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

Chemotherapy in Multiple Myeloma

Clinical SettingsHDT 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, yr No. Pts Age (yrs.) B2M (mg/L) CR (%) EFS (yrs) OS (yrs) Alexanian et al, Blood, Vesole et al, Blood Singhal et al, BMT, Kumar et al, BMT, Alexanian et al, BMT * * In patients achiving CR after HDT/SCT

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

Clinical SettingsHDT 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 Author CR (%) PFS (meses) OS (meses) Attal et al (IFM), vs 528 vs 1857 vs 42 Morgan et al (MRC), vs 932 vs 2055 vs 42 Bladé et al, (PETHEMA), vs 1142 vs 3467 vs 65 Fermand et al (GMA), vs 625 vs 1948 vs 48 Barlogie et al, (US Intergroup), 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.

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

CR after HDT According to Tumor Burden Pretransplant M-protein sizeCR (%)P-value Serum* - < 10g/L  10 g/L 15 Serum and urine** - < 10 g/L and < 0.5 g/24h – 20 g/L and / or 0.5 to 1 g/24h > 20 g/L and / or > 1 g/24h 7 *Alexanian et al, BMT 2001; 27: ** 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* 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: ; 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

Clinical SettingsHDT 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 AuthorNo. PtsRR (%)EFS mos.OS mos. Attal et al, NEJM vs 50* (p=NS) 25 vs 30 (p=0.03) 48 vs 58 (p=0.01) Cavo et al, JCO vs 47** (p=0.008) 23 vs 35 (p=0.001) 65 vs 71 (p=NS) Sonneveld et al, Haematol vs 32*** (p<0.001) 24 vs 27 (p=0.006) 50 vs 55 (p=NS) Fermand et al, IMW vs 39*** (p=NS) 31 vs 34 (p=0.75) 57 vs 73 (p=0.09) Abdelkefi et al, Blood 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 1 st graft < 90% P < Tandem Single

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

Single versus Tandem Auto-SCT AuthorNo. PtsRR (%)EFS mos.OS mos. Attal et al, NEJM vs 50* (p=NS) 25 vs 30 (p=0.03) 48 vs 58 (p=0.01) Cavo et al, JCO vs 47** (p=0.008) 23 vs 35 (p=0.001) 65 vs 71 (p=NS) Sonneveld et al, Haematol vs 32*** (p<0.001) 24 vs 27 (p=0.006) 50 vs 55 (p=NS) Fermand et al, IMW vs 39*** (p=NS) 31 vs 34 (p=0.75) 57 vs 73 (p=0.09) Abdelkefi et al, Blood 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

Clinical SettingsHDT 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. of patients TRM CR rate 4-years survival %53%32% %54%50% %53%51% Gahrton G et al. Br J Haematol 2001; 113: Crawly et al, Blood 2007; 109: EBMT 1983  2002 Cy-TBI Mel-TBI Bu-Mel

Myeloablative versus Allo-RIC transplantation High TRM: 30-50% High relapse rate: 45% at 3 yrs Cure rate: 10-20% 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 Usually DLI Included in protocols

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

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

Clinical SettingsHDT 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 / % Bruno et al &, Blood /505337NR Tandem HSCT: ASCT followed by Allo-RIC *TBI 2 Gy +/- Fluda & TBI 2 Gy

Double ASCT versus tandem ASCT/Allo-RIC AuthorNo. Pts CR rate (%) EFS mos. OS mos. Garban et al, Blood vs vs 62 (p=NS) 35 vs 32 (p=NS) 47 vs 35 (p=0.07) Bruno et al, NEJM 2007& vs vs 55 (p=0.004) 29 vs 35 (p=0.02) 54 vs 80 (p=0.01) Rosiñol et al, Blood vs vs 40 (p=0.01) 26 vs 19.6 (p=NS) 58 vs NR (p=NS) Knop et al, Blood vs vs 59 (p=0.003) - 72% vs 60% (at 36 mos, p=NS) Bjorkstrand et al, JCO vs 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 vs 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

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

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

Progression-free Survival Overall Survival Progression-free Survival Overall Survival Probability, % Mp10_5.ppt Auto/Allo, 3yr Auto/Auto, 3yr p-value = 0.67p-value = 0.19 Auto/Allo, 3yr Auto/Auto, 3yr Survival Outcomes after the First Transplant: Auto- Auto vs. Auto-Allo: Intent-to-treat analysis Months # at risk: Auto/Auto Auto/Allo 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 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

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