Hematopoietic Stem Cell Transplant in Myeloma. Gary Simmons, DO

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1 Hematopoietic Stem Cell Transplant in Myeloma Gary Simmons, DO

2 Objectives What is the benefit of ASCT What is Upfront therapy and with novel agent era- does it include ASCT Is response before and after ASCT prognostic in myeloma Prep regimens for ASCT myeloma Role of Tandems ASCT

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4 Initial Therapy What is your goal with initial therapy? Are you thinking HCT? Why not? How many cycles before HCT? When should you refer? Does response before HCT matter? Doublet s Revlimid, Dex Velcade, Dex Triplet s Cytoxan, Velcade, Dex Velcade, Rev, Dex Carfilzomib, Rev, Dex

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6 All regimens no difference between : VGPR range 50-58% CR range 23-40% 1yr PFS 88%

7 Does depth of response VGPR or CR matter?

8 Depth of Response is Prognostic in Myeloma Martinez- Lopez et al. demonstrated outcomes were significantly better for patients achieving CR > VGPR Hoering et al. demonstrated that CR duration > 3yrs was associated with increased 10 yr survival (54% vs 17%)

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12 What is the benefit if any of HCT?

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16 N = 399 patients All received Induction Chemotherapy Rd Consolidation n= 251 Randomized between 2 arms Mel/Pred/Rev (MPR) High Dose Melphalan 200mg/m2 Maintenance Revlimid or not Palumbo et al. NEJM 2014.

17 Palumbo et al. NEJM 2014.

18 Palumbo et al. NEJM 2014.

19 Autologous Transplantation for Multiple Myeloma in the Era of New Drugs: A Phase III Study of the Intergroupe Francophone Du Myelome (IFM/DFCI 2009 Trial) Michel Attal, et al., Blood 2015, Abstract Form Only not published N = 700 patients between One Arm VRD x 8 cycles à Revlimid maintenance Second Arm VRD x 3 cycles à collect cells/ Melphalan 200/ASCT à 2 cycles consolidation followed by maintenance Revlimid 3 yr PFS was 48% VRD 3yr PFS was 61% ASCT arm No difference in Overall survival CR rates 48% in VRD CR rates 60% in ASCT arm

20 Upfront autologous stem cell transplantation (ASCT) versus novel agent- based therapy for multiple myeloma (MM): A randomized phase 3 study of the European Myeloma Network (EMN02/HO95 MM trial). Abstract Number: 8000, Michele Cavo, Antonio Palumbo et al. Methods: A phase 3 study was designed, CyBORDà 4 cycles of bortezomib- melphalan- prednisone (VMP) vs high- dose melphalan (HDM/ASCT) as intensification à maintenance Results: February 2011 through April 2014 & VMP (512 pts) or HD Melphalan/ASCT) (754 pt). PFS was significantly prolonged in pts randomized to HDM P=0.010, a benefit retained across predefined pt subgroups, including those with revised ISS stage III and high- risk cytogenetics [t(4;14) ± del(17p) ± del(1p) ± 1q gain] Superior rate of VGPR was observed with HDM (84%) vs VMP (74%) P<0.0001). In a Cox regression analysis, randomization to HDM (HR=0.61, CI= ; P=0.001) was confirmed to be an independent predictor of prolonged PFS. Overall survival was not yet mature and no difference between the treatment groups was evident. Conclusions: Upfront ASCT still remains the preferred treatment for younger NDMM pts. Further follow- up of the study is needed.

21 Conclusion High Dose Melphalan and autologous stem cell transplant remains standard of care and is ASBMT grade A recommendation Repeat Studies Confirm ASCT Increases depth of response which is prognostic Increases DFS Increases OS (older studies, novel agent trials not enough time to assess yet )

22 Retrospective data, no prospective data available Results Early < 12 months vs. Late > 12 months even in era of novel agents NO Difference in DFS or OS

23 Complete Remission Status before Autologous Stem Cell Transplantation Is an Important Prognostic Factor in Patients with Multiple Myeloma Undergoing Upfront Single Autologous Transplantation, Jin Seok Kim,Biology of Blood and Marrow Transplantation 2009

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26 ASBMT Guideline, 2015

27 Tandem HCT 54 yo with IgA myeloma R- ISS stage III did not respond to VRD. Second line KPD and he had a PR. He is here to discuss HCT. Should we discuss tandem?

28 RCT, N = 399 patients 3 cycles VAD and randomized to Single or Double ASCT 7 yr DFS and OS favored tandem when time stretched out past 5 years Benefit was those patients < VGPR at 3 months that received tandem ASCT and 7yr survival increased from 11 to 40%

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33 Optimizing Outcomes in Multiple Myeloma Using Risk Stratified Allocation to Single Versus Tandem Autologous SCT. by Matthew Risendal, Roy T Sabo, Allison F Hazlett, Priscilla Mpasi, Joan Bolling, William B Clark, John M McCarty, Harold M Chung, Catherine H Roberts, and Amir A Toor. Nov 2012 N = 146 patients retrospectively that had single vs. tandem Risk stratify by high risk (defined as Beta 2 > 5.5, adverse CA, > 1 primary tx for remission Results High risk myeloma had improved CR with tandem CR 41% vs. single 18% 2012 by American Society of Hematology

34 Relapse Incidence Curves. Matthew Risendal et al. Blood 2012;;120: by American Society of Hematology

35 Overall Survival Curves. Matthew Risendal et al. Blood 2012;;120: by American Society of Hematology

36 Limitations of Tandem Data Tandems have routinely increased CR rates to 30-40% (now achieved with novel therapies) Conflicting data some studies support, others refute benefit of tandem Older studies using wide range of conditioning, chemotherapy and compare to historical controls Currently, ASBMT does NOT recommend tandem to all patients with myeloma Except unable to achieve VGPR or better after ASCT BMT CTN 0702 investigating tandem as part of 4 arm trial with novel agent (IMIDs, PI)

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