DREAMM-7 Trial

[Slide 1] Kaplan-Meier Analysis of Progression-free Survival Patients with Patients with Median Censored Censored Progression- Data, Data, free Patients with Follow-up Follow-up Survival an Event Ended Ongoing (95% CI) no. (%) mo BVd 91 (37) 44 (18) 108 (44) 36.6 (28.4-NR) 100 12 mo 18 mo DVd 158 (63) 41 (16) 52 (21) 13.4 (11.1-17.5) 90 Hazard ratio for disease progression or death, 0.41 78 (95% CI, 0.31-0.53) 80 P<0.001 Percentage of Patients Alive 70 69, and Progression-free 60 53 50 43 BVd 40 30 20 DVd 10 0 0 1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 Months since Randomization No. at Risk (no. of events) BVd 243 230 211 200 183 171 158 150 140 131 127 122 118 110 94 72 41 25 11 6 2 0 (0) (6) (17) (25) (32) (39) (46) (51) (59) (63) (67) (69) (71) (78) (81) (86) (88) (89) (90) (91) (91) (91) DVd 251 230 205 183 155 141 124 107 99 91 80 73 67 61 52 33 19 11 2 1 1 0 (0) (9) (29) (47) (71) (81) (97) (113) (119) (124) (133) (138) (144) (148) (151) (154) (154) (156) (158) (158) (158) (158)

[Slide 1] ORIGINAL ARTICLE f X in Belantamab Mafodotin, Bortezomib, and Dexamethasone for Multiple Myeloma Authors: Vania Hungria, M.D., Ph.D., Pawel Robak, M.D., Ph.D., Marek Hus, M.D., Ph.D., D.Sc., Vera Zherebtsova, M.D., Christopher Ward, M.D., Ph.D., P. Joy Ho, M.B., B.S., D.Phil., Ana Carolina Ribas de Almeida, M.Sc., Ph.D., Roman Hajek, M.D., Ph.D., Kihyun Kim, M.D., Sebastian Grosicki, M.D., Ph.D., Hanlon Sia, M.B., B.S., Adam Bryant, M.B., B.S., Ph.D., Marcelo Pitombeira de Lacerda, M.D., Ph.D. ID Gracia Aparecida Martinez, Ph.D., Anna Maria Sureda Balarí, M.D., Ph.D., Irwindeep Sandhu, M.D., Claudio Cerchione, M.D., Ph.D. ID Peter Ganly, B.M., B.Ch., Ph.D., Meletios Dimopoulos, M.D., Chengcheng Fu, M.D., Ph.D., Mamta Garg, M.D., Al-Ola Abdallah, M.D., Albert Oriol, M.D., Moshe E. Gatt, M.D., Michele Cavo, M.D., Robert Rifkin, M.D., Tomoaki Fujisaki, M.D., Ph.D., Michał Mielnik, M.D., Nick Pirooz, M.H.A. ID , Astrid McKeown, Ph.D., Simon McNamara, Ph.D., Xiangdong Zhou, Ph.D., Maureen Nichols, B.S., Eric Lewis, M.D., Rachel --- [Slide 2] Recruitment period Treatment period ~13 month from FPI (May 7, 2020)to LPI Until end of study, withdrawal of consent, PD, death, or Follow-up period (June 28, 2021) unacceptable toxicity Cycle 1-8 Cycle 9+ Eligibility criteria Belantamab mafodotin Belantamab Follow-up for PFS Follow-up for OS Age ≥18 years 2.5 mg/kg q3w IV q3w q12w mafodotin with MM Arm A (BVd) + (for patients who (for patients who monotherapy discontinue due to Bortezomib 1.3 mg/m2 SC on days 1,4,8, discontinue due to ≥1 prior line of and 11 of cycles 1-8 2.5 mg/kg IV q3w End-of-treatment visit reasons other than PD or other MM therapy and (21-day cycles) PD) reasons) documented PD 1:1 Randomization Dexamethasone 20 mg (IV or PO) on the Disease during or after day of and day after bortezomib in cycles 1-8* assessments q3w most recent therapy Daratumumab Daratumumab No prior treatment 16 mg/kg IV cycles 1-3; qw and monotherapy with anti-BCMA No intolerance of or disease that is Arm B (DVd) cycles 4-8; q3w + 16 mg/kg IV cycle 9+ q4w Bortezomib 1.3 mg/m2 SC on days 1,4,8, and 11 of cycles 1-8 refractory to (21-day cycles) daratumumab or Dexamethasone 20 mg (IV or PO) on the bortezomib day of and day after bortezomib in cycles 1-8* Disease assessment visits: q3w from cycle 1, day 1 until PD Stratification: Prior lines of treatment (1 VS 2 or 3 VS >4) Primary endpoint: Key secondary endpoints: Additional secondary endpoints: R-ISS stage (I vs II/III) PFS OS, DOR, and MRD CRR, ORR, CBR, TTR, TTP, PFS2, AEs, Prior bortezomib (yes VS no) and ocular findings

[Slide 1] Where might we use belantamab vedotin? Scenario #1: Post-MAIA relapse (i.e., after Dara-Rd) - DREAMM-7: Bela-Vd beat Dara-Vd, even in dara-naïve patients - DREAMM-8: Bela-Pd beat PVd. KPd may have been a more formidable foe, but not routinely available and concern about toxicities. Scenario #2: BCMA CAR-T not planned as third-line therapy: - Medical comorbidities precluding CAR-T, e.g. cardiac dysfunction - Logistical complexities (caregiver, geographic relocation for 2 months) - Patient concerned about toxicities of CAR-T therapy - Patient lives in a country where CAR-T not available in any line Will this be worth getting REMS-authed for? Yes, please! - With dose holds until ocular AEs resolve to ≤Gr1, belantamab is a great option. Fred Hutchinson Cancer Center 12 Abbreviations: Bela-Pd, belantamab pomalidomide dexamethasone; Bela-Vd, belantamab bortezomib dexamethasone; REMS, Risk Evaluation and Mitigation Strategy. @rahulbanerieemd

[Slide 1] Figure 1 A B IM9 U266 0.8 Scr MALT1-KO 0.5 Scr MALT1-KO CD138(-)#1 CD138(-)#2 CD138(+)#1 CD138(+)#2 RPMI8226 KMS11 Absorbance (OD 450nm Scr KO 0.4 Scr KO U266 MOLP8 0.6 OPM2 H929 JJN3 MM1s MALT1 MALT1 0.3 GAPDH GAPDH 0.4 MALT1 0.2 0.2 GAPDH 0.1 0.0 0.0 1 2 3 4 1 2 3 4 Days Days C RPMI1640 medium HS-5 (conditioned medium) VEGF (100 ng/ml) IGF (100 ng/ml) IL6 (25 ng/ml) 0.8 0.8 0.8 ns ns * * 0.8 0.8 ns ns Scramble MALT1-KO Absorbance (OD₄₅₀ₙₘ) 0.6 0.6 0.6 0.6 0.6 ns ns ns ns 0.4 0.4 0.4 0.4 0.4 0.2 0.2 0.2 0.2 0.2 0.0 0.0 0.0 0.0 0.0 24h 48h 72h 24h 48h 72h 24h 48h 72h 24h 48h 72h 24h 48h 72h D E IM9 MALT1 Median survival 100 ** SCR (n=6) 27.5days 30 MALT1-KO (n=6) 37.5days NR (n=14) Probability of Survival 50 Relative mRNA expression MM (n=25) 20 -ДДСТ 10 p=0.044 0 0 20 40 60 0 Days from the first day of cell injected NR MM F G 1.0 MALT1 Plasma Cell(n=30) 0.8 + data=High su Downloaded dfrom htp:/ashpublications.org/bloodadvances/article-pd/doi/10.1182/blodadvances.2023012394/2227680/blodadvances2023012394.pd by Rob from by Robert on 01 June 2024 Lymphocyte(n=126) + data=Low Blood(n=96) Survival probability 0.6 0.4 Solid tumors(n=491) 0.2 P=0.026 0.0 0 2 4 6 8 10 0 500 1000 1500 2000 Expression of MALT1 Time(days) --- [Slide 2] Figure 3 A B Enrichment plot: HALLMARK- HALLMARK_SPERMATOGENESIS TNFA-SIGNALING-VIA-NFKB HALLMARK_ALLOGRAFT_REJECTION HALLMARK_MYC_TARGETS_V2 MI-2 MALT1-KD Enrichment score(ES) 0.0 HALLMARK_G2M_CHECKPOINT -0.1 HALLMARK_MYC_TARGETS_V1 -0.2 HALLMARK_E2F_TARGETS -0.3 NES=-1.73 HALLMARK_PROTEIN_SECRETION -0.4 FDR=0.009 HALLMARK_KRAS_SIGNALING_UP HALLMARK_MITOTIC_SPINDLE HALLMARK_HYPOXIA HALLMARK_ESTROGEN_RESPONSE_EARLY DMSO Mi-2 HALLMARK_EPITHELIAL_MESENCHYMAL_TRANSITION HALLMARK_TNFA_SIGNALING_VIA_NFKB RPMI8226 U266 IM9 C HALLMARK_APOPTOSIS Scr MALT1-KO Scr MALT1-KO Scr MALT1-KO HALLMARK_INFLAMMATORY_RESPONSE HALLMARK_INTERFERON_ALPHA_RESPONSE p-p65 HALLMARK_INTERFERON_GAMMA_RESPONSE p65 -4 -2 0 2 4 NES GAPDH D Scr MALT1-KO c-Rel DAPI Merge c-Rel DAPI Merge E IM9 RPMI 8226 Scr MALT1-KO p-lkB IkB U266 GAPDH F G Mi-2 (1.5uM) PMA(10ng/ml) - - + + 0 0.5 2 4 8 Mi-2(uM) + 1.5 3 - 1.5 Time (hours) 1 c-Rel p-NF-kB p65 GAPDH Histone H3 H p65 DAPI Merge c-Rel DAPI Merge Downloaded apublication.org/boodadances/arice/do/10 1182/boodadvances.2023012394/227680bloodadvances2023012394.pdf by Robe from http://ashpublications.org/bloodadvances/article by Robert Orlowski on 01 June 2024 DMSO Mi-2

[Slide 1] The NEW ENGLAND JOURNAL of MEDICINE A Kaplan-Meier Analysis of Progression-free Survival Patients with Patients with Median Censored Censored Progression- Data, Data, free Patients with Follow-up Follow-up Survival an Event Ended Ongoing (95% CI) no. (%) mo BVd 91 (37) 44 (18) 108 (44) 36.6 (28.4-NR) 100 12 mo 18 mo DVd 158 (63) 41 (16) 52 (21) 13.4 (11.1-17.5) 90 Hazard ratio for disease progression or death, 0.41 78 (95% CI, 0.31-0.53) 80 P<0.001 Percentage of Patients Alive 69, 70 and Progression-free 60 53 50 43 BVd 40 30 20 DVd 10 0 0 1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 Months since Randomization No. at Risk (no. of events) BVd 243 230 211 200 183 171 158 150 140 131 127 122 118 110 94 72 41 25 11 6 2 0 (0) (6) (17) (25) (32) (39) (46) (51) (59) (63) (67) (69) (71) (78) (81) (86) (88) (89) (90) (91) (91) (91) DVd 251 230 205 183 155 141 124 107 99 91 80 73 67 61 52 33 19 11 2 1 1 0 (0) (9) (29) (47) (71) (81) (97) (113) (119) (124) (133) (138) (144) (148) (151) (154) (154) (156) (158) (158) (158) (158) B Post Hoc Supplementary Analyses of Progression-free Survival BVd DVd Analysis (N=243) (N=251) no. of patients with event (%) Disease progression or death 100 (41) 173 (69) Disease progression 67 (28) 139 (55) Disease progression after extended loss to follow-up 1 (<1) 6 (2) Disease progression after the start of new antimyeloma therapy 0 0 Death 24 (10) 19 (8) Death after extended loss to follow-up 4 (2) 2 (<1) Death after the start of new antimyeloma therapy 4 (2) 7 (3) Censored, follow-up ended 35 (14) 26 (10) Censored, follow-up ongoing 108 (44) 52 (21) Hazard ratio (95% CI) 0.41 (0.32-0.53) Figure 1. Progression-free Survival. Panel A shows the Kaplan-Meier analysis of independent review committee-assessed progression-free survival in the intention-to-treat population. Panel B shows a post hoc supplementary analysis of progression-free survival in the intention-to-treat population in which any occurrence of disease progression or death after the start of a new antimyeloma therapy or after extended loss to follow-up was con- sidered to be an event. Patients had censored data with follow-up ended if they had not had an event and had been withdrawn from the trial or if they had started a new antimyeloma therapy and therefore had missing outcome data; no further data collection is expected. Patients had censored data with follow-up ongoing if they had not been withdrawn from the trial, had not started a new antimyeloma therapy, and continued to be followed for the outcome. Two patients in the intention-to-treat population underwent randomization but were not treated and underwent repeat screening and randomization; they are counted as four unique patients. Hazard ratios were esti- mated with a Cox proportional-hazards model stratified according to the number of previous lines of therapy (one vs. two or three vs. four or more), previous exposure to bortezomib (yes VS. no), and the Revised International Staging System stage at screening (I vs. II or III), with treatment as a covariate. Confidence intervals were estimated with the Brookmeyer-Crowley method. The confidence intervals have not been adjusted for multiplicity and cannot be used in place of hypothesis testing. The P value was estimated with a one-sided stratified log-rank test; a two-sided P value is reported. BVd denotes belantamab mafodotin, bortezomib, and dexamethasone, DVd daratumumab, bortezomib, and dexamethasone, and NR not reached.