1. AUTOLOGOUS AND ALLOGENEIC TRANSPLANTATION IN MULTIPLE MYELOMA
Vienna, May, 2014
Montserrat Rovira,
Laura Rosiñol, Enric Carreras
Hospital Clinic, Barcelona

2. Chemotherapy in Multiple Myeloma
Mirar si hi han “noves coses” en auto després de 2008

3. SCT in Multiple Myeloma
Clinical Settings
HDT Approaches
- Primary resistance
- Responders
Single
- Auto-SCT
- Allo-SCT
Tandem
- Double auto
- Auto plus allo-RIC

4. HDT/SCT in Primary Refractory Myeloma
Author, yr
No. Pts
Age
(yrs.)
B2M
(mg/L) CR
(%)
EFS
(yrs) OS
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 56
2.7 20
2.5 5
BMT 2004 89 52
3.7 16 7*
* In patients achiving CR after HDT/SCT

5. Overall Survival: Progressive vs Chemosensitive Disease vs No-change
Non-responsive, non-progressive
Chemosensitive
Progressive disease

6. SCT in Multiple Myeloma
Clinical Settings
HDT Approaches
- Primary resistance
- Responders
Single
- Auto-SCT
- Allo-SCT
Tandem
- Double auto
- Auto plus allo-RIC

7. Randomized trials: Single auto-SCT vs. conventional chemotherapy
Author CR
(%)
PFS
(meses) OS
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
Auto-SCT
“Gold-standard” for initial
treatment in patients
younger than 65 y.
Only chemosensitive patients
Higher intensity prior SCT

8. Probability of SRV according remission after HDTOS CR
Median not reached
Non-CR
Median: 60 months
Nadal et al. BMT 2004

9. 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:
** Nadal et al, BMT 2004; 33: 61-64

10. Which is the best treatment before HSCT?

11. Treatment options for patients eligible for transplantation
Induction
‘Traditional’
VAD
CyDex
Bortezomib-based:
VelDex
VTD
PAD
IMiD-based:
Thal/Dex
TAD
CTD Rd
VRD
Stem cell harvest
High-dose melphalan
Stem cell infusion

12. Pre and Post-ASCT CR Rate with “Novel” Induction Regimens*
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: ; Rosiñol et al, JCO 2007; 25: ; 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

13. SCT in Multiple Myeloma
Clinical Settings
HDT Approaches
- Primary resistance
- Responders
Single
- Auto-SCT
- Allo-SCT
Tandem
- Double auto
- Auto plus allo-RIC

14. 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
Fermand et al,
IMW 2005
227
37 vs 39***
31 vs 34
(p=0.75)
57 vs 73
(p=0.09)
Abdelkefi et al,
Blood 2007
202
67 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

15. IFM 94 : Overall survival
P < 0.01
Tandem
Single

16. IFM 94 : OS if response to 1stgraft < 90%
Tandem
Single

17. IFM 94 : OS if response to 1st graft > 90 %
Tandem
Single

18. Single versus Tandem Auto-SCT
Problem
Many of patient relapsing after single SCT recived a second 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
Fermand et al,
IMW 2005
227
37 vs 39***
31 vs 34
(p=0.75)
57 vs 73
(p=0.09)
Abdelkefi et al,
Blood 2007
202
67 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

19. SCT in Multiple Myeloma
Clinical Settings
HDT Approaches
- Primary resistance
- Responders
Single
- Auto-SCT
- Allo-SCT
Tandem
- Double auto
- Auto plus allo-RIC

20. MM. SYNGENEIC TRANSPLANT “Treatment of Choice”
Bensinger et al, BMT 1996
Gahrton et al, BMT 1999

21. Allogeneic Transplant in MM
Cy-TBI
Mel-TBI
Bu-Mel
Allogeneic Transplant in MM
EBMT 1983  2002
Period
Nº. of
patients
TRM CR
rate
4-years
survival
334
46%
53%
32%
356
30%
54%
50%
196
37%
51%
Gahrton G et al. Br J Haematol 2001; 113:
Crawly et al, Blood 2007; 109:

22. Myeloablative versus Allo-RIC transplantation
High TRM: 30-50%
High relapse rate: 45% at 3 yrs
Cure rate: 10-20%
Allo-RIC

23. 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%
Usually
DLI
Included in protocols

24. Myeloablative versus Allo-RIC transplantation
EBMT Experience ( )
Crawley et al, Blood 2007; 109:

25. Allogeneic Transplant with Dose-Reduced Intensity Conditioning (RIC)
Better results
Chemosensitive disease
Development of GVHD
No ATG or Campath-1H
Previous auto-transplantation

26. SCT in Multiple Myeloma
Clinical Settings
HDT Approaches
- Primary resistance
- Responders
Single
- Auto-SCT
- Allo-SCT
Tandem
- Double auto
- Auto plus allo-RIC

27. Median follow-up (yrs)
Tandem HSCT: ASCT followed by Allo-RIC
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&,
100 5
38/50 53 37 NR
Es veritat aixó, doble TASP seguit de alo-RIC?
*TBI 2 Gy +/- Fluda
&TBI 2 Gy

28. Double ASCT versus tandem ASCT/Allo-RIC
Author
No. Pts
CR rate
(%)
EFS
mos. OS
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 26
11 vs 40
26 vs 19.6
58 vs NR
Knop et al,
Blood 2009
73 vs 126
32 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 al
Lancet Onc 2011
185 vs 397
35 vs 48
(p=0.009)
46% vs 43%
( at 3 yrs p=NS)
80% vs 77%
(at 3 yrs, p=NS)
High Risk
Use ATG
Allo only
if no CR/nCR w auto
13q
ATG in UNR
Short
Follow-up

29. Auto-Allo Vs Auto-Auto
Patients who completed protocols (58 vs 46 pts) Median follow up: 6 years
Auto-Allo Vs Auto-Auto
37 mo.
64 mo.
33 mo.
Median Overall Survival
Median Event Free Survival
Bruno B et al.
EBMT Goteborg 2009

30. Auto/RIC-allo versus Auto in Myeloma Progression Free Survival since 1st transplant
Reduction of risk in time: p= (Cox)
Auto+Allo
At 60 mns: 35% (CI: 27% - 45%)
At 60 mns: 18% (CI: 13% - 24%)
Auto only
Auto (N=249)
Auto+allo (N=109)
Bjorkstrand et al, JCO 2011 30

31. Progression-free Survival Overall Survival
Survival Outcomes after the First Transplant: Auto-Auto vs. Auto-Allo:
Intent-to-treat analysis
Krishnan et al Lancet Onc 2011
Progression-free Survival Overall Survival
100 20 40 60 80 90 10 30 50 70
100 20 40 60 80 90 10 30 50 70
Auto/Allo, 3yr
Auto/Auto, 3yr
p-value = 0.67
p-value = 0.19
Auto/Allo, 3yr
Auto/Auto, 3yr
Probability, %
Auto auto 436 vs 189 auto allo
Months
# at risk: Auto/Auto Auto/Allo
Mp10_5.ppt

32. Allo-RIC limitation as first line approach: high TRM
Indications:
High risk patients (cytogenetics, < VGPR?)
First sensible relapse

33. HSCT in MM: Take-home messages
- Auto-HSCT: Standard of care
- Allo-RIC after auto: individualize
Cytogenetics CR
Post-ASCT
Allo-RIC
High risk NO
YES ?
To individualize (+)*
YES
High risk ?
To individualize (-)*
Standard risk NO
Standard risk
YES NO
*Age, ISS 3 stage, extramedular afectation, IgD, PCL, MRD (+)

34. Thanks for your attention