Nuove indicazioni e nuove terapie nel mieloma mul2plo

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1 Nuove indicazioni e nuove terapie nel mieloma mul2plo Paola Tacche* Seràgnoli Ins3tute of Hematology Bologna University School of Medicine

2 Mul2ple factors contribute to the clonal evolu2on and treatment resistance in MM Intrinsic gene3c changes within clones IgH transloca3on Hyperdiploidy Epigene3c events Muta3ons Bone marrow microenviroment Treatment-driven clonal selec3on MM cell MM clones Treatmentresistant clones Bone marrow Mul3linear branching of clonal architecture Morgan GJ et al. Nat Rev Cancer 212;12:

3 Why do we fail?: genomic clompexity War of the clones! 5 unique clones at diagnosis! Variable chemotherapy response! Minor drug resistant clone may become lethal Keats JJ et al. Blood 212;12(5):

4 Implica2ons of biology for treatment Mul3ple clones with variable drug sensi3vity Combina3on chemotherapy a necessity Resuscita3on of drug-sensi3ve clones Once resistant, not always resistant Con3nuous suppressive therapy logical Minor drug-resistant clones lethal Complete response is required Keats JJ et al. Blood 212;12(5):

5 Front line treatment ESMO guidelines 217 VRd vs Rd improved PFS and OS and had an acceptable risk benefit profile, in a phase 3 trial. Nevertheless, this triplet combina3on is not yet approved by the EMA Durie BGM et al. Lancet 216 In Feb 217, the EMA approved lena as monotherapy for the maintenance treatment of pts with newly diagnosed MM who have undergone ASCT Aaal M et al, ASCO 216 Moreau P et al. Ann Oncol. 217

6 Relapsed/Refractory Mul2ple Myeloma: Changing the Paradigm M-protein (g/l) Active MM MGUS or SMM Plateau remission FIRST RELAPSE Newer agents? SECOND RELAPSE REFRACTORY THIRD RELAPSE RELAPSE First-line therapy Second-line therapy Third-line therapy ACTIVE MYELOMA MGUS, monoclonal gammopathy of unknown significance; MM, multiple myeloma; SMM, smoldering multiple myeloma. Figure adapted from Durie BGM. Concise review of the disease and treatment options. Multiple myeloma; 211/212. Available at:

7 Current novel therapies for RRMM by the drug s mechanism of ac2on Immunomodulators Thalidomide Lenalidomide Pomalidomide Proteasome inhibitors Bortezomib Carfilzomib Ixazomib Monoclonal an3bodies Daratumumab Elotuzumab Histone deacetylase Panobinostat

8 Treatment op2ons for R/R MM Transplant Eligible Pa2ents Bortezomib-based Induc2on Transplant Inelegible Pa2ents VMP, Rd (MPT) Autologous Transplant Second Transplant Rd, KRd,,ERd, IRd, Dara-Rd FIRST RELAPSE Vd, Kd, Dara-Vd SECOND RELAPSE Rd, KRd, ERd, Ird, Dara-Rd Vd, Kd, Dara-Vd, PanVd Pomalidomide- Dexamethasone Daratumumab Single Agent Clinical trials (MoAbs, check-point inhibitors, venetoclax, selinexor, an2 BCMA )

9 Key clinical considera2ons at relapse Age Support network QoL Oral vs IV Pa2ent Co-morbidi3es Performance status Bone marrow reserve Prior treatment ASCT PI-based IMiD-based Alkylators Maintenance CONSIDERATIONS Disease and molecular assessment Extramedullary disease Clinical vs biochemical relapse Cytogene3c risk status Aggressiveness of relapse Focal lesions Speed paraprotein increase Response and tolerability Response to prior therapy Side effects PFS TFI

10 Plethora of new randomized studies to help guide treatment decisions Control Arm Comparator Arm Trial Bortezomib-Dexamethasone Lenalidomide-Dexamethasone Carfilzomib-dexamethasone Panobinostat-bortezomib-dexamethasone Daratumumab-bortezomib-dexamethasone Carfilzomib-lenalidomide-dexamethasone Ixazomib-lenalidomide-dexamethasone Elotuzumab-lenalidomide-dexamethasone Daratumumab-lenalidomide-dexamethasone ENDEAVOR PANORAMA1 CASTOR ASPIRE TOURMALINE1 ELOQUENT2 POLLUX

11 Op2ons of therapy for RRMM pa2ents Induc2on Bortezomib-based combina2on ASCT (melphalan 2) Induc2on Bortezomib-based combo Lenalidomide-dex Nothing/Consolida2on/Maintenance Second ASCT/Allo-RIC 1st relapse IMiD s-based combina2ons Carfilzomib plus Rd Daratumumab plus Rd Elotuzumab plus Rd Ixazomib plus Rd 1. Stewart AK, et al. N Engl J Med 215;372:142-52; 2. Lonial S, et al. N Engl J Med 215; 373(7):621 31; 3. Dimopoulos et al. N Engl J Med 216; 375: Moreau P et al. N Engl J Med 216;374(17):

12 Proportion Surviving Without Progression KRd Rd ASPIRE: KRd vs Rd (N=792) ORR: 87% vs 66% CR rate: 32% vs 9% KRd Rd (n=396) (n=396) Median PFS, mo HR (KRd/Rd) (95% CI),69 (.57.83) P value (one-sided) < Months Since Randomization No. at Risk: KRd 396 Median 332 follow-up 279 was months 179 for KRd and months 24 for 1 Rd KRd-treated Rd pts had 396 a 31% 287 reduc2on 26 in the 151 risk of disease 117 progression 72 or 18 death in 1 comparison with Rd Stewart K et al, NEJM 215

13 Primary Endpoint: PFS by previous treatment 1 previous line of tp 2 previous lines of tp Dimopoulos MA, Blood Cancer Journal 217

14 Primary Endpoint: PFS by previous treatment Previous Btz exposure Previous Len exposure Dimopoulos MA, Blood Cancer Journal 217

15 TOURMALINE-MM1: IRd vs Placebo-Rd Number of pa2ents at risk: Time from randomization (months) IRd Placebo-Rd Probability of progression-free survival Log-rank test p=.12 Hazard ratio (95% CI):.742 (.587,.939) Number of events: IRd 129; placebo-rd 157 ORR: 78% vs 72% CR rate: 12% vs 7% Median PFS: IRd: 2.6 months Placebo-Rd: 14.7 months Median follow-up: 14.8 months in the IRd group and 14.6 months in the placebo-rd group 26% reduc2on in the risk of progression of death Moreau P et al. NEJM 216

16 Consistent PFS benefit across pre-specified pa2ent 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 Favors IRd Favors placebo-rd

17 ELOQUENT-2: Elo-Ld vs Ld ORR: 79% vs 66% CR rate: 5% vs 9% 1. 1-year PFS 2-year PFS 3-year PFS.9 E-Ld Ld Probability progression free % 57% 41% 27% 26% 18% HR.73 (95% CI.6,.89); p=.14 Median PFS (95% CI) 19.4 mos (16.6, 22.2) E-Ld Ld 14.9 mos (12.1, 17.2). No. of pa2ents at risk: E-Ld Ld PFS (months) PFS benefit with Elo-Rd was maintained over time (vs Rd): Overall 27% reduction in the risk of disease progression or death Lonial S et al, NEJM 215 Dimopoulos MA, et al ASH 215

18 ELOQUENT-2 Probability of patients without next treatment ELOQUENT-2: EloRd vs Rd Time to Next Treatment Median TTNT (95% CI) E-Ld HR.62 (95% CI.5,.77) 33 mos (26.15, 4.21) E-Ld Ld Ld 21 mos (18.7, 23.2). No. of patients at risk: E-Ld Ld Time to next treatment (months) E-Ld-treated patients had a median delay of 1 year in the time to next treatment vs Ld-treated patients Lonial S et al, NEJM 215

19 Progression-Free Survival in Predefined Subgroups Subgroup Hazard ratio (95% CI) Age (<65 years).75 ( ) Age ( 65 years).65 (.5.85) ß 2 microglobulin (<3.5 mg/l).61 (.46.81) ß 2 microglobulin ( 3.5 mg/l).79 (.6 1.5) ISS stage (I).63 (.46.87) ISS stage (II).86 ( ) ISS stage (III).7 ( ) Response to most recent therapy (refractory).56 (.4.78) Response to most recent therapy (relapsed).77 (.6 1.) Lines of prior therapy (1).75 (.56 1.) Lines prior therapy (2 or 3).65 (.49.87) Prior IMiD (none).78 ( ) Prior IMiD (prior thalidomide only).64 (.48.85) Prior IMiD (other).59 ( ) Prior bortezomib (yes).68 (.54.86) Prior bortezomib (no).72 ( ) Prior lenalidomide (yes).59 ( ) Prior lenalidomide (no).7 (.57.87) Prior SCT (yes).75 (.58.99) Prior SCT (no).63 (.46.86) del(17p) (yes).65 (.45.94) 1q21 (yes).75 (.56.99) t(4;14) (yes).53 (.29.95) CrCl (<6 ml/min).56 (.39.82) CrCl ( 6 ml/min).74 (.58.94) Favors E-Ld Favors control Hazard ratio (95% CI) From N Engl J Med, Lonial, S et al, Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma. Copyright (215) Massachusetts Medical Society. Reprinted with permission

20 Pa2ents With Median Time From Diagnosis (3.5 yrs) Probability progression-free Probability progression-free Median 2me from diagnosis; 1 prior line of therapy HR.47 Probability progression-free Median 2me from diagnosis; >1 prior line of therapy HR.59 ERd (n=48).2 ERd (n=111) Rd (n=61) Rd (n=96) Time (months) Time (months) Pa2ents With < Median Time From Diagnosis < Median 2me from diagnosis; < Median 2me from diagnosis; 1. 1 prior with line of median therapy time from diagnosis more than 1 prior line of therapy Greater magnitude of benefit was observed in patients ERd (n=98) Rd (n=96) HR Time (months) Probability progression-free ERd (n=56) Rd (n=63) HR Time (months)

21 POLLUX: DaraRd vs Rd % surviving without progression No. at risk Rd DRd HR:.37 (95% CI,.28-.5; P <.1) Months month PFS* % 49% 5 15 Median: not reached DRd Rd Median: 17.5 months 1 1 Overall response rate, % CR: 46% a ORR = 93% P <.1 CR: 2% VGPR: 78% a ORR = 76% DRd (n = 281) Rd (n = 276) VGPR: 45% scr CR VGP R PR Median follow-up: 17.3 (range, -24.5) months DRd-treated pa2ents had a 63% reduc2on in the risk of disease progression or death in comparison with Rd Responses con2nue to deepen in the DRd group with longer follow-up Note: PFS: ITT population; TEAE, ORR: treatment-emergent response-evaluable adverse population. event; IRR, infusion-related reaction. * Kaplan-Meier estimate; a Common TEAEs listed are either 25% all grade OR 5% grade 3/4. a P <.1 for DRd vs b Vd Rd. arm treated for 8 cycles and DVd arm treated until progressive disease, per protocol. Usmani SZ, et al. Presented at ASH 216 (Abstract 1151), oral presenta3on.

22 Dimopoulos MA, et al. N Engl J Med 216;375:

23 POLLUX: DaraRd vs Rd Lenalidomide-naïve a Lenalidomide-exposed a 1 18-month PFS b 1 18-month PFS b % surviving without progression % 49% DRd Rd Median: 17.1 months % surviving without progression % 59% DRd Rd No. at risk Rd DRd HR:.37 (95% CI, ; P <.1) Months No. at risk Rd 45 DRd 46 HR:.45 (95% CI,.2-.99; P =.42) Months DRd maintains treatment benefit in lenalidomide-naïve and exposed pa2ents a in 1 to 3 prior lines b Kaplan-Meier estimate. Moreau P, et al. Presented at ASH 216 (Abstract 489), oral presenta3on

24 POLLUX: DaraRd vs Rd Refractory to Last Line of Therapy a (28% of patients in both arms) Bortezomib-refractory a 1 18-month PFS b 1 18-month PFS b % surviving without progression % 37% Median: 8.8 months DRd Rd % surviving without progression % 4% Rd Median: 1.3 months DRd Rd DRd No. at risk Months HR:.45 (95% CI, ; P =.14) No. at risk Rd DRd HR:.51 (95% CI, ; P =.21) Months DRd treatment benefit observed in pa2ents refractory to last line of therapy, including bortezomib-refractory pa2ents a in 1 to 3 prior lines b Kaplan-Meier estimate. Moreau P, et al. Presented at ASH 216 (Abstract 489), oral presenta3on

25 POLLUX: DaraRd vs Rd MRD-negative Rate (1 5 ) by Prior Treatment Status MRD negative, % *** 3.6X 32 9 *** 4.2X *** 4.X 3 % surviving without progression Rd MRD negative DRd MRD negative DRd MRD positive Rd MRD positive Sensitivity threshold *** P <.1 DRd Rd No. at risk Rd MRD negative DRd MRD negative Rd MRD positive DRd MRD positive Months MRD-nega2ve pa2ents achieve prolonged PFS Moreau P, et al. Presented at ASH 216 (Abstract 489), oral presenta3on

26 Options of therapy for RRMM patients Induction Bortezomib-based combination ASCT (melphalan 2) Induction Bortezomib-based combo Lenalidomide-dex Nothing/Consolidation/Maintenance Second ASCT/ Allo-RIC 1st relapse IMiDs-based combinations Carfilzomib plus Rd PFS: 26.3m, HR:.69 1 Elotuzumab plus Rd PFS: 19.4m, HR:.73 2 Daratumumab plus Rd PFS: NR (76%@18m), HR:.37 3 Ixazomib plus Rd PFS: 2.6m, HR: Stewart AK, et al. N Engl J Med 215;372:142-52; 2. Dimopoulos MA et al. presented at ASH 215 (Abstract 28), oral presenta3on; 3. Usmani SZ, et al. Presented at ASH 216 (Abstract 1151), oral presenta3on; 4. Moreau P et al. N Engl J Med 216;374(17):

27 Options of therapy for RRMM patients Induction Bortezomib-based combination ASCT (melphalan 2) Induction Bortezomib-based combo Lenalidomide-dex Nothing/Consolidation/Maintenance Second ASCT/ Allo-RIC PIs-based combinations 1st relapse IMiDs-based combinations Kd VD + Daratumumab Carfilzomib plus Rd PFS: 26.3m, HR:.69 1 Elotuzumab plus Rd PFS: 19.4m, HR:.73 2 Daratumumab plus Rd PFS: NR, HR:.37 3 Ixazomib plus Rd PFS: 2.6m, HR: Stewart AK, et al. N Engl J Med 215;372:142-52; 2. Dimopoulos MA et al. presented at ASH 215 (Abstract 28), oral presenta3on; 3. Usmani SZ, et al. Presented at ASH 216 (Abstract 1151), oral presenta3on; 4. Moreau P et al. N Engl J Med 216;374(17):

28 Proportion Surviving Without Progression ENDEAVOR: Kd at double dose (56 mg/sm) vs Vd (N=929) ORR: 77% vs 63% CR rate: 13% vs 6% Kd Vd Disease progression or death n (%) Median PFS months HR for Kd vs Vd (95% CI) Kd (n=464) 171 (37) 18.7 Vd (n=465) 243 (52) (.44.65) 1-sided P< Months Since Randomization " Median follow-up: 11.9 in the carfilzomib group vs 11.1 in the bortezomib group Dimopoulos D et al, Lancet Oncology 216

29 Progression-Free Survival by Subgroup Kd Vd All patients, n (%) 464 (1) 465 (1) Age, n (%) < (48) 21 (45) (35) 189 (41) (17) 66 (14) ECOG performance status, n (%) 221 (48) 232 (5) (45) 23 (44) 2 32 (7) 3 (6) Baseline creatinine clearance, ml / min, n (%) <3 28 (6) 28 (6) 3 <5 57 (12) 71 (15) 5 <8 186 (4) 177 (38) (42) 189 (41) Prior peripheral neuropathy, n (%) No 249 (54) 221 (48) Yes 215 (46) 244 (52) ISS stage, n (%) I 25 (44) 24 (44) II or III 259 (56) 261 (56) Risk group by FISH, n (%) High 97 (21) 113 (24) Standard 284 (61) 291 (63) Kd better Vd better HR (95% CI).53 (.44.65).58 (.44.78).53 (.38.73).38 (.23.65).51 (.38.68).6 (.45.81).25 (.12.55).99 ( ).35 (.2.6).48 (.35.65).6 (.43.83).52 (.4.69).54 (.41.72).45 (.32.63).57 (.45.72).65 (.45.92).44 (.33.58) Dimopoulos D et al, Lancet Oncology 216

30 Progression-Free Survival by Subgroup (con2nued) Kd Vd Kd better Vd better HR (95% CI) All patients, n (%) 464 (1) 465 (1) Number of prior regimens, n (%) (5) 229 (49) 2 3* 233 (5) 236 (51) Prior stem cell transplant, n (%) No 198 (43) 193 (42) Yes 266 (57) 272 (58) Prior bortezomib, n (%) No 214 (46) 213 (46) Yes 25 (54) 252 (54) Prior lenalidomide, n (%) No 287 (62) 288 (62) Yes 177 (38) 177 (38) Prior IMiD and bortezomib, n (%) No 36 (66) 298 (64) Yes 158 (34) 167 (36) Refractory to lenalidomide, n (%) No 351 (76) 343 (74) Yes 113 (24) 122 (26).53 (.44.65).45 (.33.61).6 (.47.78).43 (.32.59).61 (.47.79).48 (.36.66).56 (.44.73).43 (.32.56).69 (.52.92).47 (.36.61).64 (.47.86).44 (.34.56).8 ( ) Dimopoulos D et al, Lancet Oncology 216

31 CASTOR: DaraVd vs Vd % surviving without progression 1 Vd DVd month PFS a 6% 22% Vd DVd Median: 7.1 months HR:.33 (95% CI, ; P <.1) Months ORR, % CR 26% b ORR = 84% 7% 19% 35% 22% P <.1 CR 1% VGPR 62% b ORR = 63% 2% 8% 19% 34% DVd (n = 24) Vd (n = 234) VGPR 29% scr CR VGPR PR! Median (range) follow-up: 13. (-21.3) months! An addi3onal 7% of pa3ents receiving DVd achieved CR with DVd-treated longer pa2ents follow-up had a 67% reduc2on in the risk of disease progression or death in comparison with Vd Responses con2nue to deepen in the DVd group with longer follow-up ITT, intent-to-treat. Note: PFS = ITT population; ORR = response-evaluable population. a Kaplan-Meier estimate. b P <.1 for DVd versus Vd. Mateos M, et al. Presented at ASH 216 (Abstract 115), oral presenta3on;

32 PFS: Subgroup Analysis HR (95% CI) HR (95% CI) Age Prior bortezomib tx <65 years.44 (.28,.68) Yes.46 (.32,.66) 65 ISS staging.35 (.22,.57) No Prior IMiD.25 (.13,.47) I.25 (.13,.48) Yes.38 (.27,.55) II.37 (.23,.61) No.5 (.24, 1.4) III.55 (.31,.98) Refractory to IMiD Prior lines of tx Yes.5 (.31,.8) 1.31 (.18,.52) No.32 (.18,.59) 2.5 (.28,.89) Refractory to last line of prior tx 3.66 (.31, 1.41) Yes.42 (.25,.7) >3.48 (.2, 1.16) No.38 (.25,.59) Prior ASCT Renal function (baseline CrCl) Yes No.38 (.26,.57).34 (.19,.59) >6 ml/min 6 ml/min.3 (.2,.44).55 (.3, 1.2) Favor DVd Favor VD Favor DVd Favor VD Tx, treatment; CrCl, creatinine clearance. CrCl, creatinine clearance. Palumbo. N Engl J Med

33 PFS by Prior Bortezomib Exposure: 1 Prior Line Popula2on 1 % surviving without progression DVd No prior bortezomib DVd DVd Prior bortezomib Vd No prior bortezomib Vd Vd Prior bortezomib No. at risk Vd DVd Vd No prior bortezomib DVd - No prior bortezomib Vd Prior bortezomib DVd - Prior bortezomib Months DVd provides treatment benefit regardless of prior bortezomib exposure Mateos M, et al. Presented at ASH 216 (Abstract 115), oral presenta3on;

34 PFS: Prior Lines of Treatment % surviving without progression No. at risk Vd 113 DVd prior line 12-month PFS a 77% 25% Vd DVd Median: 7.9 months HR:.22 (95% CI, ; P <.1) Months % surviving without progression to 3 prior lines HR:.51 (95% CI, ; P =.2) month PFS a Months % 22% Median: 9.8 months 4 1 Vd 1 DVd Median: 6.3 months DVd is superior to Vd regardless of prior lines of therapy, with greatest benefit observed in 1 prior line a Kaplan-Meier estimate. Mateos M, et al. Presented at ASH 216 (Abstract 115), oral presenta3on;

35 MRD-negative rate, % Sensiti vity thresh old MRD rates and PFS MRD rates on ITT (N = 498) *** 5.1X 18,3 3,6 1,4 ** ** 4.3X 5.5X 2,4 4,4,8 DVd Vd DVd Vd DVd Vd ! MRD was evaluated by ClonoSEQ-NGS-based assay in a central lab at three sensitivity thresholds, for patients with suspected CR and also for patients who maintain CR at C9 and C15 % surviving without progression PFS on ITT (1-5 ) Months Vd MRD negative DVd MRD negative DVd MRD positive Vd MRD positive MRD-negative rates for DVd were 3-fold higher across all thresholds MRD negativity is associated with better outcomes ***P <.1; **P <.1; NS, not significant. P values calculated using likelihood-ratio chi-square test. MRD-negativity rate = proportion of pti with negative MRD test results at any time during treatment. Mateos M, et al. Presented at ASH 216 (Abstract 115), oral presenta3on;

36 Options of therapy for RRMM patients Induction Bortezomib-based combination ASCT (melphalan 2) Induction Bortezomib-based combo Lenalidomide-dex Nothing/Consolidation/Maintenance PIs based combinations 1st relapse IMiDs based combinations Kd PFS: 18.7 months, HR:.53 1 VD + Daratumumab PFS: NR (6%@12m) HR:.33 7 Carfilzomib plus Rd PFS: 26.3m, HR:.69 2 Elotuzumab plus Rd PFS: 19.4m, HR:.73 3 Panobinostat-bz/cz PFS: 12 months, HR:.63 6 Elo-Bd PFS: 9.7m, HR:.72 8 Daratumumab plus Rd PFS: NR (76%@18m), HR:.37 4 Ixazomib plus Rd PFS: 2.6m, HR: Dimopoulos MA, et al. Lancet Oncology 216; 17: ; 2. Stewart AK, et al. N Engl J Med 215;372:142-52; 3. Dimopoulos MA et al. presented at ASH 215 (Abstract 28), oral presenta3on; 4. Usmani SZ, et al. Presented at ASH 216 (Abstract 1151), oral presenta3on; 5. Moreau P et al. N Engl J Med 216;374(17): ; 6. San Miguel JF, et al. Lancet Oncol. 214;15(11): ; 7. Mateos M, et al. Presented at ASH 216 (Abstract 115), oral presenta3on; 8. Jakubowiak A et al. Blood 216: 127(23):2833-4

37 Adverse events ASPIRE COMBINATION GRADE 3 / 4 (%) Rd + Carfilzomib HYPERTENSION (4) CARDIAC FAILURE (4) ACUTE RENAL FAILURE (3) ELOQUENT TOURMALINE POLLUX PANORAMA ENDEAVOR POLLUX Rd + Elotuzumab Rd + Ixazomib Rd + Daratumumab Vd + Panobinostat Kd Vd + Daratumumab INFUSION REACTION (1) RASH (5) INFUSION REACTION (5) DIARRHEA (25) FATIGUE (24) VOMITING (7) HYPERTENSION (9) DYSPNEA (5) CARDIAC FAILURE (5) INFUSION REACTION (9) HYPERTENSION (7)

38 How are we going to proceed in the clinical prac2ce? Type of relapse: aggressive, - KRd/DaraRd for aggressive relapses with rapid control required

39 How are we going to proceed in the clinical prac2ce? Type of relapse: aggressive, - KRd/DaraRd for aggressive relapses with rapid control required Age: all combos work be-er in young pts - IMiDs-based combos: DaraRd & EloRd... 1st preference for elderly - PIs-based combos: DaraVd & Kd... 1st preference for elderly Stewart AK, et al. N Engl J Med 215;372:142-52; Dimopoulos MA et al. presented at ASH 215 (Abstract 28), oral presenta3on; Moreau P et al. N Engl J Med 216;374(17): ; Dimopoulos et al. Presented at EHA 216 (Abstract LB2238), oral presenta3on; Palumbo A, et al. Poster presented at ASH 215 (Abstract 1844), oral presenta3on; Palumbo, A. N Engl J Med (8):

40 How are we going to proceed in the clinical prac2ce? Type of relapse: aggressive, - KRd/DaraRd for aggressive relapses with rapid control required Age: all combos work be-er in young pts - IMiDs-based combos: DaraRd & EloRd... 1st preference for elderly - PIs-based combos: DaraVd & Kd... 1st preference for elderly Number and type of prior lines of therapy - KRd: aser PIs/PIs-sensi3ve; aser 1 and 2 lines - IRd: aser PIs/PIs-sensi3ve; aser 2-3 prior lines; primary refractory - DaraRd: aser PIs/regardless PIs-sensi3vity; aser 1 and 2 lines - EloRd: aser PIs/regardless PIs-sensi3vity; 3me from dx is > 3.5 yrs (regardless 1 vs 2) - Kd: aser PIs/IMiDs (s/r); aser 1 or 2 prior lines - DaraVd: aser PIs/IMiDs (s/r); aser 1 line Dimopoulos MA, et al. Presented at EHA 215 (Abstract S427); Moreau P et al. N Engl J Med 216;374(17): ; Dimopoulos et al. Presented at EHA 216 (Abstract LB2238), oral presenta3on; Mateos MV, personal communica3on; Moreau P et al. Leukemia 217;31: ; Mateos M, et al. Presented at ASH 216 (Abstract 115), oral presenta3on; Nihof IS, et al. Blood 216; 128(19):

41 How are we going to proceed in the clinical prac2ce? Type of relapse: aggressive, - KRd/DaraRd for aggressive relapses with rapid control required Age: all combos work be-er in young pts - IMiDs-based combos: DaraRd & EloRd... 1st preference for elderly - PIs-based combos: DaraVd & Kd... 1st preference for elderly Number and type of prior lines of therapy Cytogene2c abnormali2es: - KRd/IRd: best op3on in pa3ents 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 op3on for high risk CA - DaraVd: improve and almost overcome Avet Loiseau H et al. Blood 216;128(9): ; Richardson P et al. ASCO 216 (Abstract 818); Usmani SZ, et al. Presented at ASH 216 (Abstract 1151), oral presenta3on; Mateos MV, personal communica3on; Chng W-J, et al. Leukemia 217 Feb 3. doi: 1.138/leu [Epub ahead of print]; Mateos M, et al. Presented at ASH 216 (Abstract 115), oral presenta3on; Nihof IS, et al. Blood 216; 128(19):

42 ASPIRE: KRd vs Rd PFS by cytogene2c risk status at baseline High risk defined by: t(4;14) or t(14;16) or with del(17p) in 6% of PCs Avet-Loiseau H et al, Blood 216

43 TOURMALINE-MM1: Outcomes by cytogenetic risk group IRd ORR, % VGPR, % CR, % Median PFS, months Placebo- Rd IRd Placebo- Rd IRd Placebo- Rd IRd Placebo- Rd All pa3ents 78.3* * * * Standard-risk pa3ents * All high-risk pa3ents 79* 6 45* 21 12* HR Pa3ents with del(17p) Pa3ents with t(4;14) alone * *p<.5 for comparison between regimens. Alone or in combina3on with t(4;14) or t(14;16). Data not included on pa3ents with t(14:16) alone due to small numbers (n=7).! Median OS could not be es3mated! In the IRd arm, median PFS in high-risk pa3ents was similar to that in the overall pa3ent popula3on and in pa3ents with standard-risk cytogene3cs Moreau P et al, NEJM 216

44 POLLUX: PFS by Cytogene2c Risk a! Comparable results in 1-3 prior line population! ORR for DRd vs Rd: High risk: 85% vs 67% (P =.14) Std risk: 95% vs 82% (P =.2) 1 High risk DRd n = 28 Rd n = 37 % surviving without progression No. at risk Rd std Risk DRd std risk Rd high risk DRd high risk Months DRd standard risk DRd high risk Rd standard risk Rd high risk Median PFS, mo NR 1.2 HR (95% CI) Median PFS, mo NR 17.1 HR (95% CI).44 ( ) P-value.475 Standard risk a Central next-generation sequencing. High risk patients had any of t(4;14), t(14;16), del17p. Standard risk had an absence of high risk abnormalities. DRd n = ( ) P-value <.1 Rd n = 113 Usmani SZ, et al. Presented at ASH 216 (Abstract 1151), oral presenta3on.

45 ELOQUENT-2: EloRd vs Rd PFS according to del(17p) and t(4;14) del(17p)+ t(4;14)+ Probability progression free HR.65 (95% CI:.45,.94) Ld E-Ld Probability progression free HR.53 (95% CI.29,.95) Ld E-Ld PFS (months) PFS (months) E-Ld: median (95% CI): (16.62, NE) Ld: median (95% CI): (1.61, 18.5) E-Ld: median (95% CI): (8.41, 18.46) Ld: median (95% CI): 5.55 (3.9, 1.25) Elo-Rd del(17p) nega3vity: median (95% CI): (15.84, 22.77) Dimopoulos M et al, ASH 215 Lonial S et al, NEJM 215

46 Kd vs Vd: PFS by Cytogene2c Risk Status at Baseline High risk PFS, median months (95% CI) HR (95% CI) Kd (n=97) 8.8 ( ) Vd (n=113) 6. ( ).646 ( ) P-value.75 Standard risk PFS, median months (95% CI) HR (95% CI) Kd (n=284) NE (18.7 NE) Vd (n=291) 1.2 ( ).439 ( ) P-value <.1 NE, not estimable Chng W-J, et al. Leukemia 217

47 CASTOR: PFS: Cytogene2c Risk in All Evaluable Pa2ents a 1 High risk b DVd n = 44 Vd n = 51 % surviving without progression 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 Median PFS, mo HR (95% CI) P value Standard risk Median PFS, mo HR (95% CI) P value ORR, % P value ( ) DVd n = n = 44 n = 47 ORR, % P value.39 Vd n = 135 NR (.2-.43) <.1 n = 118 n = NR, not reached. a ITT/Biomarker risk evaluable analysis set. DVd improves outcomes regardless of cytogenetic risk b Central next-generation sequencing. 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 216 (Abstract 115), oral presentation

48 Sub-groups analysis of PFS for Novel Combos POLLUX DRd CASTOR DVd ASPIRE KRd ENDEAVOR Kd ELOQUENT-2 ERd TOURMALINE- MM1 IxaRd HR overall popula2on Higher Age HR.11 (>75 yr) HR.35 ( 65 yr) HR.87 (>65 yr) HR.38 ( 75 yr) HR.65 ( 65 yr) HR.87 (>75 yr) HR cyto HR.44 HR.49 HR.7 HR.65 HR.65 HR.54 pos vs neg Moderate RI Refractory mos: 66% vs 85% UK Med PFS 11.2 mos vs NR HR.55 (CrCl<6) HR.47 HR.42 Med PFS 23.1 vs 29.6 mos UK (93% crcl>5) Med PFS NR vs 6. mos HR.6 (crcl<5) (del17p) PFS 21.2 vs 18.4 HR.56 (CrCl<6) Med PFS 21.4 vs 2.6 mos UK IMiDs refractory - HR.5 vs.32 - HR.8 vs Bort refractory HR.5 vs.27 - HR.79 vs.69 - UK - 1. Dimopoulos M, et al. NEJM Palumbo A et al, NEJM Stewart AK, et al. N Engl J Med. 215;372: Dimopoulos MA, et al. Lancet Oncol. 216;17: Lonial S, et al. N Engl J Med. 215;373: Moreau P, et al. N Engl J Med. 216;374:

49 Novel combos POLLUX DRd vs Rd CASTOR DVd vs Vd ASPIRE KRd vs Rd ENDEAVOR Kd vs Vd ELOQUENT-2 ERd vs Rd TOURMALINE- MM1 IRd vs Rd N Median lines 1 (1-11) 82% % 1-2 Prior Len (%) Prior Bort (%) 86 (PI) Refractory pop. (%) Bort-refractory (%) 28 3 UK UK (7% primary) NA Len-refractory HR cyto (%) 9 16 (del 17p) 8 (t 4;14) Dimopoulos M, et al. NEJM Palumbo A et al, NEJM Stewart AK, et al. N Engl J Med. 215;372: Dimopoulos MA, et al. Lancet Oncol. 216;17: Lonial S, et al. N Engl J Med. 215;373: Moreau P, et al. N Engl J Med. 216;374:

50 # Nov 215: FDA Approval Daratumumab single agent Update Regolatorio Darzalex is indicated for the treatment of pa5ents with mul5ple myeloma who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent. h>p:// # Apr 216: EMA Approval Darzalex as monotherapy is indicated for the treatment of adult pa5ents with relapsed and refractory mul5ple myeloma, whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on the last therapy. 5

51 DARATUMUMAB SINGLE AGENT Daratumumab as a single agent 1,2 Approved by FDA and EMA in relapsed/ refractory multiple myeloma 1 Responders MR/SD PD/NE Patients received a median of 5 prior lines of therapy 86.5% of patients were double refractory to a proteasome inhibitor (PI) and immunomodulatory drug (IMiD) 3 Combined overall response rate (ORR): 31% 3 Median PFS of 4. months Median overall survival (OS) of 2.1 months 3 2-year OS was ~75% in responders Median OS was 18.5 months in MR/ SD patients Patients Alive (%) No. at risk Responders MR/SD PD/NE Median OS=NE (95% CI, NE-NE) Median OS=18.5 months (95% CI, ) Median OS=3.7 months (95% CI, ) Months MR, minimal response; SD, stable disease; PD, progressive disease; OS, overall survival; CI, confidence interval; NE, not evaluable Lokhorst HM, et al. N Engl J Med. 215;373: Lonial S, et al. Lancet. 216;387: Usmani SZ, et al. Blood. 216; 128(1):

52 Efficacy in Combined Analysis n (%) 16 mg/kg (N = 148) 95% CI ORR (scr+cr+vgpr+pr) 46 (31) PR VGPR CR scr ORR = 31% 2% 1% CBR 83% Best response scr CR VGPR PR MR SD PD NE 3 (2) 2 (1) 14 (1) 27 (18) 9 (6) 68 (46) 18 (12) 7 (5) VGPR or beaer (scr+cr+vgpr) 19 (13) ORR, % % 18% CR or beaer (scr+cr) 5 (3) ORR = 31% CBR = 83% $ OS benefit observed also in SD/MR pts mg/kg ORR was consistent in subgroups including age, number of prior lines of therapy, refractory status, or renal function Usmani S, et al. Oral presentation: 57th American Society of Hematology (ASH) Annual Meeting & Exposition; December 5-8, 215; Orlando, FL. Abstract 29.

53 The Breakthrough (BT) population outcome Patients alive, % Kumar SK, et al. Leukemia Usmani S, et al. ASH 215. Abstract OS 13m OS 2 m Time, months 1. Kumar SK, et al. Leukemia. 212;26(1): Usmani S, et al. Presented at: 57th American Society of Hematology (ASH) Annual Meeting & Exposition; December 5-8, 215; Orlando, FL. Abstract mos 5-9 months in patients relapsed or refractory MM after 3 prior lines of therapy, including IMID and PI Pomalidomide: mos 13,1months in patients relapsed or refractory MM after 2 prior lines of therapy, including IMID and PI Daratumumab: mos of 2 months in patients with relapsed or refractory, double refractory or relapsed after 3 L, including pomalidomide and carfilzomib

54 mabs: clinical trial endponits New mechanism of ac3on Need for new endpoints? Dara mono Overall Dara mono PR Median PFS m (ex3mated) Dara mono SD/MR PomDex Overall 3.2 m 4. m Median OS 19.9 NR 17.5 m 13.1 m Elo-Rd Rd Median PFS 19.4 m 14.9 m Median TTNT 33. m 21. m

55 1983: High-dose melphalan : Melphalanprednisone 1 Conclusions and future directions 1986: High-dose dexamethasone : ABMT VAD 1 26: Lenalidomide : High-dose therapy with autologous stem cell rescue 1 Bisphosphonates 1 27: Pegylated liposomal doxorubicin 1 Availability of newer combos in early R/R MM 212: Carfilzomib 2 213: Pomalidomide 3 215/216: Ixazomib Panobinostat Daratumumab Elotuzumab 25: High response rates and extended Bortezomib PFS 1 Similarity but also 1999: differences in between studies (previous drugs exposure/ Thalidomide refractoriness, drugs dura3on, 1 cytogene3c high-risk cut off) Need to iden2fy sub-groups of pa2ents mostly benefi2ng from each combo Need to iden2fy from the very beginning a long-term treatment strategy ABMT=autologous bone marrow transplant; VAD=vincris3ne/doxorubicin/dexamethasone. 1. La3f T et al. Exp Hematol Oncol. 212;1: Kyprolis [prescribing informa3on]. Onyx Pharmaceu3cals, Inc; South San Francisco, CA. 3. Pomalyst [prescribing informa3on]. Celgene Corpora3on; Summit, NJ.