New Treatment Approaches in Myeloma in 2017

Transcription

1 New Treatment Approaches in Myeloma in 2017 Jesus San-Miguel University of Navarra, Spain

2 Multiple myeloma Second most common hematological malignancy Incidence: ~4/100,000 persons/year Prevalence: 60,000 patients (Europe) Incidence increases with age: 80% of patients > 60 years (rare in < 35 y.) Clinical Course: Remitting and Relapsing disease - In spite of the progress in survival with novel agents. eventually refractory state (incurable) With current treatment 5-year surival 50% - 70% Potentially cured ~ 10%

3 Myeloma treatment in the last century Mr McBean Chest brace, blood letting Quinine and iron Dover powder (opium) Melphalan (1958, Blokhin) Ann NY Acad Sci Alkylating glucocorticoids (1969) Combination chemotherapy Vincristine Doxorubicin Dexamethasone Ara-C High-dose chemotherapy Stem-cell transplantation Thalidomide Bortezomib Lenalidomide HDACs, Histone deacetylases; IMiDs, immunomodulatory drugs; mabs, monoclonal antibodies; PIs, proteasome inhibitors New IMiDs: pomalidomide New PIs: carfilzomib; ixazomib; oprozomib mabs: elotuzumab, daratumumab, isatuximab HDACs: panobinostat

4 Myeloma Treatment - Newly diagnosed - Transplant candidates (Young) - Non-Transplant candidates (Elderly) - Relapsed patient - Experimental Agents

5 TREATMENT OF MULTIPLE MYELOMA: Should all patients be treated? PATIENTS WHO SHOULD NOT BE TREATED "Smoldering MM (MC >3 g/dl &/or PC > 10%...No CRAB) Early MP vs. deferred MP 1,2,3.No benefit Thalidomide 4,5 only 30% PR & No benefit in TTP/OS Bisphosphonates 6,7.No benefit in OR/TTP/OS Hjorth M, et al. Eur J Haematol. 1993;50: Grignani G, et al. Br J Cancer. 1996;73: Riccardi A, et al. Br J Cancer. 2000;82 4. Rajkumar SV, et al. Am J Hematol 2010; 85(10): Barlogie B, et al. Blood. 2008;112: Musto P, et al. Leuk Lymphoma. 2011;52(5): Musto P, et al. Cancer. 2008;113:

6 Smoldering multiple myeloma: Risk of transformation into Symptomatic MM based on the % of aberrant PCs by immunophenotype plus immunoparesis 1.0 p = High Risk 0.8 Median 23 months >95% apc/bmpc + paresis n = 39 (28 progr.) TTP (%) Median 73 months > 95% apc/bmpc or paresis n = 22 (10 progr.) 0.2 No adverse factors n = 28 (1 progr.) 0.0 Median not reached Low Risk Months Perez-Persona E, et al. Blood. 2007;110:

7 Randomized trial Lenalidomide+dex vs no treatment in High Risk SMM (n = 120) ITT analysis: Median follow-up: 64 months TTP OS Proportion of patients progression-free 1,0 0,8 0,6 0,4 0,2 0,0 No treatment TTP: 21m 53 Progressions (85%) Bone disease (21); RI (8) Lenalidomide + dex 14 Progressions (25%) HR: 6.1; p < Proportion of patients alive 1,0 0,8 0,6 0,4 0,2 0,0 Lenalidomide + Dex No treatment HR: 4.6; p=0.001 Lena + Dex 94% at 7 yrs No treatment. 64% at 7 yrs Time from inclusion Time from inclusion Mateos et al NEJM 2013, Lancet Oncology 2016

8 Revised International Myeloma Working Group Diagnostic Criteria for Multiple Myeloma Clonal BM PC 10% or biopsy proven bony or extramedullary plasmacytoma and ANY ONE OR MORE OF THE FOLLOWING MYELOMA DEFINING EVENTS (MDE) End organ damage (CRAB) that attributed to the PC disorder, Hypercalcemia: > 11 mg/dl Renal insufficiency: Cr Cl <40 ml/minute or Serum Cr > 2 mg/dl Anemia: Hb value <10 g/dl or >2 g/dl below the lower limit of normal Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT, Any one or more of the following New biomarkers of malignancy (Early MM) 60% PC in BM Involved/uninvolved serum free light chain ratio 100 >1 focal lesions on magnetic resonance imaging studies Rajkumar V et al Lancet Oncol 2014, 15: e538-48

9 Myeloma Treatment - Newly diagnosed - Transplant candidates (Young) - Non-Transplant candidates (Elderly) - Relapsed patient - Experimental Agents

10 What are the Optimal Induction Regimens?: Response to induction Percent Response ORR CR 0 VAD TD TAD LD BzD BzCD BzTD BzRD Induction Regimen VCD VRD This translates into prolonged PFS KRD IRD - Adapted from: How I treat MM in younger patients by Stewart K, Richardson P, San Miguel JF. Blood 2009; 114:

11 Early (up-front) vs. Late (at relapse) Transplant Doctor, what about continuous optimized treatment with novel agents, with the goal of controlling the disease for as long as possilbe, and to reserve ASCT for relapse? Bz-Len-Dex x3 Bz-Len-Dex x3 Stem Collection Stem Collection ASCT Bz-Len-Dex x5 Bz-Len-Dex x2 Lenalid x12m Lenalid x12m IFM-DFCI Attal, M, NEJM 2017 ASCT at relapse

12 Early vs Late ASCT (VRD x3) IFM/DFCI 2009 Response, PFS & OS (median Fw/up 41m) At least VGPR 88% 78% Patients (%) N at risk HDT no HDT HR O,69 P<0.001 PFS median 34m 35% at 4y Months of follow-up HDT no HDT median 43m 47% at 4y Patients (%) N at risk HDT no HDT 4-year survival: 81% vs 83% P NS HDT no HD T Months of follow-up OS Myeloma as cause of death: 40/48 (83%) 35/54 (65%) Attal, M, NEJM 2017

13 Early vs. late ASCT (MPR or CRD) Pooled analysis of two trials (n=529) GIMEMA MM-RV-209. Rd-MPR x6 vs. Rd-Mel200 (x2) (2nd rand: +/- maintenance) EMN MM-RV Rd-CRD x6 vs. Rd-Mel200(x2) (2nd rand: R vs RP Maint.) Early ASCT Late ASCT P PFS (months) < year OS 84% 70% < y OS (Upfront vs Rescue ASCT) 84% 73% <0.001 only 53% of CCT patients received ASCT at relapse Palumbo et al NEJM 371: , 2014; Gay et al Lancet Oncol 2015; 16(16): Gay (EHA 2016): ( benefit in all subgoups, but higher in good prognosis (Stage I and low risk cytog)

14 Early vs. late ASCT (VMPx4) EMN02/HO95 MM trial (VCD X3 induction) PFS ASCT vs VMP Median PFS: NR vs 42 (m) PFS at 3y: 65% vs 57% PFS by high-risk cytogenetics Median PFS: 42 vs 20(m) PFS at 3y: 52% vs 29% Progression-free survival (%) ASCT VMP HR (95% CI): 0.73 ( ); p = % Probability VMP ASCT HR (95% CI): 0.53 ( ); p = r at risk Time (months) t i k months Standard-risk cytogenetics Randomizationto ASCT <0.001 Cavo M el al. ASH Abstract nº 673

15 Is there still room for Double ASCT? Double vs. single ASCT In patients with high-risk cytogenetics and who failed CR after bortezomib-based induction (EU Phase 3 trials : 606 patients) Double ASCT Single ASCT P PFS (months) OS (months) <0.001 Cavo et al. ASH 2013 (Abstract 767),

16 Double vs Single ASCT Phase III EMN02/HO95 MM trial 1.00 PFS Double vs Single PFS at 3 y: 74% vs 62% 1.00 PFS by high-risk cytogenetics PFS at 3y: 65% vs 41% % Probability er at risk HDM2 HDM1 Double months HDM2 Single PFS median, mos NR NR HR (95% CI): 0.70 ( ); p = 0.05 HDM1 % Probability 0.50 Double months er at risk HDM HDM HDM2 Single PFS median, mos HR (95% CI): 0.49 ( ); p = HDM1 Benefit in all subgroups Median follow-up: 32 months (IQR 26-41) Cavo M el al. ASH Oral presentation. Abstract nº 691

17 What is the role of Consolidation or Maintenance Therapy?? Consolidation Improve response/deeper following therapy By administration of treatment for a limited period Maintenance Maintain response achieved following therapy By administration of treatment for prolonged period VTD: Upgrade to CR post-consolidation by 30% (molecular and PFS) Cavo et al Blood 2012 Thalidomide (6 trials) PFS: + 6/6 OS: +3/6 Bortezomib (2 Trials). PFS: + 2/2 OS: +1/2 Lenalidomide (3 trials) PFS: +3/3 OS: + 1/3 Morgan et al. Blood 2012;119(1):7-15; Kagoya et al. Leuk Res 2012;36(8): ; Attal et al. ASH 2013 (Abstract 406), McCarthy P. IMW 2013, Gay et al. ASH 2013 (Abstract 2089), Sonneveld et al. ASH 2013 (Abstract 404), Rosinol et al. ASH 2012 (

18 VRD(x2) consolidation vs No consolidation Phase III EMN02/HO95 MM trial Upgrade of response with consolidation: CR rate ( 38% vs 26%) 100 Progression free survival Cumulative percentage VRD no consolidation HR = 0.78 ( ) 0 no consolidation VRD N 435 F 137 no consolidation VRD Cox LR P=0.045 (adjusted for 1st random.) months 36 At risk: EMN02 / HO95 MM Consolidation treatment and PFS (except in high-risk FISH). but not OS Sonneveld et al. ASH 2016

19 Lenalidomide vs. Placebo after ASCT: PFS from randomization IFM CALGB PFS PFS P < Placebo Revlimid P < 10-7 Lena 42 m Placebo 24 m OS: 75% at 5y in both arms P < 10-8 Lena 53 m Placebo 27 m OS: 76 vs. NR, p=0.001 Attal M. NEJM 2012, 366: McCarthy P, NEJM 2012, 366: nd Malignancies: 7% vs 2,5% GIMEMA MM-RV-209 PFS Lena 42 m Placebo 22 m 3-year OS: 88% vs. 79%. p=0.14 Palumbo et al NEJM 371: , 2014 Myeloma XI: 22m increase in PFS (HR=0.47) Jackson G el al. ASH Abst. 1143

20 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 Survival Probability Patients at risk N = 1209 Median OS (95% CI), mos LENALIDOMID E NE (NE-NE) CONTROL 86.0 ( ) 50% HR (95% CI) 0.74 ( ) P value Overall Survival, mos 62% 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 M ASCO 2016

21 Consolidation vs Double ASCT vs Maintenance BMT CTN 0702 Stamina Trial N=750 pts (250 in each arm) Lenalidomide Maintenance N=257 ** Register and Randomize Prior induction tt: Bort/Len/Dex Cy/Bort/Dex Len/Dex Bort/Dex MEL VRD x 4* 200mg/m 2 N=254 MEL 200mg/m 2 N=247 Lenalidomide Maintenance** Lenalidomide Maintenance** **Lenalidomide x 3years Amendment in 2014 changed Lenalidomide maintenance until disease progression after report of CALGB Median follow-up: 37.8 m Stadtmauer EA, et al. ASH Oral presentation. LBA-!

22 Transplant candidate patient: standard treatment Induction (VTD or KRD)+(Dara) KRD+Dar ASCT(Mel 200) (Bu-MEL) (Tandem) KRD+Dar KRD+Dar CR No CR Consolidation(Bz-Len-Dx)..... Maintenance (Len +/- Ixz ) Late ASCT

23 Auto/Allo-RIC vs.tandem Auto 4 studies (IFM 1, HOVON 2, PETHEMA 3, BMTCTN 4 ).. No benefit 2 studies (GIMEMA 5, EBMT 6 ) Significant benefit (EFS, OS) The role of Allo should be revisited in the era of novel drugs: integrated programs...early relapses (after optimized induction & ASCT) + high risk cytogenetics 1.Garban, Blood 2006 and Moreau, Blood 2008; 2. Lokhorst ASH 2008 (Abstr 461); 3.Rosinol, Blood 2008; 4. Krishnan, ASH 2010 (abst 41) 5. Bruno, NEJM 2007 (updated EBMT 2009); 5. Gahrton, ASH 2009 (Abst 52) 6. Knop, ASH 2009 (abst 51)

24 Myeloma Treatment - Newly diagnosed - Transplant candidates (Young) - Non-Transplant candidates (Elderly) Until recently only MP, but now Thal, Lena, Bortz - Relapsed patient - Experimental Agents

25 Thalidomide + MP (MPT) vs. MP: Efficacy in Newly Diagnosed Elderly Patients With Myeloma 6 Randomized trials.. > PFS in 5 >OS in 3 PFS: 20.4 vs. 15 m (6 m)..hr 0.67 OS: 39.3 vs. 33 m (6 m)..hr 0.82 Thal maintenance in Italian, Nordic, Hovon 1 Facon. Lancet. 2007;370: ; 2 Hulin. J Clin Oncol. 2009; 27(22): ; 3 Wijermans. J Clin Oncol. 2010; 28: ; 4 Palumbo. Blood. 2008; 112: ; 5 Beksac. Eur J Haematol. 2010; 86:16-22; 6 Waage. Blood. 2010;116(9): & ASCO 2010 (abstr 8130); Kapoor. Leukemia

26 Bortezomib + MP (VMP) vs. MP (682 Patients) Patients without event (%) TTP VMP: 24.0 months MP: 16.6 months, P< VMP MP Patients without event (%) OS: 13.3 months benefit Median follow-up 60.1 m VMP: 56.4m MP: 43m, P= VMP MP Time (months) Time (months) San Miguel. N Engl J Med. 2008;359:906; San Miguel JCO 2013,31: * Weekly and/or subcutanous administration reduced PN (G3) from 14% to 5% - 3% Mateos MV et al. Lancet Oncology. 2010;10(11):934-42; (Palumbo et al JCO 2010, 28:5101-9)

27 Carfilzomib+MP (KMP) Bortezomib+MP (VMP) in elderly newly diagnosed MM patients CLARION Trial The trial did not meet the primary endpoint of superiority in PFS (median 22.3 months for KMP vs 22.1 months for VMP, HR = 0.91, 95% CI ) TTP: 27,5 VS 23,5 While data for OS (secondary endpoint) are not yet mature, observed HR was 1.08 (KMP versus VMP, 95% CI ) Neither result was statistically significant AEs in KMP arm were consistent with known safety profile of Kyprolis Incidence of Grade 3 AEs: 74.7% KMP arm, 76.2% VMP arm. Fatal treatment-emergent AEs: 6.5% KMP patients, 4.3% VMP patients. Cardiac G3 (8,2 vs 2,8%); Hypertension ( 10 vs 3,6%) Incidence of Grade 2 PN (secondary endpoint): 2.5% KMP arm, 35.1% VMP arm.

28 RD continuous: Final analysis of FIRST trial Progression-Free Survival Overall survival Median PFS, m Rd continuous 26.0 Rd MPT Median OS, m Rd 59.1 continuous Rd MPT year OS Survival Probability year PFS 32.6% Survival Probability % 59.0% 58.0% % % Progression-Free Survival (Months) HR (95% CI) Rd continuous vs MPT: 0.69 ( ), P < Overall Survival (Months) HR (95% CI) Rd continuous vs MPT: 0.78 ( ), P =.0023 Facon T, et al. NEJM 371: ; 2014 Facon T el al. ASH Oral pr. Absnº241

29 GEM/Pethema GEM2010 trial MPV x 9cycles Lendex x 9 cycles 1,0 0,8 PFS 1,0 Alternating: 34 m 1,0 0,8 OS Alternating: 71% at 3 yrs group 0,6 0,6 Sequential : 73% at 3 yrs Sequential: 32m 0,4 0,4 0,2 0,2 0,2 0,0 p=ns 0,0 p=ns , , , VISTA: 21m FIRST: 25m (cont Rd); 21m (Rd18) VISTA: 68% at 3 yrs FIRST: 59% at 4yrs (cont Rd); 56% at 4yrs (Rd18) Mateos et al Blood Jan 28;127(4):420-5

30 ortezomib-rd versus Rd (SWOG S0777 study): PFS and OS analysis ORR: 82% vs 72% % CR: 16 vs 8 Progression-free survival Overall survival 100% Events / N Median in months VRd 137 / (39, 52) Rd 166 / (25, 39) 100% Events / N Median in months VRd 76 / (66,.) Rd 100 / (56,.) 80% 80% 60% 60% 40% 40% 20% Log-rank P value = (one sided)* 0% HR = (0.560, 0.906)* Months from registration 20% HR = (0.516, 0.973)* Log-rank P value = (one sided)* 0% Months from registration VRd (8 cycles) or Rd (6 cycles) induction, followed by Rd maintenance until PD, toxicity or withdrawal Median (range) age = 63 (28 87) years Age 65 years = 43% ISS stage III = 33%; Creatinine 2 mg/dl = 5% AE: 82 vs 75%; Discontinuations: 23 vs 10% Median overall follow-up = 55 months VRd = 54 months Rd = 56 months Multivariate analysis: VRd, stage III, and >65y *Stratified VRd, bortezomib, lenalidomide and dexamethasone ;Rd, lenalidomide and dexamethasone Durie, BGM et al. Lancet Feb 4;389(10068):

31 Future MP based : VMP + / - daratumumab: Alcyone RD based : MLN-RD vs RD: Tourmaline 1 Elotuzumab-RD vs RD: Eloquent 2 Daratumumab-RD vs RD: Maia

32 Myeloma Treatment - Newly diagnosed - Transplant candidates (Young) - Non-Transplant candidates (Elderly) - Relapsed patient - Experimental Agents

33 Strategies at relapse: How to make the RIGHT CHOICE? Disease-related Factors Type of relapse, cytogenetic risk, extramedullary disease Efficacy and Toxicity of previous treatments Patient-related factors Age (Trx elegibility), comorbidities, frailty 2 nd ASCT if PFS >3y Further options

34 Novel drugs in MM Derivatives from already approved Novel PIs Novel IMiDs Novel mechanisms of action - MoAb: anti CS1 & anti-cd38 - Deacetylase Inhibitors - BCL2 inhibitors - XPO-1 inhibitors - Adoptive cell Therapy - Check point Inhibitors Ocio EM, et al. Leukemia 2014; 28:

35 Proteasome inhibitors The proteasome is an intracellular enzyme complex responsible for the degradation of regulatory & misfolded and potentially toxic proteins. Biological effects of proteasome inhibition: - Inhibition of Proliferation - Cell Cycle Arrest - ER stress and unfolded protein response - Blockade of NFkB pathway β-subunit ring of the proteasome: Catalytic sites Caspase-L Trypsin-L Bortezomib β1 MLN-9708 β7 β2 β6 β3 NPI-0052 β5 β4 Carfilzomib Chymotrypsin-L Type Catalytic inhibition Chymotryp Casp Tryp Reversibility po/ iv Dosing Bortezomib Boronate X X Reversible Iv 1, 4, 8, 11 Ixazomib MLN-9708 Boronate X X Reversible po 1, 8, 15 Carfilzomib Epoxi-ketone X Irreversible iv 1-2, 8-9, Oprozomib Epoxi-ketone x Irreversible po BID Marizomib Salinospore X X X Irreversible iv 1, 4, 8, 11 CEP Boronate X X Reversible iv 1, 4, 8, 11

36 Doublets & Triplets with new Proteasome inhibitors in relapsed MM: survival on Phase III trials Carfilzomib (Kd vs. Vd) ENDEAVOR trial 2 : PFS 18.7 vs. 9.4 months (HR 0.53, p=0.0001) 9.3 months OS NE vs. 24 months (HR 0.79, p=0.06) Carfilzomib (KRd vs. Rd) ASPIRE trial 1 : PFS 26.3 vs months (HR 0.69, p=0.0001) 8.7 months OS at 2 years: 73% vs. 65% (HR 0.79, p=0.01) Ixazomib (IRd vs. Rd) TOURMALINE trial 3 : PFS 20.6 vs months (HR 0.74, p=0.01) 5.9 months IRd, ixazomib+lenalidomide+dexamethasone; Kd, carfilzomib+dexamethasone; KRd, carfilzomib+lenalidomide+dexamethasone; Vd, bortezomib+dexamethasone 1. Stewart AK, et al. N Engl J Med 2015; 372: ; 2. Dimopoulos MA, et al. Lancet Oncol 2016; 17: 27-38; 3. Moreau P, N Engl J Med 2016; 374: ;

37 Novel Drugs in MM - Derivatives from the already approved - Novel Proteasome Inhibitors - Novel IMIDs - Novel Mechanisms of action - MoAb: anti CS1 & anti-cd38 - Deacetylase Inhibitors - XPO-1 inhibitors - Checkpoint inhibitors

38 Comparison of Pom-Dex trials (& combinations) MM STRATUS (MM-010) 2 Pom-Dex vs Pom-Cyclo-Dex 3 Pom-Btz-Dex 4 Treatment PD PD PD PCD PVD n Population Failed Bort & Len & refr to last line At least 2 prior lines & Lenrefractory 1-4 prior lines & Len-refractory ORR, % VGPR, % PFS, months OS, months NR - *EFS at 12 months 1. San Miguel, Lancet Oncology 2013; 2. Dimopoulos MA, et al. ASH Abstract 80; 3. Baz et al. ASH Abstract 303; 4. Richardson et al. ASH Abstract 3036

39 Novel drugs in MM Derivatives from already approved Novel PIs Novel IMiDs Novel mechanisms of action - MoAb: anti CS1 & anti-cd38 - Deacetylase Inhibitors - BCL2 inhibitors - XPO-1 inhibitors - Adoptive cell Therapy - Check point Inhibitors Ocio EM, et al. Leukemia 2014; 28:

40 Monoclonal antibodies in Multiple Myeloma Activation of macrophages Antibody-dependent cell-mediated phagocytosis (ADCP) Macrophage Direct effects Alterations in intracellular signalling Inhibition of growth factor receptor function Inhibition of adhesion molecule function Antigen Signalling cascades Membrane attack complex Fc Receptor C1q NK cell Activation of natural killer (NK) cells Antibody-dependent cellular cytotoxicity (ADCC) Lysis Myeloma cell Cell death Activation of the complement system Complement-dependent cytotoxicity (CDC) van de Donk NW et al. Blood 2016;127: Elotuzumab (Anti-SLAMF7) - Single Agent: 26% SD - Anti-CD38: Daratumumab * & Isatuximab - Single agent: 30-35% ORR, Depletes CD38-expressing immunosuppressive regulatory cells (myeloid derived suppressor cells and regulatory T and B cells), which in turn promotes T-cell expansion and activation and increased T-cell clonality

41 Elotuzumab (SLAMF7:Signaling Lymphocytic Activation Molecule F7: Anti-CS1) PHASE III (Eloquent): ELd vs Ld ORR (ELd vs Ld): 79% vs 66%. VGPR: 32.7% vs 27.9% PFS (19.4 vs 14.9 m) TNT (33 vs 21 m) Probability progression free year PFS 2-year PFS 3-year PFS 68% 57% PFS: 19.4 vs 14.9 HR 0.73 (95% CI 0.60, 0.89) p= % 27% 26% 18% PFS (months) E-Ld Ld 48 Probability of patients without next treatment TNT: 33 vs 21 m HR 0.62 (95% CI 0.50, 0.77) E-Ld Time to next treatment (months) Ld Median OS : 43.7 vs 39.6 mos, P= 0.02, Prespecified interim analysis for overall survival indicates a strong trend (p=0.0257) with early separation sustained over time Len prepares immune cells & then Elotuzumab induces ADCC Lonial N Engl J Med 2015; 373: ; Dimopoulos M, ASH 2015 Abst 28

42 Daratumumab-Len-Dex (DRd) vs Len-Dex (Rd) in Relapsed MM - Phase III POLLUX trial % surviving without progression month PFS a 76% 49% Median: not reached Rd Median: 17.5 months DRd ORR, % MRD negative, % ClonoSeq for MRD evaluation 31,8 8,8 24,8 5,7 11,9 2,5 0 No. at risk Rd DRd Months HR: 0.37 (95% CI, ; P <0.0001) DRd Rd DRd Rd DRd Rd Median (range) follow-up: 17.3 (0-24.5) months HR, hazard ratio; CI, confidence interval; scr, stringent complete response; PR, partial response; ITT, intent-to-treat. Note: PFS = ITT population; ORR = response-evaluable population. a Kaplan-Meier estimate. b P < for DRd vs Rd. 43

43 Dara-Vd vs Vd IN relapsed MM (Castor) Updated efficacy % surviving without progression Vd DVd month PFS a 60% 22% Median: 7.1 months Vd DVd HR: 0.33 (95% CI, ; P <0.0001) Months ORR, % CR 26% b ORR = 84% 7% 19% 35% 22% P < CR 10% VGPR 62% b ORR = 63% 2% 8% 19% 34% DVd (n = 240) Vd (n = 234) VGPR 29% scr CR VGPR PR Median (range) follow-up: 13.0 (0-21.3) months An additional 7% of patients receiving DVd achieved CR with longer follow-up Responses continue 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 < for DVd versus Vd. Mateos M, et al. Presented at ASH 2016 (Abstract 1150), oral presentation

44 MoAbs: Futures perspectives Bispecific T cell engagers: BCMA CD3 phase I trials Conjugated MoAb: ABBV-838: MMAE-CS1 GSK : BCMA - MMAF

45 Novel drugs in MM Derivatives from already approved Novel PIs Novel IMiDs Novel mechanisms of action - MoAb: anti CS1 & anti-cd38 - Deacetylase Inhibitors - BCL2 inhibitors - XPO-1 inhibitors - Adoptive cell Therapy - Check point Inhibitors Ocio EM, et al. Leukemia 2014; 28:

46 HDAC Inhibitors : Panobinostat + Bort + Dex vs Bort + Dex ORR PanoBD vs PcboBD: 60.7% vs 54.6% CR: 27.6% vs 15.7% PFS Subgroup Analysis by Prior Treatment: PFS Prior BTZ + IMiDs w/ 2 Prior Lines PAN-BTZ-Dex Pbo-BTZ-Dex PAN-BTZ-Dex Pbo-BTZ-Dex 100 Median PFS(m) 12 ( ) 8.1 ( ) HR (95% CI) 0.63 ( ) 100 Median PFS(m) 12.5 ( ) 4.7 ( ) HR (95% CI) 0.47 ( ) PFS Probability, % PAN-BTZ-Dex Pbo-BTZ-Dex Number of patients at risk PAN-BTZ-Dex Pbo-BTZ-Dex No benefit in OS Months PFS Probability, % Censoring times PAN-BTZ-Dex (n/n = 44/73) Pbo-BTZ-Dex (n/n = 54/74) Months Number of Patients at Risk PAN-BTZ-Dex Pbo-BTZ-Dex San Miguel JF, et al. Lancet Oncol. 2014;15(11):

47 XPO1-Inhibitors: Selinexor First-in-class, oral Selective Inhibitor of Nuclear Export (SINE) that inhibits XPO1 and activates Tumor Suppressor Proteins & reduces Oncoproteins Cancer cells (and MM) overexpress XPO1, causing increased export of tumor suppressors and growth regulatory proteins from the nucleus Selinexor inhibit XPO1 mediated nuclearcytoplasmic transport by transiently binding to XPO1 cargo binding site. Accumulation of Tumor suppressors in the nucleus amplifies the natural apoptotic function in cancer cells with damaged DNA. Tai et al. Leukemia 2014 PHASE I OF SELINEXOR PLUS/MINUS DEX IN RRMM - Single agent (oral:3-45 mg twice/ w).. 17% MR Chen et al. ASH Dex (78)...20% ORR (Penta-Refrct) Vogl, ASH 2016 (Abst977), - + Bortz/dex (27)... 77% (67% in Btz Rfct) Bahlis NJ, ASH 2016 (Abstrt 977), Main AEs: Anorexia Nausea/Vomiting; Fatigue; Thrombocytopenia. Improve with Dex.

48 Ventoclax Anti-apoptotic proteins BCL-2 and MCL-1 promote multiple myeloma (MM) cell survival Venetoclax is a selective, orally available small molecule BCL-2 inhibitor 1, induces cell death in multiple myeloma (MM) cell lines and primary samples, particularly those Background positive for the translocation t(11;14), which correlates with higher ratios of BCL2 to MCL1 and BCL2 to BCL2L1 (BCL-X L ) mrna 1, Venetoclax enhanced bortezomib activity since bortezomib can indirectly inhibit MCL-1 1. Roberts AW et al. NEJM Punnoose E et al. Mol Cancer Ther Monotherapy (66)... ORR 21% (40% in t(11;14) - +Btz/Dex (66)... ORR 67% (90% in BTz sensitive & 94% in BCL2 high) - Kumar, et al. ASH 2016 (Abst 977), - Moreau P, et al. ASH 2016 (Abst975),

49 How can we improve anti-cancer immunity? Four major targets for cancer immunotherapy Monoclonal antibodies Adoptive cell therapy Vaccins Immunomodulators: IMIDs, Checkpoint inh

50 BCMA-CAR T cells in MM (UPenn) ORR: 44% Median number of prior lines: 9 (4 11) 89% refractory to bortezomib, pomalidomide, carfilzomib. 78% refractory to Lenalidomide. 44% refractory to Dara. Safety: 89% CRS (grade 3-4: 33%) Grade 4 PRES Sd Cohen et al. ASH 2016 Abstract 1147

51 PD-1/ PD-L1: Programmed Death Receptor (releasing the brakes) Pembrolizumab treatment in RRMM Study design Patient population Refractory status ORR Safety KEYNOTE-023 (PhI): PEMBRO-LEN-DEX 1 PEMBRO 200mg/2QW LEN 25mg 1-21 DEX 40mg weekly - > 2 prior lines - PI & IMID exposure 75% Len-refractory 63% Bort-refractory 50% double/triple/cuadruple refractory Efficacy populat. (n= 40): 50% Len-refr (n=29): 38% AEs consistent with individual drug safety profiles for approved indications IRAEs: no pneumonitis. No colitis. 65% AEs grade 3-5, 33% neutropenia Ph I/II: PEMBRO POMA DEX 2 PEMBRO 200mg/2QW POMA 4mg 1-21 DEX 40mg weekly - >2 prior lines - RRMM - PI & IMID exposure 89% Len-refractory 82% Bort-refractory 70% double-refractory Total (n=38): ORR: 66% Double refractory (n=31): 65% Median PFS 14m Goodsafety profile iraes: 38% Pneumonitis: 14% 1 San Miguel JF, ASH 2015 oral presentation 505; 2 Badros A, ASH oral presentation 585

52 Multiple myeloma: A model for scientific and clinical progress From biology to therapeutics Progress in MM Cell Biology Discovery of New Drugs Prognostic factors and Myeloma subtypes* Singular mechanism of action Individualised and tailored treatment *MM should not be considered a single entity.