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Monoclonal Antibody-Purged Bone Marrow Transplantation
Therapy for Multiple Myeloma
By
Kenneth
C.
Anderson, Janet Andersen, Robert Soiffer, Arnold
S.
Freedman, Susan N. Rabinowe, Michael J. Robertson,
Neil
Spector,
Kelly
Blake, Christine Murray, Andrea Freeman, Felice Coral, Karen
C.
Marcus,
Peter Mauch,
Lee
M.
Nadler, and Jerome Ritz
Forty
patients with plasma cell dyscrasias underwent
high-dose chemoradiotherapy and either anti-B-cell mono-
clonal antibody (MoAb)-treated autologous, anti-T-cell
MoAb-treated HLA-matched sibling allogeneic or synge-
neic bone marrow transplantation (BMT). The majority of
patients had advanced Durie-Salmon stage myeloma at
diagnosis, all were pretreated with chemotherapy, and 17
had received prior radiotherapy. At the time of BMT, all
patients demonstrated good performance status with Kar-
nofsky score of 80% or greater and had less than
10%
marrow tumor cells; 34 patients had residual monoclonal
marrow plasma cells and 38 patients had paraprotein.
Fol-
lowing high-dose chemoradiotherapy, there were
18
com-
plete responses
(CR),
18 partial responses, one non-re-
sponder, and three toxic deaths. Granulocytes greater than
500/pL and untransfused platelets greater than 20,00O/pL
were noted at a median of 23 (range, 12 to 46) and 25
(range,
10
to 175) days posttransplant (PT), respectively,
in
24
of the 26 patients who underwent autografting. In
the
14
patients who received allogeneic or syngeneic
grafts, granulocytes greater than 500/pL and untransfused
ULTIPLE MYELOMA remains an incurable malig-
M
nancy with
a
median survival at best of only 48
months when conventional therapies are used. Such conven-
tional treatments (ie, melphalan and prednisone or combi-
nation chemotherapy) have been associated with a 50%
to
60%
probability of transient disease regression.’ Although
several reports have suggested improved survival after treat-
ment with combination chemotherapy than after melpha-
Ian with or without prednisone:-’ this remains controver-
~ial.~,~ a2b interferon (IFN) has recently been used to treat
patients during initial and/or as a maintenance therapy&I4;
although requiring confirmation, those patients with either
near complete or complete response (CR) to chemotherapy
in some studies appear to have prolonged survival with IFN
maintenance treatment. Disease inevitably recurs, and al-
though several effective salvage chemotherapy regimens
achieve response rates of up to 50% to 75%,l5-I7 these re-
sponses are rarely complete and durable. To date, therefore,
From the Divisions
of
Tumor Immunology and Biostatistics,
Dana-Farber Cancer Institute, and the Departments
of
Medicine
and Radiation Therapy, Harvard Medical School, Boston, MA.
Submitted February 2, 1993; accepted June
18,
1993.
Supported by National Institutes
of
Health Grants No. CAS0947
and CA06516.
Address reprint requests to Kenneth C. Anderson, MD, Division
of
Tumor Immunology, Dana-Farber Cancer Institute, 44 Binney St.
Boston, MA 02115.
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.
section 1734 solely to
indicate this fact.
0
I993
by
The American Society
of
Hematology.
0006-49 71 /93/8208-0028$3.00/0
platelets greater than 20,00O/pL were noted at a median
of
19
(range, 12 to 24) and 16 (range, 5 to 32) days PT,
respectively. With
24
months median follow-up for sur-
vival after autologous BMT,
1
6 of 26 patients are alive free
from progression at
2+
to 55+ months PT; of these,
5
patients remain in
CR
at 6+ to 55+ months PT. With
24
months median follow-up for survival after allogeneic and
syngeneic BMT,
8
of
14
patients are alive free from pro-
gression at
8+
to 34+ months PT; of these, 5 patients
remain in
CR
at
8+
to
34+
months PT. This therapy has
achieved high response rates and prolonged progression-
free survival
in
some patients and proven to have accept-
able toxicity. However, relapses post-BMT, coupled
with
slow engraftment post-BMT
in
heavily pretreated pa-
tients, suggest that such treatment strategies should be
used earlier in the disease course. To define the role of
BMT in the treatment of myeloma, its efficacy should be
compared with that of conventional chemotherapy in a ran-
domized trial.
0
1993
by The American Society
of
Hematology.
no therapies have achieved prolonged disease-free survival
or cure.
A promising treatment approach for multiple myeloma
stems from reports of CR after the administration ofalkylat-
ing agents (melphalan, cyclophosphamide, busulfan) in
higher than conventional doses, with or without total body
irradiation, followed by transplantation of syngeneic, alloge-
neic, or autologous bone marrow (BM),
or
of autologous
peripheral blood stem cells (PBSC).’8-39 Reduction in tumor
mass in
some
cases has been dramatic, with CR rates rang-
ing up to 50% to
60%.
Moreover, there are now relapse-free
survivors as long as
14
years,
6
to 7 years, and 5 years post-
syngeneic, allogeneic, and autologous grafting, respectively.
In the European Bone Marrow Transplant Group
median relapse-free survival for 37 of90 (41%) patients who
entered CR was 48 months; however, it remains unclear as
to whether a plateau in the survival curve has yet been
achieved in this and all other studies. Those patients who
have sensitive disease and who are less heavily pretreated
achieve the highest response rates and prolonged progres-
sion-free survival. More recent studies have therefore used
high-dose alkylating agents, with or without radiotherapy,
followed by transplantation
of
allogeneic BM or autologous
BM and/or PBSC as initial therapy for patients with my-
e10ma.’8,28~37.38 Although response rates are high, their dura-
tion and the relative efficacy of these approaches compared
with conventional initial therapies remains to be deter-
mined.
In the present study, we report the results of treatment
with high-dose chemoradiotherapy and bone marrow trans-
plantation (BMT) in 40 patients with responsive multiple
myeloma. Thirteen patients less than 55 years of age with
related histocompatible siblings received allografts, and
a
single patient underwent syngeneic BMT. Twenty-six pa-
2568
Blood,
Vol82,
No
8
(October
15),
1993:
pp
2568-2576
For personal use only.on June 19, 2019. by guest www.bloodjournal.orgFrom
MoAE-PURGED BMT
FOR
MYELOMA
2569
tients less than
60
years of age, including those less than
55
years
of
age without related histocompatible siblings,
re-
ceived autografts.
T
cells were depleted from allografts and
tumor cells from autografts, using in vitro lysis with mono-
clonal antibodies (MoAbs) and complement. The majority
of patients were heavily pretreated and underwent BMT at
the time of sensitive relapse. Although this therapy has
achieved high response rates and prolonged progression-
free survival in some patients and proven to have acceptable
toxicity, relapses post-BMT support the view that such
treatment strategies should
be
used earlier in the disease
course and their efficacy compared with that of conven-
tional chemotherapy.
MATERIALS AND METHODS
Selection ofpatients and treatment protocol.
Patients were eligi-
ble for autologous BMT if they were less than 60 years of age; pa-
tients less than
55
years of age who had histocompatible sibling
donors underwent allogeneic BMT. All patients had multiple my-
eloma," as well
as
reactivity of tumor cells with anti-plasma cell
associated-
1
(PCA-
I)
MOA^.^'
All original laboratory parameters
were reviewed to establish a proper Dune-Salmon stage at diagno-
sis. Patients must have achieved a minimal tumor burden, defined
as less than
10%
BM tumor cells (regardless of serum paraprotein)
before BMT. Pretransplant therapy was administered to achieve
maximum cytoreduction either at Dana-Farber Cancer Institute
(DFCI) or, under its supervision, administered at local institutions.
Sites of bony disease received additional radiation therapy before
BMT. Additional criteria for entry included the absence of comor-
bid disease of the heart, kidney, lung, and liver, and a Karnovsky
score above 80%. Patients whose prior radiotherapy obviated the
ability to deliver full-dose total body irradiation (TBI) received ab-
lative therapy with chemotherapy only. In patients less than
55
years of age who had HLA identical mixed lymphocyte culture
(MLC) nonreactive sibling donors, allogeneic grafting was per-
formed in preference to autologous BMT; autologous grafting was
done for patients less than 60 years of age, including those less than
55
years of age who did not have histocompatible sibling donors.
Written informed consent was obtained from all patients for treat-
ment protocols approved by the Human Protection Committee at
DFCI.
Preparative therapy for patients undergoing autologous BMT in-
cluded melphalan 70 mg/m2 of body weight, infused
on
each of 2
consecutive days before 1,200 cGy TBI in 20 patients; and cyclo-
phosphamide 60 mg/kg ofbody weight, infused
on
each of 2 consec-
utive days before TBI ( 1,200
cGy
in one patient and 1,400
cGy
in
five patients). The initial
11
patients who received melphalan 70
mg/m2
on
2 consecutive days followed by 1,200 cGy TBI were
evaluated for toxicity in a phase
I
study." Ablative therapy included
cyclophosphamide 60 mg/kg of body weight, infused on each of 2
consecutive days before 1,400 cGy TBI in
1
1
recipients of allografts
and the sole recipient of syngeneic marrow; and busulfan
1
mg/kg
of body weight orally every 6 hours for 16 doses over 4 consecutive
days before cyclophosphamide 60 mg/kg of body weight infused
on
2
consecutive days in two allotransplant patients who had received
prior radiotherapy which precluded TBI. Within 18 hours of the
completion of radiotherapy, either
(
1)
cryopreserved autologous
BM that had been previously treated in vitro with anti-CD10, anti-
CD20, and anti-PCA-1 MoAbs and rabbit complement to deplete
tumor cells was thawed rapidly and reinfused; or (2) allogeneic
marrow that had been treated with anti-CD6 MoAb and rabbit
complement to deplete T cells was reinfused fresh. Marrows were
administered through a central venous catheter.
Collection, processing,
and
infusion of marrow.
Bone marrow
mononuclear cells (BMMCs) were obtained from the iliac crests,
collected in RPMI-1640 medium with preservative-free heparin,
filtered through stainless-steel mesh, and then washed and concen-
trated using a COBE 2991 cell washer (COBE Laboratories, Lake-
wood, CO). Ex vivo treatment of autologous BM was based
on
previously reported methods developed at the Dana-Farber Cancer
Institute that reproducibly deplete two to three logs of antigen (Ag)
positive-cells without depleting hematopoietic stem
cell^."^
Specifi-
cally, anti-PCA-1 MoAb and complement in vitro can lyse two to
three logs of the RPMI 8226 myeloma cell line. Mononuclear cells
were isolated
on
Ficoll-Hypaque gradients and resuspended in
RPMI-I 640 at a concentration of 2
X
lo7 cells/mL. These cells were
subjected to three treatments, each consisting of a 30-minute incu-
bation with MoAb at 20°C followed by incubation for 30 minutes
at 37°C with rabbit complement (Pel Freeze, Brown Deer, WI).
Marrow cells were treated with MoAbs directed at three Ags, in-
cluding CALLA (CD
lo),
which detects the common acute lympho-
blastic leukemia Ag43; B1 (CD20), a pan-B cell AgU; and PCA-1,
which detects a plasma-cell-associated Ag:' This MoAb cocktail
was
used
to target cells in the malignant clone from the pre-B-cell
to the plasma stage.45 Before in vitro marrow treatment, phenotypic
analysis demonstrated less than 10% of cells bearing the CALLA,
B1, or PCA-1 Ags; after treatment, repeat analysis showed absence
ofcells bearing these Ags. Cells were then cryopreserved in medium
containing
10%
dimethyl sulfoxide and 90% autologous serum at
-196°C in the vapor phase of liquid nitrogen. Before infusion, the
cryopreserved marrow cells were rapidly thawed and diluted in me-
dium containing
25
IU DNase/mL to minimize clumping. The
median number of reinfused marrow cells was
2.1
X
lo9
(range, 1.4
to 5.2
X
IO9),
or
a median of 3.1
X
107/kg (range, 1.8 to 7.8
X
107/kg), with 85% to 95% viability
as
measured by Trypan blue
exclusion.
For allogeneic BMT, BM was harvested from histocompatible
sibling donors under general anesthesia using standard techniques.
Marrow was anticoagulated with preservative-free heparin in
RPMI 1640. After BM harvest, marrow cells were washed free of
the anticoagulant and plasma proteins and concentrated into a
50
to 100 mL bufFy-coat fraction using a COBE 299
1
blood-cell proces-
sor. Bone marrow mononuclear cells were isolated from the bufFy-
coat fraction
on
discontinuous gradients of Ficoll-Hypaque.
Mono-
nuclear cells were placed at a cell concentration of 2
X
107/mL and
were incubated with anti-T12 (CD6) MoAb (IgM isotype) for 15
minutes at 20°C followed by the addition of rabbit complement at a
ratio of 1:s or 1:lO final dilution for further incubation at 37°C for
45 minutes. Our method for in vitro treatment of marrow with
anti-T 12 MoAb to abrogate graft-versus-host disease (GVHD) was
described previously.46 Incubation with anti-TI 2 and complement
was repeated twice. After completion of treatment, marrow cells
were combined and washed five times to remove both MoAb and
complement, and were then resuspended in
50
mL media that con-
tained 10% human AB serum. After T12 treatment, patients re-
ceived a median of 6.3
x
IO9
(range, 2.5 to 10
x
lo9)
or a median of
7.4
X
lo7
(range, 2.7 to 13
x
10') cells/kg.
The single patient who underwent syngeneic BMT received
non-
purged marrow with 82.5
x
IO9
total cells, or 101.2
x
IO7
cells/kg.
Supportive care.
Patients were treated in reverse-isolation
rooms until they were discharged. Discharge was permitted if the
absolute granulocyte count was stable at greater than 5OO/pL, and
no
fever had occurred in the absence of antibiotics for 24 to 48
hours.
Trimethoprim-sulfamethoxazole
or ciprofloxacin prophy-
laxis was begun in all patients when chemotherapy was initiated,
but was discontinued if intravenous broad-spectrum antibiotics
were required. Patients received prophylactic acyclovir
(5
mg/kg
or
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2570 ANDERSON ET AL
400 mg orally every
8
hours) for Herpes simplex infections. Prophy-
laxis with
trimethoprim-sulfamethoxazole
or pentamidine inhaler
was instituted at the time ofdischarge and continued for 12 months
to prevent
Pneumocystis carinii
pneumonia. Patients were also
treated with acyclovir to prevent Herpes zoster infection during the
first
I2
months posttransplant. Cytomegalovirus-negative blood
products were used in all patients, regardless of prior exposure to
the virus. Blood products were irradiated (2,500 cGy) to prevent
transfusion-related GVHD.
Clinical evaluation.
Before treatment, all patients were evalu-
ated as follows: physical examination, blood chemistry profile,
complete blood count, serum and urinary protein immunoelectro-
phoresis and immunofixation, human immunodeficiency virus
se-
rology, bone survey, bilateral BM biopsies and phenotypic analysis
of
BMMCs, pulmonary function tests, and ventriculogram. Criteria
for CR included, for at least 3 months, both
(1)
the absence
of
serum
paraprotein and Bence Jones proteinuria by immunoelectro-
phoresis and immunofixation; and (2) fewer than
5%
polyclonal
plasma cells, as demonstrated by immunoperoxidase staining of
BM biopsy specimens for Ig heavy and light chains.
A
50% decrease
in measurable protein sustained for at least
1
month constituted a
partial response. Follow-up evaluations included serum protein
studies monthly and BM aspiration and biopsy at 3-month inter-
vals
for
the first year PT; protein studies at 3-month intervals and
BM aspiration and biopsy at 6-month intervals for the second year
PT; and protein studies at 3-month intervals thereafter. Radio-
graphic bone surveys were performed at 12 month intervals.
a
26
IFN
maintenancetherapy.
For patients treated since 1990,
01
2b
IFN
therapy, 3
X
IO6
U
subcutaneously 3 times weekly, has
been used beginning at 3 months
PT
and continued for at least 9
months PT in an attempt to prolong the duration of responses
achieved.
IFN
was not used in patients who did not achieve transfu-
sion independence with granulocytes
2
1,50O/pL and PLTs
2
lOO,OOO/fiL by 3 months
IT.
Statistical methods.
Survival and failure-free survival (FFS)
were calculated from date
of
BMT. Cases were censored for
FFS
if
alive and disease free at analysis. Three patients who underwent
autologous BMT died free from progression at 2,6, and 19 months,
and are considered failures
for
this analysis. This underestimates
FFS,
but perhaps better reflects the experience
of
the patients.
RESULTS
Twenty-five patients with my-
eloma and
1
patient with recurrent extramedullary plasma-
cytomas underwent autologous BMT between February
1987 and November 1992 (Table
1).
There were
16
men
Patient characteristics.
and
10
women with
a
median age of 47 (35 to 59) years,
including 2,4, 13, and
6
patients with Durie-Salmon stages
IA, IIA, IIIA, and IIIB disease, respectively,
at
time of diag-
nosis. Serum
p2
microglobulin and BM labeling indices
were not routinely performed. Patients received
a
median of
three (two
to
four) treatment regimens over
a
period of 23 (8
to 52) months before BMT. Fourteen patients had received
radiotherapy before BMT. At the time of autologous BMT,
all patients had sensitive disease in that they had achieved
minimal disease status, defined as less than
10%
BM plasma
cells. Three patients had polyclonal plasma cells evident on
bilateral bone marrow biopsy;
1
of these also had no serum
and/or urine monoclonal protein and was therefore the only
patient in complete remission. The remaining patients dem-
onstrated both monoclonal marrow plasma cells and mono-
clonal paraprotein at the time of autologous BMT.
Thirteen patients with multiple myeloma underwent allo-
geneic BMT between February 1990 and November 1992
(Table
1).
There were 9 men and 4 women with
a
median
age of 43 (37 to 52) years, including 2, 3,
6,
and 2 patients
with Durie-Salmon stages IA, IIA, IIIA, and IIIB disease,
respectively, at the time
of
diagnosis. Serum
p2
microglobu-
lin and BM-labeling indices were not routinely performed.
Patients received a median
of
two (one to four) treatment
regimens over a period
of
a median of 25 (9
to
48) months
before BMT. Three patients had received radiotherapy be-
fore BMT. At the time of allogeneic BMT, all patients again
had sensitive disease and achieved minimal disease status,
defined as less than
10%
BM plasma cells. Three patients
had polyclonal plasma cells evident on bilateral bone
marrow biopsy;
1
of these also had no serum and/or urine
monoclonal protein and was therefore the only patient in
complete remission. The remaining patients demonstrated
both monoclonal marrow plasma cells and monoclonal par-
aprotein at the time of allogeneic BMT.
A 44-year-old man with stage IIIB myeloma received che-
motherapy without radiotherapy and achieved less than
10% monoclonal marrow cells, with persistent serum para-
protein (Table
1).
After ablative chemoradiotherapy, he re-
ceived nonpurged syngeneic marrow.
Hematologic engraftment.
Engraftment post-autolo-
gous BMT with granulocytes greater than
500/pL
was noted
Table
1.
Characteristics of Patients Undergoing
BMT
for Myeloma
No.
of
No.
of
No.
of
No.
of
Patients: Patients Patients Patients
No.
of With
(+)
or Median With
(+)
or With
(+)
or
No.
of
ChemoRx Without
(-)
Interval Without
(-1
Without
(-)
Source Median Patients:
No.
of Regimens RadioRx Diagnosis Monoclonal Monoclonal
of Stem
No.
of Age (yr) Stage at Patients: Before Before to Transplant Plasma Cells Protein at
Cells Patients (rangel Sex Diagnosis lsotype Transplant Transplant
(mo)
(range)
at
Transplant Transplant
~~~
Purged autologous 26 47 (35-59) 16
M
2:IA 16:lgG 7:2 14+ 23 (8-52)
23+
25+
marrow 10 F 4:llA 7:lgA 11.3 12- 3- 1-
13:lllA 3:Kor
X
8:4
6:lllB
T
depleted allogeneic 13 43 (37-52)
9
M
2:IA 7:lgG 1:l 3+ 25 (9-48) 1
o+
12+
marrow 4F 3:llA 2:lgA 7:2 10- 3- 1-
6:lllA 4:K 3:3
2:MB 2:4
- -
Syngeneic marrow 1 44 1
M
IllB
IgG 1:l
8
+
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MoAB-PURGED BMT FOR MYELOMA
257
1
at a median of 23 (range, 12 to 46) days
PT
in 25 patients
and untransfused platelets greater than 20,00O/pL at a me-
dian of 25 (range,
IO
to 175) days PT in 24 ofthe 26 patients
(Table 2).
A
median of 9
U
(range, 4 to 30
U)
of red blood
cells (RBCs) and 56
U
(range, 4 to 329
U)
of platelets were
transfused. Patients were discharged from the hospital at a
median of 3 1 (range, 24 to 67) days
PT.
A single patient who
was heavily pretreated with chemotherapy including nitro-
sourea developed pneumonia, typhlitis, and refractory
thrombocytopenia and succumbed of a central nervous sys-
tem hemorrhage at day 67
PT.
She did not engraft and re-
quired 29
U
of RBCs and 329
U
of platelet transfusion
support during her 67-day hospitalization. Another patient
remained platelet transfusion dependent until his death at 6
months
PT.
Engraftment post-allogeneic BMT with granulocytes
greater than
500/pL
was noted at a median of 19 (range, 12
to 24) days
PT
and untransfused platelets greater than
20,0OO/pL at a median of 16 (range,
5
to 32) days
PT
(Table
2).
A
median of
8
U
(range, 4 to 23
U)
of RBCs and 45
U
(
17
to 307
U)
of platelets were transfused.
A
single patient re-
quired 307 units of platelet transfusion support in the set-
ting of venocclusive disease (VOD). Patients were dis-
charged from the hospital at a median of 3
1
(27 to 52) days
PT.
The single patient who underwent syngeneic BMT
achieved granulocytes >500/pL and untransfused platelets
greater than 20,00O/pL at I9 and 25 days PT, respectively
(Table 2). He required 6
U
of RBCs and 76
U
of platelets
during a 33-day hospitalization.
Acute and chronic toxicity.
Of the 26 patients who un-
derwent autologous grafting, all developed fevers
(>
10
1
OF)
while leukopenic, but only 3 patients had positive blood
cultures: Staphylococcus epidermidis in 2 patients and
a
hemolytic streptococcus in a single patient (Table 2). Eigh-
teen patients developed mucositis. Herpes zoster and ve-
nous thrombosis occurred in 4 and
l
patient, respectively.
Three patients developed hypothyroidism and a single pa-
tient hypoparathyroidism PT.
As noted above, there was
1
acute in-hospital treatment-
related death. This death occurred in a 50-year-old woman
who presented with plasmacytoma of the proximal left fe-
mur necessitating total hip replacement, associated with
Durie-Salmon stage IIIB multiple myeloma. Over the next 2
years she received therapy with four combination chemo-
therapy regimens (total dose of 90 mg carmustine). After
melphalan and TBI-ablative therapy, she received 2.9
X
lo7
cells/kg body weight marrow infusion. Fever without source
was noted on
day
5
PT and leukocytes reappeared as ex-
pected on day 10 PT. Her hospital course was complicated
by pneumonia (day 11
PT),
a diffuse rash thought to
be
drug-related (day 30 PT), and clinical and radiographic find-
ings consistent with typhlitis (day
50
PT).
BM aspirate at
day 41 PT was hypocellular, but without evidence of my-
eloma, and leukocyte count peaked on day 48
PT
at 800/pL
with 40% granulocytes. Despite aggressive antibiotic and
transfusion support, the patient became alloimmunized
and refractory even to HLA-matched platelet transfusions
and succumbed with a central nervous system hemorrhage
on day 67 PT. Postmortem examination showed numerous
petecchial and ecchymotic lesions of the skin and serosal
surfaces of the peritoneum, pleura, and pericardium,
as
well
as hemorrhage of the respiratory, gastrointestinal, and uro-
thelial mucosa. The BM was hypocellular but all cell lines
were recovering; immunoperoxidase studies of marrow in-
dicated that the scattered plasma cells were of a polyclonal
nature.
Of the 13 patients who underwent allogeneic grafting,
1 1
developed fever
(>
101
OF)
while leukopenic (Table 2).
Blood cultures were positive in 3 patients: Staphylococcus
Table
2.
Hematologic Engraftment and Toxicity After
BMT
for Myeloma
Median
Median Days Median Units
of
Median
PT With Median Days Units
of
RBCs
Platelets Days in
Source
of
No.
of
Granulocytes PT to Platelets Transfused Transfused Hospital
No.
of
Patients:
Stem Cells Patients
>500/rL
(range)
>2O,OOO/pL
(range) (range) (range) (range) Complication
Purged autologous
26 23 (12-46)’ 25 (10-175)’ 9 (4-30) 56 (4-329) 31 (24-67) 26:
Fever
marrow
3:
Bacteremia
18:
Mucositis
4:
Herpes zoster
1
:
Venous thrombosis
3:
Hypothyroidism
1
:
Hypoparathyroidism
T-depleted allogeneic
13 19 (1 2-24) 16 (5-32)
8
(4-23) 45
(1
7-307) 3
1
(27-52)
1 1
:
Fever
marrow
3:
Bacteremia
6:
GVH disease
(4
grade
I,
1
grade
II,
1
grade
111)
1
:
Chronic GVH disease
2:
Venocclusive disease
1
:
Graft failure
Syngeneic marrow
1
19 25 6 76 33 1:
Fever
Abbreviation: PT, posttransplant.
One patient did not achieve greater than
500
granulocytes/pL and
2
patients did not achieve untransfused platelets greater than
2O,OOO/pL.
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2572
ANDERSON ET
AL
epidermidis,
Escherichia coli,
and enterobacter in
1
patient
each. Six of the 13 patients developed acute GVHD: grade
I
in 4 patients, grade
I1
in
1
patient, and grade
111
in
I
patient.
Acute GVHD resolved in 3 patients with topical and/or oral
corticosteroid therapy, and in
2
patients without treatment.
A
single patient developed chronic GVHD and was treated
with corticosteroids and cyclosporine for
4
months, and has
required no therapy thereafter.
Two patients developed VOD characterized by weight
gain, ascites, and liver function test abnormalities in the first
month PT. In the first patient, total bilirubin peaked at 4.3
mg/dL on day
I5
PT;
treatment with pentoxyphylline led to
resolution of VOD and discharge at day 33 PT. The other
patient developed clinical VOD and rising total bilirubin on
day
11
PT; despite treatment with tissue plasminogen acti-
vator, heparin, pentoxyphylline, and prostaglandin
E
1,
he
expired on day 40
PT
with total bilirubin of
40
mg/dL. At
postmortem examination, the liver showed signs of pro-
found venous congestion and biliary stasis and ascites was
present. Characteristic signs of GVHD in the gastrointesti-
nal tract, skin, and liver were not present, nor was there any
evidence of residual myeloma in marrow.
A third patient engrafted promptly, with granulocytes
greater than
5OO/pL
and platelets greater than
20,00O/pL
at
days 17 and 19 PT, respectively. The marrow donor was her
brother who was both HLA and AB0 compatible. On day
2
1
PT, the patient was begun on Bactrim therapy for a uri-
nary tract infection; by day 49 PT she had developed pro-
found pancytopenia, with fewer than
100
lymphocytes/pL,
all of which were of her own type. No evidence of viral or
other infection was documented, and a trial of granulocyte
colony stimulating factor did not increase her leukocyte
counts. She therefore underwent a second allograft with her
brother’s non-T-cell depleted marrow, after preparation
with cyclophosphamide
50
mg/kg on 4 consecutive days
and antithymocyte globulin. Although she engrafted
promptly with greater than
500
granulocytes/pL and un-
transfused platelets greater than
2O,OOO/pL
on days
1
1
and
14
PT, respectively, she died in the setting of GVHD, which
was refractory to immunosuppressive therapy including cor-
ticosteroids and cyclosporine as well as IL-
I
receptor antago-
nist.
Therapeutic results.
Among the patients who under-
went autografting, there were
11
complete and 14 partial
responders, and
1
toxic death. All responding patients
achieved pathologically normal marrows with less than
5%
marrow plasma cells; in complete responders, monoclonal
proteins were
also
absent in serum and urine, and marrow
plasma cells were polyclonal on immunoperoxidase stain-
ing. Staging marrow biopsies routinely performed during
the first 24 months PT confirmed the presence of less than
5%
polyclonal plasma cells in
2
1
patients
(1
I
complete and
10 partial responders) at a median of 3 (range, 3 to 10)
months PT. Monoclonal proteins disappeared in the
1
1
pa-
tients with CR at a median of
3
(range, 2 to
19)
months PT.
Of the
1
1
complete responders to autologous BMT, normal
levels of IgG, IgA, and
IgM
were noted in
5,8,
and 9 patients
at
9
(range, 6 to I3),
5
(range,
1
to lo), and 6 (range,
1
to
10)
months PT, respectively. Of the
I4
partial responders, nor-
mal levels of IgG,
IgA,
and
IgM
were noted in 2, 6, and
I2
patients at
1
and 24,9 (range,
5
to
I2),
and
4
(range,
I
to
12)
months PT, respectively. One patient had free
X
light chains
in serum and urine before BMT and recurred with IgG
X
after BMT. Another patient had
IgA
X
myeloma before
BMT and recurred with IgA
X
as well as IgG
X
monoclonal
proteins.
As of November 1,
1992
with 24 months median follow-
up,
21
of the 26 patients who underwent autografting are
alive at
2+
to 68+ months PT, and 16 patients remain alive
free from progression at
2+
to
55+
months
PT
(Fig
1);
of
these, five patients remain in CR at 6+ to
55+
months PT.
Three patients died free from progression at 2, 6, and 19
months
PT.
Seven patients relapsed at 3 to 36 months PT;
of these,
5
patients remain alive at
22+
to 68+ months PT,
and 2 patients died at
14
and 27 months PT. The median
progression-free survival is 36 months and median overall
survival has not yet been reached.
Among the 14 patients who received either allogeneic or
syngeneic grafts, there were 7 complete responders,
4
partial
responders,
1
non-responder, and
2
toxic deaths. Again, all
responding patients achieved pathologically normal
marrows with less than
5%
marrow plasma cells; in com-
plete responders, monoclonal proteins were also absent in
serum and urine, and monoclonal plasma cells were polyclo-
nal on immunoperoxidase staining. On staging marrow
biopsies performed routinely during the first
24
months PT,
the presence
of
less than
5%
polyclonal plasma cells was
confirmed in
11
patients (7 complete and
4
partial re-
sponders) at a median of
4
(2 to
8)
months
PT.
In
2
of the 7
complete responders, monoclonal plasma cells have re-
turned at 6 and 7 months PT. Monoclonal proteins disap-
peared in the
7
patients with CR at a median of 3 (1 to
4)
months PT; in 2 of the
7
complete responders, monoclonal
protein also returned at 6 and
7
months PT. Of the 7 com-
plete responders to allogeneic BMT, normal levels of IgG,
IgA,
and IgM were noted in 5,6, and 7 patients at
5
(range, 2
to 12),
5
(range,
2
to
14),
and
5
(range,
1
to 6) months PT,
respectively. Of the 4 partial responders, normal levels
of
the uninvolved IgG,
IgA,
and IgM were noted in
4,
1, and
1
patient at 5,2, and 3 (range,
2
to
5)
months PT, respectively.
Polyclonal elevation of IgG and monoclonal IgG protein
have each been noted in a single patient at 14 and 9 months
PT, respectively.
As of November
1,
1992
with
24
months median follow-
up, 9 of the
14
patients who received either allogeneic or
syngeneic grafts are alive and
8
patients remain alive free
from progression at
8+
to 34+ months PT (Fig
2);
ofthese,
5
patients remain in CR at
8-t
to 34+ months PT. Two pa-
tients died free of relapse from VOD and graft failure at
l
and
4
months PT, respectively. Four patients relapsed at 2,
6, 7, and
17
months PT; of these,
1
patient remains alive at
24 months
PT
and
3
patients have died at
4,
9,
and 13
months
PT.
The median progression-free and overall sur-
vival have not yet been reached.
Of the 26 patients who underwent
autologous BMT, 13 patients received
IFN:
3
patients pre-
BMT,
3
patients at the time of relapse post-BMT, 6 patients
(Y
2b
IFN
therapy.
For personal use only.on June 19, 2019. by guest www.bloodjournal.orgFrom
MoAB-PURGED BMT
FOR
MYELOMA
2573
1
.O
0.8
..............................................................................................
I
0.0
I
I
0
I
2
3
4
5
6
Years
Time Interval
Group
0-1
1-2 2-3 3-4 4-5 5-6
FFS
5/26 3/13 2fl
OD
O/I
OD
Fig
,
.
MM
autologous
trans-
....................
Survival
2/26
2/16
1/10
0/6
OB
011
plant.
(#
eventsl#
at
risk)
as maintenance therapy post-BMT, and
1
patient both be-
fore BMT and as maintenance therapy post-BMT. Five pa-
tients did not receive maintenance
IFN
post-BMT because
of
low counts;
of
those receiving maintenance therapy, dose
reduction
(1
patient) or discontinuation
(1
patient) was re-
quired due to pancytopenia;
IF"
was discontinued in an
additional patient due
to
the development
of
pulmonary
infiltrates. One of the
6
patients on maintenance
IF"
ther-
apy has progressed.
Of the
14
patients who underwent allogeneic or syngeneic
BMT,
10
patients received
IFN
therapy:
1
patient pre-BMT,
2
patients at the time
of
relapse post-BMT, and
7
patients as
maintenance therapy post-BMT. Two patients did not re-
ceive
IFN
post-BMT because of low counts; discontinua-
1
.O
0.8
0.6
0.4
I
1
0.2
1
0.0
0.5
1
.o
1.5
2.0 2.5 3
.O
Years
Time Interval
Group
0-0.5
0.5-1
1-1.5 1.5-2 2-2.5 2.5-3
FFS
5/14
Of9
lfl
0/5
0/4
OB
Survival 3/14
1/11
1/8
016
0/4
013
....................
Fig
2.
MM
allogeneic trans-
(I
event#
at
risk)
plant.
For personal use only.on June 19, 2019. by guest www.bloodjournal.orgFrom
2574
ANDERSON
ET
AL
tion of maintenance
IFN
post-BMT was required in 3 pa-
tients due to the development of thrombocytopenia and fa-
tigue. One of the 7 patients on maintenance
IFN
post-BMT
has progressed.
DISCUSSION
In this study, we report the results of 40 patients with
multiple myeloma who underwent high-dose chemora-
diotherapy and either anti-B-cell MoAb-treated autologous
BMT
or
anti-T-cell MoAb-treated allogeneic BMT. The
majority of patients had advanced Dune-Salmon stage my-
eloma, had sensitive relapsed myeloma and were heavily
pretreated with chemotherapy; 17 had received prior radio-
therapy. At the time of BMT, all patients demonstrated
good performance status with Karnofsky score of 80%
or
greater and had less than 10% marrow tumor cells; 34 pa-
tients had residual monoclonal marrow plasma cells and 38
patients had paraprotein. There were 18 CRs, 18 partial
responses,
1
nonresponse, and 3 toxic deaths. Less than 5%
polyclonal marrow plasma cells were noted in all responders
after BMT. As of November 1, 1992 with 24 months me-
dian follow-up for survival among the autologous BMT
cases, 16 of 26 patients are alive free from progression at 2+
to 55+ months PT; of these, 5 patients remain in CR at 6+
to 55+ months PT. With 24 months median follow-up for
survival among the allogeneic and syngeneic BMT cases,
8
of 14 patients are alive free from progression at 8+ to 34+
months PT; of these, 5 patients remain in CR
at
8+ to 34+
months PT. Although this therapy has achieved high re-
sponse rates and prolonged progression-free survival in
some patients and proven to have acceptable toxicity, re-
lapses post-BMT suggest that such treatment strategies
should be used earlier in the disease course and their efficacy
compared with that of conventional chemotherapy in a ran-
domized trial.
Melphalan and prednisone therapy can result in response
rates of 50% to 60% and
a
median survival of 48 months;
and to date it remains controversial as to whether combina-
tion chemotherapy programs have improved on this out-
~ome.',~,~ Once patients become refractory to initial thera-
pies, salvage therapies such as vincristine, doxorubicin, and
dexamethasone" can achieve response rates of
50%
to 75%;
however, these responses are uncommonly either complete
or durable. High-dose melphalan with or without total body
irradiation and hematopoietic stem cell support was ini-
tially used by McElwain et al.27328 This strategy has achieved
responses even in the setting of patients refractory to initial
However, in most studies, significant relapse-
free survival was noted only in
a
minority of patients with
sensitive disease, and those patients with resistant relapse
or
with a combination of risk factors (ie, advanced tumor bur-
den, absence of IgG i~otype)~' did particularly poorly. None-
theless, as is true in B-cell non-Hodgkin's lymphomas
(NHL), high-dose therapy followed by autologous BMT is
the only strategy to have achieved significant relapse-free
survival. For example,
at
our
institute, MoAb-purged autol-
ogous BMT for patients with relapsed
B-
and T-cell NHL
sensitive to chemotherapy has resulted in 40% to
50%
re-
lapse-free survival at
2
to
3
years.'"-49 Although follow-up is
short and long-term outcome remains to be determined, the
current study of either MoAb-purged autologous or alloge-
neic BMT in myeloma sensitive
to
therapy has achieved
significant overall and relapse-free survivals (Figs
1
and 2).
However, only 5 of 26 patients undergoing autologous
BMT and 5 of 14 patients undergoing allogeneic BMT re-
main in CR at 6+ to 55+ and 8+ to 34+ months PT, respec-
tively. In the largest reported series to date of high-dose ther-
apy followed by allogeneic BMT in myeloma, median
relapse-free survival for 37 of 90 (4
1
%)
patients who entered
complete remission was 48 months.23 In this study, those
patients with sensitive disease and who were less heavily
pretreated achieved the highest response rates and pro-
longed progression-free survival. These studies suggest, as
has occurred in leukemias and lymphomas, that high-dose
approaches should be evaluated earlier in the disease, before
the emergence of drug resistance and refractory disease.
An additional impetus for using high-dose approaches ear-
lier in the disease course, now that toxicities of such ap-
proaches have proven to be tolerable, relates to the quality
of autologous hematopoietic stem cells and related speed
and completeness of hematologic recovery after high-dose
therapies.
For
example, Jagannath et a1 have attempted
PBSC collection in 75 previously treated patients with
myeloma after the administration of high-dose cyclo-
phosphamide with
or
without granulocyte-macrophage col-
ony-stimulating factor (GM-CSF).39 Among 72 patients
undergoing PBSC apheresis, good mobilization (>50 col-
ony-forming units GM per lo5 mononuclear cells) was
achieved when prior chemotherapy did not exceed
1
year
and when GM-CSF was used post-high-dose cyclophospha-
mide; similarly, rapid platelet recovery (to
50,00O/pL)
was
associated with good PBSC mobilization. In the present
study of high-dose chemoradiotherapy followed by autolo-
gous
BMT in heavily pretreated patients with myeloma, de-
layed engraftment was also noted; greater than
500
granulo-
cytes/pL and greater than 20,00O/pL platelets were noted as
long as 46 days and 175 days PT, respectively, and
2
pa-
tients did not achieve platelet transfusion independence at
the time of their deaths at
2
and 6 months
PT.
Moreover, it
was not possible to treat all patients with
IFN
post-BMT due
to related myelosuppression. Treatment of patients with
high-dose approaches earlier in their disease course may
therefore be useful not only for the avoidance of drug resis-
tance, but
also
to assure preservation of sufficient hemato-
poietic stem cells to permit rapid hematologic recovery and
low treatment-related morbidity and mortality.
Several investigators have used intensive treatment of
multiple myeloma supported by autologous BM and/or
PBSC transplantation as initial therapy in myel~ma.'**~*-~~~~~
For example, Gore et
a1
treated 50 patients with myeloma
with repeated cycles of 4-day infusions with vincristine,
doxorubicin, and methylprednisolone followed by high-
dose melphalan, with autologous BMT where possible.**
The overall response rate was 74%, with 50% complete he-
matologic and biochemical remissions. More recently, these
investigators have demonstrated that patients who receive
maintenance
IFN
post-autologous BMT have prolonged
median progression-free survival (39 months) compared
For personal use only.on June 19, 2019. by guest www.bloodjournal.orgFrom
MOAB-PURGED
BMT
FOR
MYELOMA
2575
with those patients who are not treated with
IFN
(27
months)
(P
<
.025).” Attal et al recently treated
35
patients
with myeloma with repeated cycles of either vincristine,
doxorubicin, and dexamethasone, or vincristine, melpha-
lan, cyclophosphamide, and prednisone until plateau phase
was a~hieved.~’ High-dose melphalan, and TBI followed by
autologous BMT and maintenance
IFN
resulted in 43% and
40% complete and partial responses, respectively. The
33-
month post-BMT probability of progression-free survival
was
85%
for patients in complete and 24% for patients in
partial response. The 42-month post-diagnosis probability
of survival was
8
1
%.
These and other similar studies3’
sug-
gest that high-dose approaches early in the disease course
can achieve high response rates and that therapeutic inter-
ventions post-BMT, such as
IFN
maintenance, may be bet-
ter tolerated by such patients than in more heavily pre-
treated patients. They provide the basis on which a
randomized trial comparing high-dose versus conventional-
dose chemoradiotherapy for patients with untreated my-
eloma can be based.
ACKNOWLEDGMENT
We are indebted to the house staff of the Brigham and Women’s
Hospital and Beth Israel Hospital, the fellows of the Dana-Farber
Cancer Institute, as well as the nurses and social workers of the
Dana-Farber Cancer Institute for their excellent care of these pa-
tients. We also thank Barbara Barrett and co-workers of the Blood
Component Laboratory, and the technicians of the Clinical Immu-
nology Laboratory (DFCI) for processing of the BM; the oncologic
surgeons of the Brigham and Women’s Hospital and New England
Deaconess Hospital for their surgical assistance; and Drs William
Kaplan and Robert Finberg and staffs in their respective depart-
ments of Radiology, Nuclear Medicine, and Infectious Disease for
their excellent assistance in patient care. We also thank Bernadette
Miner for preparation of the manuscript. The authors are especially
grateful to the many physicians who referred patients for these stud-
ies.
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For personal use only.on June 19, 2019. by guest www.bloodjournal.orgFrom
1993 82: 2568-2576
Blake, C Murray and A Freeman
KC Anderson, J Andersen, R Soiffer, AS Freedman, SN Rabinowe, MJ Robertson, N Spector, K
multiple myeloma
Monoclonal antibody-purged bone marrow transplantation therapy for
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