Consolidation and Maintenance therapy

University of Salamanca Consolidation and Maintenance therapy María-Victoria Mateos, MD, PhD University Hospital of Salamanca, Spain

Disclosure form MVM has served as member of advisory boards or received honoraria from lectures for Takeda, Celgene, Janssen, BMS, Amgen.

Definition and Aims of consolidation and maintenance therapy Consolidation Improve response/induce deeper response following therapy by administration of treatment for a limited period Maintenance Maintain response achieved following therapy by administration of treatment for a prolonged period Overall goal: Improve the quality of response Sustain MRD-/+ Extend progression free survival Prolong survival

The true value of CR relies on the MRD status, and CR w/o MRD is no better than PR 100 90 MRD-negative vs CR: p < 0.001 CR vs ncr: p = 0.127 100 90 MRD-negative vs CR: p < 0.001 CR vs ncr: p = 0.657 80 80 Progression-free survival (%) 70 60 50 40 30 Overall survival (%) 70 60 50 40 30 20 20 10 10 p < 0.001 p < 0.001 0 0 0 24 48 72 96 120 144 168 192 0 24 48 72 96 120 144 168 192 Time from response assessment (months) Time from response assessment (months) MRD-negative (n = 316) median PFS: 58 months CR (n = 128) median PFS: 24 months ncr (n = 96) median PFS: 21 months PR (n = 199) median PFS: 26 months MRD-positive < PR (n = 38) median PFS: 9 months MRD-negative (n = 316) median OS: 145 months CR (n = 128) median OS: 59 months ncr (n = 96) median OS: 63 months PR (n = 199) median OS: 59 months < PR (n = 38) median OS: 32 months GEM2000, GEM2005MENOS65, GEM2005MAS65, GEM2010MAS65 (n = 777) ncr, near complete response;; OS, overall survival;; PFS, progression-free survival;; PR, partial response. Lahuerta JJ, et al. manuscript under review.

All levels of MRD are usually associated with unsustained remissions Next-generation flow 1 Next-generation sequencing 2 Progression-free survival (%) 100 80 60 40 20 0 NGF-negative (n = 37), 75% PFS: NR* NGF-positive/2 nd gen-positive (n = 26), 75% PFS: 12 months NGF-positive/2 nd gen-negative (n = 16), 75% PFS: 10 months p = 0.04 Patients without progression (%) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 MRD at post-maintenance p value (trend) < 0.0001 <10-6 [10-6 ;; 10-5 ] [10-5 ;; 10-4 ] ³ 10-4 0 5 10 15 20 25 30 Time from MRD assessment (months) 0 6 12 18 24 30 36 42 48 Months since randomization Heterogeneous patient population (not enrolled in clinical trials) NGF, next-generation flow. IFM 2009 trial: patients who received either 8 cycles of VRD (arm A) or 3 VRD cycles, high-dose melphalan, followed by 2 consolidation VRD cycles (arm B). All patients received a lenalidomide maintenance dose for 12 months. 1. Flores-Montero J, et al. manuscript under review. 2. Avet-Loiseau H, et al. Blood. 2015;;126:abstract 191. As presented at ASH 2015.

Undetectable MRD can be associated with operational cure Total number of tumour cells 10 8-10 7-10 6-10 5-10 4-10 3-10 2-10 1-10 0 Presentation PR VGPR CR scr MRD Undetectable MRD - (Operational cure) - Diagnosis End of therapy Time to progression Rationale for maintenance would be based on the continuous control of MRD, negative or even positive CR, complete response;; MRD, minimal residual disease;; PR, partial response;; scr, stringent CR;; VGPR, very good PR. Mateos MV, et al. Blood Rev. 2015;;29:387-403.

Long-term survival is possible for a few MRD-positive patients with a unique immune profile Dcs, dendritic cells;; MO, monocyte;; NK, natural killer;; TAMs, tumour associated macrophages;; T-Reg, T-regulatory cell. Pessoa de Magalhães RJ, et al. Haematologica. 2013;;98:79-86. As presented at ASH 2011.

Prognostic value of immune reconstitution in patients with persistent MRD Single 8-colour combination (CD45, CD138, CD38, CD56, CD27, CD19, CD117, CD81): enumeration of 15 different BM cell populations MRD-positive MRD-positive high normal PC recovery and favourable immune profile MRD-negative 100 80 B-precursors Erythroblasts PCA3 Individual patients immune signatures Time to progression (%) 60 40 20 0 p = 0.001 Median TTP: NR Median TTP: NR Median TTP: 16 m PCA1 Clonal PCs Normal PCs 0 10 20 30 40 Time from MRD assessment (months) 50 Patients with favourable immune profile are characterized by an increased compartment of mature B cells BM, bone marrow;; PCA, principal component analysis;; PCs, plasma cells. Paiva B, et al. Blood. 2016;;127:3165-74. As presented at ASH 2015.

Transplant Candidate: Consolidation/Maintenance What are the options? Consolidation High-dose chemotherapy + transplant, single or tandem Regimens based on Bortezomib Thalidomide Lenalidomide Maintenance Interferon-alpha Steroids Thalidomide Bortezomib Lenalidomide

IFM 2009: PFS and OS RVD arm vs Transplant arm CR: 49% 59% VGPR: 78% 88% PFS OS 100 90 80 70 HDT no HDT 100 90 80 70 Patients (%) 60 50 40 P<0.001 Patients (%) 60 50 40 P NS 30 30 20 20 10 0 0 12 24 36 48 Months of follow-up N at risk HDT 350 309 261 153 27 no HDT 350 296 228 128 24 10 0 0 12 24 36 48 Months of follow-up N at risk HDT 350 328 309 226 55 no HDT 350 338 320 244 56 HDT no HDT Attal M. ASH 2015

EMN02/HO95 MM trial: study design (n = 1192) VMP arm vs Transplant arm after VCD x 3 cycles CR: 43% 42% VGPR: 73% 85% Progression-free survival (%) 1,00 0,50 0,00 Number at risk ASCT VMP PFS ASCT 0 12 24 36 48 60 Time (months) 695 570 349 108 5 0 497 383 230 74 10 0 ASCT VMP PFS median, mos NR 44 PFS at 3 yrs, % 66.1 57.5 HR (95% CI): 0.73 (0.59-0.90);; p = 0.003 Superior PFS with ASCT vs VMP was retained across prespecified subgroups of patients at low (NR vs 46m) and high risk (42 vs 32m) Cavo M. ASCO 2015 VMP

Double ASCT after bortezomib-based induction as consolidation therapy PFS and OS in patients with 2 adverse variables Double ASCT Single ASCT P PFS 41 months 20 months 0.003 OS 67 months 31.5 months <0.001 PFS and OS for pts with high-risk cytogenetics and who failed CR after bortezomib-based induction regimens PFS OS Cavo M et al. Blood 2013;;122:767.

Consolidation Therapy Induction Regimen Response Post- Induction Response Post- ASCT Response Post- Consolidation CR (%) CR (%) CR (%) VTD 1 22.5 48.7 61 RVD 2 23 42 48 KTD 3 33 38 67 KRd 4 10 25 70 Consolidation upgraded response in approximately 30%. 1. Cavo M et al. Blood. 2012;; 120:9. 2. Roussel M et al. Blood. 2011;;118: Abstract 1872. 3. Sonneveld P et al. Blood. 2015;;125:449. 4. Zimmerman TM et al. J Clin Oncol. 2015;;33. Abstract 8510.

Phase III BMT CTN 0702 Trial: SCHEMA - Lenalidomide maintenance* Register and randomize ASCT MEL 200 mg/m 2 RVD 4* Lenalidomide maintenance *Bortezomib 1.3 mg /m 2 days 1, 4, 8, 11 Lenalidomide 15 mg days 1 15 Dexamethasone 40 mg days 1, 8, 15 Lenalidomide 15 mg daily 3 years ASCT MEL 200 mg/m 2 Lenalidomide maintenance https://clinicaltrials.gov/ct2/show/nct01109004.

Transplant Candidate: Consolidation/Maintenance What are the options? Consolidation High-dose chemotherapy ± transplant, single or tandem Regimens based on Bortezomib Thalidomide Lenalidomide Maintenance Interferon-alpha Steroids Thalidomide Bortezomib Lenalidomide

Thalidomide maintenance studies Significant improvement in PFS with maintenance therapy Significant improvement in OS with maintenance therapy Survival after relapse Spencer 2009 Yes Yes (3-year follow-up) Similar in all groups Attal 2006 Yes Yes (at 39 months), but OS advantage disappeared with longer follow-up (5.7 years) Similar in all groups Barlogie 2006, 2008, 2010 Yes Yes (7.2-year follow-up) Reduced OS after thalidomide exposure Lokhorst 2010 Yes No Reduced OS after thalidomide exposure Morgan 2012 Yes No Reduced OS after thalidomide exposure Stewart 2013 Yes No Reduced OS after thalidomide exposure Toxicity, particularly neurological, leads to discontinuation rates up to 60%, and worse QoL Worse OS in patients with adverse FISH This table is provided for ease of viewing information from multiple trials. Direct comparisons across trials is not intended and should not be inferred. FISH, in situ fluorescence hybridization;; QoL, quality of life. Attal M, et al. Blood. 2006;;108:3289-94. Barlogie B, et al. N Engl J Med. 2006;;354:1021-30. Barlogie B, et al. Blood. 2008;;112:3115-21. Barlogie B, et al. J Clin Oncol. 2010;;28:1209-14. Lokhorst HM, et al. Blood. 2010;;115:1113-20. Morgan GJ, et al. Blood. 2012;;119:7-15. Spencer A, et al. J Clin Oncol. 2009;;27:1788-93. Stewart AK, et al. Blood. 2013;;121:1517-23.

Studies included in meta-analysis (N = 1,209) CALGB 100104 (accrual 8/2005 11/2009) IFM 2005-02 (accrual 6/2006 8/2008) GIMEMA (RV-MM-PI-209) (accrual 11/2007 7/2009) INDUCTION ASCT 1:1 RANDOMIZATION NO EVIDENCE OF PD INDUCTION ASCT 1:1 RANDOMIZATION NO EVIDENCE OF PD ASCT 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 TREATMENT (n = 68) LEN MNTC b (n = 67) NO TREATMENT LEN MNTC b INTERIM ANALYSIS INTERIM AND ANALYSIS AND UNBLINDING UNBLINDING Dec 2009 Dec 2009 Jan 2010 CROSSOVER BEFORE PD ALLOWED CONTINUED TREATMENT NO CROSSOVER BEFORE PD ALLOWED CONTINUED TREATMENT ALL TREATMENT DISCONTINUED Jan 2011 PRIMARY ANALYSIS CONTINUED TREATMENT CONTINUED TREATMENT Target population of patients with NDMM who received LEN maintenance or placebo/no maintenance after ASCT 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. The PFS in the LEN arm was doubled vs placebo arms (41-46 months vs 21-23 months) in all studies DEX, dexamethasone;; LEN, lenalidomide;; MNTC, maintenance;; NDMM, newly diagnosed multiple myeloma;; PD, progressive disease. Attal M, et al. J Clin Oncol. 2016;;34 Suppl:abstract 8001.

Lenalidomide maintenance: OS meta-analysis 26% reduction in risk of death, representing an estimated 2.5-year increase in median survival a 1.0 0.8 7-year OS Median follow-up: 80 months Survival probability 0.6 0.4 0.2 N = 1,209 N = 1209 LEN CONTROL Median OS (95% CI), months NE (NE NE) 86.0 (79.8 96.0) 50% 62% 0 Patients at risk HR (95% CI) p value 0.74 (0.62 0.89) 0.001 0 10 20 30 40 50 60 70 80 90 100 110 120 Overall survival (months) 605 578 555 509 474 431 385 282 200 95 20 1 0 604 569 542 505 458 425 350 271 174 71 10 0 The OS benefit was observed in all investigated subgroups of patients (except high-risk CA and ISS stage III) LEN maintenance after ASCT can be considered a standard of care a Median for LEN treatment arm was extrapolated to be 116 months based on median of the control arm and HR (median 86 months;; HR = 0.74). Attal M, et al. J Clin Oncol. 2016;;34 Suppl:abstract 8001. CA, cytogenetic abnormality;; ISS, International Staging System;; NE, not estimable.

Bortezomib maintenance therapy Study details n Treatment Outcome PFS OS HOVON 65 MM/ GMMG-HD4 1 413 PAD x 3 à HDM à bortezomib every 2 weeks for 2 years 34 months 90 Median follow-up: 91 months 414 VAD x 3 à HDM à thalidomide daily for 2 years 28 months p = 0.001 83 months RMS 8y (4.8 months) p = 0.04 PETHEMA/GEM 2 Median follow-up: 34.9 months 89 87 VT (1 cycle bortezomib every 3 months, thalidomide daily) for 3 years Thalidomide (daily for 3 years) Significant PFS benefit for VT p < 0.0009 OS not significantly different between arms 90 Interferon-a 2b (3 x per week for 3 years) HOVON 65 MM PAD x3 tandem HDM bortezomib maintenance: benefit for patients with del(17p) Bortezomib maintenance after double ASCT is effective in patients with del(17p) Bortezomib administered at 1.3 mg/m 2 i.v. in both studies HDM, high-dose melphalan;; i.v., intravenous;; PAD, bortezomib, doxorubicin, dexamethasone;; RMS 8y, restricted mean survival time at 8 years;; VAD, vincristine, doxorubicin, dexamethasone. 1. Sonneveld P, et al. Blood. 2015;;126:abstract 27. Presented at ASH 2015. 2. Rosinol L, et al. Blood. 2012;;120:334. Presented at ASH 2012.

Ixazomib: oral proteasome inhibitor Best response to treatment in phase 2 patients receiving maintenance with ixazomib after IRd as induction (N = 21) 100% 90% 80% 5 19 n = 2 n = 1 19 70% 60% 50% 40% 30% 48 n = 5 n = 2 33 10 10 scr CR ncr VGPR PR 20% 10% 29 29 0% Best response to induction Best response overall 10 (48%) patients improved their response during maintenance 2 VGPR to ncr, 5 VGPR to CR, 1 VGPR to scr, and 2 CR to scr Ixazomib maintenance promising but data from phase 3 trial are pending IRd, ixazomib, lenalidomide, dexamethasone;; ncr, near partial response. Kumar S, et al. Lancet Oncol. 2014 (13):1503-12.

Non-Transplant Candidate: Consolidation/Maintenance What are the options? Consolidation Maintenance Thalidomide No trials Bortezomib Lenalidomide

GEM2016FIT: Consolidation (R1) Induction 18 cycles Consolidation (R2) Maintenance NDMM patients NS CTC >65 y n= 462 elderly Fit Patients (GHA) ARM 1 VMP N=154 Mel: 9mg/m 2 D1-4 Pred: 60mg/m 2 D1-4 BTZ: 1.3mg/m 2 D1, 8,15,22 ª One 6 week cycle followed by eight 4-week cycle N=159 ARM 2a KRd.N=154 CFZ: 20/70 mg/m 2, d1, 8, 15 LEN: 25 mg, d1 21 DEX: 20/10 mg, d1, 2, 8, 9, 15, 16, 22, 23 18 28-day cycles N=159 ARM 2b KRD- DARA n=154 Rd LEN: 25 mg, d1 21 DEX: 20/10 mg, d1, 2, 8, 9, 15, 16, 22, 23 Nine 28-day cycles CFZ: 20/70 mg/m 2, d1, 8, 15 LEN: 25 mg, d1 21 DEX: 20/10 mg, d1, 2, 8, 9, 15, 16, 22, 23 Dara 16 mg/kg IV Days 1, 8, 15, 22 of cycles 1-2; Days 1 and 15 of cycles 3 and 4; Day 1 of cycles 5 to 18 Rd LEN: 25 mg, d1 21 DEX: 20/10 mg, d1, 2, 8, 9, 15, 16, 22, 23 Dara 16 mg/kg Days 1, 8, 15, 22 of cycles 1-2; Days 1 and 15 of cycles 3 and 4 Four 28-day cycles Directly to the R2 maintenance fase MRD+ MRD- No maintenance Dara 16 mg/kg IV Day 1 of cycles 1-24 + R 15 mg, d1 21 Until progresion No maintenance Dara 16 mg/kg IV Day 1 of cycles 1-24 + R 15 mg, d1 21 Until progresion * * MRD 9 cy MRD 18 cy MRD 22 cy Primary endpoint immonuphenotipic complete response Secondary exploratory outcome: PFS * Patientes in Biological relapse will be rechallenge by Dra + R a During the first cycle (6 weeks), bortezomib is given on D1, 4, 8, 11, 22, 25, 29, and 32.; GAH: J Geriatr Oncol. 2015 Sep;;6(5):353-61;; R1: first randomization;; R2: second randomization ;; IMF imnunofenotipicresponse NGF ( next generation flow) 2

FIRST trial: lenalidomide as continuous therapy Rd until DP vs Rd for 18 cycles vs MPT x 18 cycles, N = 1,623 patients 100 PFS Median PFS 100 OS 4-year OS Rd (n = 535) 59.4% 80 Rd (n = 535) Rd18 (n = 541) MPT (n = 547) 25.5 m 20.7 m 21.2 m 80 Rd18 (n = 541) 55.7% MPT (n = 547) 51.4% Patients (%) 60 Patients (%) 60 40 40 20 0 HR Rd vs MPT: 0.72;; p = 0.0006 Rd vs Rd18: 0.70;; p = 0.0001 Rd18 vs MPT: 1.03;; p = 0.70349 0 6 12 18 24 30 36 42 48 54 60 Months 20 0 HR Rd vs MPT: 0.78;; p = 0.017 (È 22% risk of death with Rd) Rd vs Rd18: 0.90;; p = 0.307 Rd18 vs MPT: 0.88;; p = 0.184 0 6 12 18 24 30 36 42 48 54 60 Months Continuous Rd reduced the risk of DP and death by 28% and 22% vs MPT, respectively. Rd as continuous therapy is a standard of care DP, disease progression;; m, months;; MPT, melphalan, prednisolone, thalidomide;; Rd18, lenalidomide and low-dose dexametasone for 18 cycles. Facon T, et al. N Engl J Med. 2014;;371:906-17.

Bortezomib as maintenance: VMPT VT x 2 y vs VMP with no maintenance (GIMEMA-MM-03-05;; N = 511) VMPT VMPT Progression-free survival Landmark analysis VT maintenance Maintenance Off therapy VMPT Overall Overall Survival survival (OS) 30% reduced risk of death 30% Reduced Risk of Death VT maintenance Maintenance Off therapy 1.00 4-years PFS Median PFS 1.00 5-years OS Median OS VMPT-VT 33% 31.5 months VMPT-VT 61% Not reached 0.75 VMP 16% 17.8 months 0.75 VMP 51% 60.6 months Patients (%) 0.50 Patients (%) 0.50 0.25 0.25 0.00 0 10 20 30 40 50 60 70 Time (months) 0.00 HR 0.70, HR 95% 0.70, CI 95% 0.52 0.92, CI, 0.52-0.92, p = 0.01 P = 0.01 0 10 20 30 40 50 60 70 80 90 Time (months) Time to next therapy: 46.6 vs 27.8 months and OS from relapse identical Bortezomib as maintenance is feasible during a fixed time y, years. Palumbo A, et al. J Clin Oncol. 2014;;32:634-40.

Summary (I) Maintenance therapy seems to benefit patients with MM after ASCT and as continuous therapy in non-asct candidates. However,... Some questions remain open: What is the optimal duration of maintenance? Can we personalize the maintenance?

Maintenance therapy after ASCT: future Sponsor/cooperative group IFM/DFCI 2009 Myeloma XI GEM14MAIN GMMHD6 GIMEMA SWOG US Cooperative group trials (pick the winner) ECOG-ACRIN study AFT-40 C16019 HOVON-IFM CCT-PNK-004-mmy001 Treatment Lenalidomide-based Lenalidomide x 1 year vs lenalidomide until DP Lenalidomide vs lenalidomide + vorinostat vs no maintenance Lenalidomide vs lenalidomide + ixazomib for up to 2 years Patients with MRD will continue 3 additional years Lenalidomide-dexamethasone vs lenalidomide-dexamethasone + elotuzumab Lenalidomide vs lenalidomide + carfilzomib Lenalidomide vs lenalidomide + ixazomib until DP Lenalidomide vs lenalidomide + vaccination/lenalidomide x 2 years vs lenalidomide until DP Lenalidomide vs lenalidomide + ixazomib Lenalidomide x 2 years vs lenalidomide until DP Lenalidomide vs lenalidomide + durvalumab vs lenalidomide + daratumumab vs lenalidomide + ACY-241 Other Ixazomib for up to 2 years vs placebo Daratumumab vs placebo Human cord blood derived, cultured and expanded NK cells NK, natural killer.

Maintenance therapy in transplant-ineligible patients Transplant-ineligible patients benefit from CT until DP Some studies are investigating maintenance therapy Sponsor/cooperative group Treatment C16019 Takeda Millennium Ixazomib for up to 2 years vs placebo Myeloma XI Future new standards of care LEN vs LEN + vorinostat vs no maintenance LEN-DEX + daratumumab until DP LEN-DEX + elotuzumab until DP LEN-DEX + ixazomib until DP LEN-DEX + carfilzomib LEN-DEX + bortezomib followed by LEN-DEX

Will it be possible to personalize maintenance? Personalization of maintenance type: standard risk versus high risk, based on cytogenetic abnormalities, ISS, LDH, etc. - Single agent for standard risk patients, len or ixa? - PI & IMiDs for high risk or just PI? toxicity during maintenance, QoL Personalization of maintenance duration response status at start of maintenance: MRD-negative versus MRD-positive MRD status during maintenance biomarkers: which maintenance drug or drug combination will my individual patient benefit most from? MRD only at the Bone Marrow level, or combine MRD by NGS/NGF with PET-CT?? ISS, International Staging System;; LDH, lactate dehydrogenase;; MRD, minimal residual disease;; QoL, quality of life.

PETHEMA GEM 2014 study European trial investigating different durations of maintenance MRD negative: 2 years MRD positive: up to 5 years GEM2012MENOS65 n = 316 R Len + dex Len + dex + Ixazomib MRD evaluation at 2 years MRD negative MRD positive End of treatment Len + dex up to 3 years PFS Annual MRD dex, dexamethasone;; Len, lenalidomide;; R, randomization. NCT02406144 at www.clinicaltrials.gov.

Summary Maintenance therapy seems to benefit patients with MM after ASCT and as continuous therapy in non- ASCT candidates. Understanding the role of MRD and immune reconstitution should allow us to further improve the optimal maintenance therapy, duration, to prolong OS Developing early endpoints as surrogate markers for long-term outcomes and OS is critically important;; otherwise, trials may continue for 10 years or longer