100 mg/M2, 17
patients) with a relapse-free
and overall survival of only 3
and 5 months, respectively
(Table 2).' In contrast,
and
stressing the cytoreductive
potency of added TBI in plasma
cell myeloma,6
HDM/TBI
provided more frequent and
marked cytoreduction
with a median remission time of 15
months and five of seven patients surviving from 2 to 21
months (median, 9+ months). When administered
without
BMT, HDM was associated with a high early mortality rate
of about 25%, which was reduced markedly by BMT support
despite higher doses ofcytotoxic
therapy (Table 2). The poor
marrow engraftment
in one of our patients may be attnibut-
able to a high degree of plasmacytosis
(27%), although a
similar patient had prompt hematologic
recovery and
remains in remission
with normal marrow
and peripheral
hemogram more than 1 `/2 years after therapy.
Because of the reduced tolerance to graft-v-host
disease
with allogeneic
BMT in older patients, marrow-ablative
therapy has not been explored systematically
in multiple
myeloma. Cyclophosphamide/TBI
and modifications
with
Table 2. High-Dos e Melphalan for Ref ractory Myeloma
HDM (mg/M2)
TBI (85OcGy)
Median Age
BMT N
(yr)
A (CR) ED
Median Survival
(mo)
<90 90-100
140 140 140
- - 13 - - 17 - Auto 7
+ Auto 7
+ Allo 2
62 46 63
50 40
3 (0)
4
4
8 (1) 4
4
4 (0) 1
6
6 (0)
1 Not reached
2 (2)
0
6,14
Abbreviations: HDM, high-dose melphalan; TBI, total body irradiation; BMT. bone marrow transplantation;
N, no. of patients;
tumor reduction including three achieving complete disappearance of M protein by immunofixation
(CR); ED, early death;
allogeneic bone marrow transplantation. #{149}lndividualsurvival of two patients.
A, patients with Auto, autologous;
>75% Allo,
872 BARLOGIE ET AL
syngeneic or allogeneic BMT have been effective in about a
dozen patients, many of whom still had drug-responsive
myeloma."'9
However, myeloma protein disappearance
did
not occur in any patient with progressive
or unresponsive
disease and was also not observed in the current study with
TBI/HDM
when supported by autologous BMT. The induc-
tion of complete remission in two additional
patients with
advanced and VAD-refractory
myeloma receiving allogeneic
BMT with TBI/HDM
may suggest superior activity of
HDM to high dose cyclophosphamide,
as was evident from
previous trials where only two of 1 5 patients responded
briefly to high dose cyclophosphamide
alone in contrast to a
48% response rate with HDM."#{176} Thus, HDM appears to be
at least as effective as high dose cyclophosphamide
when
combined with TBI. One allogeneic BMT recipient died 6
months after therapy from pneumocystis
carinii pneumonia
with signs of early disease recurrence; and the second patient
committed suicide still in complete remission 14 months after
treatment (Table 2).
Because of their older age and the risk of fatal graft-v-host
disease, most myeloma patients are candidates
for autolo-
gous rather than allogeneic BMT. The tolerance of TBI/
HDM by a 63-year-old
patient with primary unresponsive
myeloma despite VAD and even HDM alone, with hemato-
logic reconstitution
from bone marrow harvested 1 year after
HDM, suggests that this program can also be considered for
patients initially requiring HDM alone because of marked
marrow plasmacytosis.
While the reinfusion of tumor cells is
potentially detrimental
to the use of autologous BMT, such
an application
seemed justified by the slower cell cycle
kinetics of myeloma cells, in comparison
with regenerating
normal bone marrow.2' In addition, the terminally differen-
tiated B calls that comprise this tumor have an unusually low
in vitro, and perhaps in vivo, cloning efficiency.22 Thus, a
selective growth advantage of normal hemopoietic
cells over
reinfused malignant plasma cells might be expected. While
there is considerable
interest in removing tumor cells from
autologous marrow grafts by immunologic
and/or cytotoxic
means, such purging procedures
must be specific for tumor
cells so that hemopoietic
engraftment
is not compromised.
The effectiveness
of TBI/HDM,
when supported by autolo-
gous BMT, provides a new approach
to the therapy of
patients with refractory myeloma and justifies further study
in selected responding patients at high risk for relapse.
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