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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