Monoclonal antibodies and multiple myeloma Pr Philippe Moreau Nantes, France

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1 Monoclonal antibodies and multiple myeloma Pr Philippe Moreau Nantes, France

2 Disclosures Advisory boards and honoraria: Janssen, Takeda, Celgene, BMS, Novartis, Amgen Stockholder: no

3 Rituximab + CHOP in diffuse large B-cell lymphoma Coiffier et al. N Engl J Med 2002 Coiffier et al. Blood 2010

4 Rituximab in B-cell malignancies Target (CD20) highly expressed PFS and OS benefit: follicular/diffuse/burkitt/all No severe toxicity / feasible in frail patients Relapse setting / frontline / maintenance Retreatment is feasible No long-term toxicity SubQ administration

5 Monoclonal antibodies act through different modes of action in Multiple Myeloma Activation of macrophages Antibody-dependent cellmediated phagocytosis (ADCP) NK cell Activation of natural killer (NK) cells Antibody-dependent cellular cytotoxicity (ADCC) Fc Receptor Macrophage Lysis Signalling cascades Myeloma cell Cell death Antigen Direct effects Alterations in intracellular signalling Inhibition of growth factor receptor function Inhibition of adhesion molecule function Membrane attack complex C1q Activation of the complement system Complement-dependent cytotoxicity (CDC) van de Donk NW et al. Blood 2016;127:681-95

6 Monoclonal antibodies in Multiple Myeloma Targets? CD138 CD20 CD40 CD56 IGF1-R Plasmocyte CD38 CS1 Il-6

7 Monoclonal antibodies in Multiple Myeloma Targets? Rituximab Phase 2, monotherapy, n=10 No response 1 Phase 2, monotherapy, MM CD20+, n=14 1 Minor Response 2 CD20 Plasmocyte 1. Zojer, Leuk Lymph Moreau, Leukemia 2007

8 Monoclonal antibodies in Multiple Myeloma Targets? Lucatumumab Humanized Anti CD40 Phase 1, signe-agent, n=28 1 patient Partial Response 1 Dacetuzumab Humanized Anti C40 Phase 1, signe-agent, n=44 CD20 CD40 Plasmocyte No response 2 1. Bensinger, BJH Hussein, Haematologica 2010

9 Monoclonal antibodies in Multiple Myeloma Targets? Lorvotuzumab Humanized Anti CD56 + maytansine Phase 1, monotherapy, n=37 : 1 patient: Partial response Phase 2, + Len Dex, n=44 Overall Response Rate = 56% CD20 CD40 CD56 Plasmocyte Berdeja, Fr Bio 2014

10 Monoclonal antibodies in Multiple Myeloma Targets? AVE1642 Humanized Anti IGF1-R (CD221) Phase 1, monotherapy, n=15 : 1 minor response Phase 2, + Vel Dex, n=11 1 partial response CD20 CD40 CD56 IGF1-R Plasmocyte Moreau, Leukemia 2011

11 Monoclonal antibodies in Multiple Myeloma Targets? BT062 Chimeric Anti CD138 + maytansine Phase 1, monotherapy, n=32 1 Partial response 1 Phase 1-2, + Len Dex, n=45 Overall response rate = 78% 2 Radioimmunotherapy Anti CD138 conjugated with 213Bi CD20 CD40 CD56 CD138 IGF1-R Plasmocyte Mouse model 3 1.Jagannath, ASH Kelly, ASH Cherel, J Nucl Med 2014

12 Monoclonal antibodies in Multiple Myeloma Targets? Siltuximab Chimeric Anti Il-6 Phase 2, monotherapy, n=14 : No response 1 Randomized Phase 2, Vel Dex +- Siltux, n=281 No benefit 2 CD20 CD40 CD56 CD138 Randomized Phase 2, MPV +- Siltux, n=106 IGF1-R Plasmocyte No benefit 3 1. Voorhees, BJH Orlowski, Am J Hematol San Miguel, Blood 2014 Il-6

13 Monoclonal antibodies in Multiple Myeloma Targets? CD138 CD20 CD40 CD56 IGF1-R Plasmocyte CS1 Il-6

14 SLAMF7 Background SLAMF7 is highly expressed on >95% of myeloma cells 1-3 It shows lower expression on NK cells and little to no expression on normal tissues Normal plasma cells Plasmacytoma Lymphoplasmacytic lymphoma Myeloma cells in bone marrow 1. Hsi ED et al. Clin Cancer Res. 2008;14: ; 2. Tai YT et al. Blood. 2008;112: Van Rhee F et al. Mol Cancer Ther. 2009;8: ;

15 Elotuzumab Mechanism of Action Elotuzumab works via a dual mechanism of action by both directly activating Natural Killer Cells and through antibody-dependent cell-mediated cytotoxicity (ADCC) to cause targeted Myeloma cell death A B Elotuzumab Direct activation Tagging for recognition SLAMF7 EAT-2 Downstream activating Signaling cascade SLAMF7 Natural Killer Cell Granule synthesis Polarization Elotuzumab Myeloma Cell death SLAMF7 SLAMF7 SLP-76 Degranulation Perforin, granzyme B release Myeloma Cell

16 Tumor volume (mm 3 ) Tumor volume (mm 3 ) Elotuzumab Exhibits Synergy with both Lenalidomide and Bortezomib Lenalidomide and Bortezomib Enhance Elotuzumab s NKC-Mediated Anti-Myeloma Activity clgg Elo Len 800 Elo+Len Study Day elotuzumab/lenalidomide 2 Lenalidomide enhances T Cell Activation & cytokine production leading to Natural Killer Cell stimulation Lenalidomide also exhibits direct anti-myeloma activity which enhances the cells sensitivity to Natural Killer Cell mediated killing A, B in vivo tumor growth inhibition of OPM2 xenograft in SCID mice. 1. Van Rhee F et al, Mol CanTher, Balasa et al, Cancer Imm and Immunothe, cont Study Day elotuzumab/bortezomib 1 Bortezomib exhibits direct anti-myeloma activity which augments the cells sensitivity to Natural Killer Cell mediated killing by enhancing activating ligands and reducing inhibitory ligands on myeloma cells Elo Bort Elo/Bort 19

17 Summary of Study Design: Phase II (Study 1703) Phase 1* N=28 Phase 2 N=73 R A N D O M I Z E Elotuzumab 10 mg/kg IV + L/d n=36 Elotuzumab 20 mg/kg IV + L/d n=37 Phase 2: Patients (n=73) with relapsed and/or refractory MM with 1-3 prior therapies were randomized to elotuzumab 10 or 20 mg/kg IV combined with Lenalidomide 25 mg PO Low-dose dexamethasone 40 mg PO P R O G R E S S I O N

18 Study Design Phase II (Study 1703) Elotuzumab Dosing Lenalidomide Dexamethasone Response Assessments CYCLE 1 CYCLE 2 CYCLE 3 CYCLE 4 CYCLE N-1 5 CYCLE 6 N daily dose daily dose Cycle day daily dose daily dose daily dose daily dose Treatment continued until disease progression or unacceptable toxicity Pre-medication (30-60 min prior) included: methylprednisolone 50 mg IV or dexamethasone 8 mg IV, diphenhydramine mg PO or IV (or equivalent), ranitidine 50 mg IV (or equivalent), and acetaminophen mg PO Endpoints Primary: ORR ( PR per IMWG Criteria) Key secondary endpoints: PFS and safety

19 Percentage of patients with PFS Phase 2: Progression-Free Survival Lenalidomide -dexamethasone + Elotuzumab Number at risk: Total Total (N=73) Median PFS=28.62 mo Time (months) Richardson PG, Jagannath S, Moreau P, et al. Lancet Haematol. 2(12), e (2015). 24

20 ELOQUENT-2 Study Design Open-label, international, randomized, multicenter, phase 3 trial (168 global sites) Key inclusion criteria RRMM 1 3 prior lines of therapy Prior Len exposure permitted in 10% of study population (patients not refractory to Len) Endpoints: Co-primary: PFS and ORR Elo plus Len/Dex (E-Ld) schedule (n=321) Elo (10 mg/kg IV): Cycle 1 and 2: weekly; Cycles 3+: every other week Len (25 mg PO): days 1 21 Dex: weekly equivalent, 40 mg Len/Dex (Ld) schedule (n=325) Len (25 mg PO): days 1 21; Dex: 40 mg PO days 1, 8, 15, 22 Repeat every 28 days Assessment Tumor response: every 4 wks until progressive disease Survival: every 12 wks after disease progression Other: overall survival (data not yet mature); duration of response, quality of life, safety All patients received premedication to mitigate infusion reactions prior to Elo administration

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22 Key Adverse Events Reported in 30% of Patients Adverse event, n (%) E-Ld (n=318) Any grade Grade 3/4 Any grade Ld (n=317) Grade 3/4 Common non-hematologic adverse events Fatigue 149 (47) 27 (9) 123 (39) 26 (8) Pyrexia 119 (37) 8 (3) 78 (25) 9 (3) Diarrhea 149 (47) 16 (5) 114 (36) 13 (4) Constipation 113 (36) 4 (1) 86 (27) 1 (0.3) Muscle spasms 95 (30) 1 (0.3) 84 (27) 3 (1) Cough 100 (31) 1 (0.3) 57 (18) 0 Common hematologic toxicities Lymphopenia 316 (99) 244 (77) 311 (98) 154 (49) Neutropenia 260 (82) 107 (34) 281 (89) 138 (44) Infections 259 (81) 89 (28) 236 (74) 77 (24) Exposure-adjusted infection rate was 197 (incidence rate per 100 person years of exposure) in both arms There was no detriment to overall health-related quality of life with the addition of Elo to Ld

23 Infusion Reactions Events, n (%) E-Ld (n=318) Grade 1/2 Grade 3 Grade 4/5 Infusion reaction 29 (9) 4 (1) 0 Pyrexia 10 (3) 0 0 Chills 4 (1) 0 0 Hypertension 3 (1) 1(<1) 0 Infusion reactions occurred in 10% of patients 70% of infusion reactions occurred with the first dose No Grade 4 or 5 infusion reactions Elotuzumab infusion was interrupted in 15 (5%) patients due to an infusion reaction (median interruption duration 25 minutes) 2 (1%) patients discontinued the study due to an infusion reaction

24 ELOTUZUMAB in combination with Len Dex : ELOQUENT-2 phase 3 randomized study Elotuzumab is approved by FDA and EMA in combination with lenalidomide and dexamethasone for the treatment of multiple myeloma patients who have received at least one prior therapy

25 NCT Available from: Accessed 8 October EudraCT Phase 3 ELOQUENT-1 (CA ): ERd vs Rd in TNE NDMM 234 sites 21 countries Stratified by ISS stage, age and ECOG Randomization n=375 n=375 ERd ELO: 10 mg/kg, d1, 8, 15, 22 (cycles 1 2); d1, 15 (cycles 3 18); 20 mg/kg, d1 (cycles 19) LEN: 25 mg, d1 21 DEX: 28mg orally d1, 8, 15, 22 (cycles 1 2); d1, 15 (cycles 3 18); d1 (cycles 19) 28-day cycles, until PD Rd LEN: 25 mg, d1 21 DEX: 40 mg, d1, 8, 15, day cycles, until PD Tumor assessments: every 4 weeks from Day 1 until progression Follow-Up Survival every 16 weeks Primary endpoint: PFS (EBMT) Primary endpoint analysis expected Q Secondary endpoints: ORR, OS

26 SCREEN RANDOMIZE Phase 3: Elotuzumab + VRD induction/consolidation + Lenalidomide maintenance in newly diagnosed MM (GMMG-HD6) Induction Consolidation Maintenance RVD RVD RVD + elotuzumab auto-sct auto-sct auto-sct RVD RVD + elotuzumab RVD Len/Dex Len/Dex + elotuzumab Len/Dex RVD + elotuzumab auto-sct RVD + elotuzumab Len/Dex + elotuzumab NCT

27 Elotuzumab in Multiple Myeloma Target (SLAM-F7) highly expressed PFS and OS benefit / high-risk patients No severe toxicity / feasible in frail patients Relapse setting / frontline / maintenance Retreatment is feasible No long-term toxicity SubQ administration: no

28 Monoclonal antibodies in Multiple Myeloma Targets? CD138 CD20 CD40 CD56 IGF1-R Plasmocyte CD38 CS1 Il-6

29 Three anti-cd38 monoclonal antibodies Chimeric: Isatuximab (SAR650984) Fully human: Daratumumab (DARA) MOR202 (MOR) de Weers et al. J Immunol 2011;186: ;

30 Daratumumab

31 CD38 enzymatic inhibition DARA: Mechanisms of Action Decreased immunosuppression Apoptosis via cross-linking CD38 is highly and ubiquitously expressed on myeloma cells 1,2 DARA is a human IgG1 monoclonal antibody that binds CD38-expressing cells DARA binding to CD38 induces tumor cell death through direct and indirect mechanisms 3-5 MM cell NAD cadpr ADPR Ca 2+ AMP NAADP Ca 2+ Ca 2+ Ca 2+ Adenosine Immunomodulation Adenosine CD38 + T reg CD8 + T cell DARA DARA Immune-mediated activity CDC Complement ADPC Macrophage CD38 CD38 MM cell DARA ADCC NK cell Direct anti-tumor effect CD38 MDSC B reg CD38 Tumor cell death 1. Lin P, et al. Am J Clin Pathol. 2004;121(4): Santonocito AM, et al. Leuk Res. 2004;28(5): de Weers M, et al. J Immunol. 2011;186(3): Overdijk MB, et al. MAbs. 2015;7(2): Krejcik J, et al. Presented at: 57th American Society of Hematology (ASH) Annual Meeting & Exposition; December 5-8, 2015; Orlando, FL. Abstract 3037.

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33 GEN501 : Phase ½ study in Europe

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36 DARA Monotherapy Studies 18 years of age, ECOG status 2 1,2 GEN501 1 Open-label, multicenter, phase 1/2, dose-escalation and dose-expansion study Relapsed from or refractory to 2 prior lines of therapy including PIs and IMiDs SIRIUS 2 Open-label, multicenter, phase 2 study Patients had received 3 prior lines of therapy, including a PI and an IMiD, or were double refractory to a PI and an IMID DARA was approved by the FDA on November 16, 2015, based on these studies GEN501 Dose-escalation Doses from mg/kg (n = 32) Safety and response evaluated Dose-expansion 16 mg/kg (n = 42) 8 mg/kg (n = 30) 16 mg/kg N = mg/kg (n = 16) SIRIUS Randomization 16 mg/kg (n = 106) 8 mg/kg (n = 18) Response evaluated Additional 90 patients enrolled at DARA 16 mg/kg 1. Lokhorst HM, et al. N Engl J Med. 2015;373(13): Lonial S, et al. Lancet In press. 72

37 Baseline Refractory Status Refractory to, n (%) GEN501, Part 2 n = mg/kg SIRIUS n = 106 Combined N = 148 Last line of therapy 32 (76) 103 (97) 135 (91) Both PI and IMiD PI only IMiD only 27 (64) 3 (7) 4 (10) 101 (95) 3 (3) 1 (1) 128 (86) 6 (4) 5 (3) PI + IMiD + alkylating agent 21 (50) 79 (75) 100 (68) Bortezomib 30 (71) 95 (90) 125 (84) Carfilzomib 7 (17) 51 (48) 58 (39) Lenalidomide 31 (74) 93 (88) 124 (84) Pomalidomide 15 (36) 67 (63) 82 (55) Thalidomide 12 (29) 29 (27) 41 (28) Alkylating agent only 25 (60) 82 (77) 107 (72) 73

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43 Summary of Clinical Safety Treatment-emergent adverse event, n (%) Any grade N = 148 Grade 3 N = 148 Fatigue 61 (41) 3 (2) Nausea 42 (28) 0 Anemia 41 (28) 26 (18) Back pain 36 (24) 3 (2) Cough 33 (22) 0 Neutropenia 30 (20) 15 (10) Thrombocytopenia 30 (20) 21 (14) Upper respiratory tract infection 30 (20) 1 (<1) 48% of patients had infusion-related reactions 46%, 4%, and 3% occurred during the first, second, and subsequent infusions, respectively 79

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45 CASTOR: Study Design Multicenter, randomized, open-label, active-controlled phase 3 study 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 - cycle 1-3 Every 3 weeks - cycle 4-8 Every 4 weeks - cycles 9+ Vel: 1.3 mg/m 2 SC, days 1,4,8,11 - cycle 1-8 dex: 20 mg PO-IV, days 1,2,4,5,8,9,11,12 - cycle 1-8 Vd (n = 247) Vel: 1.3 mg/m 2 SC, days 1,4,8,11 - cycle 1-8 dex: 20 mg PO-IV, days 1,2,4,5,8,9,11,12 - cycle 1-8 Cycles 1-8: repeat every 21 days Cycles 9+: repeat every 28 days Primary Endpoint PFS Secondary Endpoints TTP OS ORR, VGPR, CR MRD Time to response Duration of response Palumbo et al. ASCO

46 Proportion surviving without progression Progression-free Survival 1.0 Median : not reached 1-year PFS* No. at risk Vd DVd Months Median : 7.2 months HR: 0.39 (95% CI, ); P< % 26.9% Vd 0 0 DVd 61% reduction in the risk of disease progression or death for DVd vs Vd *KM estimate; HR, hazard ratio. Palumbo et al. ASCO

47 Non-hematologic Hematologic Most Common (>5%) Grade 3-4 TEAE Thrombocytopenia Anemia Neutropenia Lymphopenia Pneumonia Hypertension Sensory PN Vd Grade 3 Vd Grade 4 DVd Grade 3 DVd Grade Patients, % Bleeding: All grades: 7% in DVd vs 4% in Vd Grade 3-4: 3 pts in DVd vs 2 pts in Vd Infections: Grade 3-4 AEs: 21% in DVd vs 19% in Vd Serious AEs: 20% in DVd vs 18% in Vd Discontinued for sensory peripheral neuropathy: All grades: 0.4% in DVd vs 3% in Vd Discontinued for TEAE: 7% in DVd vs 9% in Vd Palumbo et al. ASCO

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49 POLLUX: Study Design Multicenter, randomized (1:1), open-label, active-controlled, phase 3 study Key eligibility criteria RRMM 1 prior line of therapy Prior lenalidomide exposure, but not refractory Creatinine clearance 30 ml/min Stratification factors No. of prior lines of therapy ISS stage at study entry Prior lenalidomide R A N D O M I Z E 1:1 DRd (n = 286) Daratumumab 16 mg/kg IV Qw in Cycles 1 to 2, q2w in Cycles 3 to 6, then q4w until PD R 25 mg PO Days 1 to 21 of each cycle until PD d 40 mg PO 40 mg weekly until PD Rd (n = 283) R 25 mg PO Days 1 to 21 of each cycle until PD d 40 mg PO 40 mg weekly until PD Cycles: 28 days Primary endpoint PFS Secondary endpoints TTP OS ORR, VGPR, CR MRD Time to response Duration of response Statistical analyses Primary analysis: ~177 PFS events Combination with standard of care regimens in RRMM after 1 prior therapy (POLLUX and CASTOR) approved by the FDA ISS, International Staging System; DRd, daratumumab/lenalidomide/dexamethasone; IV, intravenous; qw, weekly; q2w, every 2 weeks; q4w, every 4 weeks; R, lenalidomide; PO, oral; PD, progressive disease; d, dexamethasone; Rd, lenalidomide/dexamethasone; PFS, progression-free survival; TTP, time to progression; OS, overall survival; ORR, overall response rate; VGPR, very good partial response; CR, complete response; MRD, minimal residual disease. 99

50 Proportion surviving without progression Progression-free Survival month PFS* 18-month PFS* No. at risk % 78% 60% 52% Months DRd Rd Median PFS: 18.4 months HR: 0.37 (95% CI, ; P <0.0001) Rd DRd *KM estimate; HR, hazard ratio. 63% reduction in the risk of disease progression or death for DRd vs Rd 101

51 MRD-negative rate (%) MRD-negative Rate P < % 8% P < % 5% P < % 2% DRd Rd 0 MRD-neg (10-4 ) MRD-neg (10-5 ) MRD-neg (10-6 ) Significantly higher MRD-negative rates for DRd vs Rd Response-evaluable set. Assessed by next generation sequencing in bone marrow. 103

52 MRD-negative rate, % MRD-negative Rate (10 5 ) by Prior Treatment Status % surviving without progression DRd (n = 272) P < Rd (n = 264) 1-3 prior 1-3 pllines population No. at risk Rd MRD negative DRd MRD negative Rd MRD positive DRd MRD positive MRD-negative patients achieve prolonged PFS Months Rd MRD negative DRd MRD negative DRd MRD positive Rd MRD positive

53 ORR, % % surviving without progression Responses and PFS by Cytogenetic Status ORR = 85% DRd (n = 27) High risk Total population (response evaluable) ORR = 67% Rd (n = 36) ORR = 95% DRd (n = 132) Rd (n = 111) Standard risk ORR = 82% scr CR VGPR PR 100 No. at risk Rd standard risk DRd standard risk Rd high risk DRd high risk DRd std risk DRd high risk Rd std risk Rd high risk to 3 prior lines population Months DRd improves outcomes in high-risk and standard-risk patients 105

54 Ongoing daratumumab studies in the non-transplant setting ALCYONE MAIA Arm A VMP 6-week cycles, total of 9 cycles Screening phase (-21 days) Randomization Follow-up phase Arm B DARA + VMP 6-week cycles, total of 9 cycles Post-VMP DARA Q4W until PD, unacceptable toxicity, or study end Arm A Rd 28 day cycles LEN:25 mg PO d 1-21 DEX: 40 mg PO d 1, 8, 15, 22 Until PD or unacceptable toxicity Screening Phase (-21 days) Randomization 1:1 End-of-Treatment Visit Long Term Follow-up Arm B Rd + DARA 28 day cycles LEN:25 mg PO d 1-21 (up to 2 years) DEX: 40 mg PO d 1, 8, 15, 22 (up to 2 years) DARA: 16 mg/kg Q1W for 8 weeks, then Q2W for 16 weeks, then Q4W Until PD or unacceptable toxicity NCT , NCT

55 Study Scheme

56 Open-label, Multicenter, Dose-escalation Phase 1b Study to Assess the Subcutaneous Delivery of Daratumumab in Patients (Pts) With Relapsed or Refractory Multiple Myeloma (PAVO) Saad Z. Usmani, 1, * Hareth Nahi, 2, * Maria-Victoria Mateos, 3 Henk M. Lokhorst, 4 Ajai Chari, 5 Jonathan L. Kaufman, 6 Philippe Moreau, 7 Albert Oriol, 8 Torben Plesner, 9 Lotfi Benboubker, 10 Peter Hellemans, 11 Tara Masterson, 12 Pamela L. Clemens, 12 Tahamtan Ahmadi, 12 Kevin Liu, 13 Jesus San-Miguel 14 1 Levine Cancer Institute/Carolinas HealthCare System, Charlotte, NC, USA; 2 Karolinska Institute, Department of Medicine, Division of Hematology, Karolinska University Hospital at Huddinge, Stockholm, Sweden; 3 University Hospital of Salamanca/IBSAL, Salamanca, Spain; 4 Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands; 5 Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY, USA; 6 Winship Cancer Institute, Emory University, Atlanta, GA, USA; 7 University Hospital of Nantes, Nantes, France; 8 Institut Català d Oncologia, HGTiP, Barcelona, Spain; 9 Vejle Hospital and University of Southern Denmark, Vejle, Denmark; 10 CHU Tours Hopital Bretonneau, Tours, France; 11 Janssen Research & Development, Beerse, Belgium; 12 Janssen Research & Development, LLC, Spring House, PA, USA; 13 Janssen Research & Development, LLC, Raritan, NJ, USA; 14 Clínica Universidad de Navarra-CIMA, IDISNA, Pamplona, Spain. *Joint first author. ClinicalTrials.gov Identifier: NCT

57 IRRs 1,200 mg n = 8 1,800 mg n = 45 IRR, % (n) 13 (1) 24 (11) Chills 13 (1) 9 (4) Pyrexia 0 (0) 9 (4) Pruritus 0 (0) 4 (2) Dyspnea 13 (1) 0 (0) Flushing 0 (0) 2 (1) Hypertension 0 (0) 2 (1) Hypotension 0 (0) 2 (1) Nausea 0 (0) 2 (1) Non-cardiac chest pain 13 (1) 0 (0) Oropharyngeal pain 0 (0) 2 (1) Paresthesia 0 (0) 2 (1) Rash 0 (0) 2 (1) Sinus headache 0 (0) 2 (1) Tongue edema 0 (0) 2 (1) Vomiting 0 (0) 2 (1) Wheezing 0 (0) 2 (1) All IRRs in the 1,800-mg group were grade 1 or 2 One grade 3 IRR of dyspnea in the 1,200-mg group No grade 4 IRRs were observed All IRRs occurred during or within 4 hours of the first infusion No IRRs occurred during subsequent infusions in either group Abdominal wall SC injections were well tolerated Low IRR incidence and severity with DARA SC 114

58 DARA mean serum concentration (µg/ml) DARA mean serum concentration (µg/ml) Dose Mean (SD) Profiles st dose mean 8 th dose mean 16 mg/kg IV (n = 20 a,b ) 1, mg/kg IV (n = 2 a,c ) 1,200 mg SC (n = 8 a ) 1,400 1,200 mg SC (n = 5 a ) 1,800 mg SC (n = 44 a ) 1,800 mg SC (n = 42 a ) 1,200 1,100 1, Normal time after 1 st dose (hours) Normal time after 8 th dose (hours) PK for 1,800 mg SC dose is consistent with the 16 mg/kg IV dose, with comparable C trough and variability SD, standard deviation. a Number of patients with full PK profile at pre-dose. b From study GEN501 Part 2. c From study GEN501 Part

59 Daratumumab in Multiple Myeloma Target (CD38) highly expressed PFS and OS benefit / high-risk patients No severe toxicity / feasible in frail patients Relapse setting / frontline / maintenance / indolent Retreatment is feasible No long-term toxicity SubQ administration

60 Phase 1 trial: Isatuximab (SAR) monotherapy in relapsed or refractory MM Martin et al. ASCO 2014 (Abstract 8532), poster presentation

61 Isatuximab (SAR) : escalating doses : 1-20 mg/kg q2w Response summary ORR 27% ORR 18% ORR 32% Minor responses or better : 33.7% ( 38.3% at >10 mg) Time to response 4.6 weeks MTD not reached Martin et al. ASCO 2014 (Abstract 8532), poster presentation

62 Phase 1b: Isatuximab + Len/dex in rel/ref MM dose escalation + expansion study Patients: n=31 Median 6 prior lines 94% prior Len Refractory to IMiD: 81% Martin et al. ASH 2014 (Abstract 83); oral presentation

63 Response rate by prior anticancer treatment Very good partial response Partial response Lenalidomide refractory (n=25) Lenalidomide non-refractory (n=6) Pomalidomide refractory (n=9) Pomalidomide non-refractory (n=22) Bortezomib refractory (n=16) Bortezomib non-refractory (n=15) Carfilzomib refractory (n=15) ORR 33% 41 ORR 48% Minimal response 67 5 ORR 44% ORR 40% ORR 68% ORR 73% ORR 100% Carfilzomib non-refractory (n=16) ORR 75% Patients, % Martin et al. ASH 2014 (Abstract 83); oral presentation

64 Isatuximab Pom-dex +/- Isatuximab

65 A phase 1/2a study of the human anti-cd38 antibody MOR202 (MOR03087) in relapsed or refractory multiple myeloma Raab et al. ASCO 2015 (Abstract 8574), poster presentation

66 Impact on clinical guidelines?

67 Eligibility for ASCT Yes Induction: 3-drug regimens VTD VCD RVD PAD 200 mg/m2 Melphalan followed by ASCT Maintenance Lenalidomide No First option: VMP, Rd, VRD Second option: VCD, MPT Other options : BP, CTD, MP FRONTLINE THERAPY ESMO guidelines Moreau et al, Ann Oncol 2017, in press

68 Phase 3 Rd-based studies for elderly patients Rd R 25 : mg PO ; D1 21 DEX: 40 mg PO ; D1, 8, 15 & 22-28d cycles until PD NCT NCT NCT Elotuzumab Ixazomib Daratumumab ELO-Rd ELO: 10 mg/kg; D1, 8, 15 & 22 (cycles 1 2); D1 & 15 (cycles 3 18); 20 mg/kg on D1 (cycles 19) R: 25 mg, D1 21 DEX: 40 mg D1, 8, 15 & 22 (cycles 1 2); D1 & 15 (cycles 3 18); D1 (cycles 19) 28-d cycles, until PD Rd R 25 : mg PO ; D1 21 DEX: 40 mg PO ; D1, 8, 15 & 22-28d cycles/18 mos DEX Discontinued Placebo + R R 10 mg Until PD Ixazomib-Rd Ixazomib: 4 mg R 25 : mg DEX: 40 mg; D1, 8, 15 & d cycles/18 mos DEX Discontinued Ixazomib+ R Ixazomib: 3 mg R: 10 mg Until PD Rd R 25 : mg PO ; D1 21 DEX: 40 mg PO ; D1, 8, 15 & 22-28d cycles until PD DARA-Rd DARA: 16 mg/kg q1wk for 8 wks; q2wk for 16 wks; q4wk thereafter R 25 : mg PO d; D1 21 DEX: 40 mg PO d; D1, 8, 15 & 22-28d cycles; Rd for up to 2 years ; DARA until PD

69 Eligibility for ASCT Yes Induction: 3-drug regimens VTD VCD RVD PAD 200 mg/m2 Melphalan followed by ASCT Maintenance Lenalidomide No First option: VMP + DARA, Rd + DARA, Rd + Elo, Rd + Ixazomib, VRD Second option: VCD, MPT Other options : BP, CTD, MP FRONTLINE THERAPY ESMO guidelines ?

70 Eligibility for ASCT Yes Induction: 3-drug regimens VTD VCD RVD PAD 200 mg/m2 Melphalan followed by ASCT Maintenance Lenalidomide No First option: VMP, Rd, VRD Second option: VCD, MPT Other options : BP, CTD, MP FRONTLINE THERAPY ESMO guidelines Moreau et al, Ann Oncol 2017, in press

71 Eligibility for ASCT Yes Induction: 3-drug regimens VTD + DARA VCD VRD + DARA VRD + Elo PAD 200 mg/m2 Melphalan followed by ASCT Maintenance Lenalidomide + Elo Lenalidomide + DARA No First option: VMP + DARA, Rd + DARA, RD + Elo, Rd + Ixazomib, VRD Second option: VCD, MPT Other options : BP, CTD, MP FRONTLINE THERAPY ESMO guidelines

72 ESMO Guidelines 2017; Moreau et al; Ann Oncol RELAPSE / REFRACTORY MULTIPLE MYELOMA First relapse after IMiD-based induction First relapse after Bortezomib-based induction Doublets Kd / Vd Pomalidomide-Dex (as a backbone) + Cyclo or Ixa or Bort or Dara or Elo Triplets based on Bortezomib DaraVD or PanoVD or EloVD or VCD Rd At second or subsequent relapse Daratumumab (single agent or combination) Triplets (with Rd as backbone) DaraRd or KRd or IxaRd or EloRd Clinical trial

73 ESMO Guidelines 2022?? RELAPSE / REFRACTORY MULTIPLE MYELOMA First relapse after IMiD-based induction First relapse after Bortezomib-based induction Doublets Kd + Isa / Vd Pomalidomide-Dex (as a backbone) + Cyclo or Ixa or Bort or Dara or Elo or Isa Triplets based on Bortezomib DaraVD or PanoVD or EloVD or VCD Rd At second or subsequent relapse Daratumumab (single agent or combination) Triplets (with Rd as backbone) DaraRd or KRd or IxaRd or EloRd or Pom-dex dara Clinical trial

74 Conclusions Elotuzumab + Lenalidomide/dex: Approved Daratumumab single-agent: Approved Daratumumab + Lenalidomide/dex: Approved Daratumumab + Bortezomib/dex: Approved Daratumumab : Backbone?