Timing of Transplant for Multiple Myeloma

Timing of Transplant for Multiple Myeloma Wenming CHEN Beijing Chaoyang Hospital Capital Medical University Multiple myeloma resrarch center of Beijing

Initial Approach to Treatment of Myeloma Nontransplantation candidate (based on age, performance score, and comorbidities) Induction treatment Maintenance Transplantation candidate Induction treatment (nonalkylator-based induction x 4-6 cycles) Stem cell harvest Stem cell transplantation Consolidation therapy? Maintenance

VGPR/CR Postinduction and Post-ASCT in Phase III Trials of Novel Therapies vs VAD CR/VGPR 100% 50% 0% P =.002 34.7% CR/VGPR VGPR CR/nCR Doublet P =.87 44.4% P =.004 41.7% 37.7% P <.001 54.3% 19.3% P <.001 37.2% 37% P =.03 40% 22.9% 18.8% 21% 35.0% 18% 32% 31% 12.6% 15.1% 34% 30% 16% 15% 14.8% 8.7% 18.4% 15% 3% 14% 6.4% 2% 12% 11% 5% TD VAD TD VAD VD VAD VD VAD TAD VAD TAD VAD PAD VAD PAD VAD Pre-HDT Post-HDT Pre-HDT Post-HDT Pre-HDT Post-HDT Pre-HDT Post-HDT Macro IFM2005-01 HOVON 50 HOVON 65 54% 44% P <.001 42% 73.7% P <.001 P <.0001 18.6% 66% 61% 62.3% 31% 36% Triplet P <.0001 43.2% 55.1% 27.2% 27.5% 40.9% 17.1% 16% 10.4% P =.44 21.4% CTD CVAD CTD CVAD Pre-HDT Post-HDT MRC IX 35% 31% 28% 17% 11% P <.0001 87% 32% 55% 64% 23% TD 41% 60% 100% 67% CR/nCR 43% CR/nCR 33% VTD TD VTD TD CyBorD RVD Pre-HDT Post-HDT GIMEMA Macro M, et al. Blood. 2006;108:57-62. Harousseau JL, et al. J Clin Oncol. 2010;28:4621-4629. Lokhorst HM, et al. Blood. 2010;115:1113-1120. Sonneveld P, et al. IMW 2010. Abstract 40. Cavo M, et al. Lancet. 2010;376:2075-2085. Reeder CB, et al. Blood. 2009;114: abstract 616. Richardson PG, et al. Blood. 2009;114: abstract 1218. Kumar SK, et al. Leukemia. 2010;24:1352-1356.

Chemotherapy vs. Transplant Not all randomized studies, however, have shown a benefit San-Miguel, JF & Mateos, M-V. Hematology 2009, ASH Education Book.

Autologous SCT vs. CCT Progression-free survival is improved by autologous stem-cell transplantation vs. conventional chemotherapy Koreth, J et al. Biol Blood Marrow Transplant. 13: 183, 2007.

Overall Survival Impact Survival benefit is less impressive in this metaanalysis Koreth, J et al. Biol Blood Marrow Transplant. 13: 183, 2007.

Single or Double ASCT? Double autologous stem cell transplantation provides advantages over single transplantation Attal, M et al. N Engl J Med. 349: 2495, 2003.

Subgroup Benefits Benefits were especially notable in patients who did not achieve a CR or VGPR after their first autologous stem cell transplant Attal, M et al. N Engl J Med. 349: 2495, 2003.

Consolidation Therapy Post-transplant consolidation with 4 cycles of VTD CR 15% 49% Molecular CR 3% 18% Tumor burden reduced 4.14 logs Ladetto, M et al. J Clin Oncol. 28: 2077, 2010.

PFS (%) OS (%) PETHEMA: Long-term Follow-up 1. 0 1. 0 0.9 0.8 P =.00001 0.9 0.8 P =.00001 0.7 0.7 0.6 0.6 0.5 0.5 0.4 0.4 0.3 0.3 0.2 0.2 0.1 0.1 0 0 5 10 15 20 0 0 5 10 15 20 Yrs From Transplantation Yrs From Transplantation CR (n = 84) ncr (n = 66) + VGPR (n = 54) + PR (n = 114) SD (n = 12) + PD (n = 14) Functional cure? Martinez-Lopez J, et al. Blood. 2011;118:529-534.

MRD and outcomes DNA(VDJ: sequenta method) 2013ASH abstract # 1848 Martinez-Lopez et al

Lenalidomide Maintenance : CALGB 100104 TTP 46 mos. with len vs. 27 mos. for placebo 35 deaths on len arm vs. 53 on placebo arm McCarthy, P et al. N Engl J Med. 366:1770, 2012.

Phase 3 GIMEMA: VTD vs TD Bortezomib/Thalidomide/Dexamethasone vs Thalidomide/Dexamethasone Untreated multiple myeloma in pts 65 yrs of age (N = 474) Bort Thal Dex 1:1 Thal Dex CTX Melphalan + ASCT Bort Thal Dex 1:1 Thal Dex Dex Induction: Three 21-day cycles; bortezomib 1.3 mg/m 2 on Days 1, 4, 8, 11; thalidomide 100-200 mg/day on Days 1-63; dexamethasone 320 mg/cycle Consolidation: Two 35-day cycles; bortezomib 1.3 mg/m 2 on Days 1, 8, 15, 22; thalidomide 100 mg/day on Days 1-70; dexamethasone 320 mg/cycle Cavo M, et al. Lancet. 2010;376:2075. Cavo M, et al. Blood. 2012;120:9-19.

GIMEMA: VTD vs TD Results Response to Induction,* % Bort/Thal/Dex (n = 236) OS at 30 mos was not significantly different Thal/Dex (n = 238) P Value CR 19 5 <.0001 CR + ncr 31 11 <.0001 VGPR 62 28 <.0001 Response to Protocol,* % Bort/Thal/Dex Thal/Dex P Value CR 58 41.0001 CR + ncr 71 54 <.0001 VGPR 89 74 <.0001 PR 96 89.0031 3-yr PFS 68 56.0057 PFS remained superior with VTD when analyzed by age, ISS stage, LDH level, albumin level, del(13q), t(4;14), and del(17p) *Centrally assessed. Cavo M, et al. Lancet. 2010;376:2075-2085.

Probability of Survival Without Progression GIMEMA: VTD vs TD PFS 100 37% relative reduction of risk of progression or death in VTD arm 80 60 VTD 40 20 HR: 0.63 (CI: 0.45-0.88; P =.0061) Probability at 3 yrs, % P =.0057 VTD 68 TD 56 TD 0 Cavo M, et al. Lancet. 2010;376:2075-2085. 0 6 12 18 24 30 36 42 48 Mos

Early vs. Salvage Transplant Untreated, symptomatic patients < 56 (N = 202) Successf ul PBSC collection (N = 185) Early HDT 1 Induction VAMP x 3-4 cycles Preparatory lomustine, VP-16, cyclophosphamide, melphalan at 140 mg/m 2 + TBI Then auto-pbsct (n = 91) Late HDT 1 Monthly VMCP For patients PR continue to plateau Transplant as per above if progression, resistance after 6 cycles, or in relapse (n = 94) Fermand, JP et al. Blood 92: 3131, 1998.

Consort Chart Fermand, JP et al. Blood 92: 3131, 1998.

Overall Survival 80% 73% 78% 66% 71% 61% No difference in overall survival at median follow-up of 58 months Fermand, JP et al. Blood 92: 3131, 1998.

Quality of Life Longer time without symptoms, treatment, and treatment toxicity (TwiSTT) 27.8 months for early HDT, vs. 22.3 months for salvage HDT Fermand, JP et al. Blood 92: 3131, 1998.

Data After Longer Follow-up Comparable OS (A; 47.8 vs. 47.6 mos.) and EFS (B; 25.3 vs. 18.7 mos.) with median follow-up of 120 months Fermand, J-P et al. J Clin Oncol. 23: 9227, 2005.

Improved Quality of Life Maintained longer time without symptoms, treatment, and treatment toxicity (TwiSTT) Fermand, J-P et al. J Clin Oncol. 23: 9227, 2005.

Early Harvest and Late Transplant Stem cells collected within 6 mos. of diagnosis Received VAD Transplant at progression Median 38 mos. Gertz, MA et al. Bone Marrow Transplant. 23: 221, 1999.

Concluded Late Transplant Feasible Median survival 58.5 months Underlying biology of the disease has a greater impact on survival than the timing of transplant Gertz, MA et al. Bone Marrow Transplant. 23: 221, 1999.

E4A03 Study Design Lenalidomide R E G I S T R A T I O N 25 mg po days 1-21 + High dose Dex 40 mg days 1-4, 9-12, 17-20 x 4 cycles 445 patients Lenalidomide 25 mg po days 1-21 + Low dose Dex 40 mg days 1, 8, 15, 22 x 4 cycles CR/PR/ Stable Less than PR SCT possible as early as 4 months Thal/dex x 4 cycles Rajkumar, SV et al. Lancet Oncol. 11: 29, 2010.

RD vs. Rd 96% 87% Stopped early; recommendatio n of IDMC; median followup of 12.5 months 87% 75% More is not necessar ily better in the novel agent era Rajkumar, SV et al. Lancet Oncol. 11: 29, 2010.

With Longer Follow-up Rajkumar, SV et al. Lancet Oncol. 11: 29, 2010.

Off after 4 No SCT Off after 4 + SCT Continued past 4 cycles Landmark Analysis 90 patients went off LD or Ld after 4 cycles for SCT OS 92% at 3 years 248 patients continued on therapy past the initial 4 cycles 79% 3-year overall survival PFS at 3 years 46% for RD vs. 50% for Rd Rajkumar, SV et al. Lancet Oncol. 11: 29, 2010.

Landmark Analysis 431 patients alive at 4 cycles Off therapy at 4 cycles n=183 Primary therapy beyond 4 cycles n=248 no transplant N=93 (median age 68) Transplant n=90 (median age 57) Ld n=140 (median age 66) LD n=108 (median age 65)

Outcomes in Younger Patients (<65) Progression Free Survival Overall Survival

Outcomes in Older Patients ( 70) Progression Free Survival Overall Survival

Case Control Study 290 patients treated with an IMiD-based induction regimen prior to transplant 123 got TD, 167 got LD Late transplant: occurred after 12 months 42 had gotten SCT; median 44.5 mos. Early transplant: within 2 months of harvest, 12 months of diagnosis Median 5.3 mos. to SCT Kumar, SK et al. Cancer 118: 1585, 2012.

Outcomes Four year overall survival was identical in the two groups (73%) TD 68% vs. 64% LD 82% vs. 86% Time to progression after transplant similar 20 mos. (early) vs. 16 mos. (late) Kumar, SK et al. Cancer 118: 1585, 2012.

IFM/DFCI 2009 Study Randomize RVDx3 Induction RVDx3 CY (3 g/m 2 ) MOBILIZATION Goal: 5 x 10 6 cells/kg Collection CY (3 g/m 2 ) MOBILIZATION Goal: 5 x 10 6 cells/kg Melphalan 200mg/m 2 + ASCT Consolidation RVD x 5 RVD x 2 Maintenance Lenalidomide 18 mos Lenalidomide 18 mos SCT at relapse

Is Achieving CR the Key? GEM2000 trial 1,075 pts enrolled 632 responseassessable Uniform induction VBMCP followed by VBAD Lahuerta, JJ et al. J Clin Oncol. 26: 5775, 2008.

Value of CR Post-transplant After induction, patients went on to single or tandem high dose chemotherapy with autologous stem cell rescue Lahuerta, JJ et al. J Clin Oncol. 26: 5775, 2008.

Value of CR in IFM Studies IFM 99-02 and 99-04 trials VAD, then tandem ASCT Best post-asct data available for 802 pts Harousseau, J-L et al. J Clin Oncol. 27: 5720, 2009.

Value of CR in Asia Korean Multiple Myeloma Working Party study of 197 chemosensitive patients who received a single SCT CR prior to transplant (upper panel) and after transplant (lower panel) predicted a better outcome Kim, JS et al. Biol Blood Marrow Transplant. 15: 463, 2009.

Role of CR in Total Therapy 3 Barlogie, B et al. Br J Haematol. 138: 176, 2007.

Achieving and Maintaining CR Sustaining CR within a 3-year landmark from treatment initiation was associated with a highly superior survival (P <0.0001) Achieving and losing CR worse than no CR Barlogie, B et al. Cancer 113: 355, 2008.

Allogeneic Transplantation Only curative procedure in MM but recommended only in context of a clinical trial Associated with high TRM and morbidity Superior outcomes with use of novel agents in standard-risk patients Lack of allogeneic transplantation benefit in high-risk patients Several RIC regimens developed to avoid high TRM; offers short-term decrease in TRM, but higher rate of relapse Only 2 of 6 randomized trials of double ASCT vs ASCT with allogeneic RIC showed superior PFS and OS for allogeneic regimen Most recent data: tandem ASCT vs ASCT/allogeneic RIC from matched siblings; no benefit seen with early allogeneic RIC (relatively short follow-up) Lonial S, et al. J Natl Compr Canc Netw. 2013;11:19-28. Lokhorst H, et al. J Clin Oncol. 2010;28:4521-4530. Krishnan A, et al. Lancet Oncol. 2011;12:1195-1203. Stadtmauer EA, et al. Blood. 2010;116: Abstract 526. Lokhorst H, et al. Blood. 2012;119:6219-6225. Moreau P. Blood. 2012;119:6178-6179.

Long survival after AUTO/ALLO transplant Hospital Maisonneuve-Rosemont Montreal 93 pts: tandem Auto/mini-Allo PFS 44% at 10 years; OS 64% GVHD: grade 2-4 acute 9%; extensive chronic 85% ASH abstract #3353 Ahmad et al

M. D. Anderson Data Retrospective analysis of 758 patients with newly-diagnosed myeloma Received dex-based induction -/+ highdose therapy (+ in 395) within 1 year Groups were comparable in b 2 m, SCr, ISS stage Wang, M et al. Bone Marrow Transpl. 45: 498, 2010.

SCT in CR High dose therapy did not improve outcomes for patients already in CR Wang, M et al. Bone Marrow Transpl. 45: 498, 2010.

Other Considerations Access to novel agents SCT may best achieve cytoreduction/cr if novel agent access is limited Cost of chemotherapy vs. transplant SCT is a cost-effective way to achieve rapid cytoreduction vs. long-term novel drugs Allows novel agents to be reserved for the time of relapse, thereby saving healthcare resources

Conclusions Randomized trials are needed in the novel agent era comparing the effectiveness of early vs. delayed transplant Available (albeit limited) data do not suggest that patient outcomes are compromised by reserving transplant until first relapse Possibility remains that relapse after novel agent induction/consolidation/maintenance may be less sensitive to melphalan-based approaches