New standards of care for NDMM patients not eligible for transplant

Transcription

1 New standards of care for NDMM patients not eligible for transplant Thierry FACON, MD Professor of Hematology Service des Maladies du Sang University of Lille Lille, France

2 Epidemiology of Elderly Changing demographics Increase in life expectancy Aging of the population Increase in the number of elderly 30, World population: % of people , ,5 18,8 22,9 16,3 18,8 21,1 20,1 16,2 19, , 12,1 12, 13,3 11,1 7,5 3,4 4,4 6,7 7, 6,8 0, Africa Asia Europe Latin Am/ Caribbean Northen Am Oceania 65+ in the United States: Census.gov; U.S (June 2014). Census Bureau, 2012b; International Data Base

3 New cases (%) Multiple Myeloma affects primarily elderly patients SEER: New MM Cases by Age Group 40, 30, 23, 27,7 24,7 Myeloma is most frequently diagnosed among people aged , 10, 0, 11,4 9,5 3,1 0, 0,6 < > 84 Median age at diagnosis 69 Age Available from Accessed on 06/2014.

4 ESMO Guidelines 2017 Eligibility for ASCT Yes Induction: 3-drug regimens VTD VCD RVD PAD No First option: VMP, Rd, VRD Second option: VCD, MPT Other options: BP, CTD, MP 200 mg/m 2 Melphalan followed by ASCT Maintenance Lenalidomide FRONTLINE THERAPY. ESMO guidelines. Moreau, et al. Ann Oncol. 2017, in press. Courtesy of Dr. Moreau, April 2017.

5 MPT Becomes a Standard of Care Facon T, et al. Lancet. 2007;370: Fayers PM, et al. Blood. 2011;118:

6 VMP Becomes a Standard of Care San Miguel JF, et al. N Engl J Med. 2008;359:

7 Patients without event (%) Patients without event (%) VMP becomes a standard of care; VISTA Trial: Final analysis RR (CR) (%): 71(30) vs. 35(4) TTP VMP MP OS VMP: 24.0 months MP: 16.6 months, P < Time (months) 20 0 Median follow-up 60 months Median OS: VMP: 56m MP: 43m, P = Time (months) San Miguel et al. JCO 2013; 31(4):

8 RANDOMIZATION 1:1:1 (N = 1623) PD or Unacceptable Toxicity PD, OS, and Subsequent anti-mm Tx Rd becomes a standard of care IFM MM-020- FIRST: Study Design Screening Active Tx + PFS Follow-Up Phase LT Follow-Up Stratification: Age ( 75 vs > 75 yrs), country, and ISS stage (I/II vs III) Arm A Rd Continuous (n = 535) LEN + LoDEX: Continuously LENALIDOMIDE 25 mg days 1-21/28 LoDEX 40 mg days 1, 8, 15,22/28 Thromboprophylaxis was mandatory Arm B Rd18 (n = 541) LEN + LoDEX: 18 Cycles (72 weeks) LENALIDOMIDE 25 mg days 1-21/28 LoDEX 40 mg days 1, 8, 15, 22/28 Data cutoff: January 21, 2016 Arm C MPT (n = 547) MEL + PRED + THAL 12 Cycles (72 weeks) MELPHALAN 0.25 mg/kg days 1-4/42 PREDNISONE 2 mg/kg days 1-4/42 THALIDOMIDE 200 mg days 1-42/42 Pts aged > 75 yrs: LoDEX 20 mg days 1, 8, 15, 22/28; THAL 100 mg days 1-42/42; MEL 0.2 mg/kg days 1-4 FIRST, Frontline Investigation of Revlimid and Dexamethasone versus Standard Thalidomide; ISS, International Staging System; LoDex, low-dose dexamethasone; LT, long-term; MM, multiple myeloma; OS, overall survival; PD, progressive disease; PFS, progression-free survival; pts, patients; Tx, treatment. Benboubker L, et al. N Engl J Med. 2014;371:

9 Survival Probability Survival Probability Progression-Free Survival by Response Median PFS was prolonged in patients who responded to Rd continuous vs MPT and Rd18, particularly in those who achieved a deeper response (CR/VGPR) PFS (CR/VGPR) Median 4-year PFS, PFS, % mos Rd cont (n = 260) Rd18 (n = 255) MPT (n = 167) year PFS PFS ( PR) Median PFS, mos 4-year PFS, % Rd cont (n = 432) Rd18 (n = 425) MPT (n = 369) year PFS 53.8% % % HR (95% CI) Rd continuous vs MPT: 0.52 ( ), P < % Progression-Free Survival (Months) HR (95% CI) Rd continuous vs MPT: 0.65 ( ),P < % 16.0% Progression-Free Survival (Months) CR, complete response; HR, hazard ratio; MPT, melphalan, prednisone, thalidomide; PFS, progression-free survival; PR, partial response; Rd continuous, lenalidomide plus low-dose dexamethasone until disease progression; Rd18, lenalidomide plus low-dose dexamethasone for 18 cycles; VGPR, very good partial response.

10 Survival Probability Final Analysis of Overall Survival From the First Trial The pre-specified final OS analysis for the primary comparison showed that Rd continuous significantly extended OS vs MPT year OS 59.0% 58.0% Median OS, 4-yr OS, mos % Rd continuous Rd MPT % HR (95% CI) Rd continuous vs MPT: 0.78 ( ), P = Overall Survival (Months) HR, hazard ratio; MPT, melphalan, prednisone, thalidomide; OS, overall survival; Rd continuous, lenalidomide plus low-dose dexamethasone until disease progression; Rd18, lenalidomide plus low-dose dexamethasone for 18 cycles.

11 SWOG S0777: Study Design Eight 21-day Cycles of VRd Randomization N = 525 Stratification: ISS (I, II, III) Intent to progression (yes/no) Bortezomib 1.3/mg 2 IV Days 1, 4, 8, and 11 Lenalidomide 25 mg/day PO Days 1-14 Dexamethasone 20 mg/day PO Days 1, 2, 4, 5, 8, 9, 11, 12 Six 28-day Cycles of Rd After induction Rd Maintenance Until PD, Toxicity or Withdrawal Lenalidomide 25 mg PO days 1-21 Dexamethasone 40 mg PO days 1, 8,15, 22 Lenalidomide 25 mg/day PO Days 1-21 Dexamethasone 40 mg/day PO Days 1, 8, 15, 22 All patients received aspirin 325mg/day VRd patients received HSV prophylaxis HSV, herpes simplex virus; ISS, international staging system; PD, progressive disease; Rd, lenalidomide plus low dose dexamethasone; VRd, bortezomib, lenalidomide and dexamethasone. Durie et al. Lancet 2017;389:

12 Patients (%) Patients (%) SWOG S0777: PFS and OS by Assigned Treatment Arm PFS by assigned treatment arm OS by assigned treatment arm Events/N Median in months VRd 137/ (39, 52) Rd 166/ (25, 39) Events/N Median in months VRd 76/ (66, -) Rd 100/ (56, -) HR = (0.560, 0.906)* Log-rank P value = (one sided)* VRd Rd HR = (0.516, 0.973)* Log-rank P value = (two sided)* VRd Rd Months from registration Months from registration * Stratified HR, hazard ratio; OS, overall survival; PFS progression free survival; Rd, lenalidomide plus low dose dexamethasone; VRd, bortezomib, lenalidomide and dexamethasone. Durie et al. Lancet 2017;389:

13 Phase 3 Rd-based Continuous Studies for Elderly Patients NCT NCT NCT Elotuzumab Ixazomib Daratumumab Rd R: 25 mg PO ; D1 21 DEX: 40 mg PO ; D1, 8, 15 & d cycles until PD ELO-Rd ELO: 10 mg/kg; D1, 8, 15 & 22 (cycles 1 2); D1 & 15 (cycles 3 18); 20 mg/kg on D1 (cycles 19) R: 25 mg, D1 21 Rd R: 25 mg PO ; D1 21 DEX: 40 mg PO ; D1, 8, 15 & d cycles/18 mos Ixazomib-Rd Ixazomib: 4 mg R: 25 mg DEX: 40 mg; D1, 8, 15 & d cycles/18 mos Rd R: 25 mg PO ; D1 21 DEX: 40 mg PO ; D1, 8, 15 & d cycles until PD DARA-Rd DARA: 16 mg/kg q1wk for 8 wks; q2wk for 16 wks; q4wk thereafter R: 25 mg PO d; D1 21 DEX: 40 mg D1, 8, 15 & 22 (cycles 1 2); D1 & 15 (cycles 3 18); D1 (cycles 19) DEX Discontinued DEX Discontinued DEX: 40 mg PO d; D1, 8, 15 & d cycles, until PD Placebo + R Ixazomib+ R R 10 mg Until PD Ixazomib: 3 mg R: 10 mg Until PD Primary endpoint for all studies is PFS 1. NCT NCT NCT

14 But the upcoming (academic) studies will be Risk stratified and Response adapted A new generation of clinical trials. Courtesy Dr Faith Davies, modified

15 Asessment of fitness and frailty is relevant for optimal treatment selection

16 Stratification of Myeloma Patients; IMWG frailty score PATIENT STATUS ASSESSMENT Age (score 0 1 2) Charlson (score 0 1) ADL (score 0 1) IADL (score 0 1) FIT INTERMEDIATE FRAIL Additive total score = 0 Additive total score = 1 Additive total score 2 Full-dose Full-dose Reduced dose TRIPLET REGIMENS VMP MPT DOUBLET REGIMENS Rd Vd Doublet regimens rd vd Palumbo A et al, Blood 25(13): , 2015

17 MM Frailty Score: long-term outcome Overall Survival Progression-free Survival yrs P-value Fit 84% - Intermediate 76% Frail 57% < Months Cumulative Incidence Non-hematologic mo P-value yrs P-value Fit 48% - Intermediate 41% Frail 33% < Months Cumulative Incidence Drug mo P-value 0.50 Fit 22% - Intermediate 26% Frail 34% < Fit 16% - Intermediate 21% Frail 31% < Months Months Palumbo A et al, Blood 25(13): , 2015

18 IFM Revised Frailty Algorithm with ECOG Category 75 years years > 80 years Charlson 1 Charlson > 1 ECOG =0 ECOG=1 ECOG 2 Score Sum of Scores = 0 or 1 Sum of Scores >=2 NON-FRAIL FRAIL

19 Survival probability Survival probability PFS and OS by Frailty Level in the FIRST study N at risk Non-frail Frail Product-limit survival estimates with number of subjects at risk Subjects Events Censored Survival 95% CL Non-frail Frail censored Log rank P< PFS (months) Non-frail Frail N at risk Non-frail Frail Product-limit survival estimates with number of subjects at risk + censored Log rank P< Non-frail Frail Subjects Events Censored Survival 95% CL Non-frail Frail OS (months)

20 Conclusions VMP, Rd, and VRD are standards of care for newly diagnosed Transplant ineligible patients with MM Assessment of fitness and frailty is relevant for optimal treatment selection - the new generation of (academic) clinical studies in elderly patients will likely differentiate fit vs.frail elderly patients (risk stratification), and some will implement response adapted therapy 4 drug combination regimens (ImiD-PI-CD38Mab-Dex) will likely be suitable for fit elderly, and the need for ASCT in elderly may become uncertain. Frail elderly patients still have a poor clinical outcome and may benefit from an ImiD (or PI) + CD38Mab gentle regimen

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22 A spanish study for fit elderly NDMM patients; GEMFIT2016 NDMM patients NSCTC >65 y n= 462 elderly Fit Patients 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, day cycles (R1) Induction 18 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 Consolidation RdDara 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 phase MRD+ MRD- (R2) Maintenance No maintenance Dara 16 mg/kg IV Day 1 of cycles R 15 mg, d1 21 Until progresion No maintenance Dara 16 mg/kg IV Day 1 of cycles R 15 mg, d1 21 Until progresion * * MRD 9 cy MRD 18 cy MRD 22 cy Primary endpoint immonuphenotypic complete response Secondary exploratory outcome: PFS Courtesy of Dr MV Mateos

23 RANDOMIZATION 1:2 PD or Unacceptable Toxicity PD, OS and Subsequent anti-mm Tx A french study for frail elderly NDMM patients; IFM A dexamethasone sparing study Active Treatment + PFS Follow-up Phase LT Follow-Up 2 Arm A R-DaraSC LEN + Dara SC continuously: LENALIDOMIDE 25mg D1-21/28 DARATUMUMAB SC 1800 mgsc Q1Wk for 8 weeks 1800 mg SC Q2Wk for 16 weeks 1800 mg SC Q4Wk thereafter 1 Arm B Rd LEN + Lo-DEX continously: LENALIDOMIDE 25mg D1-21/28 Lo-DEXAMETHASONE 20mg D1,8,15 & 22/28 Randomization will be stratified by International Staging System (I vs II vs III) and age (<80 vs 80 In Arm A Low Dose Dex (20mg/week) during Cycle 1 and 2 then Methylprednisolone (with SC Dara)

24 What about ASCT in Elderly patients? Do we need a new Transplant Study in Elderly Fit MM patients? If yes, is it still possible? Yes - No clear answer on the benefit of ASCT in Elderly - No randomized study in the era new agents (also considering that anti CD38 will provide additional clinical benefit) No - IFM 2009 and EMN studies positive but not sure ALL young pts benefit from ASCT - The PFS benefit in young pts is 14mo. and will be likely less in elderly - Control Arm will be excellent with a Imid PI - CD38 Dex regimen (median PFS # 50 mo?) - Risk will overweight the benefit (esp for pts y)

25 Disclosures Member of the speaker s bureau of Celgene and Janssen Advisory boards for Celgene, Janssen, BMS, Takeda, Amgen, Novartis, Karyopharm This presentation will discuss off-label use of myeloma drugs

26 Proportion Event-Free CLARION study KMP vs VMP Progression-Free Survival and Response rates Disease progression or death n (%) Median PFS months HR for KMP vs VMP (95% CI) KMP (n=478) 207 (43.3) ( ) 1-sided P=0.16 VMP (n=477) 214 (44.9) ORR; 84.3% KMP vs. 78.8% VMP CR; 25.9% KMP vs. 23.1% VMP Number at risk: KMP VMP KMP VMP Months Median follow-up time: 22.2 months for KMP and 21.6 months for VMP The absence of PFS difference was consistent across subgroups Facon et al, IMW meeting 2017, oral presentation 0 0

27 Continuing evolution of multiple myeloma treatment: selected new classes and targets st Generation novel agents 2 nd Generation novel therapies/immunotherapy Bortezomib Lenalidomide Thalidomide Bortezomib + Doxil Carfilzomib Pomalidomide Panobinostat Ixazomib Daratumumab Elotuzumab Atezolizumab* Durvalumab* Nivolumab* Pembrolizumab* AC-241/1215* CAR-T* Isatuximab* Vaccines* Marizomib* Oprozomib* 3 rd Generation IMiDs* Melflufen* Selinexor* Venetoclax* Nelfinavir* Proteasome inhibitor IMiD HDAC inhibitor Monoclonal antibody Targeted Therapy Adoptive T cell therapy Checkpoint inhibitors Vaccines IMiD, immunomodulatory drug; HDAC, histone deacetylase *Not yet FDA-approved for MM; available in clinical trials Adapted from Richardson PG. et al ASH 2015, MMRF 2016

28 Upcoming studies in frail patients

29 MAINTENANCE INDUCTION Trial Design MRC Myeloma XIV Transplant ineligible NDMM 1:1 Frailty Indexing (FI) performed in all patients at baseline Non-adjusted Frailty Index-adjusted Therapy 1:2 FIT UNFIT FRAIL CRDa IRDa 1:2 1:2 1:2 C 500mg D1 & D8 R 25mg D1-21 D 20mg I 4mg weekly CRDa IRDa CRDa IRDa CRDa FIT: C 500mg D1 & D8, R 25mg D1-21, D 20mg/wk, I 4mg/wk UNFIT: C 350mg D1 & D8, R 15mg D1-21, D 10mg/wk, I 3mg/wk FRAIL: C 250mg D1 & D8, R 10mg D1-21, D 10mg/wk, I 3mg/wk TREAT TO MAXIMUM RESPONSE (6-8 cycles) IRDa Revlimid 1:1 Ixazomib/Revlimid

30 Final Analysis of Overall Survival From the First Trial Thierry Facon, 1 Meletios A Dimopoulos, 2 Angela Dispenzieri, 3 John V Catalano, 4 Andrew Belch, 5 Michele Cavo, 6 Antonello Pinto, 7 Katja Weisel, 8 Heinz Ludwig, 9 Nizar J Bahlis, 10 Anne Banos, 11 Mourad Tiab, 12 Michel Delforge, 13 Jamie D Cavenagh, 14 Catarina Geraldes, 15 Je-Jung Lee, 16 Christine Chen, 17 Albert Oriol, 18 Javier De La Rubia, 19 Darrell White, 20 Daniel Binder, 21 Jin Lu, 22 Kenneth C Anderson, 23 Philippe Moreau, 24 Michel Attal, 25 Jean-Paul Fermand, 26 Herve Avet-Loiseau, 27 Annette Ervin-Haynes, 28 Guang Chen, 28 Vanessa Houck, 28 Cyrille Hulin, 29 and Lofti Benboubker 30 1 Service des Maladies du Sang, Hopital Claude Huriez, Lille, France; 2 National and Kapodistrian University of Athens, School of Medicine, Athens, Greece; 3 Mayo Clinic, Rochester, MN; 4 Frankston Haematology and Oncology Center, Frankston, Australia; 5 Cross Cancer Institute, Edmonton, AB, Canada; 6 Seràgnoli Institute of Hematology, Bologna University School of Medicine, Bologna, Italy; 7 HematologyOncology and Stem Cell Transplantation Unit, National Cancer Institute, Fondazione Pascale, IRCCS, Napoli, Italy; 8 University of Tuebingen, Tuebingen, Germany; 9 Wilhelminen Cancer Research Institute, Department of Medicine, Center of Oncology, Hematology and Palliative Care, Wilhelminenspital, Vienna, Austria; 10 University of Calgary, Arnie Charbonneau Cancer Institute, Calgary, AB, Canada; 11 Centre Hospitalier de la Cote basque, Bayonne, France; 12 University Hospital, La Roche Sur Yon, France; 13 Department of Hematology, UZ Leuven, Leuven, Belgium; 14 Department of HaematoOncology, St Bartholomew's Hospital, Barts Health NHS Trust, London, United Kingdom; 15 Hospitals da Universadade de Combra, Combra, Portugal; 16 Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Jeollanamdo, Korea, The Republic of; 17 Princess Margaret Hospital, Toronto, ON, Canada; 18 Hospital Germans Trias i Pujol, Barcelona, Spain; 19 Hospital Universitari i Politècnic La Fe, Valencia, Spain; 20 QEII Health Sciences Center, Dalhousie University, Halifax, NS, Canada; 21 Kantonsspital Winterthur, Winterthur, CHE; 22 Peking University Institute of Hematology, Peking University People s Hospital, Beijing, China; 23 Harvard Medical School, DanaFarber Cancer Institute, Boston, MA; 24 University of Nantes, Nantes, France; 25 Institut Universitaire du Cancer de ToulouseOncopole, Toulouse, France; 26 Hopital SaintLouis, Paris, France; 27 Unite de Genomique du Myelome, CHU Rangueil, Toulouse, France; 28 Celgene Corporation, Summit, NJ; 29 Bordeaux Hospital University Center (CHU), Bordeaux, France; 30 CHU Tours Hopital Bretonneau, Tours, France

31 msmart Off-Study Transplant Ineligible Standard-Risk Intermediate-Risk High-Risk t(11;14), t(6;14), Trisomies t(4;14) Del 17p, t(14;16), t(14;20) VRd for ~12 months; If age 75 or frail: Rd a VRd for ~12 months VRd c for ~12 months Rd x 1 year a, b Bortezomib-based maintenance for minimum of 1 year Bortezomib-based maintenance for minimum of 1 year a In patients treated initially with Rd, continuing treatment until progression is an option for patients responding well with low toxicities; b Dex is usually discontinued after first year c Clinical trials strongly recommended as the first option Dispenzieri et al. Mayo Clin Proc 2007;82: ; Kumar et al. Mayo Clin Proc : ; Mikhael et al. Mayo Clin Proc 2013;88: v14 //last reviewed July 2016

32 Mayo Clinic recommendations Initial Treatment of Myeloma Newly Diagnosed MM Not Transplant Candidate Transplant Candidate VRd x 4 cycles VRd Rd (if frail, age 75)* Auto SCT +/- Maintenance (Len for std risk; bortez for high risk) VRd x4 cycles Len maintenance Delayed Transplant *Frailty Score; Palumbo A, Blood. 2015;125: ; VCD x 12 months is alternative Rajkumar SV. 2016

33 Conclusion Assessment of fitness and frailty is highly relevant for optimal treatment selection Fit elderly patients usually tolerate more aggressive treatments including triple combinations Carefully selected fit elderly patients may be candidates for high-dose melphalan followed by autologous transplantation

34 IMW MM Frailty Score Variable HR (CI 95%) P SCORE AGE Age <75 years 1-0 Age years 1.13 ( ) Age >80 years 2.40 ( ) < CHARLSON INDEX Charlson <1 1-0 Charlson > ( ) ADL SCORE ADL >4 1-0 ADL< ( ) IADL SCORE IADL >5 1-0 IADL< ( ) ADDITIVE TOTAL SCORE PATIENT STATUS % 0 FIT 39% 1 INTERMEDIATE 31% >2 FRAIL 30% Palumbo A et al, Blood 25(13): , 2015

35 Cumulative Incidence of Treatment Discontinuation by Frailty Level 1.0 Product-Limit Survival Estimates With Number of Subjects at Risk + Censored Logrank p= Survival Probability Fitness Status 12 Month 18 Month NON-FRAIL FRAIL NON-FRAIL FRAIL TTD (months) 2016 fitstat5 NON-FRAIL FRAIL Median Subjects Event Censored Survival 95% CL NON-FRAIL FRAIL Comparison HazardRatio pvalue CI_Lower CI_Upper non-frail vs Frail

36 Patients IFM MM-020- FIRST; Response ITT population (%) 81% 79% 67% 33% 31% 37% 27% 27% 21% 20% 18% 12% Hulin C, et al. J Clin Oncol 2016 Jun 20; DOI: /JCO [Epub ahead of print]

37 FIRST Trial: Impact of Response Cumulative Response Rate by Tx Month Of pts who achieved VGPR, 13.2% vs 2.7% achieved VGPR beyond 18 mos of Tx in the Rd continuous and Rd18 arms, respectively Rd Continuous Arm a Rd18 Arm a a Percentage shown is for pts achieving VGPR or better in the current month. pt, patient; Rd continuous, lenalidomide plus low-dose dexamethasone until disease progression; Rd18, lenalidomide and low-dose dexamethasone for 18 cycles; Tx, treatment; VGPR, very good partial response. Reprinted from Bahlis NJ, et al. Leukemia Apr 28. [Epub ahead of print]. Creative Commons Attribution 4.0 International License (

38 ESMO Guideline usual dosing schedule

39 Myeloma XI trial outline R 1:1 Induction 1 Induction 2 Maintenance CTD CRD Max. response PD SD MR PR VGPR CR R 1:1 CVD No CVD ASCT (if TE) R 1:1 Lenalidomide Observation

40 Myeloma XI - Lenalidomide Maintenance Induction Maintenance Induction 1; CTD vs.crd- Induction 2; CVD vs no CVD N=1551 TE=828; TNE=723 Median follow-up: 27 months (IQR 13 43) Exclusion criteria NDMM Treated on Myeloma XI induction protocols Failure to respond to lenalidomide as induction IMiD, or development of PD Previous or concurrent active malignancies R 1:1 Lenalidomide 10 mg/day, days 1 21/28 Observation IQR, interquartile range; NDMM, newly diagnosed multiple myeloma; PD, progressive disease

41 Patients alive and progression-free (%) Transplant non-eligible pathway Significant improvement in PFS from 11 to 24 months, HR= Median PFS, months [95% CI] Lenalidomide (n=406) 24 [21, 30] Observation (n=317) 11 [9, 13] Time since randomisation (months) No. of patients at risk: Lenalidomide Observation

42 FIRST (MM-020): Final Survival Analysis Time to Next Anti-Myeloma Treatment Rd continuous extended the median TTNT compared with MPT Median TTNT was also longer in patients who achieved CR/VGPR Subgroup Rd continuous vs MPT HR & 95% CI Median TTNT (mos) Rd continuous Rd18 MPT Rd continuous vs MPT HR (95% CI) IT T C R /V G P R P R ( ) ( ) ( ) Favors Rd Continuous Favors MPT CR, complete response; FIRST, Frontline Investigation of Revlimid and Dexamethasone versus Standard Thalidomide; HR, hazard ratio; ITT, intent to treat population; MPT, melphalan, prednisone, thalidomide; PR, partial response; Rd continuous, lenalidomide plus low-dose dexamethasone until disease progression; Rd18, lenalidomide plus low-dose dexamethasone for 18 cycles; TTNT, time to next anti-myeloma treatment; VGPR, very good partial response. Facon T, et al. Final Analysis of Overall Survival From the FIRST Trial. ASH 2016, abstract 241.