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

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

4. HDT/SCT in Primary Refractory Myeloma Author, yr No. Pts Age (yrs.) B2M (mg/L) CR (%) EFS (yrs) OS (yrs) Alexanian et al, Blood, 1994 27452.883.56 Vesole et al, Blood 1994 7250-151.74 Singhal et al, BMT, 2002 43543.3402- Kumar et al, BMT, 2004 50562.7202.55 Alexanian et al, BMT 2004 89523.7167* * 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. Clinical SettingsHDT Approaches - Primary resistance - Responders Single - Auto-SCT - Allo-SCT Tandem - Double auto - Auto plus allo-RIC SCT in Multiple Myeloma

7. Randomized trials: Single auto-SCT vs. conventional chemotherapy Author CR (%) PFS (meses) OS (meses) Attal et al (IFM), 199622 vs 528 vs 1857 vs 42 Morgan et al (MRC), 200344 vs 932 vs 2055 vs 42 Bladé et al, (PETHEMA), 200530 vs 1142 vs 3467 vs 65 Fermand et al (GMA), 20058 vs 625 vs 1948 vs 48 Barlogie et al, (US Intergroup), 200617 vs 1525 vs 2158 vs 53 Only chemosensitive patients Higher intensity prior SCT Auto-SCT “Gold-standard” for initial treatment in patients younger than 65 y.

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

9. CR after HDT According to Tumor Burden Pretransplant M-protein sizeCR (%)P-value Serum* - < 10g/L 520.01 -  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 210.03 - > 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

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* RegimenPre-ASCTPost-ASCT Thal/Dex6%23-34% Vel/Dex12%33% PAD-124%43% VRD23%42% VTD21-30%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

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

14. Single versus Tandem Auto-SCT AuthorNo. PtsRR (%)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 227 37 vs 39*** (p=NS) 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 1 st graft < 90% P < 0.001 Tandem Single

17. IFM 94 : OS if response to 1 st graft > 90 % P = 0.7 Tandem Single

18. Single versus Tandem Auto-SCT AuthorNo. PtsRR (%)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 227 37 vs 39*** (p=NS) 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 Problem Many of patient relapsing after single SCT recived a second auto-SCT

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

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

21. Allogeneic Transplant in MM Period Nº. of patients TRM CR rate 4-years survival 1983-9333446%53%32% 1994-9835630%54%50% 1998-0219637%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-TBI Mel-TBI Bu-Mel

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

23. 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 Usually DLI Included in protocols

24. Myeloablative versus Allo-RIC transplantation Crawley et al, Blood 2007; 109:3588-3594. EBMT Experience (1998-2002)

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

27. Nº pts Median follow- up (yrs) aGVHD (II-IV) /cGVHD (%) CR (%) EFS (mos) OS at 5 yrs Rotta et al*, Blood 2009 1026.642/74573664% Bruno et al &, Blood 2009 100538/505337NR Tandem HSCT: ASCT followed by Allo-RIC *TBI 2 Gy +/- Fluda & TBI 2 Gy

28. Double ASCT versus tandem ASCT/Allo-RIC AuthorNo. Pts CR 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 26 11 vs 40 (p=0.01) 26 vs 19.6 (p=NS) 58 vs NR (p=NS) 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. Patients who completed protocols (58 vs 46 pts) Median follow up: 6 years Auto-Allo Vs Auto-Auto 64 mo. 33 mo. 37 mo. Bruno B et al. EBMT Goteborg 2009 Median Overall SurvivalMedian Event Free Survival

30. Auto/RIC-allo versus Auto in Myeloma Progression Free Survival since 1 st 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

31. Progression-free Survival Overall Survival Progression-free Survival Overall Survival Probability, % 100 0 20 40 60 80 90 10 30 50 70 Mp10_5.ppt Auto/Allo, 43% @ 3yr Auto/Auto, 46% @ 3yr p-value = 0.67p-value = 0.19 Auto/Allo, 77% @ 3yr Auto/Auto, 80% @ 3yr 100 0 20 40 60 80 90 10 30 50 70 0612182430364248 43642440639537034830510779 1891831671601561431244327 Survival Outcomes after the First Transplant: Auto- Auto vs. Auto-Allo: Intent-to-treat analysis Months0612182430364248 # at risk: Auto/Auto4363953482922422131785442 Auto/Allo18916513811710589712316 Krishnan et al Lancet Onc 2011

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 Cytogenetics CR Post-ASCT Allo-RIC *Age, ISS 3 stage, extramedular afectation, IgD, PCL, MRD (+) High riskNO 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

34. Thanks for your attention