Role of consolidation therapy in Multiple Myeloma. Pieter Sonneveld. Erasmus MC Cancer Institute Rotterdam The Netherlands

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1 Role of consolidation therapy in Multiple Myeloma Pieter Sonneveld Erasmus MC Cancer Institute Rotterdam The Netherlands

2 Disclosures Research support : Amgen, Celgene, Janssen, Karyopharm Advisory Boards/Honoraria: BMS, Amgen, Celgene, Janssen, Karyopharm

3 What is consolidation therapy in TE NDMM? Additional therapy following 1 st ASCT with the goal of maintaining or even improving a stable response, before end of treatment or entering any maintenance therapy. 2 nd ASCT Additional cycles like in remission induction VTD, VRD, Bortezomib, TD Other chemotherapy (alternate, salvage)

4 Consolidation + Maintenance vs Maintenance alone PFS OS Cons/Main Main Al Ani et al, Eur J Haemat 2017

5 2nd ASCT

6 Single versus double ASCT in MM IFM94 trial VGPR after first ASCT Absence of VGPR after first ASCT P<0.001 P=0.7 Attal et al. N Engl J Med 2003;349:

7 Bologna 96 trial: single vs double ASCT All pts < ncr RFS RFS EFS EFS OS OS M. Cavo et al. JCO2007

8 HOVON65/GMMG HD4 : PFS and OS by treatment arm HOVON (single) & GMMG (double) OS@96m Treatment VAD single HDT 10% 44% PAD single HDT 18% 42% VAD double HDT 10% 47% PAD double HDT 16% 55% PAD + double ASCT the best option Sonneveld P, et alash 2015 Abstr 27.

9 Multivariate Cox analysis of HOVON65/GMMG HD4 on OS Bortezomib arm only Patients in HOVON centres received single ASCT Patients in GMMG centres received tandem transplant

10 EMN02/HO95 MM trial: study design VCD induction x 3-4 cycles + PBSC collection R1 VMP x 4 cycles Bortezomib 1.3 mg/m 2 d 1,4,8,11,22,25,29,32/42 Melphalan 9 mg/m 2 d 1-4/42 Prednisone 60 mg/m 2 d 1-4/42 (497 pts) Melphalan (HDM) 200 mg/m 2 x 1 or 2 courses* + single or double ASCT (695 pts) R2 VRD consolidat ion x 2 cycles No consolidat ion Maintenan ce lenalidomi de Stratification factor: ISS I vs. II vs. III Randomization to VMP or HDM was 1:1 in centres with a fixed single ASCT policy * Randomization to VMP or HDM-1 or HDM-2 was 1:1:1 in centers with a double ASCT policy Cavo M, et al. Presented at ASH 2017 (Abstract 397)

11 PFS by randomization (ASCT-1 vs ASCT-2) % (66.2% ; 79.4%) ASCT-1 ASCT-2 PFS probability % (57.3% ; 71.5%) HR: 0.71 (95% CI, ), P=0.040 HR: 0.71 (95% CI, ), P=0.040 ASCT-1 ASCT Months Number at risk Months

12 PFS by randomization and cytogenetic risk ASCT-1 vs ASCT-2 by High Risk ASCT-2 by Standard or High Risk ASCT-1 ASCT-2 High risk ( 1/3 CA) Standard risk (0/3 CA) PFS probability Median PFS: ASCT-2: NR; ASCT-1: 26.7 mos HR: 0.42 (95% CI, ), P= % (54.7% ; 87.5%) 44.2% (31% ; 63.2%) PFS probability HR: 0.79 (95% CI, ), P=0.483 HR: 0.79 (95% CI, ), P= % (54.7% ; 87.5%) 76.4% (69.2% ; 84.5%) ASCT-1 ASCT Months Number at risk Months Months Number at risk Months

13 Changes in response categories* after ASCT-2 SD PR VGPR CR scr 71% 24% % 38% % 36% 5% % 13% % 10% 0 ASCT-1 ASCT-2 *As reported by study investigators. Central reassessment of response categories is ongoing

14 Consolidation with chemotherapy

15 Phase 3: VTD vs TD (GIMEMA study) Impact of consolidation (triplet vs doublet) Per protocol analysis: n=321, received entire treatment program VTD TD p CR post-consolidation 61% 47% CR/nCR post-consolidation 73% 61% Upgrade to CR post-consolidation 30.4% 16.6% Landmark analysis from start of consolidation (30 months median follow up) 3-yr probability of relapse or progression 38% 52% yr PFS 62% 46% Superior PFS with VTD vs TD consolidation retained across poor prognosis subgroups: t(4;14) and/or del(17q), del(13q) β 2 M >3.5 mg/l, LDH >190 U/L, ISS stage 2 and 3 Cavo et al. Lancet 2012

16 VTD consolidation (IFM) Retrospective analysis of IFM: assessment of VTd consolidation after VTd induction and single ASCT (VTd-auto-VTd) Cohort 1 (n=121) VTd ASCT VTd consolidation Cohort 2 (n=76) VTd ASCT no consolidation (IFM ) Cohort 3 (n=40) VCd, VRd ASCT, no consolidation ORR at completion of therapy 86% 94% 80% CR at completion of therapy 53% 34% 32.5% Rate of relapse 21% 55% 32.5% Death 8% 8% 20% 0.07 Median PFS Not reached 32 mos 30 mos Free of relapse at 32 months 54.5% 32% 32% Median OS Not reached Not reached 38 mos ns 3 year OS 84% 91% 76% ns P Leleu et al. ASH 2012 (Abstract 3096)

17 VRD for induction and consolidation Roussel M et al, JCO 2014

18 Car/Len/Dex Consolidation after ASCT Phase 2 trial in NDMM, transplant eligible 42 evaluable patients 4cyclesof K36Rd induction, 2 cycles consolidation ORR 94%, CR 69%, VGPR 23% CR 25% (RI), 45% (ASCT), 69% (Cons) MRD NGS 59% Roussel M et al, ASH 2016

19 KTd: Treatment Schedule in NDMM Induction 4 cycles Carfilzomib 20/27mg/m 2 days 1,2,8,9,15,16 of a 28 day cycle. Thalidomide 200 mg daily Dexamethasone 40 mg once a week Intensification 1 cycle HDM 200 mg/m 2 ASCT Consolidation 4 cycles Carfilzomib 27mg/m 2 days 1,2,8,9,15,16 of a 28 day cycle. Thalidomide 50 mg daily Dexamethasone 40 mg once a week 4 dose levels: 20/27mg/m 2 20/36mg/m 2 20/45mg/m 2 20/56mg/m 2 Cohort 5: 8 induction cycles Sonneveld et al. Blood 2015

20 Response Wester et al. ASH 2017

21 Progression-free survival and overall survival Wester et al. ASH 2017

22 What is the role of Consolidation in Three trials: the current era? IFM2009 study (Attal et al, NEJM, 2017, 376, 14) CTN0702 (Stadtmauer et al, ASH 2016) EMN02/HO95 (Sonneveld et al, ASH 2016)

23 IFM/DFCI 2009 Parallel Phase 3 Study Newly Diagnosed MM (SCT candidates; # 1360;

24 Lenalidomide, bortezomib and dexamethasone with transplantation : IFM2009 HR 0.65, 95% CI 0.53, 0.8; p< Attal et al, NEJM, 2017, 376, 14

25 Lenalidomide, bortezomib and dexamethasone with transplantation : IFM2009 Attal et al, NEJM, 2017, 376, 14 Attal et al, NEJM, 2017, 376, 14

26 Attal et al, NEJM, 2017, 376, 14 Attal et al, NEJM, 2017, 376, 14

27 Attal et al, NEJM, 2017, 376, 14 (supplementary) Avet Loiseau et al, ASH 2017

28 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/m 2 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** 1 st presentation at ASH 2016 Slides courtesy of Prof Ed Stadtmauer **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

29 BMT CTN 0702: Demographics Treatment Arm ASCT/ASCT (N=247) ASCT/RVD (N=254) ASCT/Maint (N=257) Disease Risk N % N % N % High risk Standard risk Gender Male Female Karnofsky Performance Score 90% Cytogenetic Abnormalities t(4;14) t(14;16) t(14;20) del(17p) del(13q) by CA

30 BMT CTN 0702: Regimens prior to Transplant Auto/Auto (N=247) Auto/RVD (N=254) Auto/Maint (N=257) N % N % N % Initial Therapy Bort/Len/Dex Cy/Bort/Dex Len/Dex Bort/Dex Other Bort, bortezomib; Cy, cyclophosphamide; Dex, dexamethasone; Len, lenalidomide Stadtmauer 30et al, ASH 2016

31 Probability, % Primary Endpoint: Progression free Survival 0 38 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 Slides courtesy of Prof Ed Stadtmauer Stadtmauer et al, ASH 2016

32 100 Overall Survival Probability, % 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) Months from Randomization N at risk Auto/Auto Auto/RVD Auto/Maint Slides courtesy of Prof Ed Stadtmauer Stadtmauer et al, ASH 2016

33 PFS & OS Standard Risk Multiple Myeloma PFS OS Slides courtesy of Prof Ed Stadtmauer Stadtmauer et al, ASH 2016

34 PFS & OS High Risk Multiple Myeloma PFS OS Slides courtesy of Prof Ed Stadtmauer Stadtmauer et al, ASH 2016

35 EMN02/HO95 MM trial: study design VCD induction x 3-4 cycles + PBSC collection R1 VMP x 4 cycles Bortezomib 1.3 mg/m 2 d 1,4,8,11,22,25,29,32/42 Melphalan 9 mg/m 2 d 1-4/42 Prednisone 60 mg/m 2 d 1-4/42 (497 pts) Melphalan (HDM) 200 mg/m 2 x 1 or 2 courses* + single or double ASCT (695 pts) R2 VRD consolidat ion x 2 cycles No consolidat ion Maintenan ce lenalidomi de Stratification factor: ISS I vs. II vs. III Randomization to VMP or HDM was 1:1 in centers with a fixed single ASCT policy * Randomization to VMP or HDM-1 or HDM-2 was 1:1:1 in centers with a double ASCT policy

36 Response status at time of 2 nd randomization no consolidation VRD Patients, # Last treatment, % HDM 1 HDM 2 VMP Best response before R2, % scr CR VGPR PR < PR / unknown

37 Upgrade of response with consolidation no consolidation VRD Patients, # Best response before R2, % scr CR VGPR PR Best response after R2, % scr CR VGPR PR * * Statistically significant 37

38 100 Progression-free free survival Cumulative percentage VRD no consolidation 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 ( ) EMN / HO95 MM

39 Planned subgroup analysis for PFS PFS from consolidation randomization Characteristic Events/Patients VRD no consol HR & 95% CI (VRD : no consol) Reduction (SD) ISS stage 1 37 / / / / / / 76 Cytogenetic risk: high = del(17p) and/or standard 55 / / 248 high 34 / / 83 unknown 30 / / 110 Intensification randomization VMP 43 / / 155 HDM 72 / / 280 not randomized 4 / 8 2 / 6 Total 119 / / 441 (26%) (32%) %(16) increase 2P=0.07 no consol VRD better better EMN02 / HO95 MM 39

40 Outcome (PFS) in FISH and MRD risk groups FISH High vs Standard risk FISH + MRD Oliva et al, ASH 2017

41 IFM2009, CTN 702 & EMN02 compilation IFM2009 n=700 CTN702 n=702 EMN02 n=1192 Med. Age (range) 60 (29,66) 58 (52, 63) FISH HR Definition t(4;14), t(14;16), 17 del t(4;14), t(14;16), t(14;20), 17 del t(4;14), t(14;16), 17 del FISH HR (%) ISS III (%) 18 9 Induction VRD 81.5% Bort based VCD Consolidation VRD VRD/2 nd ASCT VRD Tandem ASCT No Yes, per protocol Yes, per clinician (received in 68% assigned) Maintenance Lena for 1 yr Lena for 3 yrs un l PD Lena until PD Med PFS (mns) (No ASCT/ASCT) 36 vs 50 PFS@ (%) HR mns (M/Con/ASCT): 52 vs 56.7 vs 56.5 OS@ (%) (No ASCT/ASCT) 82 vs 81 (No ASCT/ASCT) NR vs mns (M/RVD/ASCT2): 83 vs 85 vs 82 3yrs (No ASCT/ASCT) 57 vs 65 3yrs (No ASCT/ASCT) 84.6 vs 86.3 SPM (%) 7.4 vs vs 6 vs 5.6 No difference

42 Daratumumab-VTd trial in transplant eligible NDMM IFM /Hovon131/MMY3006 registration trial Cassiopeia n=1080 R Endpoints: scr PFS, OS Induction 4 cycles VTD + Dara VTD* q 4 w HDM ASCT Consolidation 2 cycles VTD + Dara VTD* q 4 w Ongoing, recruitment completed Stratify by: dara treatment, response, MRD status R Maintenance for 2 years Dara Observation

43 Conclusions Consolidation therapy improves response, quality and PFS, possibly OS In general 2 or 3 consolidation cycles are safe and effective Efficacy of 2 nd ASCT confirmed in EMN02

44 Controversies & Questions Impact on OS What is the optimal CONS regimen and # of cycles Should CONS use the same regimen as induction Which subgroups benefit from CONS Is CONS by chemo or by 2 nd ASCT equal What is efficacy of CONS if followed by maintenance Is CONS equally effective in treatments with novel agents Should we dose CONS based on MRD status Cost issues Lack of prospective data

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