Meu paciente realizou um TACTH na 1a linha, e agora? Tandem, Manutenção, Consolidação? Marcelo C Pasquini, MD, MS Medical College of Wisconsin

Transcription

1 Meu paciente realizou um TACTH na 1a linha, e agora? Tandem, Manutenção, Consolidação? Marcelo C Pasquini, MD, MS Medical College of Wisconsin

2 Post Auto HCT Options for MM Maintenance Lenalidomide vs. no maintenance Bortezomib maintenance Consolidation (Second HCT or triple drug combination) Considerations: Patient-, response-, or risk adapted-therapy

3 Lenalidomide Maintenance

4 4 CALGB : A Phase III Randomized, Double- Blind Study of LEN vs PBO Maintenance Therapy Following ASCT for MM McCarthy PL, et al. N Engl J Med. 2012;366:

5 CALGB : Study Design and Endpoints 5 Primary endpoint: TTP (time from ASCT to PD/death) Secondary endpoints: OS, post-asct response, long-term LEN feasibility Restaging (Within 100 days) Maintenance a N = years of age 1 yr from start of Tx Stratified by β 2 -M and THAL and LEN use during induction MEL200 ASCT CR, PR, MR, SD R 1:1 LEN 10 mg/day b (n = 231) Placebo (n = 229) a All patients received thromboprophylaxis; b LEN dose adjustments between 5-15 mg permitted. ASCT, autologous stem cell transplant; β 2 -M, β 2 -microglobulin; CALGB, Cancer and Leukemia Group B; CR, complete response; LEN, lenalidomide; MEL200, melphalan 200 mg/m 2 ; MR, minimal response; OS, overall survival; PD, progressive disease; PR, partial response; R, randomization; SD, stable disease; THAL, thalidomide; TTP, time to progression; Tx, treatment. McCarthy PL. N Engl J Med. 2012;366:

6 Proportion of Patients CALGB: OS From Randomization 6 1 1: Lenalidomide 2: Placebo 0,8 0,6 0,4 0,2 0 Lenalidomide vs Placebo Log-rank p-value =<0.001 (2-sided) HR (95% CI) (0.419, 0.761) KM median Lenalidomide=NE [NE, NE] KM median Placebo=79.04 [70.17, 88.37] Events Lenalidomide =72/231 Placebo=109/ Number of Subjects at Risk: Overall Survival Time (months) Holstein S, et al. ASCO Abstr 8523.

7 7 CALGB /2016 Analysis Revlimid (lenalidomide) [package insert]. Summit, NJ: Celgene Corporation

8 Survival Probability CALGB : Progression-Free Survival 8 At the updated data cut-off (median follow-up 72.4 months), LEN maintenance prolonged median PFS vs placebo Cut-off: March 1, 2015 Median PFS Events, n (%) LEN 68.6 months 97 (42) PBO 22.5 months 116 (51) HR (95% CI): 0.38 (0.28, 0.50) Number of patients at risk: PFS, months LEN PBO CALGB, Cancer and Leukemia Group B; HR, hazard ratio; LEN, lenalidomide; PBO, placebo; PFS, progression-free survival. Revlimid (lenalidomide) [package insert]. Summit, NJ: Celgene Corporation

9 CALGB : Overall Survival 9 With a median follow-up of 81.6 months at a Feb 1, 2016, cut-off, LEN maintenance prolonged OS vs placebo OS at Updated Analysis (1 Feb 2016) LEN (n = 231) Placebo (n = 229) OS events, n (%) 82 (35) 114 (50) Median, months (95% CI) (101.8-NE) 84.2 ( ) HR (95% CI) 0.59 ( ) CALGB, Cancer and Leukemia Group B; HR, hazard ratio; LEN, lenalidomide; NE, not estimable; OS, overall survival. Revlimid (lenalidomide) [package insert]. Summit, NJ: Celgene Corporation

10 10 IFM : Maintenance Treatment With Lenalidomide After Transplantation for MM Attal M, et al. N Engl J Med. 2012;366: IFM, Intergroupe Francophone du Myélome; MM, multiple myeloma.

11 IFM : Study Design and Endpoints Primary endpoint: PFS 11 Secondary endpoints: response rate, EFS, OS Approximately 60% of pts came from study IFM Consolidation b 2 28-day cycles Maintenance until progression N = 614 NDMM; < 65 yrs of age SD within 6 months of ASCT Stratified according to β 2 -M ( 3 or > 3, del(13), a VGPR post- ASCT R 1:1 LEN 25 mg/day days 1-21 LEN mg daily (n = 307) Placebo (n = 307) a As measured by FISH; b Consolidation phase added at first protocol amendment (Sept 2006). ASCT, autologous stem cell transplant; β 2 -M, β 2 -microglobulin; del, deletion; EFS, event-free survival; FISH, fluorescence in situ hybridization; IFM, Intergroupe Francophone du Myélome; LEN, lenalidomide; NDMM, newly diagnosed multiple myeloma; OS, overall survival; PFS, progression-free survival; pts, patients; R, randomization; SD, stable disease; VGPR, very good partial response. Attal M. N Engl J Med. 2012;366:

12 12 IFM /2016 Analysis Revlimid (lenalidomide) [package insert]. Summit, NJ: Celgene Corporation

13 Lenalidomide improves TTP and OS Median: 57.3 vs 28.9 mos Median: vs 84.1 mos Intent-to-treat analysis, data cut-off Oct 2016 Median follow-up for OS of 91 mos Primary Objective: TTP (PFS); Secondary Objectives: OS, CR, Toxicity Lancet Haematology 4:e , 2017

14 IFM : Overall Survival 14 With a median follow-up of 96.7 months at a Feb 1, 2016, cut-off, median OS was vs 88.1 months for LEN vs placebo OS at Updated Analysis (1 Feb 2016) LEN (n = 307) Placebo (n = 307) OS events, n (%) 143 (47) 160 (52) Median, months (95% CI) (88.8-NE) 88.1 ( ) HR (95% CI) 0.90 ( ) HR, hazard ratio; IFM, Intergroupe Francophone du Myélome; LEN, lenalidomide; NE, not estimable; OS, overall survival. Revlimid (lenalidomide) [package insert]. Summit, NJ: Celgene Corporation

15 Abstract Lenalidomide Maintenance After High-Dose Melphalan and Autologous Stem Cell Transplant in Multiple Myeloma: A Meta-Analysis of Overall Survival Michel Attal, 1 Antonio Palumbo, 2 Sarah A. Holstein, 3 Valérie Lauwers-Cances, 1 Maria Teresa Petrucci, 4 Paul Richardson, 5 Cyrille Hulin, 6 Patrizia Tosi, 7 Kenneth C. Anderson, 5 Denis Caillot, 8 Valeria Magarotto, 9 Philippe Moreau, 10 Gerald Marit, 11 Zhinuan Yu, 12 Philip L. McCarthy 13 1 Institut Universitaire du Cancer, Toulouse-Oncopole, France; 2 The Myeloma Unit, Department of Hematology, University of Turin, Turin, Italy; 3 Roswell Park Cancer Institute, Buffalo, NY; 4 University La Sapienza, Rome, Italy; 5 Dana-Farber Cancer Institute, Boston, MA; 6 Bordeaux Hospital University Center (CHU), Bordeaux, France; 7 Seràgnoli Institute of Hematology and Medical Oncology, Bologna University, Bologna, Italy; 8 Dijon University Hospital Center, Dijon, France; 9 University of Torino, Torino, Italy; 10 University Hospital Hôtel-Dieu, Nantes, France; 11 Centre Hospitalier Universitaire, Bordeaux, France; 12 Celgene Corporation, Summit, NJ; 13 Blood and Marrow Transplant Program, Roswell Park Cancer Institute, Buffalo, NY

16 LEN Maintenance After ASCT in MM: OS Analysis Studies Included in the Meta-Analysis 16 CALGB (accrual 8/ /2009) INDUCTION ASCT 1:1 RANDOMIZATION NO EVIDENCE OF PD IFM (accrual 6/2006 8/2008) INDUCTION ASCT 1:1 RANDOMIZATION NO EVIDENCE OF PD ASCT GIMEMA (RV-MM-PI-209) (accrual 11/2007 7/2009) 2 2 DESIGN LEN + DEX 4 INDUCTION MPR: 6 COURSES LEN: 2 COURSES PLACEBO (n = 229) LEN MNTC a (n = 231) PLACEBO (n = 307) LEN MNTC a (n = 307) NO TX (n = 68) LEN MNTC b (n = 67) NO TX LEN MNTC b INTERIM ANALYSIS AND INTERIM ANALYSIS AND UNBLINDING UNBLINDING Dec 2009 Jan 2010 Dec 2009 PRIMARY ANALYSIS CROSSOVER BEFORE PD ALLOWED CONTINUED TX NO CROSSOVER BEFORE PD ALLOWED CONTINUED TX ALL TX DISCONTINUED Jan 2011 Target population of patients with NDMM who received LEN maintenance or placebo/no maintenance after ASCT CONTINUED TX CONTINUED TX a Starting dose of 10 mg/day on days 1-28/28 was increased to 15 mg/day if tolerated and continued until PD. b Patients received 10 mg/day on days 1-21/28 until PD. ASCT, autologous stem cell transplant; DEX, dexamethasone; LEN, lenalidomide; MM, multiple myeloma; MNTC, maintenance; MPR, melphalan, prednisone, and lenalidomide; NDMM, newly diagnosed multiple myeloma; OS, overall survival; PD, progressive disease; Tx, treatment. Attal M, et al. ASCO Abstr 8001.

17 Survival Probability LEN Maintenance After ASCT in MM: OS Analysis OS 26% reduction in risk of death, with an estimated 2.5-year increase in median survival a yr OS % Pts at risk N = 1209 LEN CTL Median OS, (95% CI), mos HR (95% CI) P value NE (NE-NE) 0.74 ( ) ( ) Overall Survival, months % a Median for LEN treatment arm was extrapolated to be 116 months based on median of the CTL arm and HR (median, 86 months; HR = 0.74). ASCT, autologous stem cell transplant; CTL, control; HR, hazard ratio; LEN, lenalidomide; MM, multiple myeloma; NE, not estimable; OS, overall survival; pts, patients. Attal M, et al. ASCO Abstr 8001.

18 LEN Maintenance After ASCT in MM: OS Analysis Subgroup Analysis 18 ISS stage Response after ASCT Prior induction therapy CrCl post ASCT c Sex Age Adverse-risk cytogenetics b < M a l e F e m a l e I o r I I I I I C R C R / V G P R P R / S D / P D L E N N o n - L E N Y e s N o < 5 0 m L / m i n 5 0 m L / m i n LEN a CTL a HR (95% CI) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) H R Favors LEN Favors CTL a Number of patients. b Cytogenetic data were only available for the IFM and GIMEMA studies. c CrCl post-asct data were only available for the CALGB and IFM studies. ASCT, autologous stem cell transplant; CR, complete response; CrCl, creatinine clearance; CTL, control; HR, hazard ratio; ISS, International Staging System; LEN, lenalidomide; MM, multiple myeloma; OS, overall survival; PD, progressive disease; PR, partial response; SD, stable disease; VGPR, very good partial response. Attal M, et al. ASCO Abstr 8001.

19 Cumulative Incidence Cumulative Incidence LEN Maintenance After ASCT in MM: OS Analysis Cumulative Incidence of SPMs 19 Hematologic Solid Tumor LEN LEN 0.80 CTL 0.80 CTL 0.60 HR (95% CI): 2.03 a ( ) P =.015 b 0.60 HR (95% CI): 1.71 a ( ) P =.032 b Time to Hematologic SPM Onset (mos) Time to Solid Tumor SPM Onset (mos) Pts at risk Pts at risk a HR based on Cox proportional hazards model. b P value is based on log-rank test. ASCT, autologous stem cell transplant; CTL, control; HR, hazard ratio; LEN, lenalidomide; MM, multiple myeloma; OS, overall survival; pts, patients; SPM, second primary malignancy. Attal M, et al. ASCO Abstr 8001.

20 20 Lenalidomide Is a Highly Effective Maintenance Therapy in Myeloma Patients of All Ages; Results of the Phase III Myeloma XI Study Jackson GH, et al. ASH Abstr 1143.

21 Myeloma XI: LEN Maintenance in NDMM Study Design 21 Induction Consolidation R 1:1 TE and TNE pts (N = 1551) R 1:1 CTD < VGPR CVD No Further Tx VGPR ASCT CRD (TE only) R 1:1 Primary endpoints: PFS and OS N = 1551 (TE = 828; TNE = 723) Median follow-up: 27 months *TE pts could also receive KRD induction and proceed directly to ASCT. LEN Maintenance LEN 10 mg d d cycles Maintenance No Maintenance LEN, lenalidomide; NDMM, newly diagnosed multiple myeloma; OS, overall survival; PD, progressive disease; PFS, progression-free survival; pts, patients; TE, transplanteligible; TNE, transplant non-eligible. Jackson GH, et al. ASH Abstr 1143.

22 Myeloma XI: LEN Maintenance in NDMM Baseline Characteristics 22 Characteristic Pathway, n (%) TE TNE LEN Maintenance (n = 857) 451 (53) 406 (47) No Maintenance (n = 694) 377 (54) 317 (46) Age, median (range), yrs 68 (29-89) 68 (30-90) Sex, n (%) Male 531 (62) 435 (63) ISS stage, n (%) I II III Unknown 224 (26) 342 (40) 231 (27) 60 (7) 196 (28) 291 (42) 163 (24) 44 (6) Cytogenetics, n (%) a Standard risk High risk/ultra-high risk b Ultra-high risk b 97 (49) 99 (51) 31 (16) 118 (56) 91 (44) 21 (10) a Available for 196/857 pts in the LEN arm and 209/694 pts in the no maintenance arm. b High risk includes presence of an adverse translocation [t(4;14), t(14;16)], gain(1q), or del(17p). Ultra-high risk includes > 1 adverse lesion. ISS, International Staging System; LEN, lenalidomide; NDMM, newly diagnosed multiple myeloma; TE, transplant-eligible; TNE, transplant non-eligible. Jackson GH, et al. ASH Abstr 1143.

23 Patients alive and progression-free (%) Myeloma XI: LEN Maintenance in NDMM PFS in TE Patients Among TE pts, median PFS was significantly prolonged by 22 months with LEN maintenance vs no maintenance Median PFS, months [95% CI] Lenalidomide (n=451) 50 [44, ] Observation (n=377) 28 [23, 32] HR=0.47; 95% CI 0.38, 0.60 Log-rank p< No. of patients at risk: Lenalidomide Observation Time since maintenance randomization (months) HR, hazard ratio; LEN, lenalidomide; NDMM, newly diagnosed multiple myeloma; PFS, progression-free survival; pts, patients; TE, transplant-eligible. Jackson GH, et al. ASH Abstr 1143.

24 Transplant eligible meta-analysis Demonstrates improved OS with maintenance lenalidomide Hazard % 24 Study Ratio (95% CI) Weight IFM (0.72, 1.15) CALGB (0.42, 0.76) GIMEMA-RVMM-PI (0.37, 1.38) Myeloma XI 0.69 (0.52, 0.93) Overall (I-squared = 54.6%, p = 0.085) 0.72 (0.56, 0.91) NOTE: Weights are from random effects analysis Jackson et al ASH 2017 OS: overall survival Attal M, et al. N Engl J Med. 2012;366: McCarthy PL, et al. N Engl J Med. 2012;366: Palumbo A, et al. N Engl J Med. 2014;371: McCarthy PL et al., J Clin Oncol Oct 10;35(29):

25 25 Bortezomib Induction and Maintenance in Patients with Newly Diagnosed Multiple Myeloma: Long-Term Follow-up of the HOVON- 65/GMMG-HD4 Trial Sonneveld P, et al. ASH Abstr 27.

26 HOVON-65/GMMG-HD4: Study Design 26 Randomized, open-label phase III trial Transplanteligible pts 18 yrs of age or older with stage II or III NDMM (N = 827) INDUCTION VAD: Vincristine 0.4 mg/day IV D1-4 + Doxorubicin 9 mg/m 2 IV D1-4 + Dexamethasone 40 mg D1-4,9-12,17-20 (n = 414) PAD: Bortezomib 1.3 mg/m 2 IV D1,4,8,11 + Doxorubicin 9 mg/m 2 IV D1-4 + Dexamethasone 40 mg D1-4,9-12,17-20 (n = 413) x 3 28-day cycles HDM 200 mg/m 2 : 1 cycle for HOVON-65, 2 cycles for GMMG-HD4 Primary endpoint: PFS adjusted for ISS stage HDM ASCT Secondary endpoints: Response after induction, HDM, and on protocol; OS from randomization; PFS from HDM; safety MAINTENANCE Thalidomide 50 mg/day Bortezomib 1.3 mg/m 2 q2wk 2 yrs HDM, high-dose melphalan; ISS, International Staging System; OS, overall survival; PFS, progression-free survival; pts, patients. Sonneveld P, et al. J Clin Oncol. 2012;30: Sonneveld P, et al. ASH Abstr 27.

27 Tandem Autologous HCT Not routinely performed in the US outside clinical trials. Phase III HOVON-65/GMMG-HD4 (Bortezomib) ncr/cr (PAD vs. VAD) Median PFS (PAD vs. VAD) OS at 5y (PAD vs. VAD) HOVON (Single) 47%vs. 29% 32 mon vs. 24 mon 55% both GMMG (Double) 51% vs. 39% 36 mon vs. 31 mon 70% vs. 54% GIMEMA Single vs. Tandem + Bort and high risk features (4 groups based on ISS 3, cyto, not in CR): Tandem superior in patients with at least two high risk features Sonneveld et al JCO 2012/ Cavo M et al ASH 2013

28 Cumulative percentage Cumulative percentage HOVON-65/GMMG-HD4: Survival From Randomization PFS 96-mo PFS, % PAD/Bort (n = 413) 17 VAD/Thal (n = 414) OS HR: 0.87 (95% CI: ) P = mo OS, % PAD/Bort (n = 413) 48 0 HR: 0.77 (95% CI: ) P = Mos 0 VAD/Thal (n = 414) Mos Subgroup analysis: bortezomib + double-cycle HDM before ASCT improved OS vs single cycle of HDM before ASCT 96-mo OS: 55% vs 42%; HR: (95% CI, ; P =.018) No significant difference in PFS between subgroups ASCT, autologous stem cell transplant; Bort, bortezomib; del, deletion; HDM, high-dose melphalan; HR, hazard ratio; ISS, International Staging System; OS, overall survival; PAD, bortezomib, doxorubicin, dexamethasone; PFS, progression-free survival; pts, patients; Thal, thalidomide; VAD, vincristine, doxorubicin, dexamethasone. Sonneveld P, et al. ASH Abstr 27.

29 HOVON-65/GMMG-HD4: Survival From Start of Maintenance Cumulative percentage PFS PAD (n = 283) 25 P <.01 VAD (n = 303) At risk: Mos VAD PAD PAD, bortezomib, doxorubicin, dexamethasone; PFS, progression-free survival; VAD, vincristine, doxorubicin, dexamethasone. Sonneveld P, et al. ASH Abstr 27.

30 Post-ASCT LEN Maintenance Trials 30 Daratumumab Durvalumab Elotuzumab MMY3004 Ph II DRVd vs RVd ind, consol, maint (dara+r vs R 26 months) MEDI4736-MM-002 Ph I Durva +R post-sct maint (R 21/ mg to progression) SWOG1211 Ph I/II RVd +/- E ind + RVd or RVdE maint (R 21/28 dose unknown) GMMG HD-6 Ph III RVdE ind + R or RE maint (R 28/ mg to prog) NCI Ph II Post- ASCT ER maint (R 28/ mg to prog) Ph II ERD induction, consolidation, maintenance (24 months) Carfilzomib U of Chicago Ph III Post-ASCT KRd vs R mono (dose/duration TBD) FORTE Ph II KCyD vs KRd ind/consol + KR or R maint to prog (R dose unknown) MMRC Ph I/II KRd ind/consol + maint 10 cycles followed by R maint to prog (R dose unknown) Ixazomib Lenalidomide EM2014MAIN Ph III Post-ASCT IRd vs Rd maint (R 21/28 15 mg if MRD+ at 2 yrs, R maint up to 5 yrs) BMT CTN0702 Ph III Post-ASCT R maint (R10-15 mg frequency unspecified up to 3 yrs) Wash U Ph II Post-ASCT alternating Ixa and Rev maint 24 cycles (R dose unknown) DFCI Ph III RVd + R Myeloma XI Ph III RCyD vs maint vs RVd+ASCT + R TCyD + R maint +/- vorinostat maint (R mg 28/28 for (R 10 mg 21/21) 12 mos) Ph I/Ib FRVd ind + Rd maint (R 21/28 25 mg to prog)

31 DRAMMATIC STUDY Phase III Study of Daratumumab + Lenalidomide (LD) or Lenalidomide (L) as Post-Autologous Stem Cell Transplant Maintenance Therapy in Patients with Multiple Myeloma (MM) Using Minimal SWOG1803/BMT CTN 1706 Amrita Krishnan/ Parameswaran Hari Click to edit Master Presentation Date

32 Treatment/Schema

33 CONSOLIDATION 33

34 BMT CTN 0702 Stem Cell Transplantation for Multiple Myeloma Incorporating Novel Agents: SCHEMA N=750 pts (250 in each arm) Lenalidomide Maintenance ** Register and Randomize N=257 MEL 200mg/m 2 VRD x 4* N=254 Lenalidomide Maintenance** *Bortezomib 1.3mg/m2 days 1, 4, 8,11 Lenalidomide 15mg days 1-15 Dexamethasone 40mg days 1, 8, 15 Every 21 days MEL 200mg/m 2 N=247 Lenalidomide Maintenance** **Lenalidomide x 3years : 10mg/d for 3 cycles, then 15 mg/d Amendment in 2014 changed Lenalidomide maintenance until disease progression after report of CALGB

35 Probability, % Primary Endpoint: Progression-free Survival Month Estimate and 95% CI Auto/Auto: 56.5 (49.4, 62.9) Auto/RVD: 56.7 (50.0, 62.8) Auto/Maint: 52.2 (45.4, 58.6) Months from Randomization N at risk Auto/Auto Auto/RVD Auto/Maint

36 Probability, % Overall Survival Month Estimate and 95% CI Auto/Auto: 82.0 (76.3, 86.5) Auto/RVD: 85.7 (80.5, 89.5) Auto/Maint: 83.4 (77.9, 87.7) N at risk Months from Randomization Auto/Auto Auto/RVD Auto/Maint

37 Compliance with each intervention Auto/Auto (N=247) Auto/RVD (N=254) Auto/Maint (N=257) N % N % N % Received 2nd Intervention No Yes Started maintenance No Yes

38 Probability, % Progression-Free Survival as treated/per protocol Analysis Month Estimate and 95% CI Auto/Auto: 61.3 (53.6, 68.9) Auto/RVD: 57.8 (50.7, 64.2) Auto/Maint: 52.2 (45.4, 58.6) N at risk Months from Randomization Auto/Auto Auto/RVD Auto/Maint

39 Design of EMN02 trial 4 VCD + Stem cell apheresis R1 4 VMP HDM 1/2 R2 2 VRD None Registration Induction Stem cell mobilization in all pts Early or late ASCT, once or twice Consolidation MRD Lenalidomide Lenalidomide Maintenance until relapse HDM/ASCT at 1 st relapse Slide courtesy Sonneveld P, ASH [Accessed March 2015]

40 100 Progression-free survival Progression free survival VRD no consolidation 25 0 no consolidation VRD N 435 F 137 no consolidation VRD Cox LR P=0.045 (adjusted for 1st random.) months 36 At risk: HR = 0.78 ( ) EMN02 / HO95 MM 40

41 BMT CTN 0702: Regimens prior to Transplant Initial Therapy Auto/Auto (N=247) Auto/RVD (N=254) Auto/Maint (N=257) N % N % N % Bort/Len/Dex Cy/Bort/Dex Len/Dex Bort/Dex Other Bort, bortezomib; Cy, cyclophosphamide; Dex, dexamethasone; Len, lenalidomide 41

42 Pre-transplant induction regimens in the US 60% VAD/Similar TD VTD RD VD VCD VRD 50% 40% 30% 20% 10% 0% 2004/ / / / /14 Year of transplant VAD- Vincristine/Adriamycin/Dexamethasone T- Thalidomide V- Bortezomib R- Lenalidomide C- Cyclophosphamide D- Dexamethasone 42

43 PRIMeR- Baseline MRD Status Auto/Auto N=91 (%) Auto/Maint N1=06 (%) Auto/RVD N=99 (%) High Risk Disease VGPR or better MRD Negative MRD- MRD+ scr/cr/ncr Other Kappa=0.43 [0.33, 0.53] 43

44 PRIMeR: OS by Disease Status and MRD at 1 year after enrollment scr/cr/ncr/vgpr vs. Other at one year MRD Status at one year Unpublished Data 44

45 Considerations on Selecting post Transplant Therapy All interventions appear to have a PFS benefit. Upfront treatment and disease status at time of transplant Accessibility to agents Response post transplant Disease risk 45

46 46

47 Considerations Consider disease risks: are poor risk markers present? Response adapted approach Maximize disease control prior to transplant Consider post transplant treatment in the setting of suboptimal response (caution). Does achieving the best response (CR /MRD-) be the main goal of therapy?