AUTOLOGOUS AND ALLOGENEIC TRANSPLANTATION IN MULTIPLE
MYELOMA
Vienna, May, 2014
Montserrat Rovira,
Laura Rosiñol, Enric Carreras
Hospital Clinic, Barcelona
Chemotherapy in Multiple Myeloma
Clinical Settings HDT Approaches
- Primary resistance
- Responders
Single- Auto-SCT
- Allo-SCT Tandem - Double auto - Auto plus allo-RIC
SCT in Multiple Myeloma
HDT/SCT in Primary Refractory Myeloma
Author, yrNo. Pts
Age(yrs.)
B2M(mg/L)
CR(%)
EFS(yrs)
OS(yrs)
Alexanian et al,Blood, 1994
27 45 2.8 8 3.5 6
Vesole et al, Blood 1994 72 50 - 15 1.7 4
Singhal et al, BMT, 2002 43 54 3.3 40 2 -
Kumar et al, BMT, 2004 50 56 2.7 20 2.5 5
Alexanian et al,BMT 2004
89 52 3.7 16 7* 7*
* In patients achiving CR after HDT/SCT
0 2 4 6 8 10 12 14
Years
0,0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1,0
Cum
ulative P
roportion S
urvivin
g
Overall Survival: Progressive vs Chemosensitive Disease vs No-change
Non-responsive, non-progressive
Chemosensitive
Progressive disease
Clinical Settings HDT Approaches
- Primary resistance
- Responders
Single- Auto-SCT
- Allo-SCT Tandem - Double auto - Auto plus allo-RIC
SCT in Multiple Myeloma
Randomized trials: Single auto-SCT vs. conventional chemotherapy
AuthorCR (%)
PFS (meses)
OS (meses)
Attal et al (IFM), 1996 22 vs 5 28 vs 18 57 vs 42
Morgan et al (MRC), 2003 44 vs 9 32 vs 20 55 vs 42
Bladé et al, (PETHEMA), 2005 30 vs 11 42 vs 34 67 vs 65
Fermand et al (GMA), 2005 8 vs 6 25 vs 19 48 vs 48
Barlogie et al, (US Intergroup), 2006 17 vs 15 25 vs 21 58 vs 53
Only chemosensitive patients
Higher intensity prior SCT
Auto-SCT“Gold-standard” for initial
treatment in patients younger than 65 y.
Nadal et al. BMT 2004
Probability of SRV according remission after HDT
OS
CRMedian not reached
Non-CRMedian: 60 months
CR after HDT According to Tumor Burden Pretransplant
M-protein size CR (%) P-value
Serum*
- < 10g/L 52 0.01
- 10 g/L 15
Serum and urine**
- < 10 g/L and < 0.5 g/24h 67
- 10 – 20 g/L and / or 0.5 to 1 g/24h 21 0.03
- > 20 g/L and / or > 1 g/24h 7
*Alexanian et al, BMT 2001; 27: 1037-1043** Nadal et al, BMT 2004; 33: 61-64
• Which is the best treatment before HSCT?
Treatment options for patients eligible for transplantation
Induction
‘Traditional’VAD
CyDex
Bortezomib-based:VelDex
VTDPAD
IMiD-based:Thal/Dex
TADCTDRd
VRD
Stem cell harvestHigh-dose melphalan
Stem cell infusion
Pre and Post-ASCT CR Rate with “Novel” Induction Regimens*
Regimen Pre-ASCT Post-ASCT
Thal/Dex 6% 23-34%
Vel/Dex 12% 33%
PAD-1 24% 43%
VRD 23% 42%
VTD 21-30% 43-52%
Total Therapy III** - 56% at 2 yrs
*Cavo et al, ASH 2009 (abstract 351); Rosiñol et al, ASH 2009 (abstract 130);Harousseau et al, Haematologica 2006; 91: 1498-05; Rosiñol et al, JCO 2007; 25:1498-05; Popat et al, BJH 2008; 141: 512-6; Barlogie et al, BJH 2007; 138:176-85, Roussel et al;Blood 2011; 118(abstract 1872).
**VTD-PACE + Tandem ASCT + VTD/TD
Clinical Settings HDT Approaches
- Primary resistance
- Responders
Single- Auto-SCT
- Allo-SCT Tandem - Double auto - Auto plus allo-RIC
SCT in Multiple Myeloma
Single versus Tandem Auto-SCT
Author No. Pts RR (%) EFS mos. OS mos.
Attal et al, NEJM 2003 399 42 vs 50*
(p=NS) 25 vs 30 (p=0.03)48 vs 58(p=0.01)
Cavo et al, JCO 2007 321 33 vs 47**
(p=0.008)23 vs 35 (p=0.001)
65 vs 71 (p=NS)
Sonneveld et al, Haematol 2007 303 13 vs 32***
(p<0.001)24 vs 27 (p=0.006)
50 vs 55 (p=NS)
Fermand et al,IMW 2005
22737 vs 39***
(p=NS)31 vs 34(p=0.75)
57 vs 73(p=0.09)
Abdelkefi et al,Blood 2007
20267 vs 51*
(p=0.024)#85% vs 57%†
(p=0.038)#88% vs 63%†
(p=0.052)#
* CR/VGPR, ** CR/nCR, *** CR, †at 3 years, #In favour of single transplant
IFM 94 : Overall survival
P < 0.01
Tandem
Single
IFM 94 : OS if response to 1stgraft < 90%
P < 0.001
Tandem
Single
IFM 94 : OS if response to 1st graft > 90 %
P = 0.7
Tandem
Single
Single versus Tandem Auto-SCT
Author No. Pts RR (%) EFS mos. OS mos.
Attal et al, NEJM 2003 399 42 vs 50*
(p=NS) 25 vs 30 (p=0.03)48 vs 58(p=0.01)
Cavo et al, JCO 2007 321 33 vs 47**
(p=0.008)23 vs 35 (p=0.001)
65 vs 71 (p=NS)
Sonneveld et al, Haematol 2007 303 13 vs 32***
(p<0.001)24 vs 27 (p=0.006)
50 vs 55 (p=NS)
Fermand et al,IMW 2005
22737 vs 39***
(p=NS)31 vs 34(p=0.75)
57 vs 73(p=0.09)
Abdelkefi et al,Blood 2007
20267 vs 51*
(p=0.024)#85% vs 57%†
(p=0.038)#88% vs 63%†
(p=0.052)#
* CR/VGPR, ** CR/nCR, *** CR, †at 3 years, #In favour of single transplant
ProblemMany of patient
relapsing after single SCT recived a
second auto-SCT
Clinical Settings HDT Approaches
- Primary resistance
- Responders
Single- Auto-SCT
- Allo-SCT Tandem - Double auto - Auto plus allo-RIC
SCT in Multiple Myeloma
MM. SYNGENEIC TRANSPLANT“Treatment of Choice”
Bensinger et al, BMT 1996
Gahrton et al, BMT 1999
Allogeneic Transplant in MM
Period Nº. ofpatients TRM CR
rate4-yearssurvival
1983-93 334 46% 53% 32%
1994-98 356 30% 54% 50%
1998-02 196 37% 53% 51%
Gahrton G et al. Br J Haematol 2001; 113:209-216.Crawly et al, Blood 2007; 109: 3588-3594
EBMT 1983 2002
Cy-TBIMel-TBIBu-Mel
Myeloablative versus Allo-RIC transplantation
High TRM: 30-50%
High relapse rate: 45% at 3 yrs
Cure rate: 10-20%
Allo-RIC
Allo-RIC
Conditioning:
-- MEL/FLUDA ± ATG or Campath-1H (RIC)
-- FLUDA/low dose TBI (non-MAC)
TRM: ≈ 20% (11- 40%)
CR rate: 22-73%
aGVHD: ≈ 40%
cGVHD: 20-45%
UsuallyDLI
Included in protocols
UsuallyDLI
Included in protocols
Myeloablative versus Allo-RIC transplantation
Crawley et al, Blood 2007; 109:3588-3594.
EBMT Experience (1998-2002)
Allogeneic Transplant with Dose-Reduced Intensity Conditioning (RIC)
Better results
Chemosensitive disease
Development of GVHD
No ATG or Campath-1H
Previous auto-transplantation
Clinical Settings HDT Approaches
- Primary resistance
- Responders
Single- Auto-SCT
- Allo-SCT Tandem - Double auto - Auto plus allo-RIC
SCT in Multiple Myeloma
Nº pts
Median follow-up (yrs)
aGVHD (II-IV)/cGVHD (%)
CR (%)
EFS (mos)
OS at 5 yrs
Rotta et al*,Blood 2009
102 6.6 42/74 57 36 64%
Bruno et al&,Blood 2009
100 5 38/50 53 37 NR
Tandem HSCT: ASCT followed by Allo-RIC
*TBI 2 Gy +/- Fluda&TBI 2 Gy
Double ASCT versus tandem ASCT/Allo-RIC
Author No. PtsCR rate
(%)EFS mos.
OS mos.
Garban et al, Blood 2006 166 vs 46 51 vs 62
(p=NS)35 vs 32 (p=NS)
47 vs 35(p=0.07)
Bruno et al, NEJM 2007&2009 82 vs 80 26 vs 55
(p=0.004) 29 vs 35 (p=0.02)54 vs 80 (p=0.01)
Rosiñol et al,Blood 2008
85 vs 2611 vs 40(p=0.01)
26 vs 19.6(p=NS)
58 vs NR(p=NS)
Knop et al,Blood 2009
73 vs 12632 vs 59(p=0.003)
-72% vs 60%
(at 36 mos, p=NS)
Bjorkstrand et al, JCO 2011 249 vs 108
41 vs 51(p=0.02)
18% vs 35% (at 60 mos, p=0.001)
58% vs 65% (at 60 mos, p=0.006)
Krishnan et alLancet Onc 2011
185 vs 39735 vs 48(p=0.009)
46% vs 43%( at 3 yrs p=NS)
80% vs 77%(at 3 yrs, p=NS)
High RiskUse ATG
Allo onlyif no CR/nCR w
auto13qATG in UNR
ShortFollow-up
Patients who completed protocols (58 vs 46 pts) Median follow up: 6 yearsAuto-Allo Vs Auto-Auto
64 mo.33 mo.
37 mo.
Bruno B et al. EBMT Goteborg 2009
Median Overall Survival Median Event Free Survival
Auto/RIC-allo versus Auto in MyelomaProgression Free Survival since 1st transplant
Auto+Allo
Auto only
Reduction of risk in time: p=0.0012 (Cox)
Auto (N=249) 194 123 96 58 27 8 2
Auto+allo (N=109) 80 57 46 34 19 11 3
At 60 mns: 35% (CI: 27% - 45%)
At 60 mns: 18% (CI: 13% - 24%)
Bjorkstrand et al, JCO 2011
Progression-free Survival Overall Survival
Prob
abilit
y, %
100
0
20
40
60
80
90
10
30
50
70
Mp10_5.ppt
Auto/Allo, 43% @ 3yr
Auto/Auto, 46% @ 3yr
p-value = 0.67 p-value = 0.19
Auto/Allo, 77% @ 3yr
Auto/Auto, 80% @ 3yr 100
0
20
40
60
80
90
10
30
50
70
0 6 12 18 24 30 36 42 48
436 424 406 395 370 348 305 107 79189 183 167 160 156 143 124 43 27
Survival Outcomes after the First Transplant: Auto-Auto vs. Auto-Allo: Intent-to-treat analysis
Months 0 6 12 18 24 30 36 4248# at risk:Auto/Auto 436 395 348 292 242 213 178 5442Auto/Allo 189 165 138 117 105 89 71 23
16
Krishnan et al Lancet Onc 2011
• Allo-RIC limitation as first line approach: high TRM
• Indications:
• High risk patients (cytogenetics, < VGPR?)
• First sensible relapse
HSCT in MM: Take-home messages
CytogeneticsCR
Post-ASCTAllo-RIC
*Age, ISS 3 stage, extramedular afectation, IgD, PCL, MRD (+)
High risk NO YES
High risk YES?
To individualize (+)*
Standard risk NO?
To individualize (-)*
Standard risk YES NO
- Allo-RIC after auto: individualize
- Auto-HSCT: Standard of care
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