Tandem Autologous/Reduced-Intensity Conditioning Allogeneic Stem-Cell Transplantation Versus Autologous Transplantation in Myeloma: Long-Term Follow-Up

Abstract

Results of allogeneic stem-cell transplantation (allo) in myeloma are controversial. In this trial autologous stem-cell transplantation (auto) followed by reduced-intensity conditioning matched sibling donor allo (auto-allo) was compared with auto only in previously untreated multiple myeloma.
In all, 357 patients with myeloma up to age 69 years were enrolled from 2001 to 2005. Patients with an HLA-identical sibling donor were allocated to the auto-allo arm (n = 108) and patients without a matched sibling donor were allocated to the auto arm (n = 249). Single (n = 145) or tandem (n = 104) auto was optional. Conditioning for the auto arm was melphalan 200 mg/m(2); conditioning for the allo arm was total-body irradiation 2 Gy plus fludarabine 30 mg/m(2)/d for 3 days. Median follow-up time was 61 months. Primary end point was progression-free survival.
Progression-free survival at 60 months was significantly better with auto-allo than with auto [corrected] alone (35% v 18%; P = .001), as was the risk of death and of relapse in the long term (P = .047 and P = .003, respectively). Overall survival at 60 months was 65% versus 58%, and relapse incidence was 49% versus 78%. Complete remission rates were 51% and 41%, respectively (P = .020). Nonrelapse mortality at 24 months was 12% after auto-allo compared with 3% in the auto group (P < .001). The incidence of grade 2 to 4 acute graft-versus-host disease (GvHD) was 20%, and the incidence of limited and extensive chronic GvHD was 31% and 23%.
In patients with previously untreated multiple myeloma, long-term outcome with respect to progression-free survival, overall survival, and relapse rate is superior after auto-allo compared with auto only. Nonrelapse mortality is at a reasonable level in both groups.

Full text

Tandem Autologous/Reduced-Intensity Conditioning
Allogeneic Stem-Cell Transplantation Versus Autologous
Transplantation in Myeloma: Long-Term Follow-Up
Bo Bjo¨rkstrand, Simona Iacobelli, Ute Hegenbart, Astrid Gruber, Hildegard Greinix, Liisa Volin, Franco Narni,
Pellegrino Musto, Meral Beksac, Alberto Bosi, Giuseppe Milone, Paolo Corradini, Hartmut Goldschmidt,
Theo de Witte, Curly Morris, Dietger Niederwieser, and Go¨sta Gahrton
Bo Bjo¨ rkstrand, Astrid Gruber, and
Go¨ sta Gahrton, Karolinska Institute at
Huddinge and Solna, Stockholm,
Sweden; Simona Iacobelli, Universita`di
Roma “Tor Vergata,”Rome; Franco
Narni, University of Modena, Modena;
Alberto Bosi, Ospedale di Careggi, Flor-
ence; Giuseppe Milone, Ospedale
Ferrarotto, Catania; Paolo Corradini,
University of Milano, Milano; Pellegrino
Musto, Istituto Di Ricovero e Cura a
Carattere Scientifico, Centro Riferi-
mento Oncologico Basilicata, Rionero in
Vulture, Italy; Ute Hegenbart and Hart-
mut Goldschmidt, University of Heidel-
berg, Heidelberg; Dietger Niederwieser,
University Hospital Leipzig, Leipzig,
Germany; Hildegard Greinix, Medical
University of Vienna, Vienna, Austria;
Liisa Volin, Helsinki University Central
Hospital, Helsinki, Finland; Meral
Beksac, Ankara University, Ankara,
Turkey; Theo de Witte, Radboud
University, Nijmegen Medical Centre,
Nijmegen, the Netherlands; Curly
Morris, Belfast City Hospital, Belfast,
United Kingdom.
Submitted September 20, 2010;
accepted May 9, 2011; published online
ahead of print at www.jco.org on July
5, 2011.
Written on behalf of the European
Bone Marrow Transplantation Child-
hood Leukemia Working Party Multiple
Myeloma Subcommittee.
Supported by Grant No. CAN 2006/
1125 from the Swedish Cancer Fund
and the Stockholm Cancer Society.
Authors’ disclosures of potential con-
flicts of interest and author contribu-
tions are found at the end of this
article.
Corresponding author: Gösta Gahrton,
MD, Department of Medicine, Karolinska
Institutet, Huddinge, SE-14186 Stockholm,
Sweden; e-mail: gosta.gahrton@ki.se.
© 2011 by American Society of Clinical
Oncology
0732-183X/11/2999-1/$20.00
DOI: 10.1200/JCO.2010.32.7312
ABSTRACT
Purpose
Results of allogeneic stem-cell transplantation (allo) in myeloma are controversial. In this trial
autologous stem-cell transplantation (auto) followed by reduced-intensity conditioning mat-
ched sibling donor allo (auto-allo) was compared with auto only in previously untreated
multiple myeloma.
Patients and Methods
In all, 357 patients with myeloma up to age 69 years were enrolled from 2001 to 2005. Patients
with an HLA-identical sibling donor were allocated to the auto-allo arm (n ⫽108) and patients
without a matched sibling donor were allocated to the auto arm (n ⫽249). Single (n ⫽145) or
tandem (n ⫽104) auto was optional. Conditioning for the auto arm was melphalan 200 mg/m
2
;
conditioning for the allo arm was total-body irradiation 2 Gy plus fludarabine 30 mg/m
2
/d for 3 days.
Median follow-up time was 61 months. Primary end point was progression-free survival.
Results
Progression-free survival at 60 months was significantly better with auto-allo than with allo
alone (35% v18%; P⫽.001), as was the risk of death and of relapse in the long term (P⫽.047
and P⫽.003, respectively). Overall survival at 60 months was 65% versus 58%, and relapse
incidence was 49% versus 78%. Complete remission rates were 51% and 41%, respectively
(P⫽.020). Nonrelapse mortality at 24 months was 12% after auto-allo compared with 3% in the
auto group (P⬍.001). The incidence of grade 2 to 4 acute graft-versus-host disease (GvHD) was
20%, and the incidence of limited and extensive chronic GvHD was 31% and 23%.
Conclusion
In patients with previously untreated multiple myeloma, long-term outcome with respect to
progression-free survival, overall survival, and relapse rate is superior after auto-allo compared with
auto only. Nonrelapse mortality is at a reasonable level in both groups.
J Clin Oncol 29. © 2011 by American Society of Clinical Oncology
INTRODUCTION
Multiple myeloma is considered an incurable malig-
nancy, even though some patients attain long remis-
sions after high-dose (chemo)therapy (HDT).
1,2
HDT with autologous stem-cell transplantation
(ASCT) is part of the first-line standard treatment in
patients up to the age of 65 years on the basis of the
results of randomized trials.
3,4
Allogeneic stem-cell
transplantation (alloSCT) with myeloablative con-
ditioning has been used in myeloma since the mid-
1980s,
5
but it is hampered by severe toxicity and a
high incidence of treatment-related mortality
(TRM) in the range of 30% to 50%.
6
In a case-
control trial,
7
ASCT was demonstrated to be su-
perior to myeloablative alloSCT despite a lower
relapse rate. Reduced-intensity conditioning (RIC)
alloSCT is associated with less toxicity, and the
combination of HDT/ASCT followed by RIC al-
loSCT has reduced TRM to 15% or less.
8,9
However,
the role of RIC alloSCT in relation to ASCT—the
gold standard—is not yet defined, and previous
direct comparative studies have yielded diverg-
ing results.
10-12
In this prospective study of a large number of
patients with previously untreated multiple myelo-
ma, patients were selected for treatment with ASCT
followed by RIC alloSCT (auto-allo) or with ASCT
(auto) alone on the basis on the availability of an
HLA-identical sibling. The time of follow-up is long,
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and over time, the patients in the auto-allo treatment arm had a better
outcome with respect to survival and freedom from progression.
PATIENTS AND METHODS
Patients
From February 2001 through January 2005, 357 patients up to the age of
69 years who had complete response (CR), partial remission (PR), or stable
disease (SD) on first-line treatment were enrolled in 23 European Bone Mar-
row Transplantation (EBMT) centers. All patients had undergone HLA typ-
ing. One-hundred eight patients had an HLA-identical sibling and were
assigned to the auto-allo treatment arm, while the other 249 without a
matched sibling were treated in the auto arm. Single or tandem ASCT was
optional by decision of each study center before starting the study. Two
patients in the auto-allo arm did not have an HLA-identical donor but did
have a sibling donor with one HLA mismatch; they were mistakenly treated
according to the auto-allo arm protocol and were included in this arm in the
intention-to-treat (ITT) analysis. The study design is illustrated in Figure 1.
The time point for enrollment in the trial was at ASCT, after completion of
induction treatment. Patients with substantial renal failure (glomerular filtra-
tion rate ⬍50 mL/min), liver impairment with bilirubin more than 2⫻upper
limit of normal, severe cardiac failure (left ventricular ejection fraction
⬍40%), or other major organ system dysfunction were considered ineligible
for inclusion. Baseline characteristics (Table 1) were evenly distributed be-
tween the two cohorts, with the exception of age at diagnosis, which was
slightly higher in the auto group (median 57 years v54 years in the auto-allo
group). Median time of follow-up after inclusion (ie, the first ASCT) was 61
months (range, 21 to 91 months) for patients alive at last follow-up.
Analysis of Chromosomal Aberrations
Cytogenetic analysis with respect to chromosome 13 deletion—
del(13q14)—was performed in 214 patients by fluorescent in situ hybridiza-
tion as previously described.
13
The del(13) aberration was present in 92
patients, 29 of whom were in the auto-allo group and 63 of whom were in the
auto group. Of the 214 patients, 122 were negative for del(13), with 34 and 88
patients in the auto-allo and auto treatment arms, respectively.
Treatment
All patients had received induction chemotherapy with vincristine, doxo-
rubicin, and dexamethasone (VAD), or similar treatment: VAD was used in
73% of patients in the auto-allo arm and in 67% in the auto arm. The
remaining patients received a variety of mixed regimens, of which the majority
were cyclophosphamide- or dexamethasone-based. No patients were treated
with novel drugs such as thalidomide, lenalidomide, or bortezomib. Autolo-
gous peripheral-blood stem cells were mobilized and collected according to
the standards in each single center. Patients with at least stable disease (CR, PR,
or SD) after induction chemotherapy and with a successfully collected autol-
ogous stem-cell graft were included in the study after giving informed consent.
All 357 patients received HDT with melphalan 200 mg/m
2
followed by
the infusion of autologous stem cells. Supportive care, use of granulocyte
colony-stimulating factor, and so on was given according to the routines of
each center.
Of the 108 patients allocated to the auto-allo arm, 91 received an RIC
alloSCT according to the protocol. Seventeen patients did not receive their
planned allogeneic transplantation for the following reasons: disease progres-
sion (seven patients), patient declined transplantation (four), died before
allogeneic transplantation (one), renal failure (one), failure to mobilize donor
stem cells (one), and donor ill or unavailable for other reason (three; in one of
the latter cases in which the donor declined, the patient received a matched
Diagnosis
Induction treatment
(VAD or VAD-like)
Response: SD, PR, or CR
Autologous stem-cell harvest
HDT-melphalan + auto SCT
(n = 357)
2nd auto SCT
(n = 104)
Optional by decision
of study site
No treatment
(n = 145)
RICallo transplantation
(n = 91)
HLA-identical sibling
(n = 108)
No HLA-identical sibling
(n = 249)
Study inclusion
HLA typing
Fig 1. Design of the trial. CR, complete response; HDT, high-dose chemother-
apy; PR, partial response; RICallo, reduced-intensity conditioning allogeneic
stem-cell transplantation; auto SCT, autologous stem-cell transplantation; SD,
stable disease; VAD, vincristine, doxorubicin, and dexamethasone.
Table 1. Patient Characteristics
Characteristic
Auto-Allo Auto
PNo. % No. %
Sex .784
Male 65 146
Female 43 103
Age, years ⬍.001
Median 54 57
Range 34-66 31-69
Subtype .323
IgG 71 67 139 57
IgA 17 16 46 19
Light chain 15 14 45 18
Other Ig 1 1 5 2
Nonsecretory 2 2 10 4
Durie-Salmon stage .285
I14133012
II 22 21 35 14
III 71 66 182 74
␤
2
-microglobulin at diagnosis, mg/L .977
⬍4 58 67 129 67
⬎429336433
Del(13) .562
Present 29 46 63 42
Absent 34 54 88 58
Response status at inclusion .527
CR 7 6 20 8
PR 83 77 199 80
SD 18 17 30 12
Time from diagnosis to transplantation,
months .599
0-6 37 34 72 29
⬎6-12 57 53 141 57
⬎12 14 13 36 14
Abbreviations: Auto, autologous stem-cell transplantation; allo, allogeneic
stem-cell transplantation; CR, complete response; IgA, immunoglobin A; IgG,
immunoglobulin G; PR, partial response; SD, stable disease.
Bjo¨ rkstrand et al
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unrelated donor RIC alloSCT). All these 17 patients are analyzed as auto-allo in
the ITT analysis. Median time between autograft and allograft was 4.2 months
(range, 1.3 to 22.2 months). The RIC regimen consisted of fludarabine 30
mg/m
2
/d for 3 days plus total-body irradiation (TBI) 2 Gy.
9
Prophylaxis
against graft-versus-host disease (GvHD) with cyclosporine and mycopheno-
late mophetil was administered after transplantation (cyclosporine 6.5 mg/kg
orally twice per day from day ⫺1 or 1.5 mg/kg intravenously twice per day and
continued until oral cyclosporine could be given; mycophenolate mophetil 15
mg/kg orally twice per day from day 0 to day 24). Allo patients without GvHD
and who had not reached CR at least 3 months after transplantation were
offered treatment with donor lymphocyte infusions in escalating doses; two
patients in PR were treated accordingly.
Patients without a matched sibling donor received either no further
treatment (n ⫽145) or, at the discretion of the center, a second ASCT as part
of a tandem transplantation program (n ⫽104). After progression, treatment
was optional. The pretransplantation conditioning for the second autograft
was the same as for the first (ie, melphalan 200 mg/m
2
).
Response Criteria
The EBMT criteria for response and progression were applied as previ-
ously described.
14
Statistical Methods
The primary end point was progression-free survival (PFS) from the
time of inclusion in the study (ie, from the date of the first ASCT). Secondary
end points were overall survival (OS), relapse rate, CR rate, and nonrelapse
mortality (NRM) incidence. Relapse/progression and NRM incidence were
analyzed as competing risks, and relapse/progression and death were consid-
ered as competing risks for CR achievement. The main analysis followed an
ITT principle, that is, treatment arms defined at enrollment (on the basis of the
availability of a donor) were compared regardless of future administration of a
second transplantation. Thus, all patients enrolled contributed to the analyses
of outcomes since first ASCT (108 auto-allo; 249 auto); five patients could not be
analyzed when considering CR achievement because of missing date of response
assessment. An explorative ITT analysis was conducted in two subgroups defined
on the basis of the presence of del(13). Outcomes were also compared after the
second transplantation, including only patients who got the type of transplantation
planned according to protocol (91 auto-allo; 104 tandem auto).
All nominal and continuous characteristics were described with the usual
tables and indexes; comparisons were done by using standard nonparametric
tests (
␹
2
or Fisher’s exact test for categorical variables; Mann-Whitney Utest
for continuous variables). Among the outcomes, only NRM could be com-
pared by the Gray test, while the proportionality assumption at the basis of the
standard methods for survival (log-rank test and Cox model) and competing
risks (Gray test and Fine and Gray model) was violated (with crossing effects)
for all other end points. The regression models were amended to include a
linear time-varying effect identified from the analysis of Schoenfeld residuals.
It was thus possible to assess the amount of and significance of the improve-
ment in time of the auto-allo arm. These models were adjusted by age, since the
auto-allo patients were slightly younger both at diagnosis and at first trans-
plantation. To assess differences in the long term—when they where expected
(ie, after 2 years, except for OS, 3 years)—the landmark log-rank test was used,
applying the Z-OLS correction
15
for PFS and OS. Differences in terms of survival
probabilities at 60 months were tested according to the cloglog transform.
16
RESULTS
ITT Analysis of All Patients
The ITT analysis is illustrated in Figures 2 and 3. At 60 months
after the first ASCT, actuarial PFS was significantly better for the
patients in the auto-allo group: 35% compared with 18% in the auto
group (P⫽.001) by ITT analysis. This benefit for the auto-allo group
was emerging after 2 years of follow-up because of significantly lower
relapse/progression risk (P⫽.003). At 60 months, the incidence of
relapse/progression was 49% and 78% for the auto-allo and auto
0
P = .001
Auto + allo
Auto only
No. at risk
Auto only 249 194 123 96 58 27 8 2
Auto + allo 108 80 57 46 34 19 11 3
At 60 months:
35% (95% CI, 27% to 45%)
At 60 months:
18% (95% CI, 13% to 24%)
Progression-Free
Survival (proportion)
Time (months)
1.0
0.8
0.6
0.4
0.2
12 24 36 48 60 72 84
0
Auto + allo
Auto only
Reduction of risk in time: P = .006
Difference of hazards after 36 months: P = .047
No. at risk
Auto only 249 232 206 169 134 77 30 3
Auto + allo 108 98 85 76 65 36 19 5
At 60 months:
65% (95% CI, 56% to 74%)
At 60 months:
58% (95% CI, 52% to 65%)
Overall Survival
(proportion)
Time (months)
1.0
0.8
0.6
0.4
0.2
12 24 36 48 60 72 84
0
P = .003
Auto + allo
Auto only
No. at risk
Auto only 249 194 123 96 58 27 8 2
Auto + allo 108 80 57 46 34 19 11 3
At 60 months:
78% (95% CI, 72% to 83%)
At 60 months:
49% (95% CI, 40% to 59%)
Relapse
(proportion)
Time (months)
1.0
0.8
0.6
0.4
0.2
12 24 36 48 60 72 84
A
B
C
Fig 2. Intention-to-treat comparison of the two study arms (auto [autologous
stem-cell transplantation] ⫹allo [reduced-intensity conditioning allogeneic stem-
cell transplantation] vauto). Rates are calculated from the time point of the first
autologous transplantation. The numbers at the bottom of each plot indicate the
number of patients at risk. (A) Progression-free survival; (B) overall survival; (C)
relapse rate.
Allogeneic Versus Autologous Transplantation in Multiple Myeloma
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groups, respectively. Long-term OS was significantly superior in the
auto-allo group since that group had a significant reduction of risk in
time (P⫽.006) with lower hazard of death after 3 years (P⫽.047): OS
at 60 months was 65% compared with 58% for the auto group. The CR
rate within 60 months was 51% with the auto-allo and 41% with the
auto group (P⫽.020 for trend of improvement in time). For the
patients who did not attain CR, best response status for the auto-allo
and auto groups was PR, 43% and 50%; no response, 3% and 5%; and
progressive disease, 3% and 4%, respectively. Cumulative NRM at 24
and 60 months was 12% and 16% for the auto-allo group and 3% and
4% for the auto group (P⬍.001).
ITT Analysis of Patients With Poor-Prognosis
Chromosomal Aberrations
For patients with del(13), PFS at 60 months was 31% (95% CI,
18% to 53%) in the auto-allo group and 11% (95% CI, 5% to 22%) in
the auto group (P⫽.002). OS was 69% (95% CI, 54% to 88%) in the
auto-allo group and 55% (95% CI, 44% to 69%) in the auto group with a
significantly better improvement in time (P⫽.003) in the auto-allo
group. The relapse/progression risk after 2 years was significantly lower in
the auto-allo group (P⫽.004), in which the rate at 60 months was 55%
(95% CI, 39% to 77%) versus 86% (95% CI, 78% to 96%) for the
auto group.
For patients who were negative for del(13), PFS at 60 months was
44% (95% CI, 30% to 64%) in the auto-allo group and 20% (95% CI,
12% to 32%; P⫽.017) in the auto group. OS was 70% (95% CI, 56%
to 88%) and 61% (95% CI, 51% to 73%; P⫽.363), and relapse/
progression rate was 39% (95% CI, 25% to 60%) and 76% (95% CI,
67% to 87%; P⫽.005 for the hazard after 2 years) in the auto-allo and
auto groups, respectively. Thus, a tendency for better outcome was
found in both del(13) and non-del(13) patients, which corroborates
the findings in the total cohort patients.
Per Protocol Analysis Comparing Auto-Allo With
Tandem ASCT
In the comparison between patients who actually received their
RIC alloSCT according to protocol (n ⫽91) and patients who received
a second ASCT in a planned tandem transplantation program
(n ⫽104), outcome was superior with auto-allo (Fig 4): PFS at 60
months after the second transplantation was 39% (95% CI, 30% to
50%) and 19% (95% CI, 12% to 29%) for the auto-allo and auto
groups, respectively (P⫽.004). The corresponding figures for OS at
the same time point were 63% (95% CI, 53% to 74%) and 60% (95%
CI, 51% to 71%; P⫽.753) but with a highly significant trend of
reduction of risk in time (P⬍.001), and for relapse/progression rate
43% (95% CI, 34% to 55%) for auto-allo compared with 78% (95%
CI, 70% to 87%) for auto (P⫽.001 for the hazard after 2 years). The
CR rate within 60 months was 56% (95% CI, 47% to 68%) and 44%
(95% CI, 35% to 55%) for the auto-allo and auto groups, respectively
(P⫽.007 for improvement in time). For the patients who did not
attain CR, response status for the auto-allo and auto groups was PR
35% and 51%, no response 6% and 3%, and progressive disease 3%
and 2%, respectively. Cumulative NRM was similar to the ITT analy-
sis, namely 18% (95% CI, 11% to 28%) in the auto-allo arm versus 3%
(95% CI, 1% to 10%) in the auto arm at 60 months (P⬍.001).
GvHD
Among the 91 patients who received the RIC alloSCT, acute
GvHD (aGvHD) occurred as follows: grade 1 in 10 (11%), grade 2 in
eight (9%), grade 3 in eight (9%), and grade 4 in two patients (2%).
Sixty patients (67%) had no aGvHD. Forty-nine patients (54%) de-
veloped chronic GvHD (cGvHD) which was limited in 28 (31%) and
extensive in 21 patients (23%). GvHD information was missing in
three patients, and four died before day 100. In a landmark analysis of
the evaluable patients alive after day 100, long-term outcome was
inferior in patients with aGvHD: At 60 months, OS was 74% (95% CI,
62% to 89%) in patients without aGvHD compared with 32% (95%
CI, 15% to 69%) for patients with aGvHD (P⫽.0012). This was based
on a higher cumulative NRM from day 100 in the aGvHD patients
(36% v4% at 60 months; P⬍.001). With respect to the effect of
cGvHD, a landmark analysis was done to compare the outcomes from
12 months after the alloSCT. The basis of the landmark analysis was
whether the patient had cGvHD before 12 months (n ⫽30) or not
(n ⫽37) and was restricted to the 67 patients who were surviving after
month 12. There was no significant difference in OS, PFS, relapse
incidence, or NRM between the study arms.
0
Increase of probability
of CR in time: P = .020
Auto + allo
Auto only
No. at risk
Auto only 245 113 62 45 26 10 1 0
Auto + allo 107 46 18 12 7 2 2 0
At 60 months:
51% (95% CI, 42% to 62%)
At 60 months:
41% (95% CI, 36% to 48%)
Complete Remission
(proportion)
Time (months)
1.0
0.8
0.6
0.4
0.2
12 24 36 48 60 72 84
0
Auto + allo
Auto only
P < .001
No. at risk
Auto only 249 194 123 96 58 27 8 2
Auto + allo 108 80 57 46 34 19 11 3
Nonrelapse Mortality
(proportion)
Time (months)
1.0
0.8
0.6
0.4
0.2
12 24 36 48 60 72 84
A
B
At 24 months: 12% (95% CI, 7% to 20%)
At 24 months: 3% (95% CI, 2% to 6%)
Fig 3. Intention-to-treat comparison of the two study arms (auto [autologous
stem-cell transplantation] ⫹allo [reduced-intensity conditioning allogeneic stem-
cell transplantation] vauto). Rates are calculated from the time point of the first
autologous transplantation. The figures at the bottom of each plot indicate
patients at risk. (A) Complete remission (CR) rate; (B) nonrelapse mortality rate.
Bjo¨ rkstrand et al
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DISCUSSION
Our study demonstrates the long-term efficacy of RIC alloSCT and
illustrates the importance of prolonged follow-up in this type of trial,
since during the first 1 to 2 years the allo patients did worse, and the
difference favoring this group did not emerge until after 2 to 3 years. It
seems clear that remissions can be induced by the allogeneic antitu-
mor effect
17,18
in a manner that is not achieved by HDT alone. The
allogeneic antitumor effect after RIC alloSCT is more important for
the outcome than the adverse effect of procedure-related deaths, since
these are on a relatively low level, in contrast to myeloablative alloSCT
in which the efficacy is overshadowed by the high rate of TRM.
6
This
and similar studies in previously untreated patients have required
HLA-matched sibling donors, which naturally substantially limits the
applicability of the method in the clinical setting. Study data with RIC
alloSCT that uses matched unrelated donors are scarce and mainly
limited to patients with relapsed disease,
19
but if a treatment safety
similar to that with matched sibling transplantations could be devel-
oped, availability would be increased to include the majority of pa-
tients in need of a transplantation.
Three trials with a similar design have previously been under-
taken by the French Myeloma Intergroup (IFM [Intergroupe Franc¸ais
du Mye´ lome]),
10
an Italian collaborative group,
11
and the Spanish
Cooperative Group for Hematological Malignancies Treatment of the
Spanish Society of Hematology (PETHEMA).
12
Our trial is the largest
of these trials and has the longest time for follow-up, and there are also
some other differences in the design and outcome of these studies. The
Italian trial
11
enrolled 162 patients (80 allo; 82 auto), but all patients in
the auto group were candidates for tandem autografting. As in our
trial, PFS and OS were significantly better in the allo treatment arm.
No subgroup analysis with respect to cytogenetic prognostic factors
was undertaken. The IFM
10
(n ⫽284) and the PETHEMA
12
(n ⫽110)
trials did not demonstrate any significant differences in the outcome
of the two treatment arms, although in the latter trial there was a trend
for better PFS with alloSCT. In a long-term follow-up analysis of the
IFM trial (median follow-up, 56 months), outcomes were essentially
unchanged but showed a trend for better OS favoring the tandem auto
transplantation group.
20
The discrepancies in the results of the four
trials cannot readily be explained, but there are some important dif-
ferences and similarities between the studies that may have played a
role. The Italian trial used an RIC protocol similar to that in our study
with TBI 2 Gy but no fludarabine; the IFM trial used fludarabine,
busulphan, and antithymocyte globulin; and the PETHEMA trial used
fludarabine and high-dose melphalan. What particularly stands out is
the heavier immunosuppression in the IFM trial, and there may be a
relationship between the relatively lighter immuno- and myelosup-
pression in our trial and the Italian trial, and the fact that the outcome
after RIC alloSCT was better in these studies compared with the other
two trials. The inclusion criteria in the IFM trial allowed enrollment
only of patients with high-risk criteria in terms of del(13) and high
␤
2
-microglobulin; the other three trials, including our own, were not
restricted to high-risk patients.
The choice of del(13) as a marker for poor prognosis was based
on knowledge that was current when the study was planned
21,22
and
seemed natural and logical at that time. Later research demonstrated
other karyotypic changes (eg, del(17p) and t(4;14)) as more important
and that del(13) is a surrogate marker for these changes.
23
However,
studies
24
have suggested a crucial role for chromosome 13 in the clonal
expansion of tumors, and recent data still identify del(13) as an aber-
ration associated with inferior survival after ASCT.
25
Tandem ASCT was an option according to the decision in each
individual center; the purpose of the study was not to compare single
and tandem ASCT, and no such comparison has been made. Notably,
however, the outcome after tandem ASCT in the per-protocol analysis
was almost identical to that in the whole ASCT cohort according to
ITT. In the alloSCT group, the results of the ITT and per-protocol
analyses were quite similar, probably reflecting the fact that the num-
ber of dropouts (ie, patients who did not fulfill the second transplan-
tation) was low.
The induction chemotherapy consisted of the chemotherapy that
was standard at the time, primarily the VAD regimen.
26
With the
introduction of novel agents such as bortezomib, thalidomide, and
lenalidomide before and after ASCT, outcome for patients with mye-
loma has improved.
27,28
In particular, response rates have improved,
0
Auto + allo
Auto only
No. at risk
Auto only 104 80 56 40 21 10 3 0
Auto + allo 91 62 50 39 27 13 6 2
Progression-Free
Survival (proportion)
Time (months)
1.0
0.8
0.6
0.4
0.2
12 24 36 48 60 72 84
0
Auto + allo
Auto only
Difference of hazards: P = .005
No. at risk
Auto only 104 80 56 40 21 10 3 0
Auto + allo 91 62 50 39 27 13 6 2
Relapse
(proportion)
Time (months)
1.0
0.8
0.6
0.4
0.2
12 24 36 48 60 72 84
Reduction of risk in time: P = .002
Difference of hazards: P = .025
A
B
At 60 months:
43% (95% CI, 34% to 55%)
At 60 months:
78% (95% CI, 70% to 87%)
At 60 months:
39% (95% CI, 30% to 50%)
At 60 months:
19% (95% CI, 12% to 29%)
Fig 4. Per-protocol comparison of the two study arms (auto [autologous
stem-cell transplantation] ⫹allo [reduced-intensity conditioning allogeneic stem-
cell transplantation] vauto) of patients who actually received a second transplan-
tation (allo or planned auto). Rates are calculated from the time point of the
second transplantation (allo and second auto, respectively). The figures at the
bottom of each plot indicate patients at risk. (A) Progression-free survival; (B)
relapse rate.
Allogeneic Versus Autologous Transplantation in Multiple Myeloma
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which could argue against the validity of this study. However, our view
is that including the new drugs in the same way in the auto-allo setting
may improve the outcome even further with this approach.
We conclude that RIC alloSCT using fludarabine and low-dose
TBI is an effective treatment for patients with multiple myeloma who
are eligible for this type of therapy with respect to age, comorbidity,
and performance status. Our study demonstrates the long-term supe-
riority of a treatment program with sequential ASCT and RIC alloSCT
over therapy comprising ASCT alone. While the survival curves after
ASCT continuously drop, the level after alloSCT stabilizes with time.
The possibility that a fair number of patients might be cured can justify
the TRM and GvHD morbidity. It is likely that freedom from
progression and survival will further increase with the introduc-
tion of more effective drugs as part of induction treatment, and
post-transplantation consolidation with donor lymphocyte infusion,
other cell therapy approaches, or novel agents.
29-31
We suggest that all
patients who are eligible for HDT and have an HLA-identical sibling
should be considered as candidates for RIC alloSCT as part of first-
line treatment.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
Although all authors completed the disclosure declaration, the following
author(s) indicated a financial or other interest that is relevant to the subject
matter under consideration in this article. Certain relationships marked
with a “U” are those for which no compensation was received; those
relationships marked with a “C” were compensated. For a detailed
description of the disclosure categories, or for more information about
ASCO’s conflict of interest policy, please refer to the Author Disclosure
Declaration and the Disclosures of Potential Conflicts of Interest section in
Information for Contributors.
Employment or Leadership Position: Bo Bjo¨rkstrand, Roche (C)
Consultant or Advisory Role: Go¨sta Gahrton, Fujimoto Pharmaceutical
(C), Avaris (C) Stock Ownership: None Honoraria: Go¨sta Gahrton,
Celgene Sweden Research Funding: None Expert Testimony: None
Other Remuneration: None
AUTHOR CONTRIBUTIONS
Conception and design: Bo Bjo¨rkstrand, Dietger Niederwieser,
Go¨sta Gahrton
Collection and assembly of data: Bo Bjo¨rkstrand, Simona Iacobelli, Ute
Hegenbart, Astrid Gruber, Hildegard Greinix, Liisa Volin, Franco Narni,
Pellegrino Musto, Meral Beksac, Alberto Bosi, Giuseppe Milone, Paolo
Corradini, Hartmut Goldschmidt, Theo de Witte, Curly Morris, Dietger
Niederwieser, Go¨sta Gahrton
Data analysis and interpretation: Bo Bjo¨rkstrand, Simona Iacobelli,
Astrid Gruber, Dietger Niederwieser, Go¨sta Gahrton
Manuscript writing: All authors
Final approval of manuscript: All authors
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■■■
Acknowledgment
We thank the following investigators in all the participating centers who are not included as coauthors: Vittorio Montefusco, Istituto
Nazionale Tumori, Milan, Italy; Lene Knudsen, Copenhagen University Hospital Herlev, Herlev, Denmark; Kari Remes, University Central
Hospital, Turku, Finland; Kristina Carlson, Akademiska University Hospital, Uppsala, Sweden; Jean-Francois Rossi, University Hospital,
Montpellier, France; Andreas Sengelov, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark; Ulf-Henrik Mellqvist, Sahlg-
renska University Hospital, Gothenburg, Sweden; Gareth Morgan, Royal Marsden Hospital, Sutton, United Kingdom; Inge-Marie Dahl, Tromso
University Hospital, Tromso, Norway; Elli Koivunen, University Hospital, Tampere, Finland; Anders Waage, Trondheim University Hospital,
Trondheim, Norway. We also thank Kristina Friberg, Karolinska Institute, Stockholm, Sweden, and Anja van Biezen, Leiden Medical Centre, the
Netherlands, for excellent assistance on data management and statistics.
Allogeneic Versus Autologous Transplantation in Multiple Myeloma
www.jco.org © 2011 by American Society of Clinical Oncology 7
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CORRECTIONS
Journal Corrections
The July 10, 2008, article by Anders et al, entitled, “Young
Age at Diagnosis Correlates With Worse Prognosis and Defines
a Subset of Breast Cancers With Shared Patterns of Gene
Expression” (J Clin Oncol 26:3324-3330, 2008), contained
errors.
In the Results section, under “Univariate and Multivar-
iate Analysis: Combining Clinicopathologic Variables and
Gene Expression Profiles,” the second sentence of the first
paragraph was given as: “Lymph node status (r⫽–0.59, P⬍
.0001) and mRNA expression of ER
␤
(r⫽0.81, P⬍.0001)
correlated with age among women age ⱕ45 years, and
mRNA expression of ErbB2 (r⫽–0.14, P⫽.04) and EGFR
(r⫽–0.16, P⫽.02) correlated with age among women
age ⱖ65 years.”
Whereas it should have read:
“Lymph node status (r⫽–0.59, P⬍.0001) and mRNA
expression of ER
␤
(r⫽0.81, P⬍.0001) correlated with each
other among women aged ⱕ45 years, and mRNA expression of
ErbB2 (r⫽–0.14, P⫽.04) and EGFR (r⫽– 0.16, P⫽.02)
correlated with each other among women age ⱖ65 years.”
In Table 1, the age range for the GSE 3143 dataset (⬍40
years) was given as 27-29, whereas it should have read 27-39.
Also in Table 1, the results for HER-2 status appeared
under the Duke dataset and should have been aligned under the
GSE 3143 dataset.
The authors and Journal of Clinical Oncology apologize to
the readers for the mistakes.
DOI: 10.1200/JCO.2011.39.0351
■■■
The August 1, 2011, article by Björkstrand et al, entitled,
“Tandem Autologous/Reduced-Intensity Conditioning Allo-
geneic Stem-Cell Transplantation Versus Autologous Trans-
plantation in Myeloma: Long-Term Follow-Up” (J Clin Oncol
29:3016-3022, 2011), contained errors.
In the sidebar, it was indicated that the manuscript had been
written on behalf of “the European Bone Marrow Transplantation
Childhood Leukemia Working Party Multiple Myeloma Subcom-
mittee,” whereas it should have been “the European Group for
Blood and Marrow Transplantation (EBMT), Chronic Leukemia
Working Party, Multiple Myeloma Subcommittee.”
In the Abstract, Results section, the first sentence indicated
that progression-free survival was better with auto-allo than
with allo alone, whereas it should have been auto alone, as
follows:
“Progression-free survival at 60 months was significantly
better with auto-allo than with auto alone (35% v18%; P⫽
.001), as was the risk of death and of relapse in the long term
(P⫽.047 and P⫽.003, respectively).”
In the Acknowledgment, the following investigator and
participating center were inadvertently omitted: Angelo Mi-
chele Carella, “CSS” Hospital IRCCS, S.G. Rotondo, Italy.
The authors and Journal of Clinical Oncology apologize to
the readers for the mistakes.
DOI: 10.1200/JCO.2011.39.0369
■■■
© 2011 by American Society of Clinical Oncology 3721
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