Single or
or Double
Double Autologous
Autologous Stem-Cell
-
Tr
T ansplantation
r
Before and After the Era of Novel Agents
Michele Cavo
Bologna University School of Medicine
Seràgnoli Institute
Institute of Hematology and Medical Oncology
Oncology

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Background and rationale
· Recognition
of
a
dose-
dose response
effect
for
melphalan
· Superior rate of CR and prolonged survival with a
single autotransplantation when compared with
conventional chemotherapy in several randomized
td
stu i
dies
· Investigation of a more intensive approach with
double - or tandem - autotransplantation to
furtherly improve patient outcomes

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Total Therapy I: long-term outcome results
Barlogie B. et al, Br J Haematol 2006

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Phase III trials comparing single with double ASCT
IFM 941
Bologna 962
HOVON3
GMMG4
MAG5
Induction
VAD
VAD
VAD
VAD/VID
VAD
PBSC coll.
G-CSF
HD-CTX (7)
HD-CTX (4)
HD-CTX (4)
HD-CTX (4)
MEL 140+TBI/
TBI+CHT/
ASCT-1
MEL 200
MEL 70 x 2
MEL 200
MEL 140
MEL 140
MEL 140
140
MEL 140
140
CTX 120
MEL+
MEL V
+ P
V 16
ASCT-2
MEL 200
+TBI
+BU 12
+ TBI
+ TBI
Maintenance
IFN
IFN
IFN
IFN
IFN
the dose of MEL is mg/m2
the dose of CTX and BU is mg/kg
1Attal M. et al, N Engl J Med 2003
4Goldschmidt H, XI IMW, Kos 2007
2Cavo M et al, J Clin Oncol 2007
5Fermand J et al, X IMW, Sydney 2005
3Sonneveld P et al, Haematologica 2007

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Phase III trials comparing single with double ASCT
OUTCOME RESULTS
Author
Np
N.
t
pts
Me
Median follow-
More ef
effective AS
ASCT
CT
up (months)
CR
EFS
OS
Attal
399
75 (36-93)
Neither
Double
Double
Cavo
321
70 (32-112)
Double
Double
Neither
Sl
Sonneve d
ld
303
92 (1
(17-129)
Db
Dou l
ble
Db
Dou l
ble
Ni
Neither
Fermand
227
73 (60-89)
Neither Neither
Double
(unpurged)
Goldschimdt
358
Not rep.
Not rep. Neither
Neither
Attal M. et al, N Engl J Med 2003
Fermand J et al, X IMW, Sydney 2005
Cavo M et al, J Clin Oncol 2007
Goldschmidt H, XI IMW, Kos 2007
Sonneveld P et al, Haematologica 2007

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Tandem versus single ASCT in MM:
a systematic review and meta-analysis
· To assess the existing evidence related to the
relative
benefits
of
double
versus
a
single
autotransplantation
· Inclusion of a study comparing single ASCT +
thalidomide maintenance versus double ASCT1
thalidomide maintenance versus double ASCT
· End points: response, EFS and OS
1Abdelkefi A et al, Blood 2008

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Tandem versus single ASCT in MM:
a systematic review and meta-analysis
RESPONSE RAT
RA E
TE
Risk Ratio for response rate favoring double ASCT
(0.79, 95% CI: 0.67 - 0.93, P = 0.004)
Kumar A. et al, J Natl Cancer Inst 2009

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Tandem versus single ASCT in MM:
a systematic review and meta-analysis
EVENT-FREE SURVIVAL
Exclusion of the study by Abdelkefi et al resulted in a significant
change in the HR for EFS favoring double ASCT (HR = 0.79, 95%
CI: 0.
0 70
.
-0.
0 89
. , P < 0.
0 001
.
)
Kumar A. et al, J Natl Cancer Inst 2009

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Tandem versus single ASCT in MM:
a systematic review and meta-analysis
OVERALL SURVIV
SURV A
IV L
AL
HR = 0.94, 95% CI: 0.77 - 1.14, P = 0.533
Kumar A. et al, J Natl Cancer Inst 2009

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Phase III trials comparing single with double ASCT
OUTCOME ANALYSIS: CONFOUNDING FEATURES
· Differences in study design
· Significant dropo t
u
rate for patients randomly
assigned to double ASCT, but who never received it
· Use f
o second ASCT as salvage therapy t
a relapse
for patients randomly assigned to a single ASCT
· Bf
Bene ifi i
c l
a
ff
e ect
f
o novel
t
agen s inproli
longing
survival after relapse

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Superior benefit with double vs single ASCT
in patients failing VGPR/nCR after one transplant
Attal M. et al, N Engl
g J Med 2003
Cavo M. et al, J Clin Oncol 2007

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What is the role of double ASCT for the treatment of MM?
· Elective tandem procedure as up-front therapy or as
salvage treatment of relapsed disease after one
autotransplantation?
­ Lack of prospective studies comparing "early" versus
"late" double ASCT
· Double ASCT up-front may be an option for patients
failing to achieve a major response (CR/CR+VGPR) after
the first transplantation1
the first transplantation
· In patients who are in CR/VGPR after the first
transplantation, second ASCT could be a salvage
procedure, particularly if late relapse occurs after the
first autotransplantation
1NCCN Pratice Guidelines in Oncology, v.2.2009

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In the era of novel agents the role of (double) ASCT
for MM treatment is under re-evaluation
· Does ASCT furtherly enhance the rate of major
responses (CR/VGPR) obtained with newer
induction regimens?
· Do major responses obtained after ASCT
translate into improved clinical outcomes (PFS
d
an OS)?
· Is the role of (double) ASCT challenged by novel
agents?

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ASCT outcomes in the era of novel agents
BEFORE ASC
AS T
AFTER
E
AS
ASCT
C
REGIMENS
VGPR
CR
VGPR
CR
PFS
TAD
TA vs VAD
33 vs 15
42
4 vs 2
49 vs 32
16 vs 11
33 vs 22 mos
P < 0.001
P = n.s.
P < 0.001
P = n.s.
P < 0.001
VD vs VAD
39 vs 16
6 vs 1
57 vs 38
17 vs 9
69% vs 60%
P<0.0001
P = 0.01
P = 0.0003
P = 0.01
at 2 yrs
y
68 vs 47
n/a
P< 0.001
P<0.0001
VTD vs TD
62 vs 29
21 vs 6
43 vs 23
76 vs 58
90% vs 80%
P<0
P<0.001
P< 0.001
P<0
P<0 001
.
P<0
P<0.001
at 2 yrs
yrs
P = 0.009
Lokhorst H et
et al
al. ASH
ASH 2008 (abs. 157)
Harousseau JL et al. ASH 2008
Cavo M et al, ASH 2008 (abs 158)

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In the era of novel agents the role of (double) ASCT
for MM treatment is under re-evaluation
· Novel induction regimens followed by ASCT are
complementary
· Can ASCT be replaced, or postponed until relapse,
in patients attaining major responses (CR/
(CR/ VGPR)

after induction therapy or the first ASCT?
­ Need of prospective, randomized studies
­ Need of studies evaluating MRD by molecular/
immunophenotypic studies

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"BOLOGNA 96" CLINICAL TRIAL
PA
P R
A T
R ICIPA
ICIP T
A ING CENTERS
Aviano
Udine
Piacenza
Dl
Dolo
Reggio Emilia
Bologna
Modena
Ravenna
Genova
Geno
For
Fo lì
Siena
Cesena
Latina
Rimini
Av
A ellino
v
San Marino
Napoli
Ancona
Sassari
Bari
Potenza
Ta
T r
a anto
Cagliari
Foggia
Messina
Catania
Seràgnoli Institute -Bologna, Italy

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