Relapsed Myeloma Sequencing Treatments

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1 Relapsed Myeloma Sequencing Treatments Noopur Raje, MD Director, Center for Multiple Myeloma MGH Cancer Center Professor of Medicine Harvard Medical School

2 Disclosures Consultant /Advisory Board: Celgene, Millenium Takeda, Amgen-Onyx, Novartis, Janssen, BMS Research Funding: Acetylon, Eli-Lilly, Astra Zeneca Steering Committee: Amgen, Eli-Lilly, Roche

3 Learning Objectives: Summarize recent clinical advances in treatment of multiple myeloma Discuss novel treatment options Discuss factors which influence sequencing

4 Multiple Myeloma Second most common hematologic malignancy Estimated new diagnoses 30,330; 5 yr survival of 47% All Ca = 15,533,220 Diagnosis: Blood Lymphoid Ca = 136,960 Monoclonal immunoglobulin Bone marrow plasmacytosis Skeletal lesions CA: A Cancer Journal for Clinicians Volume 66, Issue 6, pages , 12 SEP 2016 Bone Marrow CD 138+ Kappa + t(11:14) GEP Mutational Profile

5 FDA Approved Drugs Bortezomib Thalidomide 2006 Lenalidomide 2006 Pomalidomide 2013 Carfilzomib Improved Diagnosis and monitoring Doxorubicin With Bortezomib 2007 Panobinostat 2015 Ixazomib 2015 Elotuzumab 2015 Daratumumab 2015 Melphalan 2016

6 Treatment Paradigm for Newly Diagnosed MM First Line Therapy Transplant Eligible Patients Transplant Ineligible patients Induction Therapy Transplant Consolidation Initial Therapy/ Maintenance Maintenance Treatment of Relapsed disease Supportive Care

7 Continuous Improvement in Response Seen With Combinations of Newer Agents ORR VGPR CR/nCR Response (%) VAD TD Induction Regimen RD PAD VTD CVD RVD CVRD CRD Stewart AK et al. Blood. 2009;114: Jakubowiak A et al. Blood. 2012;120:

8 IFM 2009 : Study Design. Registration RVD 1 Lenalidomide + Bortezomib + Dexamethasone 25mg/d (d1 to 14) 1.3mg/m 2 (d 1, 4, 8, 11) 20mg/d (d1,2,4,5,8,9,11,12) Randomization (stratified oniss and FISH) ) Arm A RVD 2 and 3 Arm B RVD 2 and 3 PBSC Collection (cyclophosphamide 3g/m 2 and G-CSF) 10mcg/kg/d) RVD 4 to 8 Lenalidomide Maintenance 12 months (10-15 mg/d) PBSC Collection (cyclophosphamide 3g/m 2 and G-CSF) ASCT HDM 200mg/m2 RVD 4 and 5 Lenalidomide Maintenance 12 months (10-15 mg/d) Attal et al. ASH 2015

9 IFM 2009: Response and PFS RVD arm N=350 Transplant arm N=350 p-value CR 49% 59% VGPR 29% 29% 0.02 PR 20% 11% <PR 2% 1% At least VGPR 78% 88% Neg MRD by FCM n (%) 228 (65%) 280 (80%) Attal et al Abstract 391 ASH 2015

10 Avet-Loiseau et al. ASH CR/sCR, only 131 MRD MRD at post-maintenance in CR patients Negative (<10-6) Positive 83% N at risk (events) MRD neg (<10-6 ) MRD positive P-value : p< (0) 80 (0) 80 (0) 80 (0) 80 (3) 73 (3) 57 (5) 33 (0) 9 51 (0) 51 (0) 51 (0) 51 (3) 47 (9) 36 (5) 26 (9) 6 (0) 3 30 Months since randomization %

11 Meta-Analysis of Lenalidomide Maintenance after ASCT CALGB (accrual 8/ /2009) INDUCTION ASCT 1:1 RANDOMIZATION NO EVIDENCE OF PD Primary Endpoint: PFS IFM (accrual 6/2006 8/2008) INDUCTION ASCT 1:1 RANDOMIZATION NO EVIDENCE OF PD Primary Endpoint: PFS ASCT GIMEMA (RV-MM-PI-209) (accrual 11/2007 7/2009) 2 2 DESIGN LEN + DEX 4 INDUCTION Primary Endpoint: PFS 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 Dec 2009 ANNG INTERIM ANALYSIS AND UNBLINDING Jan 2010 PRIMARY ANALYSIS CROSSOVER BEFORE PD ALLOWED CONTINUED TREATMENT NO CROSSOVER BEFORE PD ALLOWED CONTINUED TREATMENT ALL TREATMENT DISCONTINUED Jan 2011 CONTINUED TREATMENT Target population of patients with NDMM who received LEN maintenance or placebo/no maintenance after ASCT CONTINUED TREATMENT 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; LEN, lenalidomide; NDMM, newly diagnosed multiple myeloma; MNTC, maintenance; MPR, melphalan, prednisone, and Len; PD, progressive disease. Attal et al ASCO 2016 McCarthy et al EHA 2016

Overall Survival: Median Follow-Up of 80 Months There is a 26% reduction in risk of death, representing an estimated 2.5- year increase in median survival a 1.0 7-yr OS 0.8 Survival Probability 0.6 0.

12 Overall Survival: Median Follow-Up of 80 Months There is a 26% reduction in risk of death, representing an estimated 2.5- year increase in median survival a yr OS 0.8 Survival Probability Patients at risk N = 1209 LENALIDOMIDE CONTROL Median OS (95% CI), mos HR (95% CI) P value NE (NE-NE) 0.74 ( ) ( ) 50% 62% Overall Survival, mos a Median for lenalidomide treatment arm was extrapolated to be 116 months based on median of the control arm and HR (median, 86 months; HR = 0.74). HR, hazard ratio; NE, not estimable; OS, overall survival. Attal et al ASCO 2016 McCarthy et al EHA 2016

13 RVD Lite for Non Transplant Eligible Induction 35-day cycle Cycle 1 Cycle 2 Patients Dosing Regimen Cycle 3 Cycle 8 Cycle 9 Cycle Day Lenalidomide Daily dose Daily dose Daily dose Daily dose Daily dose Bortezomib x x x x x x x x x x x x x x x x x x x x Dexamethasone dd dd dd dd dd dd dd dd dd dd dd dd dd dd dd dd dd dd dd dd Cycle Day Lenalidomide Bortezomib Consolidation 28-day cycle Cycle 10 Cycle 11 Cycle 12 Cycle Daily dose Daily dose Daily dose Daily dose x x x x x x x x Cycle Day Lenalidomide Maintenance 28-day cycle Cycle 16 Cycle 17 Cycle 18 Cycle N Daily dose Daily dose Daily dose Daily dose O'Donnell E et al. ASH 2015.

14 RVD Lite for Non Transplant Eligible Patients PFS: 35 months OS: 60 % at 35 month f/u O'Donnell E et al. submitted

15 Summary RVD +/- Transplant is standard CyBorDex in some (renal failure) KRD versus RVD is under investigation

16 3 Drug Induction now STANDARD Should we add a 4 th drug? EVOLUTION Trial: CRVD- NOT Better Ongoing Phase II Studies Dara-IRD ELO-RVD Pano-RVD Dara-KRD

17 Myeloma: Scope of the Problem Median time to first relapse with current therapies: 3-4 yrs OS (%) Yrs > 100,000 pts living with myeloma Kumar SK, et al. Leukemia. 2014;28:

18 Confronting Disease Relapse in Myeloma Median Response Duration (Mos) First Second Third Fourth Fifth Sixth Pts (%) OS EFS Events, n/n 170/ /286 Median, Mos (Range) 9 (7-11) 5 (4-6) Treatment Regimen Mos Kumar SK, et al. Mayo Clin Proc. 2004;79: Kumar SK, et al. Leukemia. 2012;26:

19 SOME FACTS Although CR with MRD should be the goal of clinical trials, NOT all patients get there. Having some response translates into CBR DCR similarly translates into improved outcomes This translates into delayed TNT

20 Questions to Ask Do I really need to treat this pt? Biochemical Relapse versus Clinical Relapse Does the pt have new high-risk features? Genotypic Evolution

21 Clonal Evolution with Progression Mutation Load by Disease Stage Altered Genes per Patient

22 Additional Questions to Ask What drugs have been used so far? Response to previous treatments How well is the patient? What are the associated co-morbidities? What are the pt s goals/preferences?

23 Challenges and Opportunities in Relapsed Myeloma Many new treatments available Initial treatment options are changing (LEN moving frontline) Use of continuous treatment means that patients are refractory at progression (LEN maintenance) Data supports triplet combinations of novel agents in early relapse (exposure to multiple novel agents occurs earlier) Data from pivotal trials is lagging behind clinical practice

24 Selected phase III trials in relapsed Name of trial disease No. prior lines Arm N PFS (months) ORR VGP R ENDEAVOR 1-3 Kd % 54% 13% CR Vd % 29% 6% TOURMALINE-MM1 1-3 IRd % 48% 12% Rd % 39% 7% ELOQUENT Elo-Rd % 33% 4% Rd % 28% 7% ASPIRE 1-3 KRd % 70% 32% Rd % 40% 9% PANORAMA Pano-Vd % 11% Vd % 6% NIMBUS (MM-003) 2 Pd % 6% 1% CASTOR 1 D % 1% 0% Vd-dara 251 NE Vd % 63.2 % 59.2% 19.2% 29.1% 9% POLLUX 1 Rd-dara 286 NE 93% 76% 43% Rd % 44% 19%

25 POLLUX and CASTOR Multicenter, randomized (1:1), open-label, active-controlled, phase 3 studies in 1 prior line of therapy for MM POLLUX CASTOR R A N D O M I Z E DRd (n = 286) D 16 mg/kg IV Every week: Cycles 1-2 Every 2 weeks: Cycles 3-6 Every 4 weeks until PD R 25 mg PO (similar to Rd alone) d 40 mg Rd (n = 283) R 25 mg PO Days 1-21 of each cycle until PD d 40 mg weekly until PD R A N D O M I Z E DVd (n = 251) D 16 mg/kg IV Every week: Cycles 1-3 Every 3 weeks: Cycles 4-8 Every 4 weeks: Cycles 9+ V 1.3 mg/m 2 SC (similar to Vd alone) d 20 mg Vd (n = 247) V 1.3 mg/m 2 SC on Days 1, 4, 8, and 11 for 8 cycles d 20 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12 for 8 cycles MRD assessments At suspected CR 3 & 6 months after CR MRD assessments At suspected CR 6 & 12 months after first study dose Patient characteristics Median (range) prior lines: 1 (1-11) Prior V: 84% Prior R: 18% Patient characteristics Median (range) prior lines: 2 (1-10) Prior V: 66% Prior R: 42% Avet-Loiseau ASH 2016, abstract 246

26 Updated PFS: POLLUX and CASTOR 100 POLLUX 18-month PFS a 100 CASTOR 12-month PFS a Patients surviving without progression, % PFS, months 76% 49% Rd DRd Median (range) follow-up: 17.3 (0-24.5) months Median PFS DRd: not reached; Rd: 17.5 months HR: 0.37 (95% CI, ; P <0.0001) Patients surviving without progression, % % 22% Vd DVd PFS, months Median (range) follow-up: 13.0 (0-21.3) months Median PFS DVd: not reached; Vd: 7.1 months HR: 0.33 (95% CI, ; P <0.0001) Avet-Loiseau ASH 2016, abstract 246

27 Ricolinostat in Combination with Lenalidomide and Dexamethasone Omit from Responses - PRu Yee et al, Lancet Oncol 2016

28 SNaPshot Assay Dias-Santagata D, et al., Rapid targeted mutational analysis of human tumors: a clinical platform to guide personalized cancer medicine. EMBO Mol Med May;2(5):146-58, O Donnell and Raje, Cancer Discovery 2013

29 Tracking Genetic Hetrogeneity BRAF c.1799t>a, p.v600e Genomic control Myeloma-GT BM and Blood Biopsies Lohr et al, submitted

30 BASKET STUDY: VEMURAFENIB for BRAF mutant MM Trametinib +Dabrafenib for BRAF/NRAS/KRAS mutant MM

31 Treatment Approach in Early Relapse Early Relapse (1-3 prior lines) Participate in clinical trials with Novel Agents Imid- based regimen PI- based regimen Immune Therapy Autologous Transplant Len-naïve/ sensitive KRd, IRd, Rd-Elo BTZ-naïve/ sensitive Kd, KRd, IRd Chemo Resistant Elotuzumab Daratumumab +/- Imid/PI Long remission post 1 st transplant (>18-24 months) Transplant not part of primary therapy

32 Treatment approach in Rel and Ref MM 3 Prior Lines and/ or double refractory Participate in clinical trials with Novel Agents Pom- dex Daratumumab Re-treatment MM-003 Median no. of prior treatments: 5 (1-14) ORR/ CBR (%) 31/39 PFS: 4.0 mos Median OS: 12.7 mos SIRIUS Study Median no. of prior treatments: 5 (2-14) ORR/ CBR (%) 31/36 PFS: 3.7 mos Median OS: 17.5 mos Even if a patient has progressed on a certain agent, they may become sensitive due to reemergence of drug sensitive clones Requires a combination approach 1) San Miguel et al, 2013, Lancet. 2) Lonial et al Lancet.

33 FDA APPROVED DRUGS Bortezomib Thalidomide 2016 Lenalidomide 2016 Pomalidomide 2013 Carfilzomib Improved Diagnosis and Monitoring Doxorubicin With Bortezomib 2007 Panobinostat 2015 Ixazomib 2015 Elotuzumab 2015 Daratumumab 2015 Melphalan 2016

What is New in MM Oral proteasome inhibitors New IMiDs HDACi Kinase inhibitors Monoclonal antibodies Novel mechanisms Immunotherapies Ixazomib CC-122 Panobinostat Vermurafenib Elotuzumab

34 What is New in MM Oral proteasome inhibitors New IMiDs HDACi Kinase inhibitors Monoclonal antibodies Novel mechanisms Immunotherapies Ixazomib CC-122 Panobinostat Vermurafenib Elotuzumab Venetoclax PDL-1/PD-1 Oprozomib CC-220 Ricolinostat Afuresertib Daratumumab Selinexor CAR-T Marizomib ACY 241 Dinaciclib Isatuximab BITE PIM (LGH447) Trametinib HDACi, histone deacetylase inhibitor

bortezomib can indirectly inhibit MCL-1 Venetoclax enhanced bortezomib activity in

35 Venetoclax Background BCL-2 and MCL-1 promote multiple myeloma (MM) cell survival Venetoclax is a selective, orally available small molecule BCL-2 inhibitor 1 and bortezomib can indirectly inhibit MCL-1 Venetoclax enhanced bortezomib activity in vitro and in vivo 2 1. Roberts AW et al. NEJM Punnoose E et al. Mol Cancer Ther 2016

36 Phase 1 Venetoclax for RRMM: response and TTP in all patients and by t(11;14) status 5 0 s C R C R V G P R P R T im e to P r o g r e s s io n P e rc e n ta g e o f P a tie n ts O R R 2 1 % 3% 4% 8% 6% A ll P a t ie n t s N = 6 6 O R R 4 0 % 4% 1 0 % 1 3 % 1 3 % t( 1 1 ; 1 4 ) n = 3 0 O R R 6 % 3% 3% n o n - t ( 1 1 ; 1 4 ) n = 3 6 % N o t P r o g r e s s e d A ll P a tie n ts t(1 1 ;1 4 ) n o n -t(1 1 ;1 4 ) M o n th s s in c e firs t d o s e N o. at risk N o. at risk N o. a t ris k Data cutoff of 19Aug2016 Kumar ASH 2016 Abstract 488

PD-1 CHECKPOINT BLOCKADE PD-1 expression o Activation o Exhaustion o Alter T/DC interaction PD-1 Ligand expression o Immune evasion o Proliferative advantage o Resistance Investigators hypothesized

37 PD-1 CHECKPOINT BLOCKADE PD-1 expression o Activation o Exhaustion o Alter T/DC interaction PD-1 Ligand expression o Immune evasion o Proliferative advantage o Resistance Investigators hypothesized that in the setting of immune stimulatory properties of pomalidomide; the blockade of PD1-PD-L1 may restore MM specific cytotoxic T cells leading to clinically relevant responses. Boussiotis VA. N Engl J Med 2016;375:

38 Chimeric Antigen Receptor (CAR) T cells

39 An International, Randomized, Double Blind Trial Comparing Denosumab With Zoledronic Acid for the Treatment of Bone Disease in Patients With Newly Diagnosed Multiple Myeloma Randomization (N=1700) Stratified by: Anti-Myeloma Therapy: Novel Based (IMiDs, Proteasome Inhibitors) vs Non-Novel Based Planned Autologous PBSC Transplant: Yes/No Disease Stage: ISS 1, 2, or 3 Previous SRE: Yes/No Region: Japan; Yes/No 1:1 Denosumab 120 mg SC + Placebo IV Over 15 minutes Q4W (N = 850) Daily Supplements of Calcium and Vitamin D Zoledronic Acid 4 mg IV Over 15 minutes Q4W + Placebo SC (N = 850) 676 Events Offered Open-Label Denosumab Up to 2 Years Yes Benefit:Risk Positive? No 2-Year Follow-up for Survival *Per protocol and Zometa label, IV product was dose adjusted for baseline creatinine clearance and subsequent dose intervals were determined by serum creatinine levels. No SC dose adjustments were required.

40 Results Primary Endpoint Met: Noninferiority for Time to First On-Study Skeletal-Related Event HR (95% CI) = 0.98 (0.85, 1.14); P=0.01 (Noninferiority)

41 Results Exploratory Endpoint: Progression-Free Survival HR (95% CI) = 0.82 (0.68, 0.99); P = (Descriptive) Median Duration (95% CI), Months Denosumab (34.30, Not Estimable) Zoledronic Acid (30.19, Not Estimable)

42 How would I sequence therapy? Transplant Eligible RVD/KRD-Transplantmaintenance Pom Dex + PI Dara +PI/IMiD Cellular therapy Transplant Ineligible RVD lite/rid Pom/PI Dara + PI/IMiD Clinical trial Clinical Trial

43 Current Understanding Combinations will allow us to improve responses and cure a higher fraction of patients. Drugs with different MOA will overcome genetic heterogeneity High risk disease can be identified and specifically targeted

44 Aim for deep and durable response MRD measurements insightful in clinical trials Continuous therapy improves outcome Induction, upfront transplant and maintenance Initial treatment for 12 months followed by maintenance Prognostic factors are evolving High risk disease needs new drugs Immuno-oncology will play an important role Tailor therapy for Age and frailty Renal impairment Supportive care Bone health Thromboprophylaxis Infection Take Home Points

45 Acknowledgements Our Patients

COMy Congress The case for IMids. Xavier Leleu. Hôpital la Milétrie, PRC, CHU, Poitiers, France

COMy Congress The case for IMids. Xavier Leleu. Hôpital la Milétrie, PRC, CHU, Poitiers, France Xavier Leleu Hôpital la Milétrie, PRC, CHU, Poitiers, France The case for IMids COMy Congress 21 Disclosures Grants/research support: Amgen, Bristol-Myers Squibb, Celgene, Janssen, Millennium/Takeda, Novartis,