Role of consolidation therapy in Multiple Myeloma Pieter Sonneveld Erasmus MC Cancer Institute Rotterdam The Netherlands
Disclosures Research support : Amgen, Celgene, Janssen, Karyopharm Advisory Boards/Honoraria: BMS, Amgen, Celgene, Janssen, Karyopharm
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)
Consolidation + Maintenance vs Maintenance alone PFS OS Cons/Main Main Al Ani et al, Eur J Haemat 2017
2nd ASCT
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;349:2495 502
Bologna 96 trial: single vs double ASCT All pts < ncr RFS RFS EFS EFS OS OS M. Cavo et al. JCO2007
HOVON65/GMMG HD4 : PFS and OS by treatment arm HOVON (single) & GMMG (double) PFS @96m 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.
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
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)
PFS by randomization (ASCT-1 vs ASCT-2) 1.00 0.75 72.5% (66.2% ; 79.4%) ASCT-1 ASCT-2 PFS probability 0.50 64% (57.3% ; 71.5%) 0.25 0.00 HR: 0.71 (95% CI, 0.50-0.98), P=0.040 HR: 0.71 (95% CI, 0.50-0.98), P=0.040 ASCT-1 ASCT-2 0 12 24 36 48 Months Number at risk 208 173 135 84 25 207 185 151 97 45 0 12 24 36 48 Months
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) 1.00 1.00 PFS probability 0.75 0.50 0.25 0.00 Median PFS: ASCT-2: NR; ASCT-1: 26.7 mos HR: 0.42 (95% CI, 0.21-0.84), P=0.014 69.2% (54.7% ; 87.5%) 44.2% (31% ; 63.2%) PFS probability 0.75 0.50 0.25 0.00 HR: 0.79 (95% CI, 0.41-1.52), P=0.483 HR: 0.79 (95% CI, 0.41-1.52), P=0.483 69.2% (54.7% ; 87.5%) 76.4% (69.2% ; 84.5%) ASCT-1 ASCT-2 0 12 24 36 48 Months Number at risk 43 33 22 15 3 38 35 28 17 7 0 12 24 36 48 Months - 0 12 24 36 48 Months Number at risk 38 35 28 17 7 139 126 104 68 33 0 12 24 36 48 Months
Changes in response categories* after ASCT-2 SD PR VGPR CR scr 71% 24% 40 35 30 25 3 15 8% 38% 7 14 18% 36% 5% 20 15 10 5 16 5 41% 13% 14 4 36% 10% 0 ASCT-1 ASCT-2 *As reported by study investigators. Central reassessment of response categories is ongoing
Consolidation with chemotherapy
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% 0.012 CR/nCR post-consolidation 73% 61% 0.020 Upgrade to CR post-consolidation 30.4% 16.6% 0.030 Landmark analysis from start of consolidation (30 months median follow up) 3-yr probability of relapse or progression 38% 52% 0.039 3-yr PFS 62% 46% 0.025 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
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 (IFM2007 02) 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% 0.0001 Rate of relapse 21% 55% 32.5% 0.0001 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)
VRD for induction and consolidation Roussel M et al, JCO 2014
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
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
Response Wester et al. ASH 2017
Progression-free survival and overall survival Wester et al. ASH 2017
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)
IFM/DFCI 2009 Parallel Phase 3 Study Newly Diagnosed MM (SCT candidates; # 1360;
Lenalidomide, bortezomib and dexamethasone with transplantation : IFM2009 HR 0.65, 95% CI 0.53, 0.8; p<0.0001 Attal et al, NEJM, 2017, 376, 14
Lenalidomide, bortezomib and dexamethasone with transplantation : IFM2009 Attal et al, NEJM, 2017, 376, 14 Attal et al, NEJM, 2017, 376, 14
Attal et al, NEJM, 2017, 376, 14 Attal et al, NEJM, 2017, 376, 14
Attal et al, NEJM, 2017, 376, 14 (supplementary) Avet Loiseau et al, ASH 2017
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 100104.
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 57 23.1 65 25.6 59 23.0 Standard risk 190 76.9 189 74.4 198 77.0 Gender Male 147 59.5 146 57.5 161 62.6 Female 100 40.5 108 42.5 96 37.4 Karnofsky Performance Score 90% 182 73.7 169 66.5 172 66.9 Cytogenetic Abnormalities t(4;14) t(14;16) t(14;20) del(17p) del(13q) by CA 16 0 2 16 15 6.5 0.8 6.4 6.1 22 4 10 19 21 8.7 1.6 3.9 7.5 8.3 20 2 3 21 24 7.7.0 1.2 8.2 9.3
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 141 57.1 134 52.8 143 55.6 Cy/Bort/Dex 33 13.4 35 13.8 40 15.6 Len/Dex 24 9.7 28 11.0 22 8.6 Bort/Dex 28 11.3 32 12.6 32 12.5 Other 21 8.5 25 9.8 20 7.8 Bort, bortezomib; Cy, cyclophosphamide; Dex, dexamethasone; Len, lenalidomide Stadtmauer 30et al, ASH 2016
Probability, % 100 80 60 40 20 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) 0 12 24 38 Months from Randomization N at risk Auto/Auto 247 200 153 87 Auto/RVD 254 215 172 99 Auto/Maint 257 213 158 80 Slides courtesy of Prof Ed Stadtmauer Stadtmauer et al, ASH 2016
100 Overall Survival Probability, % 80 60 40 20 0 38 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) 0 12 24 38 Months from Randomization N at risk Auto/Auto 247 231 204 147 Auto/RVD 254 246 229 166 Auto/Maint 257 247 227 148 Slides courtesy of Prof Ed Stadtmauer Stadtmauer et al, ASH 2016
PFS & OS Standard Risk Multiple Myeloma PFS OS Slides courtesy of Prof Ed Stadtmauer Stadtmauer et al, ASH 2016
PFS & OS High Risk Multiple Myeloma PFS OS Slides courtesy of Prof Ed Stadtmauer Stadtmauer et al, ASH 2016
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
Response status at time of 2 nd randomization no consolidation VRD Patients, # 444 459 Last treatment, % HDM 1 HDM 2 VMP Best response before R2, % scr CR VGPR PR < PR / unknown 46 17 36 4 16 47 27 7 46 17 36 4 22 42 24 8 36
Upgrade of response with consolidation no consolidation VRD Patients, # 444 459 Best response before R2, % scr CR VGPR PR Best response after R2, % scr CR VGPR PR 4 16 47 34 19 22 43 16 4 22 42 32 28* 28 30 15 * Statistically significant 37
100 Progression-free free survival Cumulative percentage 75 50 25 VRD no consolidation 0 no consolidation VRD N 435 F 137 no consolidation VRD 450 115 Cox LR P=0.045 (adjusted for 1st random.) 0 12 24 months 36 At risk: 435 450 HR = 0.78 (0.61-1.00) 336 187 EMN02 371 / HO95 MM 196 38 49 52
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 / 191 50 / 187 2 52 / 172 53 / 178 3 30 / 95 36 / 76 Cytogenetic risk: high = del(17p) and/or standard 55 / 261 72 / 248 high 34 / 79 36 / 83 unknown 30 / 118 31 / 110 Intensification randomization VMP 43 / 159 52 / 155 HDM 72 / 291 85 / 280 not randomized 4 / 8 2 / 6 Total 119 / 458 139 / 441 (26%) (32%) 0 0.5 1.0 1.5 2 25%(16) increase 2P=0.07 no consol VRD better better EMN02 / HO95 MM 39
Outcome (PFS) in FISH and MRD risk groups FISH High vs Standard risk FISH + MRD Oliva et al, ASH 2017
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 (%) 17.5 24.4 24.6 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 0.65 38mns (M/Con/ASCT): 52 vs 56.7 vs 56.5 OS@ (%) (No ASCT/ASCT) 82 vs 81 (No ASCT/ASCT) NR vs 42.5 38mns (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 8.9 4 vs 6 vs 5.6 No difference
Daratumumab-VTd trial in transplant eligible NDMM IFM2015-01/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
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
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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