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

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

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

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

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

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

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

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

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 VTD PAD IMiD-based: Thal/Dex TAD CTD Rd VRD Stem cell harvest High-dose melphalan Stem cell infusion

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: 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

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

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

IFM 94 : Overall survival P < 0.01 Tandem Single

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

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

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

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

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

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 1983-93 334 46% 53% 32% 1994-98 356 30% 54% 50% 1998-02 196 37% 51% Gahrton G et al. Br J Haematol 2001; 113:209-216. Crawly et al, Blood 2007; 109: 3588-3594

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% Usually DLI Included in protocols

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

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

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

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

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

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

Auto/RIC-allo versus Auto in Myeloma Progression Free Survival since 1st transplant Reduction of risk in time: p=0.0012 (Cox) Auto+Allo At 60 mns: 35% (CI: 27% - 45%) At 60 mns: 18% (CI: 13% - 24%) Auto only Auto (N=249) 194 123 96 58 27 8 2 Auto+allo (N=109) 80 57 46 34 19 11 3 Bjorkstrand et al, JCO 2011 30

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, 43% @ 3yr Auto/Auto, 46% @ 3yr p-value = 0.67 p-value = 0.19 Auto/Allo, 77% @ 3yr Auto/Auto, 80% @ 3yr Probability, % Auto auto 436 vs 189 auto allo Months 0 6 12 18 24 30 36 42 48 # at risk: Auto/Auto 436 395 348 292 242 213 178 54 42 Auto/Allo 189 165 138 117 105 89 71 23 16 0 6 12 18 24 30 36 42 48 436 424 406 395 370 348 305 107 79 189 183 167 160 156 143 124 43 27 Mp10_5.ppt

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

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 (+)

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