AQUILA Trial

[Slide 1] AQUILA: Conclusions In this large phase 3 study in a well-defined population with high-risk SMM, DARA SC monotherapy for 36 months demonstrated a statistically significant PFS benefit versus active monitoring (HR, 0.49 [95% CI, 0.36-0.67]) - The greatest PFS benefit with DARA was observed among patients with high-risk SMM retrospectively identified by Mayo 2018 criteria (HR, 0.36 [95% CI, 0.23-0.58]) DARA prolonged PFS on first-line treatment for MM (HR, 0.58 [95% CI, 0.35-0.96]) DARA demonstrated a favorable safety profile, with a low rate of treatment discontinuation due to TEAEs There was no detriment to patients' health-related quality of life, with a trend toward improvement with DARA DARA extended overall survival (HR, 0.52 [95% CI, 0.27-0.98]) AQUILA strongly favored early intervention with DARA monotherapy in patients with high-risk SMM, representing an opportunity to delay or avoid end-organ damage and progression to MM and to extend overall survival 12 Presented by MA Dimopoulos at the 66th American Society of Hematology (ASH) Annual Meeting & Exposition: December 7-10. 2024: San Diego, CA. USA --- [Slide 2] AQUILA: Study Design AQUILA enrollment period: December 2017 and May 2019, at 124 sites in 23 countries Screening Treatment/active monitoring phase Follow-up phase Key eligibility criteria: DARA monotherapy Primary endpoint: >18 years of age PFS by IRC per IMWG 1800 mg SCb QW Cycles 1-2, Efficacy follow-up SLiM-CRAB criteria Confirmed SMM diagnosis (per IMWG criteria) for <5 years Serum M-protein >30 g/L 1:1 randomization (N = 390) Q2W Cycles 3-6, Q4W thereafter until progression in 28-day cycles until 39 cycles/36 months* by SLiM-CRAB ECOG PS score of 0 or 1 Key secondary endpoints: Clonal BMPCs >10% and >1 of the Survival follow-up ORR following risk factors: Active monitoring every 6 months Time to first-line IgA SMM No disease-specific treatment, until end of study treatment for MM PFS on first-line Immunoparesis with reduction of with AE monitoring up to 36 months* treatment for MM 2 uninvolved Ig isotypes Overall survival Serum involved:uninvolved FLC ratio >8 and <100 "or confirmed disease progression (whichever occurred first) Clonal BMPCs >50% to <60% Disease evaluation schedule Stratified by Laboratory efficacy - Every 12 weeks by central lab until disease progression All patients were required to have number of risk Imaging (CT/PET-CT, MRI)- Yearly (central review) CT/PET-CT and MRI imaging factors for Bone marrow - At least every 2 years during screening progression to MM (<3 VS >3) IMWG. International Myeloma Working Group; ECOG PS, Eastern Cooperative Oncology Group performance status; BMPC. bone marrow plasma cell; FLC, free light chain; CT. computed tomography; MRI. magnetic resonance imaging; QW. weekly; Q2W. every 2 weeks; Q4W, every 4 weeks; AE, adverse event; IRC. independent review committee; ORR, overall response rate. *Risk factors included involved:uninvolved FLC ratio >8 (yes vs no), serum M-protein >30 g/L (yes VS no), IgA SMM (yes vs no), immunoparesis (reduction of 2 uninvolved immunoglobulins vs other), or clonal BMPCs (>50% to <60% vs <50%). DARA SC (1800 mg co-formulated with recombinant human hyaluronidase PH20 [rHuPH20; 2,000 U/mL; ENHANZE® drug delivery technology: Halozyme, Inc.]). *PFS was defined as duration from randomization to initial documented progression to active MM or death due to any cause, whichever occurred first. 3 Presented by MA Dimopoulos at the 66th American Society of Hematology (ASH) Annual Meeting & Exposition: December 7-10, 2024: San Diego, CA. USA --- [Slide 3] AQUILA: Overall Survival 100 93.0% Daratumumab 80 86.9% Active monitoring Percentage of patients surviving Active DARA monitoring 60 (n 194) (n 196) Deaths, n (%) 15 (7.7) 26 (13.3) 40 Primary cause, n Disease progression 3 9 20 AE 2 4 HR, 0.52 (95% CI, 0.27-0.98) Other* 10 13 0 "Deaths due to an event occurring after the AE reporting 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 window (ie, events that happened after patient started Months since randomization subsequent therapy or >30 days after last dose) or deaths No. at risk with unknown reason. Daratumumab 194 194 194 193 192 191 188 188 188 188 188 186 184 179 177 176 175 174 172 169 162 128 86 38 11 Active monitoring 196 192 191 191 187 183 179 177 176 173 169 168 165 164 159 155 155 154 153 149 144 108 68 34 9 Early intervention with fixed duration DARA extended overall survival versus active monitoring 10 Presented by MA Dimopoulos at the 66th American Society of Hematology (ASH) Annual Meeting & Exposition; December 7-10, 2024; San Diego, CA, USA

[Slide 1] AQUILA: Safety Overview Active Active DARA monitoring DARA monitoring Event, n (%) (n = 193) (n = 196) Event, n (%) (n = 193) (n = 196) Median duration of AE reporting 35 months 26 months Treatment discontinuations due to 187 (96.9) a TEAEᵇ 11 (5.7) - Any grade TEAEs 162 (82.7) Grade 3 or 4 TEAEs 78 (40.4) 59 (30.1) Dose modifications due to a TEAE 90 (46.6) — Most common grade 3 or 4 TEAEs (≥5% in either group) COVID-19 TEAEs 17 (8.8) 10 (5.1) Hypertension 11 (5.7) 9 (4.6) Serious COVID-19 TEAEs 5 (2.6) 1 (0.5) Serious TEAEs 56 (29.0) 38 (19.4) Deaths due to COVID-19 2 (1.0) 0 Most common serious TEAEs (≥2% in either group) Pneumonia 7 (3.6) 1 (0.5) Grade 5 TEAEsᵃ 2 (1.0) 4 (2.0) Low rate of DARA discontinuation due to TEAEs, and no new safety concerns were identified TEAE, treatment-emergent adverse event TEAEs include all AEs occurring during the 36-month treatment/monitoring phase or for 30 days after discontinuation of DARA or active monitoring or until the start of subsequent treatment for MM. *Grade 5 TEAEs included COVID-19 infection and COVID-19 pneumonia in the DARA group and pulmonary edema, cardiac arrest, pulmonary embolism, and cardiac failure in the active monitoring group. The most frequently reported TEAEs leading to DARA discontinuation were fatigue, dyspnea, and anxiety (n = 2 each). Dose modifications include dose delays within a cycle, cycle delays, and skipped doses 16 Presented by MA Dimopoulos at the 66th American Society of Hematology (ASH) Annual Meeting & Exposition; December 7-10. 2024; San Diego, CA, USA

[Slide 1] Présentation I 654. Multiple Myeloma - Pharmacologic Therapies - Refining the Evidence - Randomized Trials in Multiple Myeloma Oral Abstract Sessions Phase 3 Randomized Study of Daratumumab Monotherapy Versus Active Monitoring in Patients with High-Risk Smoldering Multiple Myeloma: Primary Results of the Aquila Study Schedule Notes lun. 09 déc. Marriott Marquis - Pacific Ballroom 11:30-11:45 (UTC-8) Salons 21-22 Meletios-Athanasios Dimopoulos Oral Abstract Sessions Paper No: 0773

[Slide 1] The NEW ENGLAND JOURNAL of MEDICINE ORIGINAL ARTICLE Daratumumab or Active Monitoring for High-Risk Smoldering Multiple Myeloma M.A. Dimopoulos, P.M. Voorhees, F. Schjesvold, Y.C. Cohen, V. Hungria, I. Sandhu, J. Lindsay, R.I. Baker, K. Suzuki, H. Kosugi, M.-D. Levin, M. Beksac, K. Stockerl-Goldstein, A. Oriol, G. Mikala, G. Garate, K. Theunissen, I. Spicka, A.K. Mylin, S. Bringhen, K. Uttervall, B. Pula, E. Medvedova, A.J. Cowan, P. Moreau, M.-V. Mateos, H. Goldschmidt, T. Ahmadi, L. Sha, A. Cortoos, E.G. Katz, E. Rousseau, L. Li, R.M. Dennis, R. Carson, and S.V. Rajkumar, for the AQUILA Investigators*

[Slide 1] Variables (n; %, AQUILA trial (n=360) Heidelberg study (n=447) Mayo Clinic Study (n=406) Greek Study (n=427) unless otherwise stated) Daratumumab Active Arm (n=194) Surveil- lance Arm (n=196) Baseline Lytic lesion assessment by WB DW-MRI Not specified LDWBCT, WB DW-MRI, or imaging LDWBCT (preferred) or PET/ PET/CT during CT or CT; Focal lesion screening/ assessment by MRI spine and diagnosis pelvis Monitoring for MRI spine/pelvis every 6-12 WB DW-MRI yearlyb; Frequency and preferred LDWBCT, WB DW-MRI, or MDEs months for the first 3 years, LDWBCT for lytic lesion modality of follow-up PET/CT yearly; clinical and then every 12 months, and at assessment performed in case imaging not specified laboratory evaluation every biochemical/suspected PD; of evolving M-protein/sFLC three months for the first year, LDWBCT or PET/CT for lytic ratio, or suspected progres- every four months for the lesion assessment performed sion (85% underwent ≥1 WB second year, with follow-up only if triggered by new focal DW-MRI) beyond two years being every lesion on MRI spine/pelvis, four months in high-risk SMM biochemical PD, or suspected and every 6 months in PD to myeloma low-intermediate risk SMM Median 5.4 5.8 3.4-5.0 3.0 follow-up (years) Progression Entire Cohort HR-SMM Non-HR HR-SMM Entire Cohort HR-SMM details (n = 447) (n = 82; SMM (n = (n = 90; (n = 427) (n = 73; 18%) 226)c 22%)a 17%) Percent 34.5 50.5 28.9 56.1 39.0 71.8 10 3-year risk of progressed to progression: SLiM-CRAB 43% (%) Renal 0 (0) 0 (0) 9 (2.0) 2 (2.4) 5 (2.6); 4 3 (4.2); 1 1 (0.2) 0 (0) insufficiency (2.1%) with (1.4%) with irreversible irreversible renal failure renal failure Anemia 2 (1.0) 14 (7.1) 28 (6.3) 11 (13.4) 21 (11.0) 18 (25.4) 11 (2.6) 7 (9.6) Bone disease 10 (5.2) 18 (9.2) 60 (13.4) 14 (17.1) 30 (15.7) 19 (26.8) 11 (2.6) 8 (10.96) Fractures Not reported Not Not reported Not 4 (6.8) 5 (7.0) 1 (0.2) Not reported reported reported >60% clonal 5 (2.6) 16 (8.2) 40 (8.9) 9 (11.0) 8 (4.2) 12 (16.9%) 6 (1.4) Not reported BMPCs Serum FLC 33 (17.0) 33 (16.8) 47 (10.5) 21 (25.6) 12 (2.8) Not reported ratio >100 >1 focal lesion 12 (6.2) 16 (8.2) 32 (7.2) 11 (13.4) None None 6 (1.4) Not reported on MRI SLiM-only Not reported Not 40 Not 14 24 43 37.5 progressions reported reported (% of total progression events) 71/90 patients were observed. bence the denominator is 71 for all MDFs

[Slide 1] 2.3 Uncertain benefit-risk of Dara SC in patients with high-risk SMM Interpreting a drug's benefit-risk requires an examination of the clinical trial evidence and understanding its limitations. As discussed previously, the study endpoints, as defined in the AQUILA trial, are of uncertain clinical meaningfulness in SMM. While the trial met its primary PFS endpoint there is uncertainty in the benefit of delaying progression to MM in the absence of a significant improvement in OS. Additionally, the observed difference in progression was primarily due to differences observed in the biochemical or lab parameters (SLiM criteria). FDA has concerns with generalizing the results observed in the AQUILA trial to a high-risk SMM patient population as the majority of participants enrolled would be classified as intermediate and low-risk based on the current risk- stratification definitions. When considering the risks associated with the AQUILA trial, participants received Dara SC as monotherapy for up to three years. More participants on the Dara SC arm experienced TEAEs, Grade 3-4 TEAEs, serious adverse events, and dose discontinuations and modifications compared to the ACTM arm. Several symptomatic AEs, musculoskeletal pain (Dara SC 59%, ACTM 42%), upper respiratory tract infection (Dara SC 52%, ACTM 17%), fatigue (Dara SC 42%, ACTM 21%), diarrhea (Dara SC 27%, ACTM 5%), nasopharyngitis (Dara SC 28%, ACTM 12%), sleep disorder (Dara SC 24%, ACTM 5%), Rash (Dara SC 24%, ACTM 5%), and sensory neuropathy (Dara SC 20%, ACTM 8%) were higher in the Dara SC arm compared to the ACTM arm. Additionally, there were several limitations to the patient reported outcomes (PRO) --- [Slide 2] assessments, such as infrequent assessment. With limited and sparse collection, PRO data were not informative for determination of the benefit-risk. Overall, given the limitations of the clinical meaningfulness of the efficacy findings and the toxicity observed with three years of treatment with Dara SC, there is uncertainty regarding the benefit-risk profile of Dara SC for patients with high-risk SMM.