VOLUME
28
NUMBER
29
OCTOBER
10
2010
JOURNAL OF CLINICAL ONCOLOGY
REVIEW
ARTICLE
International Myeloma Working Group Consensus
Statement Regarding the Current Status of Allogeneic
Stem-Cell Transplantation for Multiple Myeloma
Henk Lokhorst, Hermann Einsele, David Vesole, Benedetto Bruno, Jesus San Miguel, Jose A. Pe´rez-Simon,
Nicolaus Kro¨ger, Philippe Moreau, Gosta Gahrton, Cristina Gasparetto, Sergio Giralt, and William Bensinger
From the University Hospital Utrecht,
ABSTRACT
the Netherlands; University Hospital
Wuerzburg; University Hospital
Hamburg-Eppendorf, Germany; The
Purpose
To define consensus statement regarding allogeneic stem-cell transplantation (Allo-SCT) as a
John Theurer Cancer Center at
Hackensack University Medical Center,
treatment option for multiple myeloma (MM) on behalf of International Myeloma Work-
Hackensack, NJ; Giovanni Battista
ing Group.
Hospital, University of Torino, Torino,
Italy; University Hospital of Salamanca,
Patients and Methods
In this review, results from prospective and retrospective studies of Allo-SCT in MM
Salamanca, Spain; Centre Hospitalier
Universitaire Ho^tel-Dieu, Nantes,
are summarized.
France; Karolinska Institutet, Karolinska
Results
University Hospital, Stockholm,
Although the introduction of reduced-intensity conditioning (RIC) has lowered the high treatment-
Sweden; Duke University Hospital,
related mortality associated with myeloablative conditioning, convincing evidence is lacking that
Durham, NC; M. D. Anderson Cancer
Center, Houston, TX; and the University
Allo-RIC improves the survival compared with autologous stem-cell transplantation.
of Washington, Seattle, WA.
Conclusion
Submitted April 16, 2010; accepted
New strategies are necessary to make Allo-SCT safer and more effective for patients with MM.
June 16, 2010; published online ahead
Until this is achieved, Allo-RIC in myeloma should only be recommended in the context of
of print at www.jco.org on August 9,
clinical trials.
2010.
Authors' disclosures of potential con-
J Clin Oncol 28:4521-4530. © 2010 by American Society of Clinical Oncology
flicts of interest and author contribu-
tions are found at the end of this
article.
INTRODUCTION
MYELOABLATIVE CONDITIONING
Corresponding author: Henk Lokhorst,
MD, PhD, Department of Hematology,
The survival of patients with multiple myeloma
Early data on myeloablative conditioning can be
University Medical Center Utrecht,
P.O. Box 85500, 3508 GA Utrecht, the
(MM) has improved over the past decade. 1-7 Pa-
extracted from the transplant registries: the Euro-
Netherlands; e-mail: h.lokhorst@
tients with standard risk factors (absence of t(4;14),
pean Bone Marrow Transplantation (EBMT),
umcutrecht.nl.
t(14;16), 17p ) are projected to live for 7 to 10 years
International Bone Marrow Transplantation Reg-
© 2010 by American Society of Clinical
with good quality of life.8,9 Despite these new devel-
istry (IBMTR), and the Hutchinson Cancer Cen-
Oncology
opments, however, myeloma remains incurable for
ter registries.13-16
0732-183X/10/2829-4521/$20.00
the vast majority of patients. Allogeneic stem-cell
Interpretation of these heterogeneous early
DOI: 10.1200/JCO.2010.29.7929
transplantation (Allo-SCT) is a treatment with a
data is difficult as the reported patients were not
curative potential for myeloma. This is in part due to
treated in prospective trials; many patients had
the graft-versus-myeloma effect (GVM), at best illus-
received several lines of previous chemotherapy,
trated by the induction of sustained (molecular) remis-
were chemotherapy resistant at the time of trans-
sions after donor lymphocyte infusions (DLIs), and
plant, and received a variety of conditioning and
may also be due in part to absence of contaminating
graft-versus-host disease (GVHD) prophylaxis reg-
myeloma cells in the donor graft.10-12
imens. A most consistent finding, however, was
The role of Allo-SCT in myeloma, however,
high treatment-related mortality (TRM) particu-
is debated due to the high mortality and morbid-
larly in patients who were heavily pretreated with
ity while convincing evidence for a survival bene-
chemotherapy-resistant disease. Early TRM in the
fit is lacking. This review summarizes the data
EBMT report was approximately 45%,14,15 with
from prospective and retrospective studies of
deaths due mainly to infection, GVHD, and
Allo-SCT in myeloma, but also aims to provide
regimen-related toxicities. Early TRM in the IBMTR
suggestions for new safer approaches while pre-
report of 265 patients who received transplantation
serving the GVM effect.
between 1981 and 1991 was 40% and early TRM
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Lokhorst et al
reported by the Hutchinson Center was 49% for patients predomi-
Taken together, these data suggest that myeloablative Allo-SCT is a
nantly with chemotherapy-resistant disease.17
potentially curative treatment for MM based on the achievement of sus-
Actuarial survivals for the EBMT-registered patients was 28% at
tained CRs in a subpopulation of patients.22 However, due to the high
7 years,15 for the Hutchinson Center­registered patients, it was 21% at
TRM, even when applied as part of first-line therapy, myeloablative trans-
5 years, and for the IBMTR, the probabilities of survival at 4 years were
plantsareamuchlessattractiveoptionforpatientswithMMwhomaylive
35% for patients with Karnofsky performance scores higher than 70
5 to 10 years when treated with induction therapy followed by Auto-SCT.
pretransplantation and approximately 15% for patients with scores
lower than 70. Thus, due to the exceedingly high TRM, myeloablative
Allo-SCT were largely abandoned worldwide in the 1990s. In patients
REDUCED INTENSITY CONDITIONING
who survived the procedure and achieved a complete response (CR)
after the Allo-SCT, there were apparent plateaus in relapse-free sur-
The promising results of reduced-intensity conditioning (RIC) trans-
vival (RFS) curves. In the EBMT registry, RFS at 6 years for the patients
plantation in low-grade lymphoproliferative disorders renewed the
entering CR was 34%, and for the CR patients reported by the
interest in Allo-SCT as a treatment option for MM. The pioneering
Hutchinson Center, the RFS at 5 years was 39%. The US Intergroup
studies were performed by the Seattle group who showed that donor
trial (S9321) demonstrated a progression-free survival (PFS) plateau
engraftment could be achieved with the combination of low-dose TBI
of approximately 22% at 7 years in the 36 patients undergoing Allo-
(2 Gy) plus fludarabine combined with the immune suppressive drugs
SCT, which was higher compared to the 7-year PFS of patients in the
cyclosporine and mycophenolate mofetil.23 They also introduced the
trial who received autologous stem-cell transplantation (Auto-
SCT).18 These long-term remission durations were observed almost
strategy of an autologous transplantation followed 2 to 4 months later
exclusively in patients treated within 1 year of diagnosis, after a single
by a RIC allograft. When the reduced intensity allograft followed
line of therapy, and with chemotherapy-sensitive disease.
shortly after the autograft, graft rejections were not observed even
The EBMT compared 334 patients who received transplants be-
without the use of fludarabine.24 In 52 patients treated with this
tween 1983 and 1993 and 356 patients who received transplants between
tandem modality, a CR was achieved in 48% of patients and PFS and
1994 and 1998.19 The most important observation was a marked reduc-
OS at 48 months were 48% and 69%, respectively. The same concept
tion in TRM from 46% to 30% at 2 years between the two time periods.
was piloted by Kroger et al25 using melphalan, fludarabine, and anti-
The median overall survival (OS) for the later transplants was 50 months
thymocyte globulin (ATG) with related and unrelated donors. Two
although without a plateau in PFS and OS curves. Regardless, the
large series from Seattle and Italy have recently updated reports on
transplant-related mortality of 30% was still deemed unacceptably high.
more than 200 patients using the tandem auto/allo strategy. In the
Seattle update, 102 patients received this treatment strategy with Allo-
SCT from matched-related donors.26 The overall TRM was 18% at 1
COMPARISON OF AUTOLOGOUS AND MYELOABLATIVE
ALLOGENEIC TRANSPLANTS
year and the CR rate was 62%. Chronic GVHD developed in 74%.
With a median follow-up of 6.3 years the OS was 64% and PFS of 36%.
The EBMT performed a retrospective, case-matched comparison of
In a very similar approach, an Italian consortium reported on 100
Auto-SCT and Allo-SCT in 1996.20 The median survival of 34 months
newly diagnosed patients who received vincristine, doxorubicin, and
was superior for autologous recipients versus 18 months for the Allo-
dexamethasone­ based induction followed by high-dose melphalan
SCT recipients. This was due to a higher TRM of 41% versus 13%,
with Auto-SCT, followed by a RIC Allo-SCT from an HLA identical
respectively. There was a trend, however, for better survival in the
sibling.27 The CR rate was 53%; the incidence of acute
grade 2 and
allogeneic patients surviving at 1 year (P
.09).
chronic GVHD were 38% and 50%, respectively. With a median
Two prospective trials have compared autologous with myeloa-
follow-up of 5 years, median OS was not reached while EFS was 3 years.
blative Allo-SCT. The US Intergroup trial (S9321) of early versus late
In multivariate analysis, disease in remission at Allo-SCT was significantly
Auto-SCT had a third option that allowed patients with matched
associated with longer OS and EFS, while immunoglobulin isotype, Inter-
siblings (younger than age 55) to undergo Allo-SCT using an ablative
national Staging System, and a comorbidity index 3 or higher had no
regimen of melphalan and total-body irradiation (TBI).18 This arm of
impact on outcome. Unfortunately, neither of these studies has shown a
the study was closed after 36 patients were treated, due to excessively high
plateau in EFS, even in patients with chronic GVHD.
TRM of 53%. After 7 years of follow-up, however, the OS rates were
After introduction of the Seattle regimen, a wide variety of con-
identical at 39% for both autologous and allogeneic recipients, while the
ditioning and GVHD prophylaxis regimens were pioneered in MM.
PFS were 15% for autologous recipients compared with 22% for alloge-
Conditioning regimens included fludarabine combined with either
neicrecipients.Inaddition,whiletheriskofrelapseanddeathcontinuesin
melphalan in different dosages (100 to 180 mg/m2), cyclophospha-
the groups that received autologous SCT, the OS curve for the allogeneic
mide, low-dose busulfan or thiothepa, with or without TBI. Some
group has reached a plateau with follow-up extending to 10 years.
regimens included ATG or alemtuzumab to facilitate engraftment and
The Haemato Oncology Foundation for Adults in the Nether-
reduce GVHD (Table 126-35). In a recent review of the EBMT registry,
lands (HOVON) 24 study was designed to compare Auto-SCT with
26 different conditioning schemes with and without T-cell depletion
semi-intensive treatment; however, patients with an HLA-identical
in 229 patients were identified.36 Eighty percent of patients received
sibling donor could proceed to a partially T-cell­ depleted myeloabla-
transplants with peripheral blood stem cells. Acute GVHD grades 2 to
tive Allo-SCT after cyclophosphamide/TBI conditioning. 21 Even as
4 occurred in 31% of patients and extensive chronic GVHD was
part of first-line therapy, TRM of the Allo-SCT patients exceeded 30%
reported in 25%. Although the TRM was low at 22%, the 3-year OS
while PFS and OS were inferior to the matched group of patients
and PFS were disappointing at 41% and 21%, respectively. The best
receiving only autologous SCT.
outcome after RIC was for those patients who received transplants in
4522
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143.121.239.96
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IMWG Consensus Statement Regarding the Current Status of Allo-SCT for MM
Table 1. Phase II Trials of Reduced Intensity Allogeneic Transplantation From Related and Unrelated Donors With or Without a Planned Prior Autologous
Transplant for the Treatment of Multiple Myeloma
No.
%
No. Planned
From Matched
Prior
Total
Unrelated
Autologous
Graft
AGVHD,
Survival
Reference
Patients
Donors
Regimen
Transplant
GVHD Prophylaxis
Chim
2-4
CGVH
TRM
CR
at (year)
Rotta26
102
0
Total-body irradiation 12
102
Cyclosporine
100
42
74
18
62
64 (5)
Gy,
fludarabine
Tacrolimus
Mycophenolic acid
Bruno27
100
0
Total-body irradiation 2 Gy
96
Cyclosporine
97
38
50
11
53
65 (5)
Mycophenolic acid
Lee28
45
12
High-dose melphalan 100
12
Cyclosporine
89
58
13
38
64
36 (3) 86t
(total-body irradiation 2
Gy, fludarabine)
Gerull29
52
20
Total-body irradiation 2 Gy,
0
Cyclosporine
90
37
70
17
27
41 (1,5)
fludarabine
Mycophenolic acid
Mohty30
41
Busulfan, fludarabine,
0
Cyclosporine
98
36
41
17
24
62 (2)
antithymocyte globulin
Methotrexate (13)
Kroger31
49
49
High-dose melphalan 140,
NR
Cyclosporine
NR
25
35
25
49
26 (5)
fludarabine,
antithymocyte globulin
Methotrexate
Majolino32
53
0
Thiotepa, fludarabine,
NR
Cyclosporine
80
45
64
13
62
45 (3)
melphanan
Methotrexate
Van Dorp33
59
16
Total-body irradiation 2
36
Cyclosporine
95
44
54
9
32
82 (2)
Gy,
fludarabine,
antithymocyte globulin
Mycophenolic acid
Vesole34
23
0
Fludarabine
23
Cyclosporine
17 (
3)
39
9
33
78 (2)
Cyclophosphamide
Steroid
Einsele35
22
15
Total-body irradiation 2 Gy,
0
Antithymocyte
NR
38
32
23
27
26 (2)
fludarabine,
globulin
cyclophosphamide
Cyclosporine
Mycophenolic acid
Abbreviations: GVHD, graft-versus-host-disease; AGVHD, acute graft-versus-host disease; CGVH, chronic graft-versus-host-disease; TRM, transplant-related
mortality rate; CR, complete response rate; NR, not reported.
Fourteen patients given donor lymphocyte infusion.
first remission with fewer than two previous Auto-SCT. Alemtu-
62% v 9% for myeloablative regimens and 99%, 62% and 13% for
zumab for conditioning was an adverse risk factors for TRM, PFS, and
marrow grafts, respectively). Although the TRM at 5 years decreased
OS. Post-transplantation factors for prolonged PFS were achievement
in the last period (40% and 48% v 29%), the OS at 5 years was similar
of CR and the occurrence of chronic GVHD.
among the groups (30, 32, and 29 months), primarily because of
However, due to the heterogeneity of the patient populations,
increased risk of relapse in the latter cohort.
study, and registration designs, no definite conclusions could be
drawn which of these regimens was superior in terms of toxicity or
efficacy or even whether Allo-RIC was of benefit.
PROSPECTIVE STUDIES OF RIC ALLO-SCT AS PART OF FIRST-
LINE THERAPY
COMPARISONS OF ABLATIVE AND NONABLATIVE ALLOGRAFT
One way to measure the value of Allo-SCT is to prospectively compare
an Auto/Allo-SCT treatment with a tandem Auto-SCT. It is widely
The EBMT has retrospectively compared RIC with standard ablative
accepted that a biologic randomization approach for Allo-SCT based
conditioning for Allo-SCT in MM.37 Between 1998 and 2002, 196
on the availability of an HLA-identical sibling donor is a reliable
patients conditioned with ablative regimens were compared with 320
surrogate. Three studies comparing tandem Auto/Allo-SCT with
patients undergoing RIC. TRM was significantly lower for the
double Auto-SCT in MM have been published utilizing this biologic
reduced-intensity group (P
.001). However, there was no statistical
randomization concept.
difference in OS between the two groups. Furthermore, PFS was
inferior for patients receiving RIC (P
.009) due to a doubling of the
The French Study
relapse rate in the RIC group (54% v 27%; P
.001). The CIBMTR
In the French study, patients with an HLA-identical sibling do-
has done a comparable analysis.38 A total of 1,211 patients undergoing
nor and high-risk MM defined by beta-2 microglobulin ( -2 M)
Allo-SCT for MM between 1989 and 2005 were analyzed in three
higher than 3 mg/L and deletion of chromosome 13 (13q ; by fluo-
cohorts based on year of Allo-SCT: 1989 to 1994 (n
346), 1995 to
rescent in situ hybridization [FISH]) were candidates for Auto-SCT
2000 (n
285), and 2001 to 2005 (n
580). There was decreasing use
followed by RIC Allo-SCT with a conditioning regimen consisting of
of myeloablative regimens and bone marrow grafts over time (82% v
busulfan, fludarabine, and ATG.39 Patients without a sibling donor
www.jco.org
© 2010 by American Society of Clinical Oncology
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143.121.239.96
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Lokhorst et al
were treated with double Auto-SCT using melphalan 220 mg/m2 for
group. The results from this study are anticipated to be released
the second autologous transplant with or without anti-interleukin
in 2010.
6 monoclonal antibody therapy. Utilizing an intent-to-treat anal-
In the HOVON 54 study, patients with an HLA-identical sibling
ysis, with a median follow-up of 56 months, no difference in EFS
donor included in the HOVON 50 study (phase III study for the
was observed.40 Nevertheless, there was a trend for a superior OS in
evaluation of thalidomide combined with HDM) could proceed to
the double Auto-SCT trial (median 48 v 34 months, P
.07). Also,
RIC Allo-SCT between 2 and 6 months after Auto-SCT, while the
when the analysis was restricted to the patients who completed the
other patients were assigned to thalidomide or interferon mainte-
planned tandem transplants, a trend toward improved OS was
nance after the first Auto-SCT. On the basis of an intention-to-
observed with the tandem Auto-SCT (median OS, 57 v 41 months,
treat analysis, no difference in PFS and OS were found during an
P
.08), due to a longer survival after relapse in the tandem
interim analysis that included 126 patients with a donor and 141 patients
auto-SCT arm. This study was criticized for the inclusion of high-
without a donor. In the EBMT study, PFS at 60 months was 35% for
Auto/Allo-SCT compared with 18% for tandem Auto-SCT and OS 65%
dose ATG 12.5 mg/kg in the conditioning regimen that might have
and 57%, respectively. This trend for improvement was seen in patients
negatively influenced the desired GVM effect as measured by a
with both deletion 13 and nondeletion 13. In both the HOVON as in the
relatively low CR rate of 23%.41
EBMT study, the OS of the Auto-SCT group was better compared with
the Bruno et al study, which might explain why the outcome of the Bruno
The Spanish PETHEMA Study
et al study was more positive. The final analyses of the HOVON and of the
The Spanish PETHEMA found a trend for better PFS (P
.08),
EBMT study are expected in 2010.
but did not observe a difference in EFS and OS between 85 patients
receiving tandem Auto-SCT compared with 25 patients treated with
German DSMMM
Auto/Allo-SCT, although higher CR rates after the Allo-SCT, were
German DSMMM has performed a prospective study compar-
achieved (40% v 11%; P
.001).42 Complicating the interpretation of
ing double Auto-SCT (HDM200) with Auto/Allo-SCT (fludarabine/
this study is the treatment schema which included only patients not in
melphalan).47 Inclusion was restricted to newly diagnosed patients
CR or near CR after the first Auto-SCT proceeded to the second
with of deletion 13q14 as determined by FISH. Allocation to either
transplant and the number or patients who actually completed both
treatment arm was by availability of an HLA-matched (one mismatch
planned transplants was small. However, the authors noted a plateau
allowed) sibling or matched unrelated donor (MUD). ATG was added
in PFS for the 36% of patients in CR after the Allo-SCT.
to the conditioning in case of a MUD donor. Preliminary analysis
showed a higher CR rate in FISH 13q
subjects undergoing Allo-SCT
when compared to tandem Auto-SCT (59% v 32%; P
.003). How-
The Italian Study Group
ever, the projected OS at 3 years was 70% for double Auto-SCT versus
More positive results were published by Bruno et al.43 In that
60% for the Auto/Allo-SCT patients (P
.22). TRM at 2 years from
study, 82 patients with an HLA-identical sibling donor assigned to be
Allo-SCT was only 12.7% even though 60% received MUD Allo-SCT.
treated with Auto/Allo-SCT (conditioning low-dose TBI only)
Table 2 summarizes the prospective comparative studies of RIC Allo-
achieved higher CR and significantly longer PFS and OS as compared
SCT. Taken together from these prospective studies, it should be
to the 80 patients assigned to the tandem Auto-SCT arm. After the
concluded that convincing evidence is lacking that Allo-RIC induces du-
second transplant, CR rates were 55% versus 26% (P
.004), median
rable remissions of better quality as compared to Auto-SCT. This may
PFS durations were 36 versus 29 months (P
.02), and OS dura-
become even more clear now that novel agents are given as post-
tions were 80 versus 54 months (P
.01), respectively. The TRM
transplantation therapy as demonstrated by the higher and sustained
was only 11%. Critics of the study cited that only 58 and 46 patients
molecularremissionrateafterAuto-SCTthanpreviouslyreportedwhena
in the Auto/Allo-SCT and double Auto-SCT, respectively, com-
regimen of bortezomib, thalidomide, and dexamethasone is given as con-
pleted their assigned treatments and the relatively poor outcome of
solidation therapy.48
the patients assigned to the tandem Auto-SCT.44 OS of the Auto-
SCT patients in the Bruno et al study was only a median of 48
months compared to the more than 60 months in all the recently
ALLO-SCT IN HIGH-RISK MYELOMA
published prospective phase III auto-transplant studies2-6 espe-
cially in the arms that included thalidomide.
Before the incorporation of novel therapies into pre- and postautolo-
gous transplantation regimens, the outcome of patients with poor
prognostic features defined by cytogenetics (t4;14; t14;16; 17p ) were
HOVON, EBMT, and Blood and Marrow Transplant
universally dismal.8,9 Whereas thalidomide does not appear to be able
Clinical Trials Network
to improve outcomes in these high-risk patients,5 there is increasing
A more definite conclusion about the role of Allo-SCT in MM
evidence that bortezomib-based regimens are capable of overcoming
may come from three other prospective donor versus no donor stud-
at least some of the adverse prognostic outcomes (eg, t(4;14)).49,50
ies with larger groups of patients that were performed in the United
It was hoped that the use of Allo-SCT, through a donor-
States, the Dutch HOVON,45 and the EBMT.46 The large US multi-
mediated GVM effect would also be capable of eradicating any
center trial from the Blood and Marrow Transplant Clinical Trials
residual clonal MM cells with these poor prognostic constitution.
Network (BMT CTN) comparing tandem Auto-SCT with Auto/Allo-
The older literature reporting conventional myeloablative alloge-
SCT completed the targeted accrual in March 2007 with more than
neic transplantation did not discern between risk groups deter-
150 patients biologically randomly assigned to the Auto/Allo-SCT
mined by cytogenetics.19,36 In these studies, the high-risk patients
4524
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143.121.239.96
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IMWG Consensus Statement Regarding the Current Status of Allo-SCT for MM
Table 2. Comparison Trials of Tandem Autologous Transplant With Autologous
Reduced Intensity Allografting
Response
(%)
DFS
OS
Regimen
No.
TRM (%)
CR
VGPR
%
Follow-Up Year
%
Follow-Up Year
Garban36a
Auto Mel 200/220
219
5
33
18
0
5
44
5
Auto Mel 200
65b
11
33
29
0
5
33
5
Allo Bu, Flu, ATG
Bruno40
Auto Mel 200
80c
4
26
NR
20
4
53
4
Auto Mel 200
82d
10
55
NR
42e
475e
4
Allo 2 Gy TBI, P
.001
.004
.01
.02
Rosignol37f
Auto Bu Mel-Mel, CBV
88
5
11
6
Med 26 months
Med 57 months
Auto Bu Mel-Mel
26
16
33
NR
Med 19 months
Med not reached
Allo Flu Mel 140
Lokhorst42
Auto Mel 200/IFN or Thal maintenance
141
NR
42
NR
Med 30 months
Med 60 months
Auto Mel 200
126
14
45
NR
Med 30 months
Med 50 months
Allo 2 Gy TBI
Bjorkstrand43
Auto Mel 200
251
5
38
NR
18
4
57
5
Auto Mel 200
107
13
43
NR
35
4
65
5
Allo 2 Gy TBI
Knop44g
Auto Mel 200
73
NR
32
NR
NR
70
3
Auto Mel 200
126
16
59
NR
NR
60
3
Allo Flu Mel 140
ATGh
Abbreviations: TRM, transplant-related mortality; DFS, disease-free survival; OS, overall survival; CR, complete remission; VGPR, very good partial remission; Auto,
autologous stem-cell transplantation; Mel, melphalan; Allo, allogeneic stem-cell transplantation; Bu, busulphan; Flu, fludarabin; ATG, antithymoglobulin; NR, not reported;
TBI, total-body irradiation; CBV, cyclophosphamide, carmustine, and etoposide; Med, median; IFN, interferon; Thal, thalidomide; FISH, fluorescent in situ hybridization.
aHigh-risk patients with elevated B-2 M and deletion 13 by FISH.
bNineteen of 65 patients did not receive the reduced intensity allograft.
cForty-six of 80 patients completed the tandem autograft.
dFifty-eight of 82 patients received the reduced intensity allograft.
eStatistically significant.
fATG was added to the conditioning regimen in case of unrelated donor.
gHigh-risk patients with deletion 13 by FISH.
hOnly patients not in CR after autograft 1 proceeded to second autograft or RIC allograft.
were defined by disease status at transplantation, number of prior
were no differences in response rates nor in transplantation-related
therapies, time to transplantation, and sex match. Chromosome 13
mortality with the exception that patients with 17p13 deletions had
deletions by FISH were previously considered a poor prognostic
a lower CR rate (7% v 56%). In multivariate analyses, age (hazard
factor.51-55 However, since it is detected in more than 50% of
ratio [HR], 2.8; P
.01) and del(17p13) (HR, 2.05; P
.03)
patients, it no longer considered as predictive of a negative out-
retained their negative prognostic value. Bruno et al reported their
come except when it is associated with t(4;14).56,57 Regardless,
outcomes in 100 patients undergoing Auto/Allo-SCT. For del13,
Kroger et al58 retrospectively reported their outcomes in 31 pa-
13 of 39 studied had del13 by FISH. There was no significant differ-
tients with del13q14 in comparison with 37 patients without this
ence in OS whereas EFS was better in patients without del(13) (4.3 v
deletion treated identically. Response rates and TRM were compa-
2.2 years, P
.01).26 Rotta et al27 reported the Seattle Consortium
rable between the groups. However, at 2 years they observed a
experience in 102 patients completing Auto/Allo-SCT that -2 M
significantly shorter EFS (18% v 42%), OS (18% v 67%) in patients
higher than 3.5 mg/L was a poor risk factor for relapse, PFS, and OS
with del(13) due to significantly higher relapse rates in the del(13)
(HRs, 2.3, 1.98, and 2.87, respectively). Cytogenetic abnormalities,
patients (77% v 44%). As mentioned earlier, in the Intergroupe
none of which included the high-risk features discussed above, were
Franc¸aise Myeloma, study patients with high-risk disease, defined
not predictive of outcome. Given the small number of patients in these
as -2 M higher than 3 mg/L and chromosome 13 deletion (by
various studies, it is uncertain whether reduced-intensity allogeneic
FISH), did not benefit from Auto/Allo-SCT as compared with the
transplants can overcome poor risk indicators. However, it is conceiv-
patients who were treated with double Auto-SCT. Schilling et al59
able that in exceptional cases a full Allo-SCT may be considered like in
reported their retrospective observations in 101 patients undergo-
patients with high lactate dehydogenase myeloma younger than 50
ing reduced-intensity transplantations with a variety of cytogenet-
years who are aware of their unfavorable prognosis and accept the risks
ics abnormalities: 61% with del(13q14), 19% with t(4;14)(p16.3;
of myeloablative conditioning given the US Intergroup trial (S9321)
q32), 16% with del(17p13), and 5% with t(14;16)(q32;q23). There
showing a plateau.
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Lokhorst et al
bined with tacrolimus and methotrexate proved to be a very effec-
UNDERSTANDING THE MECHANISMS OF GRAFT VERSUS
MYELOMA IS OF VITAL IMPORTANCE FOR IMPROVING THE
tive regimen to prevent GVHD after Allo-RIC with mismatched
SAFETY AND EFFICACY OF ALLO-SCT
unrelated donors.87
The GVM effect is at best illustrated by the remissions induced by DLI
in patients with relapsed or persistent disease after Allo-SCT. Re-
PROSPECTIVE EVALUATION OF LENALIDOMIDE AS
MAINTENANCE AFTER ALLO-SCT
sponse to DLI and chronic GVHD are highly associated indicating that
the targets for GVHD and GVM are similar or identical (ie, minor
histocompatibility antigens [mHa]) expressed on patients normal and
In the HOVON 76 phase II study, the effect of lenalidomide mainte-
MM cells.12,60,61 Susceptibility of malignant plasma cells to the mHa
nance after tandem Auto/Allo is being evaluated.88 After Auto/Allo-
HA-1(H) specific lysis in vitro suggests a role for the mHa HA-1 in the
SCT, lenalidomide maintenance 10 mg/d for 21 days with 7 days rest
GVM effect.62
(28 day cycle) is started between 1 and 6 months after the Allo-SCT if
Clinical support for this concept has been provided by the dem-
there are no signs of GVHD. As of October 2009, 36 patients were
onstration that, in a patient with MM who received HLA-matched,
registered with a median age of 54 years. Preliminary results found that
mHag-mismatched DLI, achievement of CR was accompanied by the
41% of patients were withdrawn from the study after two cycles and
emergence and expansion of HA-1, HA-2, and LB-ADIR-1F­specific
54% of patients were withdrawn after four cycles of lenalidomide. The
cytotoxic T cells in the circulation.63 However, responses to DLI may
major cause was rapid development of acute sometimes fulminate
occur without GVHD, indicating that tumor-associated antigens may
GVHD grade
2 to 4 after start of lenalidomide. The CIBMTR is also
be involved as well, as illustrated by strong antibody responses against
conducting a phase II trial of lenalidomide after Allo-SCT for patients
cancer testis antigens and MUC-1.64,65 The relation between GVM
with high-risk disease.
and GVHD after Allo-SCT is less clear. Although positively demon-
strated in several, mostly retrospective studies,35,36,60,66 among them
SYNGENEIC TRANSPLANTATION IN MYELOMA
one indicating the mHa HY as the target antigen in HLA-identical
female-to-male sibling transplants,67-69 more recent data from the
Two large registry analyses have compared the results of syngeneic
large prospective studies indicate that GVHD is not associated with
transplantation with Auto-SCT or Allo-SCT. Gahrton et al89 reported
better outcome from Allo-RIC.26,27,36,43,46 This intriguing observa-
on 25 syngeneic recipients reported to the EBMT and Bashay et al90
tion should stimulate more in-depth studies to unravel the mech-
reported on 43 subjects reported to the CIBMTR. The outcomes of
anisms of GVM, which could result in safer strategies with better
syngeneic transplant recipients were superior in terms of lower inci-
management of acute and chronic GVHD. New strategies might
dence of relapse/progression, PFS and, for the EMBT patients, longer
include targeted T-cell therapy with hematopoietic restricted mHa
OS compared to Auto-SCT. A possible explanation for this observa-
that can now be easily identified by a recently developed method
tion would be the presence of a syngeneic GVM (as demonstrated in
via genome-wide zygosity-genotype correlation,70-73 which are
animal models, but has not been successfully reproduced in hu-
seen preferentially in patients with MM who had received Allo-
mans)91,92 or due to absence of contaminating myeloma cells in the
SCT and not in patients with MM treated otherwise.
donor graft. This latter explanation is not supported by purging results
of Auto-SCT.93-96 These results also support the use of syngeneic
stem-cell transplantation as consolidation therapy of an initial remis-
POTENTIAL ROLE OF NOVEL ANTIMYELOMA AGENTS TO
sion in patients who have identical twin donors.
IMPROVE THE GVM EFFECT
Due to their immune modulating capacities, the novel antimyeloma
CONCLUSION AND FUTURE
agents might be of therapeutic interest for post­Allo-SCT therapy.
This is illustrated by the improved response to DLI by thalidomide
The prognosis of MM has improved substantially in the last decade
apparently without enhancing GVHD.74 Impressive results were ob-
and the majority of younger patients may enjoy remissions of excellent
tained with lenalidomide as salvage therapy in a group of patients with
quality for a median of 3 years. It is hotly debated whether patients
progressive symptomatic disease after Allo-RIC.75,76 Bortezomib has
should be subjected to the morbidity and mortality of Allo-SCT as part
also been shown to be remarkably effective in patients with relapsed
of first-line therapy even when a (late) survival benefit is further
disease after Allo-SCT, without apparent excessive stimulation
proven by the outcome of the expected donor versus no donor com-
of GVHD.77-79
parisons. However, as the prospective studies of RIC Allo-SCT did not
In a murine BMT model, bortezomib downregulated cytokine
include the novel antimyeloma agents in the Allo-SCT arm, it would
production, induced T-cell apoptosis, and prevented GVHD, while
be of interest to challenge again Auto-SCT with Allo-RIC but now
the graft-versus-tumor effects were preserved. Nonetheless, delayed
with the novel antimyeloma agents incorporated in both arms. An-
bortezomib administration in this mouse model accelerated
other option would be to explore Allo-RIC in high-risk patients only.
GVHD.80,81 Blanco et al82,83 showed that bortezomib induces selective
High risk defined by the genetic markers including t(4;14); t(14;16);
depletion of alloreactive T lymphocytes, decreases the production of T
17p , or not achieving at least very good partial response after Auto-
helper 1 cytokines while treatment of CD4 T cells preserves regulatory T
SCT. There is increasing evidence that bortezomib-based regimens are
cells, and allows the emergence of a suppressor T-cell subset.
capable of overcoming at least some of the adverse prognostic out-
In patients with MM, both stimulation and improvement of
comes, however and benefit of Allo-SCT in high-risk patients is not
GVHD has been reported.84-86 In a recent study, bortezomib com-
evident. Alternatively, Allo-SCT could be reserved for patients with a
4526
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---

IMWG Consensus Statement Regarding the Current Status of Allo-SCT for MM
chemotherapy-sensitive first relapse after Auto-SCT. Recently two
The conclusions and recommendations of the International My-
prospective studies showed the feasibility and acceptable TRM of this
eloma Working Group are as follows. Myeloablative Allo-SCT may
approach using both sibling and unrelated donors. Nonrelapse mor-
cure a minority of patients, but is associated with a high TRM even
tality at 1 year was only 10% for those transplants with completely
when applied in the first-line setting, but since smaller phase II studies
matched (10/10 alleles) donors. However, in both studies PFS with 13
suggested an improvement in TRM, myeloablative conditioning
months and 17 months and OS of 32 and 38 months, respectively,
could be evaluated in well-designed prospective clinical trials. Non-
were limited. Due to improved supportive care, early detection/treat-
myeloablative Allo-SCT in first-line therapy is associated with a lower
ment of viral infections and careful donor selection using high-
TRM, but a greater risk of relapse and convincing evidence is still
resolution HLA typing toxicity including TRM associated with
lacking that Allo-RIC improves survival as compared to autologous
unrelated transplants is comparable to related transplants.31,66,97,98
SCT. Even though different in design, the outcomes of expected donor
Under the umbrella of European Myeloma Network, two studies
versus no donor comparisons of BMT CTN, Dutch HOVON, the
have been developed for patients with a first relapse in which the
EBMT, and German DSMM may allow more definite conclusions
focus is on effective GVHD prevention, early consolidation with
about the value of first-line Allo-RIC. Even when a late survival benefit
novel antimyeloma agents and pre-emptive DLI. Both sibling and
is shown by the expected donor versus no donor comparisons, it may
unrelated donors will be used and bortezomib is also part of the
still be questionable if in the era of (Auto-SCT combined with) novel
GVHD preventive regimen.
agents Allo-RIC should be routinely offered to patients in first-line
Other strategies that can be explored are natural killer cell thera-
therapy, especially as there are no convincing data indicating that
pies, adoptive T-cell therapy, and vaccination studies.99-107 However,
high-risk myeloma may benefit from Allo-RIC.
the clinical results of such approaches in MM are few and not yet fully
Future studies of Allo-SCT in myeloma should aim at improving
evaluable. Even when proven effective these strategies can be difficult
the graft-versus-tumor effect while reducing the morbidity and mor-
to apply on a wide scale due the high costs, the specific need of Good
tality of Allo-SCT. Novel anti-MM agents in the post-Allo setting may
Clinical Practice facilities, and the laborious procedures. All authors of
favor the GVM effect. However, exact mechanisms of action as well as
this article agree that an allograft should only be recommended in the
the optimal timing and dosage of these agents after transplantation
context of clinical trials.
have yet to be determined. New strategies should be explored prospec-
In Table 3, prospective trials of Allo-SCT that are being per-
tively in selected groups of patients. Due to careful high resolution
formed or planned by the different study groups are summarized.
HLA typing and improved supportive care, the outcome and toxicity
Table 3. Currently Performed and Planned Prospective Trials With Reduced Intensity Allografting in Myeloma
Target
Time
Study Group
Coordinator(s)
No.
Patients
Design
Regimen
Proph GVHD
Post Allo Therapy
Period
DSMM XII
Einsele/Berdel/
160
Newly diagnosed Phase II
Fludarabin,
Mycophenolic acid,
Lenalidomide
2009-2010
Bunjes/Finke/
(stratification
treosulfan
cyclopsporin
Bornhäuser
by prognostic
factors)
Gimema
Bruno
53
Newly diagnosed Phase II (match- Auto/low-dose total- Mycophenolic acid,
Lenalidomide (start 2009-2013
(stratification
control
body irradiation
cyclopsporin
at month 6 after
by prognostic
analysis
transplantation)
factors)
included)
HOVON
Lokhorst
104
Chemotherapy-
Randomized
Melphalan/
Short-time
Lenalidomide v
2010-2013
sensitive first
phase II
fludarabin CD3/
cyclopsporin
lenalidomide/
relapse
CD19 depletion
bortezomib/pre-
emptive DLI
Intergroupe
Yacoub-Agha
30
Newly diagnosed Phase II
Tandem Allo/Auto
Cyclopsporin,
Lenalidomide/pre-
2010-2012
Française
17 P deletion
mycophenolic
emptive DLI
Myeloma
acid
Pethema/EUMN
Perez-Simon/
90
Chemotherapy-
Phase I/II
Melphalan/
Rapamycin/
Lenalidomid/
2010-2013
SanMiguel
sensitive first
fludarabin
bortezomib v
bortezomib
relapse
/Bortezomib
tacrolimus/
methotrexate/
bortezomib
Seattle
Mielcarek
40
High-risk first-line Phase II
Tandem Allo-Auto
Cyclopsporin,
Bortezomib
2009-2011
or failed
fludarabin/total-
mycophenolic
maintenance for
autologous
body irradiation
acid
9 months
Hamburg/Münster Kröger/Kropff
200
Newly diagnosed Auto-allo with
Melphalan 140/
Cyclopsporin/
Thalidomide 100
2009-2012
fewer than 8
thalidomide/
fludarabin/
mycophenolic
for 2 years (in
cycles
DLI v auto-
antithymoglobulin
acid/
Allo also DLI)
induction
auto/
antithymoglobulin
thalidomide
Hamburg/
Kröger/Hegenbart/
180
Relapse after
Allo v RD
Busulphan (14
Cyclopsporin/
Lenalidomide 5 mg 2011-2015
Heidelberg
Dreger
autograft
mg/kg/Cy/
mycophenolic
antithymoglobulin
acid/
antithymoglobulin
Abbreviations: GHVD, graft versus host disease; Allo, allogeneic stem-cell transplantation; Auto, autologous stem-cell transplantation; DLI, donor lymphocyte
infusions; EUMN, European Myeloma Network; RD, lenalidomide and dexamethasone; Cy, cyclophosphamide.
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---

Lokhorst et al
of transplants with related and unrelated donors are comparable.
Pharmaceuticals (C), Onyx Pharmaceuticals (C) Stock Ownership:
Allo-RIC in myeloma should only be recommended in the context of
None Honoraria: Jesus San Miguel, Celgene, Millennium
clinical trials. This recommendation is in agreement with the National
Pharmaceuticals, Johnson & Johnson; Cristina Gasparetto, Celgene,
Millennium Pharmaceuticals; William Bensinger, Celgene Research
Comprehensive Cancer Network guidelines on treatment of my-
Funding: Cristina Gasparetto, Celgene, Cephalon; William Bensinger,
eloma (http://www.nccn.com/multiple-myeloma/).
Millennium Pharmaceuticals, Celgene, Onyx Pharmaceuticals, Facet
Biotech Expert Testimony: None Other Remuneration: None
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
AUTHOR CONTRIBUTIONS
Although all authors completed the disclosure declaration, the following
authors or their immediate family members indicated a financial interest.
Conception and design: Henk Lokhorst
No conflict exists for drugs or devices used in a study if they are not being
Administrative support: Henk Lokhorst
evaluated as part of the investigation. For a detailed description of the
Collection and assembly of data: Henk Lokhorst
disclosure categories, or for more information about ASCO's conflict of
Manuscript writing: Henk Lokhorst, Hermann Einsele, David Vesole,
interest policy, please refer to the Author Disclosure Declaration and the
Benedetto Bruno, Jesus San Miguel, Jose A. Pe´rez-Simon, Nicolaus
Disclosures of Potential Conflicts of Interest section in Information
Kro¨ger, Philippe Moreau, Gosta Gahrton, Cristina Gasparetto, Sergio
for Contributors.
Giralt, William Bensinger
Employment or Leadership Position: None Consultant or Advisory
Final approval of manuscript: Henk Lokhorst, Hermann Einsele, David
Role: Jesus San Miguel, Celgene (C), Millennium Pharmaceuticals (C),
Vesole, Benedetto Bruno, Jesus San Miguel, Jose A. Pe´rez-Simon,
Johnson & Johnson (C); Gosta Gahrton, Fujimoto Pharmaceutical Co
Nicolaus Kro¨ger, Philippe Moreau, Gosta Gahrton, Cristina Gasparetto,
(C), Karolinska Institutet/Avaris AB (C); William Bensinger, Millenium
Sergio Giralt, William Bensinger
multiple myeloma after allogeneic stem-cell trans-
the European Group for Blood and Marrow Trans-
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---

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143.121.239.96
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