From www.bloodjournal.org by guest on June 14, 2017. For personal use only.
Allogeneic Marrow Transplantation for Multiple Myeloma: An Analysis of
Risk Factors on Outcome
By William I. Bensinger, C. Dean Buckner, Claudio Anasetti, Reginald Clift, Rainer Storb, Todd Barnett,
Tom Chauncey, Howard Shulman, and Frederick R. Appelbaum
Between September 1987 and December 1994, 80 patients
with multiple myeloma (MM) received high-dose busulfan
and cyclophosphamide without (n = 57) or with modified
total body irradiation (n = 23) followed by marrow from
allogeneic donors. At transplant, 71% of the patients had
disease that was refractory to chemotherapy.Thirty-five patients died of transplant-relatedcauses within 100 days and
11 deaths occurred later. The actuarial probabilities of survival and progression-freesurvival were 2 4 f: 0.17 and 2 0
f 0.10 at 4.5 years. Complete remissions were obtained in
36% of patients who had actuarial probabilities of survival
and event-free survival of .50 f 0.21 and .43 f 0.17 at 4.5
years. In a multivariate analysis, adverse risk factors for out-
come endpoints included: transplantation greater than 1
year from diagnosis; 8-2 microglobulin >2.5 at transplant;
female patients transplanted from male donors; patients
who had receivedgreater than eight cycles of chemotherapy
before transplant and Durie stage 3 disease at the time of
transplant. These results indicate that allografting for patients with MM can result in long-term disease-free survival
for a minority of patients. Efforts to reduce transplant-related mortality should focus on earlier transplantation, less
toxic treatment regimens, better supportive care, and improved prevention and treatment of graft-versus-host disease (GVHD).
0 1996 by The American Society of Hematology.
ation of marrow transplantation. Patient records, x-rays, and marrow
ULTIPLE MYELOMA (MM) is a malignant plasma
aspirates were reviewed to confirm the diagnosis of MM. To be
cell disorder arising from primitive lymphoid B cells
considered for marrow transplantation, patients had to meet the esand possibly an earlier hematopoietic cell.’.’ For the last 30
tablished criteria for active, symptomatic MM according to Durie
years conventional dose chemotherapy plus corticosteroids
and Salmon’’ and had to have received at least one cycle of convenor steroids alone have been the mainstay of treatment and
tional dose chemotherapy. Those patients who had achieved a comfew, if any, patients are cured. The median survival remains
plete response to first line therapy and were without any evidence
about 30 to 36 months, and there is no convincing evidence
of disease, as well as patients with “smoldering” myeloma, were
that new drug combinations offer a survival advantage comexcluded from transplantation. Patients with at least a 50% reduction
pared with that achievable with melphalan and predni~one.~.~in monoclonal proteins to their most recent chemotherapy were categorized as having chemotherapy-sensitive disease, while all other
Less than 3% of patients survive more than 10 years, and
patients were judged to have chemotherapy-resistant disease. Pamost of these survivors have suffered multiple relapses.’ The
tients with a Kamofsky score of less than 50, a pulmonary diffusion
lack of cures with conventional dose chemotherapy
capacity of less than 50% of predicted and symptomatic heart failure
prompted studies of high-dose therapy followed by marrow
were excluded. Standard hematologic, electrolyte, and chemistry
inf~sion.~-”
studies were used to evaluate organ function. Transplants occurred
Since the initial observations that high-dose cyclophosbetween September 1, 1987 and December 1, 1994. The date of last
phamide (CY), total body irradiation (TBI), and marrow
follow-up was March 30, 1995. Patient characteristics are shown in
infusion could cure patients with MM who had syngeneic
Table 1. A suitable marrow donor was required, which included
donors,I4there have been many reports of high-dose chemoHLA identical relatives, HLA haplo-identical relatives mismatched
radiotherapy followed by infusion of autologous or allogefor no more than one HLA A, B, or D antigen on the nonshared
neic marrow. Studies using marrow transplantation have
haplotype, or an unrelated donor who was phenotypically HLA identical with the
demonstrated true complete response rates in 30% to 60%
The higher proportion of male patients, older median age (comof patient^.'^.'^-'' Allogeneic marrow transplantation may
pared with other hematologic malignancies commonly offered transproduce a significant fraction of long-term disease-free surviplants) and myeloma subtypes were consistent with disease demovors, although late relapses do occur.lz.lsA variety of regigraphics.” The majority of patients were transplanted beyond 1 year
mens have been employed for cytoreduction including CY
+ TBI, melphalan + TBI, or busulfan (BU) + CY, but there from diagnosis. They were, in general, a heavily pretreated group,
is, as yet, no evidence about which, if any, of these regimens
From the Fred Hutchinson Cancer Research Center, the Veterans
offers a remission or survival advantage over others. One
Affairs Medical Center, The Swedish Hospital Medical Center Tureport on the results of transplantation with allogeneic marmor Institute, and the University of Washington, Seattle, WA.
row for patients with MM found that patients who had reSubmitted July 12, 1995; accepted May 22, 1996.
ceived fewer courses of chemotherapy before transplant had
Supported by National Cancer Institute Grants No. CA 47748,
a better response after transplant and an improved survival.”
CA 18221, CA 15704, CA 09319, CA 09515, CA 18029, the Jose
Questions remain, however, about which patients should be
Carreras Foundation against Leukemia, and the Joseph Steiner
offered transplantation and when in the disease course is the
Krebsstijung.
optimal time for this intervention.
Address reprint requests to William I. Bensinger, MD, Fred
This report analyzes the influence of disease and patient
Hutchinson Cancer Research Center, I124 Columbia St, M-185,
Seattle, WA 98104.
and donor characteristics on outcome following allogeneic
The publication costs of this article were defrayed in part by page
marrow transplantation for 80 patients with MM.
M
MATERIALS AND METHODS
Patients were referred to the Fred Hutchinson Cancer Research
Center or the Seattle Veterans’ Affairs Medical Center for considerBlood, Vol 88, No 7 (October 1). 1996: pp 2787-2793
chihge payment. This article must therefore be hereby marked
“advertisement” in accordance with 18 U.S.C. section 1734 solely to
indicate this fact.
0 1996 by The American Society of Hematology.
0OO6-4971/96/8807-OO39$3.00/0
2787
From www.bloodjournal.org by guest on June 14, 2017. For personal use only.
2788
BENSINGER ET AL
Table 1. Allogeneic Transplantationfor Multiple Myeloma In = 80)
Patient Characteristics
Sex M/F
Age at transplant
Time Dx Tx*
Prior therapyt
Regimens
Cycles
Radiation*
-+
Chemotherapy-resistant/responsive
Histology
IgG
IgA
IgD
Light chain
Plasma cell leukemia
Nonsecretory
0-2 Microglobulin
YO Plasma cells in marrow
Stage at transplant§
I
II
111
Mean
Median (range)
43.4
1.9
44 (28-56)
1.4 (0.4-9.3)
2.5
9.7
2 (1-5)
8 (2-29)
51/29
42
53/27
44
18
1
11
1
5
3.2
27.5
2.4 (1.2-11.9)
15 (0-99)
12
20
48
*Time in years from diagnosis to transplant.
t Number of separate chemotherapy regimens, total number of cycles of therapy.
Number of patients with prior radiation therapy.
§ Staging according to Durie and Salmon.
*
the majority having received more than two regimens, eight cycles
of chemotherapy and prior radiation. Seventy-one percent of the
patients were judged to be chemotherapy-resistant. Thirteen patients
(16%)were responding to first-line therapy. Over half of the patients
had stage 3 disease at transplant. Four patients had serum creatinine
values >2.0 mg/dL at transplant.
Treatment characteristics are shown in Table 2. Results from the
first 18 patients, who received BU and CY as part of a phase 1 dose
finding study, have been previously re~0rted.I~
The regimen for these
18 patients consisted of BU 14-16 mgkg given in 16 divided doses
6 hours apart over 4 days and CY 120-174mgkg given as a divided,
daily intravenous dose over 2 to 3 days. Sixteen patients received a
fixed dose of BU 14 mgkg and CY 150 mgkg as part of an ongoing
phase 2 study. Twenty-one patients received escalating doses of Bu
14 to 15 mg/kg and CY 147-200 mgkg given with pentoxifylline
and ciprofloxacin as part of a research protocol conducted in an
effort to reduce transplant-related to~icities.’~
Twenty-three patients
were entered into a phase 1 trial that included a modified TBI regimen delivered by a linear accelerator in 1.5 Gy fractions with 90%
lung and liver shielding. After each dose of TBI, electron beam
treatments of 1.5 Gy were given to rib areas that were shielded.
Patients received modified TBI at total doses of 7.5 (n = 2), 9.0 (n
= 20), and 10.5 Gy (n = l), followed by BU 14 mgkg and CY
120 mgkg as a fixed dose. Marrow for transplantation was obtained
from donors by standard methods and was infused 36 to 48 hours
after the last dose of CY.24
Patients received one of several regimens for graft-versus-hostdisease (GVHD) prophylaxis that included daily intravenous
cyclosporine (CSP) and intravenous methotrexate on days I , 3, 6,
and 112’; CSP and daily prednisone, CSP alone, T-cell depletion
(one patient) or FK506? GVHD was graded according to published
riter ria.'^ Patients who developed acute GVHD were treated with
prednisone, antithymocyte globulin or an anti-CD5 immunotoxin.
Patients were hospitalized in private rooms with or without laminar airflow isolation. The majority of patients received prophylactic
systemic antibiotics and weekly intravenous immunoglobulin replacement. Growth factors were not routinely given posttransplant.
but were administered to patients with graft failure.
Staging studies, performed before and 80 to 100 days after transplant, included marrow aspiration, skeletal survey with supplementation by magnetic resonance imaging when indicated, serum and 24hour urine collection for protein electrophoresis and immunofixation,
and beta 2 microglobulin. Criteria for complete response (CR) after
transplant included normal marrow cellularity with less than 5%
plasma cells, no monoclonal protein detectable in serum or urine by
immunofixation, and absence of progression of bone disease. Bone
lesions, detected by standard x-rays, were not required to resolve to
judge patients to have responded. Patients with a 75% or greater
reduction in serum or urine monoclonal protein without hone progression on x-ray were judged to have a partial response. Anything
less than a 75% reduction in monoclonal protein was considered a
nonresponse.
Patients who achieved a CR were judged to have relapsed when
any monoclonal protein reappeared in blood or urine, plasmacytosis
in marrow increased to greater than 5%, or when bone disease progressed. Patients with less than a CR were judged to have progressed
when the monoclonal proteins in serum or blood doubled from their
lowest value after transplant, or hone disease progressed.
Statistics on mortality within the first 100 days, survival, relapse
or progression and progression-free survival were calculated using
the method of Kaplan and Meier.’” A multivariate analysis was
performed using a Cox model to measure the effects of disease and
patient and donor variables on outcomes including mortality within
the first 100 days after transplant, overall survival, relapse or disease
progression-free survival. Variables with a univariate P value less
than .05 were added to the model in a step-wise fashion with appropriate adjustment of other variables not in the model.
Variables examined are shown in Table 3. Patient age was categorized as less than or greater than 40 years. All four possible donorTable 2. Allogeneic Transplantationfor Multiple Myeloma In = 80)
Treatment Characteristics
Donors*
Related HLA =
Related HLA MM1
U R D HLA =
Regimenst
BU 14-16ICy 120-174
Bu 14ICy 150
BU 14-151Cy 147-200$
TBI 7.5-10.5 Gy, BU 14, Cy 120
GVHD prophylaxis§
CSP/Mtx
CSP/Pred
CSP
T-depletion
FK506
66
5
9
20
16
21
23
46
22
3
1
8
* HLA-identical family members, family mismatched for 1 antigen.
URD, unrelated donors, HLA-identical.
t BU, busulfan, numbers are the mg/kg. CY, cyclophosphamide;
TBI, modified total body irradiation. Numbers are the radiation dose
in gray (Gy).
Pentoxifylline and ciprofloxacin.
§ CSP, cyclosporine; MTX, methotrexate; PRED, prednisone.
*
From www.bloodjournal.org by guest on June 14, 2017. For personal use only.
2789
RISK FACTORS AFTER ALLOGRAFTING FOR MYELOMA
Table 3. Allogeneic Stem Cell Transplantation for MM
Results of Multivariate Analysis
Survival
Death <lo0 Days
Variables
Age >40
Sex DiR
No. Cycles
chemo
No. Chemo
regimens
Plasma cells
>lo%
Previous XRT
Stage 3
0-2 microglobulin
Chemosensitive
Time Dx Tx
Regimen (TEI)
Donor type
-
Univariate Multivariate
Relative
Risk
Relapse or Progression
Relative
Risk
Univariate Multivariate
Relative
Risk
Univariate Multivariate
Relapse/Progression-FreeSurvival
Univariate Multivariate
0.527
0.449
0.409
0.249
0.848
0.014
0.026
0.551
3.5 11.1-11.5) 0.490
0.196
0.160
0.010
0.010
4.3 (1.2-15.9) 0.052
0.838
0.866
0.102
0.466
0.127
0.051
0.859
0.318
0.005
0.985
0.922
0.221
0.541
0.951
0.009
0.373
2.5 (1.3-4.9) 0.019
0.568
0.930
0.919
0.934
0.794
2.0 (1.1-3.7) 0.091
0.51 1
1.8 (1.0-3.1) 0.729
0.635
0.563
0.005
0,009
0.033
Relative
Risk
0.741
0.571
0.423
0.021
0.934
0.349
0.038
0.435
0.891
0.021
1.9 11.1-3.2)
See text for description of discriminant variables.
recipient gender permutations were examined in the analysis. The
number of cycles of chemotherapy and number of regimens given
before transplant were divided into two groups based on the median
values of 8 and 2, respectively. The percentage of plasma cells in
the pretransplant marrow specimen was divided into greater than or
less than 10%.Previous history of local radiation therapy and staging
before transplant using the Durie and Salmon clas~ification'~
were
entered into the model. The beta-2 microglobulin pretransplant was
divided into greater or less than 2.5. The time in years from diagnosis
to transplant was divided into less than 1 year, 1 to 3 years and
greater than 3 years. The preparative regimen containing modified
TBI was compared with the chemotherapy regimen for outcome.
Patients who were transplanted from HLA identical related donors
were compared with 14 patients transplanted from unrelated or 1
HLA antigen mismatched family members.
Ten patients received alpha interferon after transplant, eight for
persisting disease and two after relapse from a CR, but the effect of
interferon was not included in the multivariate analysis.
RESULTS
Treatment characteristics are shown in Table 2. Fourteen
patients received transplants from mismatched relatives or
fully matched unrelated donors. The preparative regimens
included BU and CY for 71% of patients and modified TBI
added to BU and CY for the remainder. All patients received
their entire prescribed conditioning regimen. Most patients
received cyclosporine and short methotrexate as prophylaxis
for GVHD.
Patients achieved a neutrophil count of 50OlpL a median
of 17 days (range, 9 to 28) and self-supporting platelets
>20,OOO/pL a median of 18 days (range, 10 to 46) after
transplant. All but one patient engrafted after transplant. The
single patient with graft failure had received a T-cell depleted
marrow graft from his HLA identical sibling after a BU +
CY regimen with an initial rise in peripheral blood counts
by day 16, but a fall thereafter. He was regrafted after conditioning with CY and TBI, but succumbed to GVHD 149
days after the first transplant.
The causes of death are shown in Table 4.A total of 53
patients have died (66%). Fourteen patients died of organ
toxicity from the transplant regimen, primarily involving
lung or liver. Infection due primarily to fungus (candida or
aspergillus) or virus (cytomegalovirus or respiratory syncytial virus) accounted for 15 early and four late deaths. The
actuarial probability of nonrelapse mortality within the first
100 days was 44%. There was no apparent difference in the
frequency of death either during the first 100 days or after
100 days according to the preparative regimen used. Fortyfour percent of those transplanted using BU CY and 43%
of those transplanted using BU + CY
TBI died within
100 days of transplant. Acute GVHD grade 3 to 4 developed
in 15 patients and directly contributed to death in four.
+
+
Table 4. Causes of Death After Transplant
~
Total transplanted
First 100 days
Toxicity
Liver (veno-occlusive disease)
Pulmonary (ARDS. idiopathic)
Multiorgan failure
Hemorrhage
GVHD
Infection
Bacterial
Fungal
Viral
Total deaths by day 100
After 100 days
GVHD
Fungal
Pulmonary insufficiency
Pneumocystis
Viyl
MM
Total deaths after day 100
EU +CY
Modified TEI
BU + CY
n = 57
n = 23
6
3
2
2
2
2
2
7
3
25
5
1
7
13
1
1
3
1
10
1
2
1
1
5
Abbreviations: ARDS, acute respiratory distress syndrome; GVHD,
graft-versus-host disease.
From www.bloodjournal.org by guest on June 14, 2017. For personal use only.
2790
BENSINGER ET AL
Probability
I
-
-1-
Chronic GVHD 2 grade 3 developed in 23 patients and was
the major cause of death in six. There was no clear association between the regimens used for acute GVHD prophylaxis
and the development of acute or chronic GVHD. Seven patients died of relapse or progressive MM.
Following transplant 29 patients achieved a CR, 18 patients had a partial response, three patients had no response,
and 30 patients were unevaluable for response due to early
death. The Kaplan-Meier probabilities of survival and relapse/progression-free survival for all 80 patients at 4.5 years
are 24% -+ 0.17% and 20% 2 0.10% (Fig l), respectively
with the lead patient 7 years from transplant. The probability
of disease relapse or progression for all 80 patients is 50%
at 4.5 years with five patients at risk (Fig 1). The KaplanMeier probabilities of survival and relapse-free survival for
the 29 patients who achieved a CR are 50% 2 0.21% and
43% 2 0.17% at 4.5 years, respectively (Fig 2). Currently,
15 patients are surviving disease-free 1 to 7 years posttransplant.
Fourteen patients received transplants from HLA matched
unrelated donors (n = 9) or one antigen mismatched family
member (n = 5). Nine of these 14 patients died of transplantrelated causes within 151 days. Three of seven patients evaluable for response achieved CR. One patient, who did not
respond, died of progressive disease at 15 months and four
patients survived between 1.5 and 7 years, two of whom are
in CR.
In the multivariate analysis of risk factors on outcome
(Table 3), mortality within the first 100 days and overall
survival after transplant were significantly influenced by the
interval from diagnosis to transplant. Patients transplanted 1
to 3 years or greater than 3 years from diagnosis had a
relative risk of early mortality 2.5 times greater than patients
transplanted within the first year. Patients transplanted beyond a year from diagnosis and patients who had Durie stage
3 disease before transplant had a 1.8 and 2.0 greater risk of
dying from any cause. The risk of relapse or disease progression was 3.5 times greater for female patients who were
transplanted from a male donor and 4.3 times greater for
patients who had received more than eight cycles of conven-
Probability
1
0.8
I
I
,
,
l
I
I
1
I
111
I1
0.6
0.4
following allogeneic trsniplant. Survival: ++t++,
lapse-free survival:
-.
re-
I
I
Years after Transplant
From www.bloodjournal.org by guest on June 14, 2017. For personal use only.
RISK FACTORS AFTER ALLOGRAFTING FOR MYELOMA
tional dose chemotherapy before transplant. Only Dune staging at the time of transplant influenced relapse/progressionfree survival with stage 3 patients having a 1.9 times greater
relative risk of death, relapse or progression than patients
with stage 1 or 2 disease. Donor type did not have a statistically significant impact on outcome.
DISCUSSION
This analysis of 80 patients with MM who were transplanted from HLA compatible siblings or unrelated donors
demonstrated that complete clinical remissions were obtained in 36% of patients. Some of these patients remain
free of disease 4 to 7 years after transplant. Although it will
require longer follow-up to determine whether some of the
patients who have undergone allografting are truly cured,
results in patients with MM transplanted from identical twins
suggest that long-term disease-free survival is possible, as
two of these patients transplanted 10 and 15years ago remain
disease-free.6 The transplant-related mortality was high at
>50%, but patients who were transplanted within a year
from diagnosis had <20% mortality.
In the multivariate analysis, five factors were found to be
independently associated with outcome. Patients transplanted within 1 year of diagnosis had a lower mortality
within the first 100 days and a better overall survival than
patients transplanted > 1 year from diagnosis. Patients with
pretransplant beta 2 microglobulin greater than 2.5 had a
poorer survival. Patients who had received more than eight
cycles of chemotherapy had a higher probability of relapse
or progression. Female patients transplanted from male donors had a 3.5-fold greater risk of relapse or disease progression, but without effect on relapsdprogression-free survival.
Finally, patients transplanted with stage 3 disease had a 1.9fold greater risk of relapse, progression, or death from any
cause.
The effect of timing of transplant could be due to several
causes including the effects of disease progression or cumulative chemotherapy and is similar to the effect of interval
from diagnosis to transplant observed for patients with
chronic myelogenous leukemia (CML).Z9This finding suggests that patients with MM who have matched related donors should be considered for transplant early in the course of
their disease and before extensive amounts of chemotherapy
have been given. However, these results are confounded
somewhat by the lower survival and lower relapse/progression-free survival, which was found in patients with a high
beta-2 microglobulin or Durie stage 3 disease at the time of
transplant. Although patients with stage 1 or stage 2 disease
and a low beta-2 microglobulin will have a higher progression-free survival, they are also the group that will have the
best survival after conventional dose chemotherapy, even
though a cure is not p o ~ s i b l e .This
~ ~ -makes
~ ~ it more difficult
to judge the risk versus benefit of an early transplant in
patients with more indolent (ie, stage 1 or low beta-2 microglobulin) MM.
The finding that female patients transplanted from male
donors had a greater risk of relapse or progression is similar
to the effect of gender after allogeneic transplantation for
CML where the probability of relapse is greater in male or
279 1
female recipients of male marr0w.3~In that study of CML
patients, only female to female transplants showed an improved leukemia-free survival.33In the current study, there
was no effect of gender on survival or progression-free survival. In one large multicenter study, however, male recipients with CML transplanted from female donors had an inferior leukemia-free survival, presumably related to an
increased incidence or severity of GVHD.29
This study did not find differences in outcomes for patients
receiving HLA mismatched related or HLA matched unrelated transplants as compared with HLA matched related
transplants. However, only 14 of 80 patients received grafts
from donors other than HLA matched siblings, and with
these small numbers, differences could be missed. In addition, the overall poor outcome for patients receiving transplants from HLA matched siblings make comparisons difficult.
Relatively few reports exist on the results of allogeneic
marrow transplantation for MM. In the largest series, the
European Bone Marrow Transplant Group (EBMT), reported
on the results of 90 patients receiving HLA compatible sibling transplants from 26 transplant centers.” This experience
was recently updated to include 162 patients with MM transplanted for HLA-identical siblings and reported to the EBMT
Myeloma Registry from approximately 35 centers.I8 The
overall CR rate was 44%, and of these 72 patients, 34%
remained in CR at 4 years. Favorable prognostic factors for
survival were female recipients, stage 1 disease at diagnosis,
less chemotherapy before transplant, and being in CR before
transplant. IgA subtypes and a low p-2 microglobulin were
also favorable prognostic indicators. Patient age was similar
to our study, but 84 (52%) of the EBMT patients were in
complete or partial response following first-line therapy. In
contrast, only 29% of patients in our study were chemotherapy-sensitive, and of these 23 patients, only 13 were responding to first-line therapy at the time of transplant. Transplant-related mortality was not reported in the EBMT study,
but appears to be approximately 40% at 6 months.’* Although the preparative regimens varied greatly, the EBMT
study found no apparent affect of regimen on outcome. Similar to our study, survival was best among patients who
achieved a CR after transplant.
The outcome for 13 patients with chemotherapy-sensitive
disease and less than 10% plasma cells in marrow who received selectively T-depleted, matched, related allografts following regimens of CY and TBI or BU + CY has recently
been reported.” Two patients (15%) died of transplant-related complications and 7 of 11 evaluable patients achieved
a CR. The failure-free survival for this group, with most
patients on prophylactic interferon is 55% at 2.5 years. The
results for 10 patients with MM who were transplanted from
HLA identical donors following a CY and TBI preparative
regimen were recently reported.34Two patients died of transplant-related complications and two are alive without disease
4 and 48 months after transplant.
Twenty-six patients with MM who received allografts
from HLA identical, one antigen mismatched or matched
unrelated donors have been reported.16 The majority of these
patients, 21, had chemotherapy-sensitive disease and had
From www.bloodjournal.org by guest on June 14, 2017. For personal use only.
2792
BENSINGER ET AL
received a median of only one regimen. In addition, the time
from diagnosis to transplant was very brief, a median of only
4 months. The preparative regimens included BU and CY
t melphalan for 22 patients or CY and TBI in 4. Transplantrelated mortality was relatively low at 31% with a 2-year
survival and progression-free survival of 47% and 40%, respectively. GVHD in this series resulted in a death rate of
23%. These four studies suggest that early transplant, relatively little previous chemotherapy, and mostly chemotherapy-sensitive patients will improve outcome by reducing
transplant-related mortality and by increasing the CR rate.
The results of the current 80 patients who received an
allogeneic marrow transplant in our center show that the best
survival is obtained among the 29 patients who achieved CR
with a relapse-free survival of 43% at 4.5 years. This is
nearly identical to the 38% re!apse-free survival at 5 years
among the 72 patients with CRs in the EBMT study. Although the CR rate was lower in our study, 36% versus 44%
for the EBMT study, the patients in our study were heavily
pretreated. Fifty-nine percent of patients died of transplantrelated complications, while only 9% died of myeloma.
There was no apparent increase in visceral or transplantrelated mortality in patients who received modified TBI in
addition to BU
CY. The observation that five patients
with MM are surviving 4 to 7 years after transplant without
disease suggests that cure is possible and efforts to reduce
transplant-related mortality are worthwhile.
From these results, it appears that future studies of allogeneic marrow transplantation in MM should focus on regimens that are less toxic, but able to preserve antitumor effects. The improvement of posttransplant supportive care
should include efforts to more effectively prevent GVHD
and infections. Because our study and others suggest that
there is a lower transplant-related mortality observed with
earlier transplant, this approach should be considered in patients with newly diagnosed MM who have HLA identical
sibling donors and who have a high labelling index or other
disease features that would predict for a poor short-term
survival with standard chemotherapy
+
REFERENCES
1. Kubagawa H, Vogler LB, Capra JD, Conrad ME, Lawton AR,
Cooper MD: Studies on the clonal origin of multiple myeloma: Use
of individually specific (idiotype) antibodies to trace the oncogenic
event to its earliest point of expression in B-cell differentiation. J
Exp Med 150:792, 1979
2. Epstein J, Xiao H, He X-Y: Markers of multiple hematopoieticcell lineages in multiple myeloma. N Engl J Med 322:664, 1990
3. Gregory WM, Richards MA, Malpas JS: Combination chemotherapy versus melphalan and prednisolone in the treatment of multiple myeloma: an overview of published trails. J Clin Oncol 10:334,
1992
4. Boccadoro M, Marmont F, Tribalto M, Avvisati G, Andnani
A, Barbui T, Cantonetti M, Carotenuto M, Comotti B, Dammacco
F, Frieri R, Gallamini A, Gallone G , Giovangrossi P, Grignani F,
Lauta VM, Liberati M, Musto P, Neretto G, Petrucci MT, Resegotti
L, Pileri A, Mandelli F: Multiple myeloma: VMCPBAP alternating
combination chemotherapy is not superior to melphalan and prednisone even in high-risk patients. J Clin Oncol 9:444, 1991
5. Kyle RA: Long-term survival in multiple myeloma. N Engl J
Med 308:3 14, 1983
6. Osserman EF, Dire LB, Dire J, Sherman WH, Hersman JA,
Storb R: Identical twin marrow transplantation in multiple myeloma.
Acta Haematol 68:215, 1982
7. McElwain TJ, Powles RL: High-dose intravenous melphalan
for plasma cell leukaemia and myeloma. Lancet 1:822, 1983
8. Fefer A, Cheever MA, Greenberg PD: Identical twin (syngeneic) marrow transplantation for hematologic cancers. J Natl Cancer
Inst 76: 1269, 1986
9. Gahrton G, Tura S, Flesch M, Gratwohl A, Gravett P, Lindeberg A, Lucarelli G, Michallet M, Reiffers J, Ringden 0, Nikoskelainen J, Van Lint MT, Vemant JP, Zwaan FE: Allogeneic bone
marrow transplantation in 24 patients with multiple myeloma reported to the EBMT Registry. Hematol Oncol 6:181, 1988
10. Gahrton G, Ringden 0, Lonnqvist B, Lindquist R, Ljungman
P: Bone marrow transplantation i n three patients with multiple myeloma. Acta Med Scand 219523, 1986
11. Gahrton G, Ringden 0, Lonnqvist B: Bone marrow transplantation in multiple myeloma. Acta Med Scand 2 I9:433, I986
12. Gahrton G, Tura S, Ljungman P. Belanger B, Brandt L, Cavo
M, Facon T, Granena A, Gratwohl A. Lowenberg B, Nikoskelainen
J, Reiffers J, Samson D, Selby P, Volin L. for the European Group
for Bone Marrow Transplantation: Allogeneic bone marrow transplantation in multiple myeloma. N Engl J Med 325: 1267, 1991
13. Tura S, Cavo M, Baccarani M. Ricci P, Gobbi M: Bone
marrow transplantation in multiple myeloma. Scand J Haematol
36:176, 1986
14. Buckner CD, Fefer A, Bensinger WI, Storb R, Durie BG,
Appelbaum FR, Petersen CB, Weiden P, Clift RA, Sanders JE,
Sullivan KM, Witherspoon RP, Hill R, Martin P, Thomas ED: Marrow transplantation for malignant plasma cell disorders: Summary
of the Seattle experience. Eur J Haematol 43: 186, 1989
15. Bensinger WI, Buckner CD, Clift RA, Petersen FB, Bianco
JA, Singer JW, Appelbaum FR, Dalton W, Beatty P, Fefer A, Storb
R, Thomas ED, Hansen JA: Phase I study of busulfan and cyclophosphamide in preparation for allogeneic marrow transplant for patients
with multiple myeloma. J Clin Oncol 10:1492, 1992
16. Reece DE, Shepherd JD, Klingemann HG, Sutherland HJ,
Nantel SH, Bamett MJ, Spinelli JJ: Treatment of myeloma using
intensive therapy and allogeneic bone marrow transplantation. Bone
Marrow Transplant 15:1 17, I995
17. Anderson KC, Andersen J, Soiffer R, Freedman AS, Rabinowe SN, Robertson MJ, Spector N , Blake K, Murray C, Freeman
A, Coral F, Marcus KC, Mauch P, Nadler LM, Ritz J: Monoclonal
antibody-purged bone marrow transplantation therapy for multiple
myeloma. Blood 82:2568, 1993
18. Gahrton G, Tura S, Ljungman P, Blade J , Brandt L, Cavo M,
Facon T, Gratwohl A, Hagenbeek A, Jacobs P, De Laurenzi A.
Van Lint M, Michallet M. Nikoskelainen J, Reiffers J, Samson D,
Verdonck L, De Witte T, Volin L: Prognostic factors in allogeneic
bone marrow transplantation for multiple myeloma. J Clin Oncol
13:1312, 1995
19. Durie BGM, Salmon SE: A clinical staging system for multiple myeloma: Correlation of measured myeloma cell mass with presenting clinical features, response to treatment. and survival. Cancer
36:842, 1975
20. Anasetti C, Amos D, Beatty PG, Appelbaum FR, Bensinger
W, Buckner CD, Clift R, Doney K, Martin PJ, Mickelson E, Nispexos
B, O’Quigley J, Ramberg R, Sanders JE. Stewart P, Storb R, Sullivan
KM, Witherspoon RP, Thomas ED, Hansen JA: Effect of HLA
compatibility on engraftment of bone marrow transplants in patients
with leukemia or lymphoma. N Engl J Med 320:197, 1989
21. Anasetti C, Howe C. Petersdorf EW. Martin PJ, Hansen JA:
Marrow transplants from HLA-matched unrelated donors: An
NMDP update and the Seattle experience. Bone Marrow Transplant
13:693, 1994
From www.bloodjournal.org by guest on June 14, 2017. For personal use only.
RISK FACTORS AFTER ALLOGRAFTING FOR MYELOMA
22. Oken MM: Multiple myeloma. Med Clin North Am 68:757,
1984
23. Bianco JA, Appelbaum FR, Nemunaitis J, Almgren J, Andrews F, Kettner P, Shields A, Singer JW: Phase 1-11trial of pentoxifylline for the prevention of transplant-related toxicities following
bone marrow transplantation. Blood 78:1205, 1991
24. Thomas ED, Storb R, Clift RA, Fefer A, Johnson FL,Neiman
PE, Lemer KG,Glucksberg H, Buckner CD: Bone-marrow transplantation. N Engl J Med 292332, 1975
25. Storb R, Deeg HJ, Whitehead J, Appelbaum F, Beatty P,
Bensinger W, Buckner CD, Clift R, Doney K, Farewell V, Hansen
J, Hill R, Lum L, Martin P, McGuffin R, Sanders J, Stewart P,
Sullivan K, Witherspoon R, Yee G, Thomas ED: Methotrexate and
cyclosporine compared with cyclosporine alone for prophylaxis of
acute graft versus host disease after marrow transplantation for leukemia. N Engl J Med 314:729, 1986
26. Nash RA, Storb R: FK506-based immunosuppression for the
prevention of acute GVHD after marrow transplantation, in Lieberman R (ed): Principles of Drug Design in Transplantation and Autoimmunity. New York, NY, Raven (in press)
27. Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE,
Clift RA, Lemer KG, Thomas ED: Clinical manifestations of graftversus-host disease in human recipients of marrow from HL-Amatched sibling donors. Transplantation 18:295, 1974
2793
28. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457, 1958
29. Gratwohl A, Hermans J, Niederwieser D, Frassoni F, Arcese
W, Gahrton G, Bandini G, Carreras E, Vemant JP, Bosi A: Bone
marrow transplantation for chronic myeloid leukemia: Long-term
results. Chronic leukemia working party of the European group for
bone marrow transplantation. Bone Marrow Transplant 12:509,1993
30. Durie BGM, Stock-Novack D, Salmon SE, Finley P, Beckord
J, Crowley J, Coltman CA: Prognostic value of pretreatment serum
p2 microglobulin in myeloma: A Southwest Oncology Group Study.
Blood 75:823, 1990
31. Bataille R, Dune BGM, Grenier J, Sany J: Prognostic factors
and staging in multiple myeloma: A reappraisal. J Clin Oncol 430,
1986
32. Durie BGM, Salmon SE, Moon TE: Pretreatment tumor mass,
cell kinetics, and prognosis in multiple myeloma. Blood 55:364, 1980
33. Clift RA: Marrow transplantation for chronic myeloid leukemia, in Buckner CD, Clift RA (4s): Technical and Biological Components of Marrow Transplantation, Norwell, MA, Kluwer Academic, 1995
34. Varterasian M, Ratanatharathom V, Karanes C, Uberti J,
Momin R, Abella E, Lum LG, Heilbrun LK, Sensenbrenner LL:
Bone marrow transplantation for multiple myeloma: The Wayne
State experience. Bone Marrow Transplant 15:328, 1995
From www.bloodjournal.org by guest on June 14, 2017. For personal use only.
1996 88: 2787-2793
Allogeneic marrow transplantation for multiple myeloma: an analysis
of risk factors on outcome
WI Bensinger, CD Buckner, C Anasetti, R Clift, R Storb, T Barnett, T Chauncey, H Shulman and
FR Appelbaum
Updated information and services can be found at:
http://www.bloodjournal.org/content/88/7/2787.full.html
Articles on similar topics can be found in the following Blood collections
Information about reproducing this article in parts or in its entirety may be found online at:
http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests
Information about ordering reprints may be found online at:
http://www.bloodjournal.org/site/misc/rights.xhtml#reprints
Information about subscriptions and ASH membership may be found online at:
http://www.bloodjournal.org/site/subscriptions/index.xhtml
Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American
Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036.
Copyright 2011 by The American Society of Hematology; all rights reserved.