DARA Monotherapy Studies

Transcription

1 Usmani, SZ. Blood Lokhorst HM, et al. N Engl J Med. 25;373(3): Lonial S, et al. Lancet. 25. I DARA Monotherapy Studies

2 Baseline Characteristics Median (range) age, y 65 years of age, n (%) GEN5, Part 2 n = (44-76) 2 (48) 6 mg/kg SIRIUS n = (3-84) 48 (45) Combined N = (3-84) 68 (46) Female/male sex, % 36/64 5/49 53/47 ECOG score, n (%) 2 2 (29) 28 (67) 2 (5) 29 (27) 69 (65) 8 (8) 4 (28) 97 (66) (7) Median (range) time since diagnosis, y 5.8 ( ) 4.8 (.-23.8) 5. ( ) Median (range) number of prior lines of therapy >3 prior lines of therapy, n (%) 4 (2-2) 26 (62) 5 (2-4) 87 (82) 5 (2-4) 3 (76) Prior ASCT, n (%) 3 (74) 85 (8) 6 (78) Prior PI, n (%) Bortezomib Carfilzomib Prior IMiD, n (%) Lenalidomide Pomalidomide Thalidomide 42 () 42 () 8 (9) 4 (95) 4 (95) 5 (36) 9 (45) 6 () 5 (99) 53 (5) 6 () 5 (99) 67 (63) 47 (44) 48 () 47 (99) 6 (4) 46 (99) 45 (98) 82 (55) 66 (45)

3 Baseline Refractory Status Refractory to, n (%) GEN5, Part 2 n = 42 6 mg/kg SIRIUS n = 6 Combined N = 48 Last line of therapy 32 (76) 3 (97) 35 (9) Both PI and IMiD PI only IMiD only 27 (64) 3 (7) 4 () (95) 3 (3) () 28 (86) 6 (4) 5 (3) PI + IMiD + alkylating agent 2 (5) 79 (75) (68) Bortezomib 3 (7) 95 (9) 25 (84) Carfilzomib 7 (7) 5 (48) 58 (39) Lenalidomide 3 (74) 93 (88) 24 (84) Pomalidomide 5 (36) 67 (63) 82 (55) Thalidomide 2 (29) 29 (27) 4 (28) Alkylating agent only 25 (6) 82 (77) 7 (72) Usmani, SZ. Blood

4 Relapsed and Refractory MM Median overall survival in the combined eligible population from the IMS LifeLink and OPTUM datasets (N = 662) and double refractory (n = 35) and triple/quadruple refractory (n = 93) patients. Usmani et al., Oncologist 26; doi:.634/theoncologist.26-4

5 Efficacy in Combined Analysis Median Follow up 2.7 months 6 mg/kg (N = 48) Response n (%) 95% CI ORR 46 (3.) Clinical benefit (ORR + MR) 55 (37.2) VGPR or better (scr+cr+vgpr) 2 (3.5) CR or better (scr+cr) 7 (4.7) % scr CR VGPR PR MR SD PD NE 3 (2.) 4 (2.7) 3 (8.8) 26 (7.6) 9 (6.) 68 (45.9) 8 (2.2) 7 (4.7) Usmani, SZ. Blood. 26. Median DOR = 7.6 (95% CI, 5.6-NE) months ORR = 3% and was consistent in subgroups including age, number of prior lines of therapy, refractory status, or renal function Time to response =.95 (.5-5.6) months

6 Efficacy in Combined Analysis - Subgroups Responses were seen across all subgroups regardless of prior lines of therapy, refractory status, renal function, and baseline percentage of plasma cells in the bone marrow Usmani, SZ. Blood

7 PFS median follow-up 2.7 months Usmani, SZ. Blood

8 OS median follow-up 2.7 months For the combined analysis, median OS = 2. months (95% CI, 6.6-NE months) 8-month and 24-month OS rate = 56.5% and 45% respectively 2-year OS was ~75% in responders Usmani, SZ. Blood

9 The Breakthrough (BT) population outcome OS 2 m OS 3m mos 5-8 months in patients relapsed or refractory MM after 3 prior lines of therapy, including IMID and PI Pomalidomide: mos 3,months 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 Usmani et al., Oncologist 26; doi:.634/theoncologist.26-4 Usmani, SZ. Blood Jesus San Miguel et.al, Lancet 23

10 Suzy van sanden,et al. Poster 9th annual european congress of the international society for pharmacoeconomics and outcomes research (ispor-eu); 29 october-2 november 26; vienna, austria.

11 MAIC of OS among patients treated with DARA versus POM+LoDex in the ITT population and POM-naïve population Due to the high percentage of POM-refractory patients (55%) treated with DARA in GEN5 and SIRIUS who were not included in the POM-naïve MM-3 study, the OS advantage of DARA may be a conservative estimate HR.56 ( );p=.4 HR.33 (.7-.66);p=.7 The primary analysis suggests a 44% reduction in the risk of death compared with POM+LoDex Comparison of POM-naïve patients from both studies suggests a 67% reduction in the risk of death compared with POM+LoDex Suzy van sanden,et al. Poster 9th annual european congress of the international society for pharmacoeconomics and outcomes research (ispor-eu); 29 october-2 november 26; vienna, austria.

12 CASTOR: Study Design Multicenter, randomized, open-label, active-controlled phase 3 study Key eligibility criteria RRMM prior line of therapy Prior bortezomib exposure, but not refractory R A N D O M I Z E : DVd (n = 25) Daratumumab (6 mg/kg IV) Every week - cycles -3 Every 3 weeks - cycles 4-8 Every 4 weeks - cycles 9+ Vel:.3 mg/m 2 SC, days,4,8, - cycles -8 dex: 2 mg PO-IV, days,2,4,5,8,9,,2 - cycles -8 Vd (n = 247) Vel:.3 mg/m 2 SC, days,4,8, - cycles -8 dex: 2 mg PO-IV, days,2,4,5,8,9,,2 - cycles -8 Primary Endpoint PFS Secondary Endpoints TTP OS ORR, VGPR, CR MRD Time to response Duration of response Cycles 4-8: repeat every 2 days Cycles 9+: repeat every 28 days Statistical analyses 295 PFS events: 85% power for 4.3 month PFS improvement Interim analysis: ~77 PFS events Daratumumab IV administered in ml to 5 ml; gradual escalation from 5 ml to 2 ml/hour permitted Palumbo, A. N Engl J Med (8):

13 Baseline Demographics and Clinical Characteristics Characteristic Age, years Median (range) 75, n (%) ISS staging, n (%) a I II III DVd (n = 25) 64 (3-88) 23 (9) 98 (39) 94 (38) 59 (24) Vd (n = 247) 64 (33-85) 35 (4) 96 (39) (4) 5 (2) Characteristic Prior lines of therapy, n (%) 2 3 >3 DVd (n = 25) 22 (49) 7 (28) 37 (5) 22 (9) Vd (n = 247) 3 (46) 74 (3) 32 (3) 28 () Prior ASCT, n (%) 56 (62) 49 (6) Prior PI, n (%) 69 (67) 72 (7) Cytogenetic profile, n (%) b Del7p t(4;4) Time from diagnosis, years Median (range) 28 (6) 4 (8) 3.87 (.7-2.7) 2 (2) 5 (9) 3.72 (.6-8.6) Prior IMiD, n (%) 79 (7) 98 (8) Prior PI + IMiD, n (%) 2 (45) 29 (52) Refractory to IMiD, n (%) 74 (3) 9 (36) Refractory to last line of therapy, n (%) 76 (3) 85 (34) Palumbo, A. N Engl J Med (8):

14 % surviving without progression ORR, % Updated Efficacy 2-month PFS a P <. 9 ORR = 84% % 22% Median: 7. months DVd CR 26% b 7% 9% 35% VGPR 62% b CR % ORR = 63% 2% 8% 9% VGPR 29% scr Vd DVd No. at risk HR:.33 (95% CI, ; P <.) Vd Months % 34% DVd (n = 24) Vd (n = 234) CR VGPR PR Median (range) follow-up: 3. (-2.3) 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. Maria-Victoria Mateos, Abstract 5 ASH 26

15 % surviving without progression % surviving without progression PFS: Prior Lines of Treatment prior line 2 to 3 prior lines 2-month PFS a 2-month PFS a 8 77% 8 DVd Median: 9.8 months % 4 4 DVd 2 25% Vd Median: 7.9 months 2 22% Median: 6.3 months No. at risk Vd 3 DVd 22 HR:.22 (95% CI,.4-.34; P <.) Months HR:.5 (95% CI, ; P =.2) Months DVd is superior to Vd regardless of prior lines of therapy, with greatest benefit observed in prior line 27 4 Vd a Kaplan-Meier estimate. Maria-Victoria Mateos, Abstract 5 ASH 26

16 ORR, % ORR, % ORR by Prior Lines a prior line 2 to 3 prior lines P =.4 P = CR: 36% b ORR = 9% 4 26 CR: 39 6 VGPR: 75% c 5% ORR = 74% DVd (n = 9) Vd (n = 9) VGPR: 42% scr CR VGPR PR CR: 9% d ORR = 79% VGPR: 52% c CR: 7% ORR = 58% 6 37 DVd (n = 99) Vd (n = ) VGPR: 2% scr CR VGPR PR More patients achieve a deeper response with DVd after prior line of treatment a Response-evaluable population. b P =.6 for DVd vs Vd. c P <. for DVd vs Vd. d P =.33 for DVd vs Vd. Maria-Victoria Mateos, Abstract 5 ASH 26

17 MRD-negative rate, % MRD-negative rate, % 25 *** 5.X MRD rates by prior lines of therapy ITT (N = 498) prior line (n = 235) *** ** NS ** ** 6.6X 4.6X 3.2X X 5.5X ,3 2 5,4 5 2,3 5 Sensitivity 3,6 2,4 4,4,8 DVd Vd DVd Vd DVd Vd threshold MRD was evaluated by ClonoSEQ-NGS based assay in a central laboratory at 3 sensitivity thresholds, for patients with suspected CR and also for patients who maintain CR at Cycle 9 and Cycle 5 MRD-negative rates for DVd were 3-fold higher across all thresholds 5 3,5 2,7 5,7,8 DVd Vd DVd Vd DVd Vd ***P <.. **P <.. NS, not significant; NGS, next-generation sequencing. P values calculated using likelihood-ratio chi-square test. MRD-negativity rate = proportion of patients with negative MRD test results at any time during treatment. Maria-Victoria Mateos, Abstract 5 ASH 26

18 % surviving without progression % surviving without progression PFS: MRD Status ( 5 ) ITT prior line Vd MRD negative DVd MRD negative DVd MRD negative Vd MRD negative 8 8 DVd MRD positive DVd MRD positive Vd MRD positive Vd MRD positive Months Months MRD negativity is associated with better outcomes Maria-Victoria Mateos, Abstract 5 ASH 26

19 % surviving without progression PFS: Cytogenetic Risk in All Evaluable Patients a 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 = 23 Vd n = 35 NR (.2-.43) <. Vd n = 5 Median PFS, mo HR (95% CI) P value.49 ( ).67 n = 44 n = 47 ORR, % P value.39 n = 8 n = NR, not reached. a ITT/Biomarker risk evaluable analysis set. b Central NGS. High-risk patients had any of t(4;4), t(4;6), or del7p. Standard-risk patients had an absence of high-risk abnormalities. DVd improves outcomes regardless of cytogenetic risk Maria-Victoria Mateos, Abstract 5 ASH 26

20 % surviving patients OS ITT OS events 8 DVd 37 (5%) in DVd 6 4 Vd 58 (24%) in Vd OS HR for DVd versus Vd by prior lines: prior line = HR:.42 (95% CI,.9-.93) 2 to 3 prior lines = HR:.54 No. at risk HR:.63 (95% CI, ) Months (95% CI, ) Vd DVd Curves are beginning to separate, but OS data are immature Median OS was NR; results did not cross the prespecified stopping boundary. Maria-Victoria Mateos, Abstract 5 ASH 26

21 Responders, % Time to Response DVd (PR or better) 8 Vd (PR or better) 6 4 DVd (CR or better) 2 Vd (CR or better) No. at risk Months Vd (PR or better) DVd (PR or better) Vd (CR or better) DVd (CR or better) Palumbo, A. N Engl J Med (8): Palumbo A, et al. ASCO 26. Abstract LBA4.

22 Most Common TEAEs (All Patients): Updated Analysis DVd (n = 243) Vd (n = 237) Hematologic, n (%) All grade Grade 3/4 All grade Grade 3/4 25% a 5% a 25% a 5% a Thrombocytopenia 45 (6) (45) 5 (44) 78 (33) Anemia 67 (28) 36 (5) 75 (32) 38 (6) Neutropenia 45 (9) 32 (3) 23 () (5) Lymphopenia 32 (3) 24 () 9 (4) 6 (3) Nonhematologic, n (%) Peripheral sensory neuropathy 2 (49) (5) 9 (38) 6 (7) Diarrhea 83 (34) 9 (4) 53 (22) 3 () Upper respiratory tract infection 72 (3) 6 (3) 43 (8) (.4) Cough 66 (27) 3 (3) Fatigue 53 (22) 2 (5) 58 (25) 8 (3) Pneumonia 33 (4) 22 (9) 28 (2) 23 () Hypertension 22 (9) 6 (7) 8 (3) 2 (.8) Grade 3/4 TEAEs: 79% of DVd patients versus 63% of Vd patients Discontinuations due to TEAEs: 9% of DVd patients versus 9% of Vd patients b No new IRRs; incidence remains stable with longer follow-up (45%) Maria-Victoria Mateos, Abstract 5 ASH 26

23 Infusion-related Reactions (IRRs) Safety Analysis Set (n = 243) All grades Grade 3 Patients with IRRs, % 45 9 Most common (>5%) IRRs Dyspnea 2 Bronchospasm 9 3 Cough 7 No grade 4 or 5 IRRs observed 98% of patients with IRRs experienced the event on the first infusion 2 patients discontinued due to IRRs Bronchospasm in the first patient Bronchospasm, laryngeal edema, and skin rash in the second patient Preinfusion: dexamethasone 2 mg, paracetamol 65- mg, diphenhydramine 25-5 mg Stop infusion immediately for mild symptoms; once resolved, resume at half the infusion rate Palumbo, A. N Engl J Med (8):

24 POLLUX: Study Design Multicenter, randomized (:), open-label, active-controlled phase 3 study DRd (n = 286) Key eligibility criteria RRMM prior line of therapy Prior lenalidomide exposure, but not refractory Patients with creatinine clearance 3 ml/min Stratification factors R A N D O M I Z E : Daratumumab 6 mg/kg IV Qw in Cycles -2, q2w in Cycles 3-6, then q4w until PD R 25 mg PO Days -2 of each cycle until PD d 4 mg PO 4 mg weekly until PD Rd (n = 283) R 25 mg PO Days -2 of each cycle until PD d 4 mg PO 4 mg weekly until PD Primary endpoint PFS Secondary endpoints TTP OS ORR, VGPR, CR MRD Time to response Duration of response Statistical analyses No. prior lines of therapy ISS stage at study entry Cycles: 28 days 295 PFS events: 85% power for 7.7 month PFS improvement Prior lenalidomide Interim analysis: ~77 PFS events Pre-medication for the DRd treatment group consisted of dexamethasone 2 mg a, paracetamol, and an antihistamine Dimopoulos MA, et al. N Engl J Med 26;375:39-33.

25 Baseline Demographics and Clinical Characteristics (cont.) Characteristic DRd (n = 286) Rd (n = 283) Prior ASCT, % Prior PI, % Prior IMiD, % Prior lenalidomide, % Prior PI + IMiD, % Refractory to PI, % 2 6 Refractory to last line of therapy, % Dimopoulos MA, et al. N Engl J Med 26;375:39-33.

26 % surviving without progression ORR, % Median (range) follow-up: 7.3 (-24.5) months Updated Efficacy 8 8-month PFS a 76% Median: not reached DRd 9 8 ORR = 93% 23 P <. ORR = 76% No. at risk HR:.37 (95% CI,.28-.5; P <.) Months 49% Rd Median: 7.5 months CR: 46% b VGPR: 78% b CR: 2% DRd (n = 28) Rd (n = 276) VGPR: 45% scr CR VGPR PR Rd DRd 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. Responses continue to deepen in the DRd group with longer follow-up Usmani abstract 489 ASH meeting 26

27 MRD-negative rate, % MRD-negative Rate ,8 * * * 3.6X 4.4X 4.8X * P < ,8 2 5,9 8,8 5 5,7 2,5 Sensitivity DRd Rd DRd Rd DRd Rd threshold MRD-negative rates were >3-fold higher at all thresholds ITT population. P values are calculated using likelihood-ratio chi-square test. Usmani abstract 489 ASH meeting 26

28 % surviving without progression ORR, % Refractory to Last Line of Therapy 8-month PFS a 9 ORR = 87% b P = No. at risk Rd DRd Median:.3 months HR:.47 (95% CI: ; P =.5) 65% 36% DRd Rd Months CR: 47% c DRd (n = 78) CR: 5% VGPR: 73% c ORR = 64% b Rd (n = 73) scr CR VGPR PR VGPR: 34% DRd benefits patients refractory to last line of therapy a Kaplan-Meier estimate. b Response-evaluable population. c P <. for DRd vs Rd. Usmani abstract 489 ASh meeting 26

29 % surviving without progression PFS: Cytogenetic Risk in All Evaluable Patients a Comparable results in to 3 prior lines population 8 DRd standard risk High risk DRd n = 28 Rd n = 37 Median PFS, mo NR.2 HR (95% CI) P value.44 (.9-.3).475 No. at risk Rd std risk DRd std risk Rd high risk DRd high risk Months DRd high risk Rd standard risk Rd high risk DRd improves outcomes regardless of cytogenetic risk ORR, % P value Standard risk Median PFS, mo HR (95% CI) P value ORR, % P value n = 27 n = 36 DRd n = 33 NS Rd n = 3 NR 7..3 (.8-.49) <. n = 32 n = NR, not reached; NS, not significant. a ITT/Biomarker risk evaluable analysis set. High-risk patients had any of t(4;4), t(4;6), or del7p. Standard-risk patients had an absence of high-risk abnormalities. Usmani abstract 489 ASH meeting 26

30 % surviving patients Median (range) follow-up: 7.3 (-24.5) months OS DRd Rd OS events 4 (4%) in DRd 56 (2%) in Rd 2 HR:.63 (95% CI: ) No. at risk Rd DRd Months Curves are beginning to separate, but OS data are immature ITT population. Median OS was not reached; results did not cross the prespecified stopping boundary. Usmani abstract 489 ASH meeting 26

31 % surviving without progression PFS: Prior Lenalidomide Treatment % surviving without progression No Prior Lenalidomide Treatment Prior Lenalidomide Treatment 8-month PFS a 8-month PFS a 79% 8 76% 8 DRd 6 49% DRd 6 59% Rd 4 Rd 4 2 Median: 7. months 2 No. at risk Rd DRd HR:.37 (95% CI,.26-.5; P <.) Months No. at risk Rd DRd HR:.45 (95% CI,.2-.99; P =.42) Months Treatment effect is consistent regardless of prior lenalidomide exposure Philippe Moreau, abstract 5 ASH 26

32 Proportion surviving without progression Time to Response. DRd (PR or better) Rd (PR or better) DRd (CR or better).2 Rd (CR or better) No. at risk Months Rd (PR or better) DRd (PR or better) Rd (CR or better) DRd (CR or better) Dimopoulos MA, et al. N Engl J Med 26;375:39-33.

33 Most Common AEs (All Patients): Updated Analysis DRd (n = 283) Rd (n = 28) Hematologic, % All grade Grade 3/4 All grade Grade 3/4 25% a 5% a 25% a 5% a Neutropenia Febrile neutropenia Anemia Thrombocytopenia Lymphopenia Nonhematologic, % Diarrhea Fatigue Upper respiratory tract infection Cough 3 3 Constipation Muscle spasms Nasopharyngitis 26 7 Nausea Pneumonia No new safety signals reported AE, adverse event. a Common treatment-emergent AEs listed are either 25% all grade OR 5% grade 3/4. Usmani abstract 489 ASH meeting 26

34 Infusion-related Reactions (IRRs) IRRs 2% Safety Analysis Set (n = 283) All grades (%) Grade 3 (%) Patients with IRRs 48 5 Cough 9 Dyspnea 9.7 Vomiting 6.4 Nausea 5 Chills 5.4 Bronchospasm 5.4 Pruritus 3.4 Throat irritation 3 Headache 3 Nasal congestion 3 Wheezing 2.7 Laryngeal edema 2.4 Rhinorrhea 2 Pyrexia 2 No grade 4 or 5 IRRs were reported 92% of all IRRs occurred during the first infusion patient discontinued daratumumab due to an IRR IRRs, infusion-related reactions. Dimopoulos MA, et al. N Engl J Med 26;375:39-33.

35 Lenalidomide-based Studies POLLUX DRd vs Rd ASPIRE KRd vs Rd ELOQUENT-2 ERd vs Rd 2,3 TOURMALINE-MM NRd vs Rd 4 PFS HR (95% CI).37 ( ).69 ( ).73 (.6-.89).74 ( ) ORR 93% VGPR 76% CR 43% 87% 79% 78% 7% 33% 48% 32% 4% 4% Duration of response, mo NE OS HR (95% CI).64 (.4-.).79 ( ).77 (.6-.97) NE. Stewart AK, et al. N Engl J Med. 25;372(2): Lonial S, et al. N Engl J Med. 25;373(7): Dimopoulos MA, et al. Blood. 25;26(23):Abstract Moreau P, et al. N Engl J Med. 26;374(7): Dimopoulos MA, et al. N Engl J Med 26;375:39-33.

36 Phase b Study of Daratumumab Plus Pomalidomide and Dexamethasone in Relapsed and/or Refractory Multiple Myeloma (RRMM) With 2 Prior Lines of Therapy Ajai Chari, Attaya Suvannasankha, 2 Joseph W. Fay, 3 Bertrand Arnulf, 4 Jonathan Kaufman, 5 Jainulabdeen J. Ifthikharuddin, 6 Brendan Weiss, 7 Amrita Krishnan, 8 Suzanne Lentzsch, 9 Raymond Comenzo, Jianping Wang, Tara Masterson, 2 Kerri Nottage, Jordan Schecter, Christopher Chiu, 2 Nushmia Khokhar, 2 Tahamtan Ahmadi, 2 Sagar Lonial 5 Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY, USA; 2 Indiana University School of Medicine and Simon Cancer Center, Richard L. Roudebush VAMC, Indianapolis, IN, USA; 3 Baylor Institute for Immunology Research, Dallas, TX, USA; 4 Hôpital Saint Louis, Paris, France; 5 Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA; 6 James P. Wilmot Cancer Center, University of Rochester Strong Memorial Hospital, Rochester, NY, USA; 7 Abramson Cancer Center and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 8 The Judy and Bernard Briskin Myeloma Center, City of Hope, Duarte, CA, USA; 9 Columbia University Medical Center, New York, NY, USA; Division of Hematology-Oncology, Tufts Medical Center, Boston, MA, USA; Janssen Research & Development, Raritan, NJ, USA; 2 Janssen Research & Development, Spring House, PA, USA. ClinicalTrials.gov Identifier: NCT99897

37 Rationale for DARA + POM-D In a randomized, phase 3 study, pomalidomide plus low-dose dexamethasone (POM-D) in patients relapsed from or refractory to previous treatment with bortezomib or lenalidomide resulted in the following : Overall response rate (ORR) = 3% Median progression-free survival (PFS) = 4. months Median overall survival (OS) = 2.7 months Pomalidomide increases CD38 expression in a time- and dose-dependent fashion in multiple myeloma (MM) cells 2 Increases in T-cell clonality were observed with DARA plus lenalidomide and dexamethasone (Rd) but not with Rd alone in POLLUX 3. San Miguel J, et al. Lancet Oncol. 23;4(): Boxhammer R, et al. Presented at: 5st American Society of Clinical Oncology (ASCO) Annual Meeting; May 29-June 2, 25; Chicago, IL. Abstract Chiu, C. et al. Presented at: 58th American Society of Hematology (ASH) Annual Meeting & Exposition; December 3-6, 26; San Diego, CA. Abstract

38 MMY: DARA + POM-D Cohort Eligibility criteria Refractory to last line of therapy 2 prior lines of therapy, including 2 consecutive cycles of lenalidomide and bortezomib Pomalidomide naïve Eastern Cooperative Oncology Group (ECOG) score 2 Absolute neutrophil count. 9 /L, and platelet count 75 9 /L for patients with >5% plasma cells Calculated creatinine clearance (CrCl) 45 ml/min/.73 m 2 Open-label, multicenter, 6-arm, phase b study (28-day cycles) DARA* IV 6 mg/kg + Pomalidomide 4 mg (Days -2) + Dexamethasone 4 mg QW *QW for Cycles -2, Q2W for Cycles 3-6, and Q4W thereafter Treat 6 patients with DARA + POM-D Expansion cohort of an additional 97 patients (N = 3 total) QW, once weekly; Q2W, every 2 weeks; Q4W, every 4 weeks; DLT, dose-limiting toxicity. 39

39 Baseline Demographics and Clinical Characteristics Characteristic Age, y Median (range) Category, n (%) <65 65-<75 75 DARA + POM-D N = 3 64 (35-86) 52 (5) 43 (42) 8 (8) Female/male, % 45/55 ECOG score, n (%) 2 Cytogenetic profile, n (%)* Standard risk High risk del7p t(4;4) t(4;6) 28 (27) 63 (6) 2 (2) n = (75) 22 (25) 6 (8) 6 (7) () Time from diagnosis, y Median (range) 5.3 (.4-6.) Characteristic Prior lines of therapy, n (%) Median (range) 2 3 >3 DARA + POM-D N = 3 4 (-3) 3 (3) 22 (2) 25 (24) 53 (52) Prior ASCT, n (%) 76 (74) Prior PI, n (%) Prior BORT Prior CARF 2 (99) (98) 34 (33) Prior LEN, n (%) 3 () Prior PI + IMiD, n (%) 2 (99) Refractory to, n (%) LEN 92 (89) BORT 73 (7) CARF 3 (3) Refractory to PI + IMiD, n (%) 73 (7) ISS, International Staging System; ASCT, autologous stem cell transplant; PI, proteasome inhibitor; BORT, bortezomib; CARF, carfilzomib; LEN, lenalidomide; IMiD, immunomodulatory drug. *Based on FISH or karyotyping. Percentages based on n = 87 as denominator. 6

40 Patient Disposition: DARA + POM-D* Median follow-up: 3. months (range: ) Median duration of treatment: 6.7 months (range:.3-2.+) DARA + POM-D N = 3 Discontinued treatment 69 (67%) Progressive disease 4 (39%) AE 6 (6%) Death 4 (4%) Investigator s decision 4 (4%) Withdrawal of consent 4 (4%) Other (%) *Clinical cut off : 3 June 26. 4

41 Safety Summary: DARA + POM-D Most common (>25%) TEAEs N = 3 n (%) Neutropenia a 82 (8) Anemia 56 (54) Fatigue 54 (52) Diarrhea 44 (43) Thrombocytopenia 43 (42) Cough 39 (38) Leukopenia 38 (37) Constipation 35 (34) Dyspnea 33 (32) Nausea 32 (3) Pyrexia 3 (3) Back pain 29 (28) Upper respiratory tract infection 29 (28) Muscle spasms 28 (27) 44% of patients had baseline grade /2 neutropenia 5% of patients discontinued due to treatment-emergent adverse events (TEAEs) None of the TEAEs occurred in > patient 3% were related to DARA 9% of patients had a TEAE leading to death None were related to DARA No patients reported secondary primary malignancies a Received G-CSF support. No new safety signals were reported with longer follow-up 42

42 Most Common (>5%) Grade 3/4 Adverse Events (AEs) Neutropenia Anemia Leukopenia Thrombocytopenia Lymphopenia Fatigue Pneumonia Dyspnea Febrile neutropenia Hyperglycemia Back pain Fall Patients (%) Serious adverse events (SAEs) occurred in 53% of patients 8% were related to DARA per investigator discretion The most common grade 3 or 4 infection/infestation TEAE was pneumonia (%) There were relatively low rates of febrile neutropenia (8%) Other than neutropenia, rates of grade 3 AEs were similar to those observed historically with POM-D alone 43

43 IRRs in >5% Patients: DARA + POM-D N = 3 IRR Any grade, % Grade 3, % Any event 5 4 Chills 5 Cough Dyspnea Nausea 9 Nasal congestion 7 Throat irritation 7 4 (4%) patients had grade 3 infusion-related reactions (IRRs) Hypertension (n = 2), hypoxia (n = ), and increased blood pressure (n = ) No grade 4 or 5 IRRs occurred patient discontinued due to an IRR (grade 3 hypoxia) All IRRs occurred during the first infusion, except for instance of laryngeal edema, which occurred during the second infusion IRRs were mostly grade 2 and occurred predominantly during the first infusion 44

44 ORR, % ORR (scr+cr+vgpr+pr) Best response scr CR VGPR PR MR SD PD NE VGPR or better (scr+cr+vgpr) ORR a : DARA + POM-D DARA + POM-D (N = 3) n (%) 95% CI 62 (6) (8) 9 (9) 26 (25) 9 (8) 2 (2) 26 (25) 3 (3) () (42) CR or better (scr+cr) 7 (7) DARA + POM-D (N = 3) Among patients with CR or better, the minimal residual disease negative rate at: 4 threshold = 6/7 (35%) 5 threshold = 5/7 (29%) 6 threshold = /7 (6%) % CR or better PR VGPR CR scr ORR = 6% % VGPR or better Deep responses were observed with DARA + POM-D a Based on independent safety monitoring board assessment. Daratumumab IFE reflex assay was used to mitigate DARA-mediated interference with assessment of CR. 45

45 ORR Subgroup Analysis: DARA + POM-D All patients Sex Male Female Age, y <65 65 Renal function (baseline CrCI): <6 ml/min 6 ml/min Baseline hepatic function: Normal Impaired a Number of prior lines of therapy: 2 lines 3 lines >3 lines Refractoriness: PI + IMiD Measurable type of MM: IgG Non-IgG Cytogenetic risk: Standard risk High risk ORR (95% CI) % N ORR 95% Cl ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) 26 b 65.4 ( ) ( ) ( ) ( ) ( ) ( ) ( ) High response rate maintained across clinically relevant subgroups a Classified as mild, moderate, or severe; 7% had mild impairment; % had moderate impairment; % had severe impairment. Patients with impaired hepatic function received fewer doses of DARA versus patients with normal hepatic function. b Discrepancy from demographics table due to update of concomitant medication data. 46

46 % surviving without progression PFS: DARA + POM-D Median PFS: 8.8 months (95% CI, ) 6-month PFS rate: 57.8% (95% CI, ) Months 2-month PFS rate: 4.9% (95% CI, ) No. at risk ~4% of patients maintain PFS after year 47

47 % surviving patients % surviving patients OS: DARA + POM-D OS OS by Response Category PR SD/MR PD/NE Median: NE (95% CI, 7.5-NE) 4 Median: 7.5 months (95% CI, 3.3-NE) 4 No. at risk Months month OS rate: 66.2% (95% CI, ) 2 No. at risk PR SD/MR PD/NE Median: 2.3 months (95% CI,.6-5.4) 52 Months Median: 8.5 months (95% CI, ) 4 2 NE, not evaluable. Patients with SD/MR derive survival benefit with DARA + POM-D 48

48 Conclusions: DARA + POM-D DARA can be safely combined with POM-D High neutropenia rates in a population with 44% baseline neutropenia Febrile neutropenia rates were consistent with POM-D alone DARA (6 mg/kg) + POM-D induced deep responses, including MRD negativity, in a heavily pretreated patient population Median of 4 prior lines of therapy 7% of patients were double refractory to a PI and an IMiD High response rate is maintained in double-refractory and high-risk patients 4% of patients remain progression-free after year The addition of DARA to POM-D is associated with encouraging OS A phase 3 study is being planned 49