HOW I TREAT RELAPSED/REFRACTORY MYELOMA? FOCUS ON FIRST RELAPSE

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1 HOW I TREAT RELAPSED/REFRACTORY MYELOMA? FOCUS ON FIRST RELAPSE Evangelos Terpos, MD, PhD Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece

2 DISCLOSURES Name of Company Research support Advisory Board Honoraria Amgen X X X Janssen X X X Celgene/Genesis X X X Novartis X Takeda X X BMS X X

3 RELAPSE SITUATIONS Two clear scenarios Fast, symptomatic relapse Symptoms Radiply progressing disease High tumor burden Organ involvement Cytogenetic high risk Poor performance status Slow, asymptomatic relapse No symptoms Slowly progressing disease Low tumor burden Cytogenetic low risk Good performance status Prompt treatment initiation needed Observation The challenge: Identify appropriate time to initiate treatment for situations in between

4 SHOULD BIOCHEMICAL/ASYMPTOMATIC RELAPSE BE TREATED? Clinical trials include patients with asymptomatic relapse; however, in clinical practice the approach is sometimes different, and current recommendations state that treatment can be delayed in the case of asymptomatic relapse 1 Analysis of the characteristics of relapse in 211 patients after ASCT 2 For patients with asymptomatic relapse: Median time to treatment requirement of 5.6 months (10 months in a recent Spanish trial) 3 26% of patients (n = 12) did not require treatment in 2 years ISS I or II at diagnosis (n = 12) IgG type (58%) No extramedullary disease (n = 11) Clinical features of aggressiveness at diagnosis were rare Renal failure, n = 1; hypercalcemia, n = 1; anaemia, n = 3 Consider early treatment if Previous aggressive presentation/clinical behaviour Clearly increasing M-protein, particularly light chains in urine Decreasing Hb level 1. Moreau P, et al. Ann Oncol 2017; 28:iv52 iv61; 2. Fernández de Larrea C, et al. BMT 2014; 49: ; 3. García Sanz R, et al. Haematologica 2015; 100:

5 MULTIPLE MYELOMA: PATIENT OUTCOMES IN REAL WORLD PRACTICE TREATMENT DURATION AND TREATMENT-FREE INTERVAL BY LINE OF THERAPY * Proportion of patients reaching this line of therapy (%) 1L 100% Diagnosis 95% 1 m 6 m 6 m Start 1L End 1L induction End 1L maintenance Start End 3L 3L Mean (95% CI): interval, 2L-3L, 11 m (10.22, 11.78); 3L, 8 m (7.63, 3 m 5 m 8.37) * Data from 4997 patient charts in Belgium, France, Germany, Italy, Spain, Switzerland, and the UK. Treatment-free interval Active treatment Maintenance treatment Median duration in months shown Mean (95% CI): diagnosis, 2 m (1.60, 2.40); 1L, 8 m (7.74, 8.26); 1L maintenance, 9 m (7.78, 10.22) 10 m 7 m 2L 61% Start End 2L 2L Mean (95% CI): interval, 1L-2L, 16 m (15.0, 17.0); 2L, 9 m (8.64, 9.36) 3L 4L 5L 38% 15% 5 m 6 m Start End 4L 4L Mean (95% CI): interval, 3L-4L, 7 m (5.9, 8.1); 4L, 6 m (5.5, 6.5) 1 m 4 m 1% Start Mean (95% CI): interval, 4L-5L, 3 m (1.8, 4.2); 5L, 4 m (3.15, 4.85) 5L The proportion of patients who had received each line are from the cross-sectional review; data on durations of treatment and treatment-free intervals are from the retrospective review. 1L-5L = first line-fifth line treatment; CI = confidence interval; m = month. Yong K, et al. Br J Haematol. 2016;175: End 5L

6 MULTIPLE FACTORS DRIVE TREATMENT CHOICE IN RELAPSED/REFRACTORY MM Comorbidity e.g. renal impairment* Tolerance to prior therapies Side effects Treatment availability Prior therapies received Influential factors Pre-existing toxicities e.g. PN Time interval since last therapy Age Previous SCT Performance status Subtype e.g. t(4;14) *Occurs in up to 50% MM patients. Can repeat induction therapy where relapse occurs >6 months after treatment. PN, peripheral neuropathy; SCT, stem cell transplant. Moreau P, et al. Ann Oncol 2013;24 (Suppl 6):vi133 7; Lonial S. Hematology Am Soc Hematol Educ Program 2010;2010:303 9.

7 CASE PROFILE 1 Initial Presentation and Evaluation 63-year-old male Presented with back pain and fatigue Hematocrit, 31%; Hb 9.2 g/dl Creatinine, 1.0 mg/dl Calcium, 9.5 mg/dl Bone marrow plasma cells, 40% (hyperdiploid) Serum electrophoresis: IgG kappa, 7 g/dl Complete skeletal survey showed lytic lesions and an L1 compression fracture Initial Treatment thalidomide, bortezomib, and dexamethasone induction therapy followed by high-dose melphalan and ASCT; no consolidation; thalidomide maintenance for 6 months; stopped due to PN One Year Later Relapse following 10 months after ASCT consolidation in the setting of mild congestive heart failure requiring furosemide therapy

8 OPTIONS OF THERAPY FOR RRMM PATIENTS Induction Bortezomib-based combination ASCT (melphalan 200) No more therapy/consolidation/maintenance 1st relapse (if ASCT is not an option) Carfilzomib plus Rd PFS: 26.3m, HR: 0.69 IMiDs based combinations OR Elotuzumab plus Rd PFS: 19.4m, HR: 0.73 Kd, HR:0.53 PFS: 18.7m DaraVD HR:0.33 PFS: NR Daratumumab plus Rd PFS: NR, HR: 0.37 Rd or Td ± chemo (cyclo) Ixazomib plus Rd PFS: 20.6m, HR: 0.74

9 CONSENSUS GUIDELINES FOR SALVAGE ASCT IN RRMM (ASBMT, EBMT, BMT CTN, AND IMWG) 1. In transplantation-eligible patients relapsing after primary therapy that did NOT include an autologous HCT, high-dose therapy with autologous HCT as part of salvage therapy should be considered standard 2. High-dose therapy and autologous HCT should be considered appropriate therapy for any patients relapsing after primary therapy that includes an autologous HCT with initial remission duration of >18 months 3. High-dose therapy and autologous HCT can be used as a bridging strategy to allogeneic HCT Girault, S. et al. Biol Blood Marrow Transplant 2015;21:

10 AUTOLOGOUS RE-TRANSPLANTATION FOR PATIENTS WITH RELAPSED MM Factors associated with improved PFS and OS after salvage ASCT: Remission duration of >18 months after upfront ASCT Bortezomib- or lenalidomide containing reinduction regimen Response to reinduction ISS stage I prior to salvage ASCT Year of salvage ASCT (2005 or thereafter) Sellner et al. Cancer 2013;119:

11 SALVAGE ASCT WITH INDUCTION BASED ON NOVEL AGENTS Zannetti et al. Ann Hematol. 2017;96:

12 PHASE 3 ASPIRE STUDY SCHEMA Randomized, multicenter, phase 3 study comparing carfilzomib, lenalidomide, and dexamethasone (KRd) vs lenalidomide and dexamethasone (Rd) in subjects with relapsed multiple myeloma (MM) Stratification β 2 -microglobulin level < 2.5 mg/l vs 2.5 mg/l Previous bortezomib Previous lenalidomide N = 792 R A N D O M I Z E 1:1 KRd N = 396 Rd N = 396 K: 18 cycles maximum Rd: Until progression or unacceptable toxicity Rd: Until progression or unacceptable toxicity Stewart AK, et al. N Engl J Med. 2015;372:

13 PHASE 3 ASPIRE (N = 792): DOSING AND ADMINISTRATION DURING THE TRIAL KRd (n = 396) Rd (n = 396) CYCLE 1 CYCLE 12 CYCLE 13 CYCLE 18 (28-day cycle) (28-day cycle) * * D A Y NO DOSING NO DOSING NO DOSING WEEK 1 WEEK 2 WEEK 3 WEEK 4 WEEK 1 WEEK 2 WEEK 3 WEEK 4 Carfilzomib: 27 mg/m 2 ; 10-min infusion *20 mg/m 2, Days 1 and 2 of Cycle 1 Only Lenalidomide: 25 mg; Days 1 21 Dexamethasone: 40 mg; Days 1, 8, 15, 22 Lenalidomide and dexamethasone administration could continue after cycle 18 until progression or unacceptable toxicity Lenalidomide 25 mg; Days 1 21 Dexamethasone 40 mg: Days 1, 8, 15, 22 If the 20 mg/m 2 priming dose was tolerated. Stewart AK, et al. N Engl J Med. 2015;372:

14 Proportion Surviving Without Progression ASPIRE: KRD EXTENDED INVESTIGATOR-ASSESSED MEDIAN PROGRESSION-FREE SURVIVAL (PFS) BY 9.5 MONTHS Median follow-up, months KRd (n = 396) Rd (n = 396) Death, n (%) 244 (61.6) 272 (68.7) Median PFS, months Hazard ratio (95% CI) 0.66 ( ; 1-sided P < 0.001) 0.2 KRd Rd Months Since Randomization Number of patients at risk: KRd Rd Carfilzomib discontinued after 18 cycles Siegel DS, et al. J Clin Oncol. 2018;36:

15 ASPIRE: KRD EXTENDED OVERALL SURVIVAL (OS) BY 7.9 MONTHS Proportion Surviving Median follow-up, months KRd (n = 396) 67.1 Rd (n = 396) Death, n (%) 246 (62.1) 267 (67.4) Median OS, months Hazard ratio (95% CI) 0.79 ( ; 1-sided P = ) KRd Rd Number of patients at risk: KRd Rd Months Since Randomization Carfilzomib discontinued after 18 cycles Events at 18 months: KRd, 71 (17.9%); Rd, 97 (24.5%); HR (95% CI) = 0.69 ( ) Using a piecewise Cox model, the 18-month OS HR was estimated as 0.69 (95% CI, ) Siegel DS, et al. J Clin Oncol. 2018;36:

16 PHASE 3 ENDEAVOR STUDY SCHEMA Randomized, multicenter, phase 3 study comparing KYPROLIS with dexamethasone (Kd) vs bortezomib with dexamethasone (Vd) in subjects with relapsed multiple myeloma Stratification Prior proteasome inhibitor therapy Prior lines of treatment ISS stage Route of bortezomib administration N = 929 R A N D O M I Z E 1:1 Carfilzomib plus dexamethasone (Kd) n = 464 Bortezomib plus dexamethasone (Vd) n = 465 *ENDEAVOR = RandomizEd, OpeN Label, Phase 3 Study of Carfilzomib Plus DExamethAsone Versus Bortezomib Plus DexamethasOne in Patients With Relapsed Multiple Myeloma. ISS = International Staging System. Dimopoulos MA, et al. Lancet Oncol. 2015;17:27-38.

17 Vd Kd (n = 465) (n = 464) ENDEAVOR: CONSECUTIVE-DAY DOSING SCHEDULE D A Y 28-day cycle WEEK 1 Priming dose (20 mg/m 2 ) WEEK 2 WEEK 3 NO DOSING WEEK 4 Carfilzomib: 56 mg/m 2 starting on Day 8 of Cycle 1 if the priming dose (20 mg/m 2 ) is tolerated on Days 1 and 2 of cycle 1; 30-minute IV infusion Dexamethasone: 20 mg; oral of IV infusion: Days 1, 2, 8, 9, 15, 16, 22, day cycle D A Y NO DOSING WEEK 1 WEEK 2 WEEK 3 Bortezomib: 1.3 mg/m 2 ; IV bolus or subcutaneous injection: Days 1, 4, 8, 11 Dexamethasone 20 mg; oral or IV infusion: Days 1, 2, 4, 5, 8, 9, 11, 12 IV = intravenous. Treatment may be continued until disease progression or unacceptable toxicity occurs. Dimopoulos MA, et al. Lancet Oncol. 2015;17:27-38.

18 ENDEAVOR: Kd Extended Progression-Free Survival by 8.2 Months Progression-Free Survival (%) Kd Vd ENDEAVOR Updated PFS Number of patients at risk: Months Kd Vd Median followup, months Median treatment duration, months Median PFS, months Hazard ratio (95% CI) Initial Analysis 2 Updated Analysis 1 Kd (n = 464) Vd (n = 465) Kd (n = 464) Vd (n = 465) ( ; P < ) 0.53 ( ; P < ) Treatment duration in the safety population: Kd (n = 463), Vd (n = 456). 1. Siegel D, et al. Presented at: International Myeloma Workshop. March 1-4, New Delhi, India. Abstract and poster. 2. Dimopoulos MA, et al. Lancet Oncol. 2016;17:27-38.

19 ENDEAVOR: Kd Extended Overall Survival by 7.6 Months Proportion Surviving Kd Vd Number of patients at risk (number censored): ENDEAVOR Final OS analysis Months Kd 464 (0) 423 (7) 373 (16) 335 (21) 308 (25) 270 (35) 162 (121) 66 (215) 10 (266) Vd 465 (0) 402 (28) 351 (40) 293 (50) 256 (56) 228 (58) 140 (130) 39 (221) 5 (251) Median follow-up, months Median OS, months Hazard ratio (95% CI) Initial OS Analysis Kd (n = 464) Vd (n = 465) Final OS Analysis Kd (n = 464) Vd (n = 465) NE ( ; P = 0.13) 0.79 ( ; P = 0.01) Dimopoulos MA, et al. Lancet Oncol. 2017;18:

20 CASTOR: Study Design Multicenter, randomized, open-label, active-controlled phase 3 study 1,2 Key eligibility criteria RRMM 1 prior line of therapy Prior bortezomib exposure, but not refractory R A N D O M I Z E 1:1 DVd (n = 251) Daratumumab (16 mg/kg IV) Every week - cycles 1 3 Every 3 weeks - cycles 4 8 Every 4 weeks - cycles 9+ Vel: 1.3 mg/m 2 SC, days 1, 4, 8, 11 - cycles 1 8 Dex: 20 mg PO-IV, days 1, 2, 4, 5, 8, 9, 11, 12 - cycles 1 8 Vd (n = 247) Vel: 1.3 mg/m 2 SC, days 1,4,8,11 - cycles 1 8 Dex: 20 mg PO-IV, days 1,2,4,5,8,9,11,12 - cycles 1 8 Primary Endpoint PFS Secondary Endpoints TTP OS ORR, VGPR, CR MRD Time to response Duration of response Cycles 1-8: repeat every 21 days Cycles 9+: repeat every 28 days Statistical analyses 295 PFS events: 85% power for 4.3 month PFS improvement Interim analysis: ~ 177 PFS events Daratumumab IV administered in 1000 ml to 500 ml; gradual escalation from 50 ml to 200 ml/hour permitted Palumbo A, et al. N Engl J Med. 2016:375: ; 2. Paulmbo A, et al. Presented at Presented at: 21st Congress of European Hematology Association. June 9-12, LB2236.

21 Surviving Without Progression (%) CASTOR Update: DVd Improved Progression-Free Survival by 9.6 Months Months Number of patients at risk: Vd DVd Median follow up: 26.9 months ITT population months PFS a % 5% Vd DVd Median follow-up, months Median treatment duration, months Initial Analysis DVd (n = 251) Vd (n = 247) Updated Analysis DVd (n = 251) (Vd) 5.6 Dara mono: 11.9 Vd (n = 247) Median PFS, months NE Hazard ratio (95% CI) 0.39 ( ; P < 0.001) 0.32 ( ; P < ) Spencer A, et al. Presented at: American Society of Hematology Annual Meeting. December 9-12, Atlanta, GA. Abstract 3145.

22 TOURMALINE-MM1: Study Design Randomization Global, double-blind, randomised, placebo-controlled study design N = 722 1:1 *10 mg for patients with creatinine clearance 50 or 60 ml/min, depending on local label/practice. ISS = International Staging System. Ixazomib + Lenalidomide + Dexamethasone (all oral) Ixazomib: 4 mg on days 1, 8, and 15 Lenalidomide: 25 mg* on days 1 21 Dexamethasone: 40 mg on days 1, 8, 15, 22 Repeat every 28 days until progression, or unacceptable toxicity Placebo + Lenalidomide + Dexamethasone (all oral) Placebo: on days 1, 8, and 15 Lenalidomide: 25 mg* on days 1 21 Dexamethasone: 40 mg on days 1, 8, 15, 22 Primary endpoint: PFS Key secondary endpoints: OS OS in patients with del(17p) Stratification: Prior therapy: 1 vs 2 or 3 ISS: I or II vs III PI exposure: yes vs no Moreau P, et al. N Engl J Med. 2016;374:

23 TOURMALINE-MM1: Ixazomib Extended Progression-Free Survival by 5.9 Months Probability of Progression-Free Survival IRd Placebo-Rd IRd (n = 360) Median follow-up, months 15 Rd (n = 360) Median PFS, months Hazard ratio (95% CI) 0.74 ( ) Log-rank test P = Number of patients at risk: Time From Randomization (months) IRd Placebo-Rd Moreau P, et al. N Engl J Med. 2016;374:

24 ELOQUENT-2: Study Design ERd (n = 321) Elotuzumab 10 mg/kg IV, Cycles 1 and 2 weekly (days 1,8,15,22), then every other week (days 1,15) Lenalidomide days 1 21, 25 mg PO Dexamethasone 40 mg PO, weekly Relapsed andor Refractory MM 1 3 Prior lines N = 646 R 1:1 Mandatory pre-medication 30 to 90 min before infusion: diphenhydramine (25 50 mg PO or IV) or equivalent, ranitidine (50 mg IV) or equivalent and acetaminophen ( mg PO) Until progression or unacceptable toxicity Primary endpoint: PFS, ORR Rd (n=325) Lenalidomide days 1 21, 25 mg PO Dexamethasone 40 mg PO, weekly Selected secondary endpoints: OS, severity of pain or interference with daily life Lonial S, et al. N Engl J Med. 2015;373:

25 ELOQUENT-2: Progression-Free Survival Weisel K et al. EHA 2018; abstract PS12998

26 POLLUX: Study Design Comparison of daratumumab (D) + lenalidomide + dexamethasone (Rd) vs Rd RRMM 1 prior line of therapy R N = 569 (1:1) D + Rd* (n = 286) D: 16 mg/kg IV, qw in cycles 1 2, q2w in cycles 3-6, then q4w in cycles 7+ R: 25 mg PO, daily (days 1 21) d: 40 mg PO, weekly Rd* (n = 283) R: 25 mg PO, daily (days 1 21) d: 40 mg PO, weekly 28-day cycle Aims: compare the efficacy and safety of D in combination with Rd vs Rd alone in patients with RRMM in a randomized, open-label, multicenter, phase 3 study Primary endpoint: PFS Selected secondary endpoints: TTP, ORR, VGPR, minimal residual disease-negative rate, OS, duration of response, time to response, safety *Patients were given the treatment until PD. D = daratumumab; PO = oral; TTP = time to progression. Dimopoulous M, et al. N Engl J Med 2016;375:

27 POLLUX: PFS DRd Reduced Risk of Progression PFS in the ITT Population DRd (n = 286) Median follow-up, months 44.3 Rd (n = 283) Median PFS, months Hazard ratio (95% CI) 0.44 ( ) P < ) Bahlis N, et al. ASH Poster 1996

28 Lenalidomide-Based Studies in RRMM Treatment duration PFS HR (95% CI) DoR = duration of response; NA = not available; NE = not evaluated. ASPIRE 1 KRd vs Rd Carfilzomib given for 18 cycles; Rd until progression 0.69 ( ) POLLUX 2,3 DRd vs Rd TOURMALINE-MM1 4 IRd vs Rd ELOQUENT-2 5,6 ERd vs Rd Until progression Until progression Until progression 0.37 ( ) 0.74 ( ) 0.73 ( ) ORR 87% 93% 78% 79% VGPR 70% 76% 48% 33% CR 32% 43% 14% 4% DoR (months) OS HR (95% CI) 28.6 NE ( ) NA This table is provided for ease of viewing information from multiple trials. Direct comparison between trials is not intended and should not be inferred. 1. Stewart AK, et al. New Engl J Med. 2015;372: ; 2. Dimopoulos MA, et al. New Engl J Med. 2016;375: ; 3. Usmani SZ, et al. Presented at: American Society of Hematology Annual Meeting. December 3-6, San Diego, CA. Abstract 1151; 4. Moreau P, et al. New Engl J Med. 2016;374: ; 5. Lonial S, et al. New Engl J Med. 2015;373: ; 6. Dimopoulos MA, et al. Presented at: 22nd Congress of European Hematology Association. June 22-25, Madrid, Spain. Abstract S456. NE 0.78 ( )

29 Lenalidomide-Based Studies in RRMM Study Populations ISS Stage ASPIRE 2 KRd Group POLLUX 1 DRd Group TOURMALINE-MM1 3 IRd Group ELOQUENT-2 4 ERd Group I 18.4% 47.9% 63% 44% II 28.4% 32.5% 25% 32% III 53.2% 19.6% 12% 21% ECOG Status % 48.6% 51% NA % 47.6% 44% NA % 3.8% 5% NA Previous SCT 54.8% 62.9% 59% 52% This table is provided for ease of viewing information from multiple trials. Direct comparison between trials is not intended and should not be inferred. K = carfilzomib; E = elotuzumab; I = ixazomib; ISS = International Staging System; ECOG = Eastern Cooperative Oncology Group; SCT = stem cell transplantation. 1. Dimopoulos MA, et al. New Engl J Med; 2016;375: Stewart AK, et al. New Engl J Med. 2015;372: ; 3. Moreau P, et al. New Engl J Med. 2016;374: ; 4. Lonial S, et al. New Engl J Med. 2015;373:

30 Lenalidomide-Based Studies in RRMM Study Populations (cont d) Prior lines of therapy Age ASPIRE 2 KRd Group POLLUX 1 DRd Group TOURMALINE-MM1 3 IRd Group ELOQUENT-2 4 ERd Group % 52% 62% 47% % 30% 27% 37% % 18% 11% 16% < 65 yrs 53.3% 46.5% 47% 42% yrs 35.9% 43.4% 53% (> 65 yrs) 58% ( 65 yrs) 75 yrs 10.9% 10.1% NA NA High-risk cytogenetics* 24.6% 15.4% 21% 32% del(17p) 9% t(4;14) *Note: High-risk cytogenetics was defined differently in each trial. NA = not available. This table is provided for ease of viewing information from multiple trials. Direct comparison between trials is not intended and should not be inferred. 1. Dimopoulos MA, et al. N Engl J Med. 2016;375: ; 2. Stewart AK, et al. N Engl J Med. 2015;372: ; 3. Moreau P, et al. N Engl J Med. 2016;374: ; 4. Lonial S, et al. N Engl J Med. 2015;373:

31 WHAT WOULD YOUR PREFERRED REGIMEN BE AT 1 ST RELAPSE AFTER ASCT?

32 Proportion Surviving Without Progression Proportion Surviving Without Progression ASPIRE: PFS BY PRIOR LINE OF THERAPY (1 VS 2) 1 prior line of therapy 2 prior lines of therapy KRd Rd KRd Rd Months from Randomization Months from Randomization PFS, median months Hazard ratio (95% CI) P value (onesided) KRd (n=184) Rd (n=157) ( ).008 PFS, median months Hazard ratio (95% CI) P value (one-sided) KRd (n=212) Rd (n=239) ( ).002 Dimopoulos MA, et al. Blood Cancer J. 2017;7:e554.

33 Proportion Surviving Without Progression ASPIRE: KRD PROLONGED PFS IN PRIOR BORTEZOMIB SUBGROUP Median PFS in the Prior Bortezomib Group in ASPIRE KRd (N = 93) Rd (N = 73) Progression/Death, n (%) 42 (49.5%) 45 (61.6%) Median PFS, mo HR (KRd/Rd) (95% CI) (0.380, 0.875) P value (1-sided) KRd Rd Months From Randomization Number of Patients at Risk: KRd Rd In the prior BTZ group The ORR for patients who received KRd vs Rd was 86.0% vs 69.9% (CR or better, 30.1% vs 6.8%) The frequency of grade 3 AEs (KRd vs Rd) was 87.9% vs 77.5% Dimopoulos MA, et al. Blood Cancer J. 2017;7:e554.

34 ASPIRE: CARFILZOMIB EXTENDED PFS IN EARLY AND LATE RELAPSE PATIENTS IN ASPIRE Proportion Surviving Without Progression Proportion Surviving Without Progression 1.0 Progression-free survival in early relapse patients KRd (n = 113) Rd (n = 104) 0.8 Progression/Death, n (%) 70 (61.9%) 64 (61.5%) 0.6 Median PFS, months KRd HR (KRd/Rd) (95% CI) (0.508, 1.004) 0.2 Rd P value (1-sided) Number at risk: KRd Rd Months From Randomization Progression-free survival in late relapse patients Number at risk: Months From Randomization KRd Rd Mateos MV, et al. Hematol Oncol. 2018;36: Rd KRd KRd (n = 263) Rd (n = 267) Progression/Death, n (%) 70 (61.9%) 64 (61.5%) Median PFS, months HR (KRd/Rd) (95% CI) (0.533, 0.854) P value (1-sided) In ASPIRE, KRd vs Rd extended PFS in RRMM patients regardless of whether they experienced early or late relapse In both arms, patients with early relapse had worse PFS outcomes than those with late relapse

35 ASPIRE: Overall Survival Subgroup Analyses at First Relapse 1 Prior Line of Therapy Prior Bortezomib Exposure Prior Transplant KRd (n = 184) Rd (n = 157) KRd (n = 93) Rd (n = 73) KRd (n = 88) Rd (n = 78) Median OS, months Hazard ratio (95% CI) 0.81 ( ) 0.82 ( ) 0.71 ( ) Siegel DS, et al. J Clin Oncol. 2018;36:

36 ENDEAVOR: PFS BY PRIOR LINES OF THERAPY INTENT-TO-TREAT POPULATION (N=929) Proportion Surviving Without Progression Proportion Surviving Without Progression Prior Line 2 or 3 Prior Lines Kd Vd 0. 4 Kd Vd Months Since Randomization Months Since Randomization 0 Kd (n=232) Vd (n=232) Median PFS, months Hazard ratio (95% CI) ( ) 0 Median PFS, months Hazard ratio (95% CI) Kd (n=232) Vd (n=233) ( ) P-value (1-sided) < P-value (1-sided) < Moreau P, et al. Leukemia 2017;31:

37 ENDEAVOR: KD56 PROLONGED PFS IN PRIOR BORTEZOMIB SUBGROUP Proportion Surviving without Progression Median PFS in the Prior Bortezomib Group in ENDEAVOR Kd (N = 96) Vd (N = 101) Progression/Death, n (%) 33 (34.4%) 53 (52.5%) Median PFS, mo HR (Kd/Vd) (95% CI) ( ) P value (1-sided) Number of Patients at Risk: Months From Randomization Kd Vd In the prior BTZ group Kd Vd The ORR for patients who received Kd vs Vd was 79.2% vs 65.3% The frequency of grade 3 AEs (Kd vs Vd) was 64.6% vs 57.1% Dimopoulos MA, et al. Lancet Oncol. 2016;17:27-38.

38 CASTOR: PROGRESSION-FREE SURVIVAL BY PRIOR BORTEZOMIB EXPOSURE Prior Bortezomib Exposure DVd (n = 162) Vd (n = 164) Median follow-up in ITT, months 13.0 Median PFS, months Hazard ratio (95% CI) 0.46 ( ; P < ) Chanan-Khan AA, et al. Presented at: American Society of Hematology Annual Meeting. December 1-4, 2016, San Diego, CA. Abstract 3313.

39 Proportion Surviving Without Progression Proportion Surviving Without Progression ENDEAVOR: CARFILZOMIB EXTENDED PROGRESSION-FREE SURVIVAL IN EARLY AND LATE RELAPSE PATIENTS Number of patients at risk: Kd Vd Progression-free survival: early relapse patients Months From Randomization Progression-free survival: late relapse patients Number of patients at risk: Months From Randomization Kd Vd Kd Vd Vd Kd Kd (n = 123) Vd (n = 116) Progression/Death, n (%) 58 (47.2%) 73 (62.9%) Median PFS, months HR (Kd/Vd) (95% CI) (0.423, 0.846) P value (1-sided) Kd (n = 335) Vd (n = 340) Progression/Death, n (%) 111 (33.1%) 167 (49.1%) Median PFS, months HR (Kd/Vd) (95% CI) (0.382, 0.620) P value (1-sided) < In ENDEAVOR, Kd vs Vd extended PFS in RRMM patients regardless of whether they experienced early or late relapse In both arms, patients with early relapse had worse PFS outcomes than those with late relapse Mateos MV, et al. Hematol Oncol. 2018;36:

40 Proportion surviving ENDEAVOR: KD56 VS KD PROVIDED OS BENEFIT REGARDLESS OF PRIOR EXPOSURE TO BORTEZOMIB 1.0 Overall survival: prior bortezomib Kd Number at risk: Kd56 Vd Death, n (%) Median OS, mo HR (Kd56/Vd) (95% CI) p-value (1-sided) Kd56 (n=250) 113 (45.2%) Vd (n=252) 124 (49.2%) (0.648, 1.080) Months from randomisation Vd Kd56 prolonged OS by 14.8 months vs retreatment with bortezomib in proteasome inhibitor sensitive patients (HR=0.837) For patients without prior bortezomib exposure, the median OS was not reached in the Kd56 arm and was 42.2 months in the Vd arm (HR=0.75; 95% CI: ). Weisel K, et al. ASH (abstract 1850).

41 KD56 OR KD70? RESULTS ON RRMM WITH 2 OR 3 PRIOR LINES Moreau P, et al. Leukemia 2017;31: Moreau P, et al. Lancet Oncol 2018;19:

42 TOURMALINE MM1: IRD VS RD: PFS IN DIFFERENT PATIENT SUBGROUPS N Median PFS (months) Variable Subgroup Placebo-Rd IRd Placebo-Rd IRd HR All patients ALL Age (yrs) 65 >65-75 > ISS stage (stratification factor) I or II III Cytogenetic risk Standard-risk High-risk Number of prior therapies NE Proteasome inhibitor Exposed Naive NE Prior IMiD therapy Exposed Naïve NE Refractory to last prior therapy Yes No NE 14.1 NE Relapsed or refractory Relapsed Refractory Ref & rel NE NE Moreau P, et al. N Engl J Med 2016;374: Favors IRd Favors placebo-rd

43 TOURMALINE-MM1: PFS ACCORDING TO THE NUMBER OF PRIOR LINES OF THERAPY After 1PL After 2-3PL Pts with 2 or 3 PL or 1PL without trx seemed to have greater benefit than pts after 1PL and trx Mateos MV, et al. Haematologica. 2017;102:

44 POLLUX: PFS BY PRIOR LINE OF THERAPY (1 VS 2) Bahlis N, et al. ASH Poster presentation, abstract 1996 Moreau P, et al. ASH Poster presentation; abstract Moreau P, et al. Presented at American ociety of Hematology Annual Meeting. December 9-12, Atlanta, GA. Abstract 1883.

45 ELOQUENT-2: PFS BY PRIOR LINE OF THERAPY (1 VS 2) Lonial S, et al. N Engl J Med 2015;373:

46 ELOQUENT-2: PROGRESSION-FREE SURVIVAL MEDIAN TIME SINCE DIAGNOSIS AND 1 PRIOR LINE OF THERAPY Weisel K et al. EHA 2018; abstract PS12998

47 OPTIONS OF THERAPY FOR RRMM PATIENTS Induction Bortezomib-based combination ASCT (melphalan 200) No more therapy/consolidation/maintenance 1st relapse Carfilzomib plus Rd PFS: 29.6m, HR: 0.69 Daratumumab plus Rd PFS: NR, HR: 0.41 Rd or Td ± chemo (cyclo) Elotuzumab plus Rd HR: 0.75 Ixazomib plus Rd PFS: 20.6m, HR: 0.83 Kd, HR:0.44 PFS: 22.2m DaraVD HR:0.33 PFS: NR

48 CASE PROFILE 2 Age and Performance Status 66 years old, ECOG 2, IgGκ MM, no high-risk cytogenetics at diagnosis, 25% of BM infiltration by PC, mainly anemia (Hb 9.2 g/dl, lytic lesions only in the skull) Treatment History VCD standard dose X 8cycles, Dex (40 mg) Patient Response Refused to have an ASCT Responded for 18 months, discontinued bortezomib due to PN but remained on 40 mg Dex Beginning to relapse at 24 months Peripheral Neuropathy Grade 3 PN while on bortezomib which hasn t improved Bone Marrow Status 40% involvement Multiple lytic lesion in the spine and pelvis Other High-risk cytogenetics (del 17p)

49 HOW ARE WE GOING TO PROCEED IN A PATIENT WITH HIGH-RISK CYTOGENETICS? Cytogenetic abnormalities: - KRd/IRd: best option in patients with t(4;14) and del(17/17p) - DaraRd: improve but not overcome - EloRd: improve t(4;14)/overcome del(17/17p) - Kd: no good option for high risk CA - DaraVd: improve and almost overcome; not a good option for high-risk CA

50 ASPIRE: KRD VS RD PFS BY CYTOGENETIC RISK STATUS AT BASELINE Proportion Surviving Without Progression Proportion Surviving Without Progression High-risk Standard-risk KRd Rd 0.2 KRd Rd Months Since Randomization Months Since Randomization PFS, median months Hazard ratio (95% CI) KRd (n=48) Rd (n=52) KRd (n=147) Rd (n=170) PFS, median months ( ) Hazard ratio (95% CI) ( ) P-value (1-sided) P-value (1-sided) KRd effective in patients with t(4;14 and del (17/17p) High risk defined by: t(4;14) or t(14;16) or with del(17p) in 60% of PCs Avet Loiseau H et al. Blood 2016;128(9):

51 TOURMALINE MM1: IRD vs RD PFS IN DIFFERENT PATIENT SUBGROUPS Richardson P et al. ASCO 2016 (Abstract 8018)

52 HOW ARE WE GOING TO PROCEED IN A PATIENT WITH HIGH-RISK CYTOGENETICS? Cytogenetic abnormalities: - KRd/IRd: best option in patients with t(4;14) and del(17/17p) - DaraRd: improve but not overcome - EloRd: improve t(4;14)/overcome del(17/17p) - Kd: no good option for high risk CA - DaraVd: improve and almost overcome; not a good option for high-risk CA

53 POLLUX: PFS BY CYTOGENETIC STATUS Bahlis N, et al. ASH Poster presentation, abstract 1996.

54 HOW ARE WE GOING TO PROCEED IN A PATIENT WITH HIGH-RISK CYTOGENETICS? Cytogenetic abnormalities: - KRd/IRd: best option in patients with t(4;14) and del(17/17p) - DaraRd: improve but not overcome - EloRd: improve t(4;14)/overcome del(17/17p) - Kd: no good option for high risk CA - DaraVd: improve and almost overcome; not a good option for high-risk CA

55 Elo-Rd vs Rd: PFS in Predefined Subgroups PFS Baseline Cytogenetics Risk (High) PFS Baseline Cytogenetics Risk (Low) EloRd improves the outcome of patients with high risk CA in comparison with Rd High risk defined by: t(4;14) or t(14;16) or with del(17p) in 1% of PCs Moreau P et al. Presented at ASH 2015 (Abstract 727), oral presentation.

56 HOW ARE WE GOING TO PROCEED IN A PATIENT WITH HIGH-RISK CYTOGENETICS? Cytogenetic abnormalities: - KRd/IRd: best option in patients with t(4;14) and del(17/17p) - DaraRd: improve but not overcome - EloRd: improve t(4;14)/overcome del(17/17p) - Kd: not a good option for high risk CA - DaraVd: improve and almost overcome; not a good option for high-risk CA

57 KD VS VD: PFS BY CYTOGENETIC RISK STATUS AT BASELINE High risk PFS, median months (95% CI) HR (95% CI) Kd (n=97) 8.8 ( ) ( ) Vd (n=113) 6.0 ( ) P-value Standard risk PFS, median months (95% CI) HR (95% CI) Kd (n=284) NE (18.7 NE) ( ) Vd (n=291) 10.2 ( ) P-value < NE, not estimable Chng W-J, et al. Leukemia 2017 Feb 3. doi: /leu

58 HOW ARE WE GOING TO PROCEED IN THE CLINICAL PRACTICE? Cytogenetic abnormalities: - KRd/IRd: best option in patients with t(4;14) and del(17/17p) - DaraRd: improve but not overcome - EloRd: improve t(4;14)/overcome del(17/17p) - Kd: no good option for high risk CA - DaraVd: improve and almost overcome; not a good option for high-risk CA

59 CASTOR: PFS BY CYTOGENETIC RISK (ALL EVALUABLE PATIENTS) % surviving without progression 100 No. at risk Vd std risk DVd std risk Vd high risk DVd high risk Vd std risk Vd high risk Months DVd std risk DVd high risk High risk b Standard risk Median PFS, mo HR (95% CI) P value ORR, % P value DVd n = 44 DVd n = 123 Vd n = 135 NR ( ) < Vd n = 51 Median PFS, mo HR (95% CI) P value 0.49 ( ) n = 44 n = 47 ORR, % P value n = 118 n = DVd improves outcomes regardless of cytogenetic risk NR, not reached. a ITT/Biomarker risk evaluable analysis set. b Central NGS. High-risk patients had any of t(4;14), t(14;16), or del17p. Standard-risk patients had an absence of high-risk abnormalities. Mateos M, et al. Presented at ASH 2016 (Abstract 1150), oral presentation.

60 OPTIONS OF THERAPY IN THIS PATIENT: at First Relapse with high-risk cytogenetics and cardiac disease Induction Bortezomib-based combination ASCT (melphalan 200) No more therapy/consolidation/maintenance In collaboration with a cardiologist 1st relapse no so effective at first relapse improve but not overcome DaraVD HR:0.33 PFS: NR no due to PN Carfilzomib plus Rd PFS: 29.6m, HR: 0.69 Daratumumab plus Rd PFS: NR, HR: 0.41 Rd or Td ± chemo (cyclo) Elotuzumab plus Rd HR: 0.75 Ixazomib plus Rd PFS: 20.6m, HR: 0.83 Kd, HR:0.44 PFS: 22.2m no good option for high-risk features

61 What Are the Factors Influencing Our Decisions for RRMM? Age Conclusions cannot be drawn from cross trial comparisons as aspects of the study designs and patient populations may be different POLLUX: Dimopoulos et al NEJM 2016;375(14): ASPIRE: Dimopoulos et al BJH 2017;177(3): ELOQUENT-2: Dimopoulos et al BJH 2017;178(6): TOURMALINE-MM1: Moreau et al NEJM 2016;374(17): ENDEAVOR: Ludwig H, et al. Leuk Lymphoma. 2017: 17:1-4 CASTOR: Palumbo et al. NEJM 2016 ;375(8): More data on POLLUX/CASTOR: presented by Mateos MV et al JCO _suppl (ASCO Abstract 8033) but only has data for 75y not <75y.

62 Regimens for RRMM After 1-3 Prior Lines Based on previous exposure or refractoriness to bortezomib or lenalidomide (according inclusion/exclusion criteria of respective studies) KRD KD Elo-RD IRD DRd DVd Pom-VD Bortezomib Exposure Refractoriness Lenalidomide Exposure Refractoriness

63 Lenalidomide refractoriness Lenalidomide-Refractory DVd (n = 45) Vd (n = 60) 0.37 Median follow-up in ITT, months 13.0 Median PFS, months Hazard ratio (95% CI) ( ; P = ) Chanan-Khan AA, et al. Presented at: American Society of Hematology Annual Meeting. December 1-4, 2016, San Diego, CA. Abstract Lenalidomide-Refractory Kd (n = 113) Vd (n = 122) ( ) 1. Dimopoulos MA, et al. Lancet Oncol. 2016;17: Moreau P, et al. Leukemia. 2017;31:

64 OPTIMISMM: PFS Richardson P, et al. manuscript in preparation

65 COMBINED ANALYSIS: KD EFFICACY AND SAFETY IN LENALIDOMIDE EXPOSED/REFRACTORY AND RRMM PATIENTS Objective: To evaluate efficacy and safety of carfilzomib plus dexamethasone (Kd) for patients with RRMM who were previously exposed or refractory to lenalidomide 1 Methods: In a post hoc analysis, pooled data from CHAMPION-1, ENDEAVOR, and ARROW studies were grouped based on prior lines of therapy and previous lenalidomide exposure 1 CHAMPION-1 2 Phase 1/2 1 3 prior lines ENDEAVOR 3 Phase prior lines ARROW 4 Phase prior lines Weekly Kd 70 mg/m 2 Twice-weekly Kd 56 mg/m 2 Weekly Kd 70 mg/m 2 Group n Combined Population Kd, 1 prior line of therapy, len exposed 71 CHAMPION-1, ENDEAVOR Kd, 1 prior line of therapy, len refractory 32 CHAMPION-1, ENDEAVOR Kd, 1-3 prior lines of therapy, len exposed 440 CHAMPION-1, ENDEAVOR, ARROW Kd, 1-3 prior lines of therapy, len refractory (any prior) 336 CHAMPION-1, ENDEAVOR, ARROW Kd, 2-3 prior lines of therapy, len refractory (immediate prior) 228 CHAMPION-1, ENDEAVOR, ARROW 1. Mateos MV, et al. Presented at: ASH Annual Meeting; December 1 4, 2018; San Diego, CA, USA. Poster (Abstract 1963). 2. Berenson JR, et al. Blood. 2016;127: Dimopoulos MA, et al. Lancet Oncol. 2016;17: Moreau P, et al. Lancet Oncol. 19:

66 COMBINED ANALYSIS: KD EFFICACY AND SAFETY IN LENALIDOMIDE EXPOSED/REFRACTORY AND RRMM PATIENTS Groups 1 prior line, lenalinomide exposed a (n=71) 1 prior line, lenalinomide refractory b (n=32) 1-3 prior lines, lenalinomide exposed c (n=440) 1-3 prior lines, lenalinomide refractory (any prior) d (n=336) 2-3 prior lines, lenalinomide refractory (immediately prior) e (n=228) Median PFS, months (95% CI) 15.6 ( ) 15.6 (9.6 NE) 11.3 ( ) 9.6 ( ) 10.2 ( ) PFS rate at 18 months, % (95% CI) 49.8 ( ) 43.1 ( ) 35.5 ( ) 29.4 ( ) 30.1 ( ) Median follow-up, months (95% CI) 11.4 ( ) 11.2 ( ) 12.1 ( ) 12.1 ( ) 12.1 ( ) ORR, % (95% CI) 85.9 ( ) 81.3 ( ) 67.0 ( ) 62.5 ( ) 61.4 ( ) CR, % VGPR, % Mateos MV, et al. Presented at: ASH Annual Meeting; December 1 4, 2018; San Diego, CA, USA. Poster (Abstract 1963).

67 CONCLUSIONS With every subsequent line of therapy, the proportion of multiple myeloma patients receiving treatment, as well as duration of response, diminishes Newer treatments are available with Rd and non-rd combinations Carfilzomib regimens improve rate and depth of response and significantly extend progression-free and overall survival in patients with RRMM Carfilzomib improved PFS in both earlier and later lines; use at first relapse was associated with improved response rates and clinical outcomes Carfilzomib is efficacious across a wide range of patients with RRMM, including patients with prior exposure to bortezomib, prior exposure to lenalidomide, high-risk cytogenetics, and prior transplant Daratumumab regimens improve depth of response and significantly extend progression-free survival in patients with RRMM Daratumumab is efficacious in earlier and later lines of therapy Other treatments available for combination therapy are ixazomib, elotuzumab, and panobinostat Optimal sequencing is an important consideration for individual patient care

68 Kd for the Treatment of RRMM who Have Received 1-3 prior Lines of Therapy BEST FOR Patients who progress on lenalidomide Patients who are candidates for bortezomib retreatment Very good results as 2 nd line therapy Very good results for elderly patients (>75 years of age)

69 KRd for the Treatment of RRMM who Have Received 1-3 prior Lines of Therapy BEST FOR Patients with symptomatic relapse after high-dose therapy (especially within 1 year) Patients with high-risk cytogenetics who are not refractory to bortezomib and/or lenalidomide KEEP IN MIND FROM ALL NOVEL STUDIES IN RRMM (1-3 PRIOR LINES OF THERAPY) ASPIRE AND ENDEAVOR HAVE SHOWN OVERALL SURVIVAL ADVANTAGE

70 PATHOGENESIS AND MANAGEMENT OF MYELOMA-RELATED BONE DISEASE Evangelos Terpos, MD, PhD Plasma Cell Dyscrasias Unit, Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece SC-IC-CARFILZOMI-

71 BONE DISEASE IN MULTIPLE MYELOMA A burdensome and frequent complication in MM Present in up to 80% of patients at diagnosis Characterized by osteolytic bone lesions secondary to increased bone resorption and impaired bone formation Sequelae At diagnosis, lytic Pathological fractures lesions by WBXR: Osteoporosis Vertebrae in 65% of Hypercalcemia patients Bone pain Ribs in 45% Spinal cord Skull in 40% compression Shoulders in 40% Pelvis in 30% Long bones in 25% 1. Terpos E, et al. J Clin Oncol. 2011;29: ; 2. Dimopoulos M, et al. Leukemia. 2009;23:

72 BONE METABOLISM: A BALANCE BETWEEN OSTEOBLASTS AND OSTEOCLASTS Blood Vessel OSTEOBLAST DIFFERENTIATION Matrix Matrix formation maturation Proliferation & mineralization Osteoblast pregenitors Early Mature osteoblast osteoblast Lining cell Apoptosis Osteocytes Lining cells Local factors Sclerostin Osteoid Osteoblasts Osteoclasts New bone Microcrack Cement line Osteocyte apoptosis Old bone New osteocytes 1. Seeman E, et al. N Engl J Med. 2006;354: ; 2. van Bezooijen RL, et al. Cytokine Growth Factor Rev. 2005;16:

73 Images courtesy of Dr. Terpos.

74 Jilka RL, et al. Bone. 2013;54:

75 Images courtesy of Dr. Terpos.

76 RANK LIGAND: AN ESSENTIAL MEDIATOR OF OSTEOCLASTS RANKL RANK Growth factors Hormones Cytokines CFU-M CFU-M Prefusion Prefusion osteoclast osteoclast Multinucleated Multinucleated osteoclast osteoclast Mature Mature osteoclast osteoclast Osteoblast lineage Bone Boyle WJ, et al. Nature. 2003;423:

77 INCREASED BONE DENSITY ASSOCIATED WITH ABSENCE OF RANKL Preclinical Experiments Normal RANKL Knockout Li J, et al. Proc Natl Acad Sci U S A. 2000;97:

78 OSTEOPROTEGERIN: THE DECOY RECEPTOR OF RANKL Osteoclast Formation, Function, and Survival Inhibited by OPG RANKL RANK OPG Growth factors Hormones Cytokines CFU-M Prefusion osteoclast Multinucleated osteoclast Inactive osteoclast Osteoblast lineage Bone Boyle WJ, et al. Nature. 2003;423:

79 BV%T V REDUCED BONE DENSITY ASSOCIATED WITH ABSENCE OF OPG * * 10 OPG +/+ OPG +/ OPG / *P < (compared with OPG +/+). Bucay N, et al. Genes Dev. 1998;12:

80 RANKL/OPG BALANCE DRIVES OSTEOCLAST ACTIVITY Alterations of the RANKL ligand/opg ratio are critical in the pathogenesis of bone diseases that result from increased bone resorption Promotes OC activation Osteoclast activity Prevents OC activation 1. Hofbauer LC, et al. JAMA. 2004;292: ; 2. Lacey DL, et al. Cell. 1998;93: ; 3. Boyle WJ, et al. Nature. 2003;423:

81 MYELOMA MICROENVIRONMENT AND BONE DISEASE Myeloma cells RANKL OPG (-) CD138 Osteoblasts balp, osteocalcin IL-6, IGF-1 BAFF, APRIL Dkk-1, sfrp-2 sclerostin, activin-a α4β1 integrin RANKL RANKL OPG VCAM-1 VCAM-1 (-) RANKL RANK IL-6 IL-11, IL-1b, βfgf TNFα, M-CSF BMSCs MIP-1α, MIP-1β, SDF-1α, IL-3, HGF, OPN Osteoclast precursor Collagen type-1 degradation products: NTX, ICTP, CTX TRACP-5b Activated osteoclasts Bone resorption Bone matrix 1. Terpos E, et al. Ann Oncol. 2005;16: ; 2. Moreaux J, et al. Blood. 2011;117:

82 OSTEOCLASTS: KEY FOR MYELOMA CELL GROWTH Without Osteoclasts With Osteoclasts Myeloma cell culture after 14 days Abe M, et al. Blood. 2004;104:

83 BrdU (%) OSTEOCLASTS AND OSTEOBLASTS: ANTAGONISTS OF MYELOMA CELL GROWTH? P < P < P < 0.02 P < 0.04 MM MM + OC MM + OB MM + OC + OB BrdU = bromodeoxyuridine; OB = osteoblast; OC = osteoclast; MM = multiple myeloma. Yaccoby S, et al. Haematologica. 2006;91:

84 Treatment of Myeloma-Related Bone Disease

85 THERAPIES FOR MYELOMA-RELATED BONE DISEASE MULTIPLE MYELOMA PLASMA CELL VCAM1 CD40 MUC1 VLA-4 CD40L ICAM1 BHQ880 BONE MARROW STROMAL CELL LY BA FF MLN38 97 MIP- 1a Wnt receptor β-catenin MESENCHYMAL CELL Integr in FMS MAP K p38 JNK AP-1 ERK TRAF 6 P50/p52 OPG RUNX-2 OSTEOBLASTS BON E OSTEOCLAST Bisphosphonat es ACTIVIN A Sotatercept Adpated from: Raje N et al. Clin Cancer Res. 2011;17:

86 TARGETING OSTEOCLASTS WITH BISPHOSPHONATES Zolendronate stained green 1. Sato G, et al. J Clin Invest. 1991;88: ; 2. Coxon F, et al. Bone. 2008;42:

87 Survival Distribution Function Estimate OS (% Patients) ZOL SIGNIFICANTLY OS VS CLO IN PATIENTS WITH BONE DISEASE AT BASELINE (N = 1,350) Clodronate (n = 682) Zoledronic acid (n = 668) + Censored P = HR = 0.82 (95% CI = ) 10 mo Time Since Initial Randomization (y) ZOL CLO Morgan G, et al. Lancet. 2010;376:

88 IMWG RECOMMENDATIONS: BPS INITIATION AND TREATMENT DURATION BPs Initiation BPs should be initiated in patients with MM, with (grade A) or without (grade B) detectable osteolytic bone lesions on conventional radiography, who are receiving antimyeloma therapy as well as patients with osteoporosis (grade A) or osteopenia (grade C) resulting from myeloma The beneficial effect of ZOL in patients without detectable bone disease by MRI or PET/CT is unknown BPs Treatment Duration ZOL improves OS and reduces SREs over CLO in patients who received treatment for more than two years; thus it should be given until disease progression in patients not in CR/vgPR and further continued at relapse (grade B) For patients in CR/vgPR, the optimal treatment duration of BPs is unclear; the panel agrees that BPs should be given for at least 12 months and up to 24 months and then at the physician s discretion (grade D; panel consensus) Terpos E, et al. J Clin Oncol. 2013;31:

89 BPS SEVERE ADVERSE EVENTS: MRC IX STUDY ZOL (n = 213) Non-Intensive Pathway (n = 851) Intensive Pathway (n = 1,111) MP (n = 424) C-TDa (n = 427) CVAD (n = 556) C-TD (n = 555) CLO (n = 211) ZOL (n = 215) CLO (n = 212) ZOL (n = 278) CLO (n = 278) ZOL (n = 277) CLO (n = 278) ONJ b 10 (5) 0 (0) a 4 (2) 1 (< 1) 13 (5) 2 (1) a 8 (3) 0 (0) a Thromboemboli c Acute renal failure Infection TESAE 10 (5) 10 (5) 43 (20) 25 (12) a 59 (21) 41 (15) 45 (16) 41 (15) 15 (7) 13 (6) 13 (6) 14 (7) 14 (5) 17 (6) 15 (5) 16 (6) 4 (2) 4 (2) 12 (6) 14 (7) 28 (10) 37 (13) 24 (9) 25 (9) All SAEs 97 (46) 81 (38) 115 (53) 117 (55) 167 (60) 155 (56) 160 (58) 125 (45) a TESAEs 27 (13) 18 (9) 63 (29) 67 (32) 74 (27) 69 (25) 84 (30) 72 (26) Morgan G, et al. Lancet. 2010;376:

90 OSTEONECROSIS OF THE JAW (ONJ) ONJ occurs in approximately 4% 11% of those who receive BPs Risk Factors: Invasive dental procedures (eg, tooth extraction and dental implants); poor oral hygiene; age; duration of BPs administration 1. Terpos E, et al. Expert Rev Hematol. 2014;7: ; 2. Melea PI, et al. Int J Dent. 2014;2014:

91 PATIENTS WITH RENAL FAILURE Patients with mild to moderate renal impairment (CrCl ml/min) should receive reduced doses of zoledronic acid and clodronate. No change to zoledronic acid infusion time is recommended Pamidronate should be administered via 4-hours infusion in patients with mild to moderate renal impairment Pamidronate and zoledronic acid are not recommended for patients with CrCl < 30 ml/min Bisphosphonate therapy should be discontinued in patients experiencing renal problems until CrCl returns to within 10% of baseline values Terpos E, et al. J Clin Oncol. 2013;31:

92 DENOSUMAB IS THE FIRST FULLY HUMAN MAB AGAINST RANKL IN CLINICAL USE 1997 Present Fc-OPG OPG-Fc RANK-Fc Denosumab = Fc = RANK Fusion proteins: Induced antibodies Short half-life Fully human antibody against RANK-ligand Simonet WS, et al. Cell. 1997;89:

93 DENOSUMAB MECHANISM OF ACTION Denosumab Inhibits Osteoclast Formation, Function, and Survival Denosuma b OPG RANKL RANK CFU-M Pre-Fusion Osteoclast Growth Factors Hormones Cytokines Multinucleated Osteoclast Mature Osteoclast Bone Boyle WJ, et al. Nature. 2003;423:

94 DENOSUMAB VS ZOLEDRONIC ACID IN MYELOMA: STUDY DESIGN Randomization (N = 1,718) Stratified by: Planned autologous PBSC transplant (yes/no) Disease stage (ISS 1, 2, or 3) Antimyeloma agent: Novel therapy-based vs non-novel therapy-based Previous SRE (yes/no) Region (Japan yes/no) Denosumab 120 mg SC + Placebo IV Q4W (n = 859) Placebo SC + Zoledronic acid 4 mg IV Q4W (n = 859) Primary endpoint: Noninferiority for First On-Study SRE 676 Events Offered open-label denosumab up to 2 years Yes Benefit:Risk positive? No 2-year follow-up for survival Raje N, et al. Lancet Oncol. 2018;19:

95 KEY ENDPOINTS Primary Time to the first on-study skeletal-related event (noninferiority). Secondary Time to the first on-study skeletal-related event (superiority). Time to the first-and-subsequent on-study skeletal-related event (superiority). Overall survival. Exploratory Raje N, et al. Lancet Oncol 2018;19:

96 BASELINE PATIENT DEMOGRAPHICS AND CHARACTERISTICS Denosumab N = 859; n (%) Zoledronic Acid N = 859; n (%) All Patients N = 1718; n (%) Male 462 (53.8) 473 (55.1) 935 (54.4) Female 397 (46.2) 386 (44.9) 783 (45.6) Mean Age (Years) Median Europe 509 (59.3) 513 (59.7) 1022 (59.5) North America 218 (25.4) 227 (26.4) 445 (25.9) Rest of the World 132 (15.4) 119 (13.9) 251 (14.6) Prior SRE History (Yes) 567 (66.0) 577 (67.2) 1144 (66.6) Multiple Myeloma ISS Stage at Diagnosis I 272 (31.7) 275 (32.0) 547 (31.8) II 307 (35.7) 326 (38.0) 633 (36.8) III 257 (29.9) 232 (27.0) 489 (28.5) Not Available 23 (2.7) 26 (3.0) 49 (2.9) Class of the First-Line Therapy Proteasome Inhibitor Only 441 (51.3) 452 (52.6) 893 (52.0) Immunomodulatory Drug Only 133 (15.5) 154 (17.9) 287 (16.7) Proteasome Inhibitor + Immunomodulatory Drug 248 (28.9) 215 (25.0) 463 (26.9) Other 33 (3.8) 36 (4.2) 69 (4.0) Intent to Undergo Autologous PBSC Transplantation: Yes 465 (54.1) 465 (54.1) 930 (54.1) Raje N, et al. Lancet Oncol 2018;19:

97 Proportion Of Subjects Without SRE RESULTS: FIRST ON-STUDY SRE Primary Endpoint Met: Noninferiority for First On-Study SRE 1.0 Denosumab 120 mg Q4W (N = 859) Zoledronic Acid 4 mg Q4W (N = 859) Denosumab 120 mg Q4W Zoledronic Acid 4 mg Q4W Study Month Raje N, et al. Lancet Oncol. 2018;19:

98 THE MAJORITY OF ON-STUDY SKELETAL-RELATED EVENT S OCCURRED WITHIN 3 MONTHS Proportion of Patients Without a Skeletal-Related Event Incidence of on-study skeletal-related events was high and occurred early 44% of patients had at least one, on study SRE, with 60% of all first skeletal-related events occurring within 3 months Multiple myeloma patients have widespread bone loss that may not be detectable and correlates with an increased risk of early vertebral collapse HR (95% CI) = 0.98 (0.85, 1.14); P = 0.01 (Noninferiority met) P = 0.82 (Superiority not met) Study Month Denosumab: Zoledronic Acid: Terpos E, et al. Presented at: 22nd Congress of the European Hematology Association. June 22-25, Madrid, Spain. Abstract S782. CI Confidence interval; HR Hazard ratio; Q4W every 4 weeks. Denosumab 120 mg Q4W (N = 859) Zoledronic Acid 4 mg Q4W (N = 859)

99 Proportion Without a SRE on Study (%) POST-HOC LANDMARK ANALYSIS AT 15 MONTHS HR (95% CI) = 0.66 ( ); P = Time Since Randomization (months) Number at risk (censored) Denosumab: (0) (72) (58) (53) (50) (36) (44) (30) (26) (25) Zoledronic Acid: (0) (78) (61) (54) (46) (43) (36) (26) (22) (21) Raje N, et al. Lancet Oncol 2018;19:

100 Proportion of Subjects Without Event RESULTS: PROGRESSION-FREE SURVIVAL 1.0 Denosumab 120 mg Q4W (N = 859) Zoledronic Acid 4 mg Q4W (N = 859) HR (95% CI) = 0.82 (0.68, 0.99); descriptive P = Denosumab 120 mg Q4W Zoledronic Acid 4 mg Q4W Denosumab median (95% CI) = mo (34.3, NE) Zoledronic acid median (95% CI) = mo (30.19, NE) Study (mo) Raje N, et al. Lancet Oncol. 2018;19:

101 1969 Progression-Free Survival Subset Analysis - Denosumab Vs Zoledronic Acid in Bone Disease Treatment of Newly Diagnosed Multiple Myeloma: An International, Double-Blind, Double-Dummy, Randomized Controlled Phase 3 Study Evangelos Terpos, MD, PhD 1, Wolfgang Willenbacher, MD 2, Kazuyuki Shimizu, MD, PhD 3*, Ramon García- Sanz, MD, PhD 4, Anthony Glennane, MD 5*, Xuesong Guan 5*, Daniela Niepel 6* and Noopur Raje, MD 7

102 1969 Progression-Free Survival Subset Analysis - Denosumab Vs Zoledronic Acid in Bone Disease Treatment of Newly Diagnosed Multiple Myeloma: An International, Double-Blind, Double-Dummy, Randomized Controlled Phase 3 Study Evangelos Terpos, MD, PhD 1, Wolfgang Willenbacher, MD 2, Kazuyuki Shimizu, MD, PhD 3*, Ramon García- Sanz, MD, PhD 4, Anthony Glennane, MD 5*, Xuesong Guan 5*, Daniela Niepel 6* and Noopur Raje, MD 7

103 Proportion of Subjects Survived RESULTS: OVERALL SURVIVAL 1.0 Denosumab 120 mg Q4W (N = 859) Zoledronic Acid 4 mg Q4W (N = 859) Denosumab 120 mg Q4W Zoledronic Acid 4 mg Q4W HR (95% CI) = 0.90 (0.70, 1.16); P = 0.41 Denosumab: 121 deaths (14.1%) Zoledronic acid: 129 deaths (15%) Study Month Raje N, et al. Lancet Oncol. 2018;19:

104 RESULTS: ADVERSE EVENTS OF INTEREST Zoledronic Acid (N = 852) n (%) Denosumab (N = 850) n (%) Hypocalcemia 106 (12.4) 144 (16.9) Serious AEs of hypoglycemia 2 (0.2) 8 (0.9) Adjudicated positive osteonecrosis of the jaw 24 (2.8) 35 (4.1) Adjudicated positive atypical femur fracture 0 0 AEs potentially associated with hypersensitivity 189 (22.2) 219 (25.8) Serious AEs potentially associated with hypersensitivity 9 (1.1) 5 (0.6) Musculoskeletal pain 425 (49.9) 407 (47.9) Infections and infestations 500 (58.7) 537 (63.2) Serious AEs of infections and infestations 163 (19.1) 165 (19.4) New primary malignancy 12 (1.4) 22 (2.6) Renal toxicity TEAEs 146 (17.1) 85 (10.0) in patients with baseline CrCl < 60 ml/min 58/220 (26.4) 30/223 (12.9) Creatinine > 2 mg/dl 54/823 (6.6) 31/824 (3.8) in patients with baseline CrCl < 60 ml/min 32/203 (15.8) 20/216 (9.3) Creatinine doubled from baseline 55/840 (6.5) 28/841 (3.3) in patients with baseline CrCl < 60 ml/min 16/220 (7.3) 6/233 (2.6) Raje N, et al. Lancet Oncol 2018;19:

105 CONCLUSIONS FOR DENOSUMAB Non-inferiority was demonstrated for the primary endpoint of time to first SRE However, the 15-month landmark analysis demonstrated an improved delay in time to first skeletal-related events for patients treated with denosumab Progression-free survival for denosumab was longer (10.7 months) compared to zoledronic acid, with an HR (95% CI) = 0.82 (0.68, 0.99), descriptive P = Safety data from this study were comparable to those seen in the previous SRE studies, with overall adverse events similar between the arms There were 35 (4.1%) and 24 (2.8%) positively adjudicated events of osteonecrosis of jaw (ONJ) in the denosumab arm and ZA arm, respectively Hypocalcemia events for denosumab and ZA were 144 (16.9%) and 106 (12.4%), respectively, with no grade 5 events Fewer AEs potentially related to renal toxicity occurred with denosumab than ZA (10% vs 17.1%), as with acute phase reactions (5.4% vs 8.7%) The bone-specific benefits and observed prolongation of progression-free survival in combination with a better renal toxicity profile provides denosumab is the new standard of care for multiple myeloma patients

106 CAN WE DISCONTINUE DENOSUMAB LIKE BPS? HOW ABOUT DENOSUMAB REBOUND EFFECT?

107 DENOSUMAB REBOUND EFFECT

108 CAN WE DISCONTINUE DENOSUMAB LIKE BPS? HOW ABOUT DENOSUMAB REBOUND EFFECT?

109 CONCLUSIONS FOR THE MANAGEMENT OF MYELOMA-RELATED BONE DISEASE Osteolytic bone disease is the main complication of myeloma BPs treatment of choice: zoledronic acid, pamidronate ZOL OS vs clodronate in MM patients with bone disease at baseline. It is recommended for use in active myeloma (not in CR/vgPR after 2 years); caution is needed for ONJ and renal impairment For patients with renal impairment (RI) bortezomib can reverse RI and then can be combined with BPs; denosumab dosing is not dependent on kidney function Denosumab is the new standard of care: its beneficial effects on bone metabolism along with prolongation of PFS and better renal safety profile makes it an appealing new treatment for bone disease management in MM

110 Thank you