STEM CELL TRANSPLANTATION IN MULTIPLE MYELOMA

STEM CELL TRANSPLANTATION IN MULTIPLE MYELOMA Sundar Jagannath MD Professor of Medicine St. Vincent s Comprehensive Cancer Center New York, NY

Where is transplant today in the management of Myeloma?

Autologous Stem Cell Transplantation Mobilization and Leukapheresis of Patient Stem Cells Autologous Stem Cells High Dose Chemotherapy Autologous Stem Cells Cryopreservation of Patient Stem Cells Autologous Stem Cells -190 o C Freezer Thawing and infusion of patient stem cells

Stem Cell Mobilization From Bone Marrow to Blood Growth factor alone: G-CSF (Neupogen ) Recent experience indicates that prior Revlimid use decreases stem cell yield Cytoxan plus G-CSF Plerixafor + G CSF is superior to G CSF alone Plerixafor + G-CSF is superior to G-CSF alone for stem cell mobilization Patients receiving the combination were more likely to achieve target collection earlier and achieve a successful transplant

Redefining Role of Transplant in Novel Therapy Era What does autotransplant represent? Melphalan given at myeloablative high dose What does transplant offer? Higher CR and VGPR Durable remission What are the Challenges? Early vs. late transplant has equivalent survival Survival Improvement is 1 year For over 65 years MP + Novel agent is better What about second transplant in tandem?

5YR Relative Survival Ratio Population Based Study from Sweden High dose melphalan vs. Low dose 0.73 0.65 0.59 0.36 0.25 0.20 Variable 1973-79 1980-86 1987-93 1994-2003 Sweden HDT 0 0 77 1124 Kristinsson et al. J Clin Oncol. 25:1993, 2007

SEERS: 5 Yr Relative Survival 1990-1992 2002-2004 PE PE increase p 5-y relative survival All ages 28.8 34.7 5.9 <.001 < 50 y 44.8 56.7 11.9.001 50 to 59 y 38.8 48.2 9.4.001 60 to 69 30.6 36.3 5.7.09 70 to 79 27.1 28.7 16 1.6.21 80+ 13.8 15.2 1.4.96 Melphalan l given as single high h dose is superior to chronic low dose therapy Brenner et al. Blood. 111:2521, 2008 PE = Point Estimate

Conventional Chemo vs. AutoTX Attal et al NEJM 1996 Child et al NEJM 2003 IFM90 MRC7 Pat (n) CR (%) EFS (mo) OS (mo) Chemo 100 5% 18 44 Auto Tx 100 22% 27 57 Chemo 200 9% 20 42.3 Auto Tx 201 44% 32 54.1 Palumbo et al IMMSG Chemo 98 6% 16 43 Blood 2004 Auto Tx 97 25% 28 58+ p Value 0.03 003 0.03 <0.001 Barlogie et al JCO 2006 USIG Chemo Auto Tx 255 261 11% 11% 27 30 65 69

IFM 90 10 year update HDT CC High Dose Therapy for patients up to age 65 years!!!

ECOG E4A03: Lenalidomide + Dexamethasone 431 Patients Alive at 4 cycles Off therapy @ 4 cycles N=176 Primary therapy beyond 4 cycles N=255 No transplant N=91 (Median Age 68) Transplant N=85 (Median Age 57) Rd N=142 (Median Age 66) RD N=113 (Median Age 65) Rajkumar ASCO 2008, Abs#74

Overall Survival: No transplant following 4 cycles of RD vs. Rd 72% Rd 69% RD p=0.632 (Wilcoxon); p=0.790 (log-rank) Rajkumar ASCO 2008, Abs#74

Overall Survival: Transplant following 4 cycles of RD vs. Rd 94% RD 92% Rd p=0.801 (Wilcoxon); p=0.776 (log-rank) Rajkumar ASCO 2008, Abs#74

Upfront vs. Rescue Transplant 70 60 PSCT (early) 50 PSCT (late) 40 30 20 10 0 Median OS Median EFS TWiSTT* *Time without symptoms and treatment toxicity Fermand J et al. Blood. 1998; 92:3131

Tandem ASCT Two planned autologous SCTs within 6 months Stem cells collected before the initial transplant Half of the stem cells used for each procedure Second transplant may benefit: Patients who do not respond or have marginal response to 1st transplant

Single vs. Tandem AutoTX Attal et al NEJM 2003 Fermand et al Hematol J 2003 abs Cavo et al J Clin Oncol 2007 Goldschmidt et al Hematol J 2003 abs Sonneveld et al Haematologica 2007 IFM94 MAG95 Bologna 96 GMMG HOVON 24 Age (yr) Pat (n) CR (%) EFS (mo) OS (mo) Single 199 42 25 48 < 61 Tandem 200 50 30 58 Single Tandem Single Tandem Single Tandem Single Tandem <56 < 61 < 66 < 66 113 114 163 158 130 131 148 156 39 37 33 47 13 32 31 33 23 35 23 NR 21 22 49 73 65 71 55 50

Overall survival after double SCT A. Very Good Partial Response after First Transplantation 100 B. Absence of Very Good Partial Response after First Transplantation 100 Survival (% %) 75 50 Survival (% %) 75 50 Double- transplant (n=46) Double- transplant (n=128) Overall 25 0 0 22 44 66 88 Overall 25 0 0 22 44 66 88 Single- transplant (n=81) Single- transplant (n=84) Months after First Transplantation Months after First Transplantation Attal et al. NEJM; 349:2495, 2003

Brtz-Dex is Better Than VAD Brtz/Dex vs. VAD (Phase III) Response* to Induction Intention-to- Treat Analysis VAD n=219 Vel/Dex n=223 P value CR 3% 10% 0.004 CR+nCR 8% 19% 0.0004 > VGPR 19% 47% 0.0001 > PR 66% 83% <0.0001 Intention-to-Treat Analysis Post-ASCT Response VAD Vel-Dex A1 + A2 B1 + B2 n=219 n=223 P value CR+nCR 23% 35% 0.0063 > VGPR 44% 63% < 0.0001 > PR 79% 83% NS *modified EBMT criteria Harousseau JL, et al. ASCO 2008, abstract #8505

Pamidronate With or Without Thalidomide as Post-transplantation Maintenance Therapy Thalidomide is effective as maintenance therapy Longer progression-free survival (PFS) Significant benefits only in patients with < 90% response at randomization (P =.05) No deletion of chromosome 13 (P <.002) Overall survival similar in all 3 groups Attal M, et al. ASH 2004. Abstract 535. Response Pamidronate No Maintenance Pamidronate + Thalidomide P Value Median PFS, mos 27 28 > 38 0.002 3-year EFS, % 36 37 52 0.009 OS at 4-year, % 77 74 87 <0.04 Bone events, % 24 21 18 0.4 3-yr risk of bone 65 26 24 0.04 events, %

Auto-Tx Followed by Thal Maintenance Superior to Tandem Auto-Txs Abdelkefi Tunisian MM Study Group ASH 2006; abs#59 Auto-Tx + Thal maintenance Tandem Auto-Txs Parameter 2 Txs (n=97) Tx + Thal (n=98) P-value CR + VGPR after 1 st Tx 39% 41% NS CR + VGPR 6 mo. after Tx2 or Thal 51% 67%.024 PFS at 3 years 57% 85%.038 OS at 3 years 63% 88% 0.52

Improving Results with Auto-transplants Age (yr) Pat (n) CR (%) EFS (mo) OS (mo) Attal et al NEJM 2003 IFM90 Single < 61 100 22 27 57 Attal et al NEJM 2003 IFM94 Single Tandem < 61 199 200 42 50 25 30 48 58 Harousseau IFM 99 02-04 Tandem < 61 1064 36 NR at 66 mo Barlogie et al Blood 1999 BrJH 2006 TT 1 Tandem < 71 231 36 31 68 Barlogie et al Blood / NEJM 2006 TT2 - Thal + Thal < 75 345 43 44% 65% at 5 yr 323 62 56% 65% Reasons for Improvement: 1. Double Auto-transplantationtransplantation 2. Further Dose Intensification 3. Novel Agents

Newly Diagnosed Bortezomib in Total Therapy 3 Patients: 303 pts with newly diagnosed MM; 28% 65 yrs Dose: 2 cycles of VTD-PACE, tandem SCT with MEL200, consolidation with 2 cycles of VTD-PACE, followed by maintenance VRD for 3 yrs Efficacy: Median follow up 3 yrs; TT3 showed improved EFS (p=0.004) and CR duration (p=0.0008) compared to TT2 100% 80% 60% 40% 20% 0% EFS TT3 (56/303) P=0.004 TT1 (204/231) TT2+Thal P=0.0006 TT2-Thal (160/323) (218/345) P=0.0003 0 5 10 15 20 Years from start of treatment 100% 80% 60% 40% 20% 0% CR Duration TT3 (13/162) P=0.0008 TT2+Thal P=0.19 TT2-Thal (78/201) (67/148) P=0.0002 TT1 (78/94) 0 5 10 15 20 Years from complete response SLIDE 23 Barlogie et al. ASCO 2008, abs # 8516

The Indomitable Gauls Obelix Data supporting transplant t Rene Goscinny and Albert Uderzo 1959

EBMTR DATA ON MM 4-YEAR SURVIVAL (case-match thanalysis) i) Syngeneic 25 pts 77% Autologous 125 pts 46% Allogeneic 125 pts 31% ALLOGENEIC TRANSPLANT (BMT vs. PBSCT) Rapid engraftment with PBSCT No difference in CR rate, OS or PFS 1-year mortality for BMT 20% vs. PBSCT 34%

Double Auto vs. Auto-Allo Transplants Italian Study Bruno et al. NEJM 356:110, 2007

Double Auto vs. Auto-Allo Transplants Italian Study Bruno et al. NEJM 356:110, 2007

Two Autotransplants vs. Auto Miniallo Transplants Survival 1.0 0.9 0.8 0.7 0.6 52.1% 0.5 0.4 P =.60 45.9% 0.3 0.2 0.1 0 0 10 20 30 40 50

Non-Ablative Allografts for Multiple Myeloma: A Work in Progress Non-ablative transplants are feasible with early transplant-related related mortality as low as 10% Response rates low unless disease is minimal pretransplantation Best regimen has not been defined Tandem auto/allo transplants are feasible Low transplant related mortality (20%) High response rate CR 57%, PR 29% Non-ablative transplants should only be performed within clinical trials

Stem Cell Transplantation for Myeloma: Conclusions High dose therapy in combination with stem cell transplantation improves survival over standard dose therapy for myeloma High dose melphalan is standard Performed in first remission or early relapse Double transplant may be superior to single transplant in select patients Allogeneic transplant has more complications than autologous transplant But tandem autologous SCT followed by non-myeloablative allogeneic SCT is promising Post-transplant maintenance therapy promising

TT1: Impact of Novel Therapy on Survival Barlogie et al. Br J Haematol. 135:158

ASCT for Relapsed MM Useful rescue treatment: t t no difference in OS between upfront and rescue ASCT Fermand Blood 1998 In the US Intergroup study medain OS after rescue ASCT is only slightly better than salvage chemo (30 mo. vs. 23 mo. P=0.13) Barlogie J Clin Oncol 2006 Results are better for chemosensitive relapses and relapses off therapy Stem cell harvest is better done upfront than in relapse Stem cell harvest is better done upfront than in relapse Gertz BMT 2000