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Background On the basis of the DREAMM‐2 study (ClinicalTrials.gov identifier NCT03525678), single‐agent belantamab mafodotin (belamaf) was approved for patients with relapsed or refractory multiple myeloma (RRMM) who received ≥4 prior therapies, including anti‐CD38 therapy. The authors investigated longer term efficacy and safety outcomes in DREAMM‐2 after 13 months of follow‐up among patients who received belamaf 2.5 mg/kg. Methods DREAMM‐2 is an ongoing, phase 2, open‐label, 2‐arm study investigating belamaf (2.5 or 3.4 mg/kg) in patients with RRMM who had disease progression after ≥3 lines of therapy and were refractory to immunomodulatory drugs and proteasome inhibitors and refractory and/or intolerant to an anti‐CD38 therapy. The primary outcome was the proportion of patients that achieved an overall response, assessed by an independent review committee. Results As of January 31, 2020, 10% of patients still received belamaf 2.5 mg/kg. Thirty‐one of 97 patients (32%; 97.5% confidence interval [CI], 21.7%‐43.6%) achieved an overall response, and 18 responders achieved a very good partial response or better. Median estimated duration of response, overall survival, and progression‐free survival were 11.0 months (95% CI, 4.2 months to not reached), 13.7 months (95% CI, 9.9 months to not reached), and 2.8 months (95% CI, 1.6‐3.6 months), respectively. Response and survival outcomes in patients who had high‐risk cytogenetics or renal impairment were consistent with outcomes in the overall population. Outcomes were poorer in patients with extramedullary disease. In patients who had a clinical response and prolonged dose delays (>63 days; mainly because of corneal events), 88% maintained or deepened responses during their first prolonged dose delay. Overall, there were no new safety signals during this follow‐up. Conclusions Extended follow‐up confirms sustained clinical activity without new safety signals with belamaf in this heavily pretreated patient population with RRMM., Extended follow‐up of patients enrolled in the ongoing phase 2 DREAMM‐2 study confirms sustained clinical activity without new safety signals in patients with relapsed or refractory multiple myeloma who receive belantamab mafodotin 2.5 mg/kg every 3 weeks. These data show that belantamab mafodotin has the potential to shift the treatment paradigm in this heavily pretreated, anti‐CD38 monoclonal antibody–exposed patient population, which has a poor prognosis and few alternative treatment options.

Belantamab mafodotin (belamaf) demonstrated deep and durable responses in patients with heavily pretreated relapsed or refractory multiple myeloma (RRMM) in DREAMM-2 (NCT03525678). Corneal events, specifically keratopathy (including superficial punctate keratopathy and/or microcyst-like epithelial changes (MECs), eye examination findings with/without symptoms), were common, consistent with reports from other antibody–drug conjugates. Given the novel nature of corneal events in RRMM management, guidelines are required for their prompt identification and appropriate management. Eye examination findings from DREAMM-2 and insights from hematology/oncology investigators and ophthalmologists, including corneal specialists, were collated and used to develop corneal event management guidelines. The following recommendations were formulated: close collaboration among hematologist/oncologists and eye care professionals is needed, in part, to provide optimal care in relation to the belamaf benefit–risk profile. Patients receiving belamaf should undergo eye examinations before and during every treatment cycle and promptly upon worsening of symptoms. Severity of corneal events should be determined based on corneal examination findings and changes in best-corrected visual acuity. Treatment decisions, including dose modifications, should be based on the most severe finding present. These guidelines are recommended for the assessment and management of belamaf-associated ocular events to help mitigate ocular risk and enable patients to continue to experience a clinical benefit with belamaf.

DREAMM-2 (NCT03525678) is an ongoing global, open-label, phase 2 study of single-agent belantamab mafodotin (belamaf; GSK2857916), a B-cell maturation antigen-targeting antibody-drug conjugate, in a frozen-liquid presentation in patients with relapsed/refractory multiple myeloma (RRMM). Alongside the main study, following identical inclusion/exclusion criteria, a separate patient cohort was enrolled to receive belamaf in a lyophilised presentation (3.4 mg/kg, every 3 weeks) until disease progression/unacceptable toxicity. Primary outcome was independent review committee-assessed overall response rate (ORR). Twenty-five patients were enrolled; 24 received ≥1 dose of belamaf. As of 31 January 2020, ORR was 52% (95% CI: 31.3–72.2); 24% of patients achieved very good partial response. Median duration of response was 9.0 months (2.8–not reached [NR]); median progression-free survival was 5.7 months (2.2–9.7); median overall survival was not reached (8.7 months–NR). Most common grade 3/4 adverse events were keratopathy (microcyst-like corneal epithelial changes, a pathological finding seen on eye examination [75%]), thrombocytopenia (21%), anaemia (17%), hypercalcaemia and hypophosphatemia (both 13%), neutropenia and blurred vision (both 8%). Pharmacokinetics supported comparability of frozen-liquid and lyophilised presentations. Single-agent belamaf in a lyophilised presentation (intended for future use) showed a deep and durable clinical response and acceptable safety profile in patients with heavily pre-treated RRMM.

Summary Background Belantamab mafodotin (GSK2857916), an immunoconjugate targeting B-cell maturation antigen, showed single-agent activity in the phase 1 DREAMM-1 study in heavily pre-treated patients with relapsed or refractory multiple myeloma. We further investigated the safety and activity of belantamab mafodotin in the DREAMM-2 study. Methods DREAMM-2 is an open-label, two-arm, phase 2 study done at 58 multiple myeloma specialty centres in eight countries. Patients (aged ≥18 years) with relapsed or refractory multiple myeloma with disease progression after three or more lines of therapy and who were refractory to immunomodulatory drugs and proteasome inhibitors, and refractory or intolerant (or both) to an anti-CD38 monoclonal antibody with an Eastern Cooperative Oncology Group performance status of 0–2 were recruited, centrally randomly assigned (1:1) with permuted blocks (block size 4), and stratified by previous lines of therapy (≤4 vs >4) and cytogenetic features to receive 2·5 mg/kg or 3·4 mg/kg belantamab mafodotin via intravenous infusion every 3 weeks on day 1 of each cycle until disease progression or unacceptable toxicity. The intention-to-treat population comprised all randomised patients, regardless of treatment administration. The safety population comprised all patients who received at least one dose of belantamab mafodotin. The primary outcome was the proportion of randomly assigned patients in the intention-to-treat population who achieved an overall response, as assessed by an independent review committee. This study is registered with ClinicalTrials.gov , NCT03525678 , and is ongoing. Findings Between June 18, 2018, and Jan 2, 2019, 293 patients were screened and 196 were included in the intention-to-treat population (97 in the 2·5 mg/kg cohort and 99 in the 3·4 mg/kg cohort). As of June 21, 2019 (the primary analysis data cutoff date), 30 (31%; 97·5% CI 20·8–42·6) of 97 patients in the 2·5 mg/kg cohort and 34 (34%; 23·9–46·0) of 99 patients in the 3·4 mg/kg cohort achieved an overall response. The most common grade 3–4 adverse events in the safety population were keratopathy (in 26 [27%] of 95 patients in the 2·5 mg/kg cohort and 21 [21%] of 99 patients in the 3·4 mg/kg cohort), thrombocytopenia (19 [20%] and 33 [33%]), and anaemia (19 [20%] and 25 [25%]); 38 (40%) of 95 patients in the 2·5 mg/kg cohort and 47 (47%) of 99 in the 3·4 mg/kg cohort reported serious adverse events. Two deaths were potentially treatment related (one case of sepsis in the 2·5 mg/kg cohort and one case of haemophagocytic lymphohistiocytosis in the 3·4 mg/kg cohort). Interpretation Single-agent belantamab mafodotin shows anti-myeloma activity with a manageable safety profile in patients with relapsed or refractory multiple myeloma. Funding GlaxoSmithKline.

Introduction: The treatment paradigm for RRMM is characterized by continuous treatment to suppress the malignant plasma cell clone. Some treatments may affect the eye, leading to a broad spectrum of ocular disorders, from dry eye to glaucoma, causing impaired quality of life. Therefore, we examined the baseline eye health of patients with RRMM receiving single-agent belamaf in the DREAMM-2 study (NCT03525678) and compared the findings to those of age-matched individuals in the general population. A better understanding of baseline ocular status is important as patients may have existing, undiagnosed eye conditions that may affect future treatment options. Methods: DREAMM-2 investigated belamaf, a B-cell maturation antigen-targeted antibody-drug conjugate in patients with RRMM. Eligible patients had received ≥3 prior therapies and were refractory to an immunomodulatory agent, a proteasome inhibitor, and refractory and/or intolerant to an anti-CD38 monoclonal antibody. Prior to receiving belamaf, patients underwent systematic ocular history collection and eye examination and completed the eye-specific National Eye Institute Visual Function Questionnaire 25 (NEI-VFQ-25). We report pretreatment eye-related findings to describe the baseline ocular status of patients with RRMM in DREAMM-2. Results: Of 221 patients enrolled, 100 (45%) were female and 121 (55%) were male, with a median age (range) of 66 years (34-89), median time from diagnosis of 5.4 years (1.1-12.1), and median 6 (3-21) prior lines of therapy; 98% patients had received bortezomib. Previous ocular history reported by patients were cataract (60%), intraocular surgery and/or laser treatment (35%), dry eye (20%), and glaucoma (6%), and history of ocular disease requiring medical treatment (12%). On examination, the mean best corrected visual acuity (BCVA) Snellen score was worse than 20/50 in one or both eyes in 20 and 4 of 218 patients with data, respectively. Blepharitis (anterior) was evident in approximately 20% and the corneal epithelium was abnormal (mainly mild-grade keratopathy) in 43% of patients. Impaired tear film production was reported with meibomian gland dysfunction (MGD) in 33% of patients, and evidence of dry eye (Schirmer's test, median 8.2 mm [normal ≥15 mm] in the worse eye. Median worse-eye tear break up time was 8.6 sec [normal >10 sec]). Slit-lamp examination revealed a cataract in approximately 50% of patients. Ten (8%) patients had evidence of prior cataract surgery with an implanted lens (pseudophakia). Dilated fundoscopy identified an abnormal optic nerve in 10% of patients in either eye; of these, glaucomatous cupping was noted in 43% (right eye) to 50% (left eye) of patients. Median (range) overall composite vision score by NEI-VFQ-25 was 95.3 (28-100). Conclusions: There was a 60% prevalence of cataract in the study cohort and an increased prevalence of glaucoma (6% vs expected 3% in patients >65 years old; Kreft et.al. BMC Public Health 2019) in RRMM patients treated in the DREAMM-2 study. Both conditions can be associated with corticosteroids, often used in MM treatments, although cataract is also an age-related phenomenon. We noted a significant number of patients with blepharitis (anterior), dry eye, and MGD, which may be associated with prior bortezomib treatment. Forty-three percent of patients had an abnormal corneal epithelium at baseline, which may be related to dry eye. This is relevant as belamaf is associated with keratopathy (microcyst-like epithelial changes visible on slit-lamp examination, with or without symptoms). Overall NEI-VFQ-25 scores were comparable to those reported in patients >65 years old (Nickels et al. Health Qual Life Outcomes 2017). Patients with RRMM may have a number of baseline ocular abnormalities suggesting a need for regular ophthalmic examinations in this vulnerable population to identify and manage underlying conditions and treatment-related complications. Specifically, attention should be paid to patients who may have ocular conditions associated with prior treatment with corticosteroids or bortezomib. The optimization of ocular heath in this population is particularly relevant given that emerging RRMM therapies such as belamaf are associated with significant ocular side effects. Funding: GSK (Study 205678); drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. Disclosures Popat: GSK: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Celgene: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other: Travel support, Research Funding; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); AbbVie: Consultancy, Honoraria. Farooq:University of Chicago: Current Employment; GlaxoSmithKline: Consultancy. Thulasi:Emory University: Current Employment. Lonial:Novartis: Consultancy, Honoraria, Other: Personal fees; Janssen: Consultancy, Honoraria, Other: Personal fees, Research Funding; BMS: Consultancy, Honoraria, Other: Personal fees, Research Funding; GSK: Consultancy, Honoraria, Other: Personal fees; Abbvie: Consultancy; Merck: Consultancy, Honoraria, Other: Personal fees; Takeda: Consultancy, Other: Personal fees, Research Funding; Amgen: Consultancy, Honoraria, Other: Personal fees; Sanofi: Consultancy; Genentech: Consultancy; Karyopharm: Consultancy; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; JUNO Therapeutics: Consultancy; Millennium: Consultancy, Honoraria; Onyx: Honoraria. Jakubowiak:AbbVie, Amgen, BMS/Celgene, GSK, Janssen, Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive, Juno: Consultancy, Honoraria. Badros:Amgen: Consultancy; University of Maryland: Current Employment. Jeng:University of Maryland: Current Employment; EyeGate: Current equity holder in publicly-traded company; Kedrion, Merck, GSK: Consultancy. Opalinska:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Baron:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Piontek:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Byrne:Adaptimmune, Novartis: Current equity holder in publicly-traded company; GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Womersley:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Gupta:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company; Novartis: Current equity holder in publicly-traded company. Degli Esposti:Moorfields Eye Hospital: Current Employment; GlaxoSmithKline: Consultancy, Honoraria.

Introduction: IRRs are commonly reported by patients receiving intravenous (IV) treatments for RRMM (Nooka et al. J Oncol Pract 2018); these can be troublesome for patients and can lead to discontinuation of treatment, negatively impacting durability of response. In the Phase II DREAMM-2 study (NCT03525678), single-agent belamaf (GSK2857916), a first-in-class B-cell maturation antigen (BCMA)-targeting antibody-drug conjugate, demonstrated deep and durable responses with a manageable safety profile in patients with heavily pre-treated RRMM (Lonial et al. ASCO 2020; poster 436). As expected with IV biologic agents, IRRs were commonly reported in this study, but were considered self-limited. Here, we report details on IRRs for patients receiving belamaf 2.5 mg/kg (the recommended dose for future clinical development) after 13-months of follow-up. Methods: In the DREAMM-2 study, patients with RRMM progressing after ≥3 prior therapies, refractory to an immunomodulatory agent and a proteasome inhibitor, and refractory and/or intolerant to an anti-CD38 monoclonal antibody, and who provided informed consent, received single-agent belamaf (2.5 or 3.4 mg/kg IV every 3 weeks) on Day 1 of each cycle until disease progression or unacceptable toxicity. Pre-medication for IRR prophylaxis was not protocol mandated (administered per investigator discretion, if deemed medically appropriate). These events were graded by Common Terminology Criteria for Adverse Events criteria version 4.03 and included the terms: IRR, pyrexia, chills, diarrhea, nausea, asthenia, hypertension, hypotension, lethargy, and tachycardia. Grade 2 IRRs were managed by stopping the infusion, providing medical treatment and continuing the infusion at half the original infusion rate until resolution to Grade ≤1. Grade 3 IRRs were managed by discontinuing the infusion until recovery to Grade ≤1, after which the treatment could only continue (with pre-medication and a longer infusion time) following discussion with the study sponsor; all future infusions were pre-medicated. Patients experiencing Grade 4 IRRs were permanently withdrawn from the study. IRRs were followed until resolution/stabilization. Results: After 13-months of follow-up, IRRs occurred in 20/95 (21%) patients; most were mild to moderate in severity, with no Grade 4 or 5 events (Grade 1, n=6 [30%]; Grade 2, n=11 [55%]; Grade 3, n=3 [15%]). Pyrexia was reported in 5/20 (25%) patients; chills, diarrhea, and nausea in 2/20 (10%) each; asthenia, hypertension, lethargy, and tachycardia in 1/20 (5%) patients each; and the adverse event term 'IRR' was recorded for 16/20 (80%) patients. In most patients (18/20 [90%]), IRRs occurred during Cycle 1, and the incidence of these events declined thereafter (Figure). Of 73/95 (77%) patients without pre-medication at Cycle 1, 12 (16%) experienced an IRR. A total of 22/95 (23%) patients received a pre-medication at Cycle 1; of these, 8 (36%) had an IRR. Among the 20 patients experiencing an IRR, 11 (55%) received ≥1 pre-medication over the course of the study (most commonly: antihistamine, n=6 [30%]; analgesic (paracetamol); n=7 [35%]; steroid, n=6 [30%]). The median time of onset of the first IRR occurrence was at Day 1 (range: 1-22). The median duration of IRRs was 1 day (range: 1-3). Most patients experiencing IRRs (12/20 [60%]) had only one event; 3 (15%) experienced two IRRs and 5 (25%) patients had ≥3 events. Treatment was permanently discontinued due to IRRs in 1 (5%) patient (Grade 3 IRR at first and second infusion); no dose reductions or interruptions/delays occurred due to an IRR. At 13-month follow-up, IRRs were considered recovered/resolved in most (18/20 [90%]) patients (recovered/resolved with sequelae; recovering/resolving, n=1 [5%] each). Conclusions: As expected with biologic treatments administered via IV infusion, IRRs were reported with belamaf in the DREAMM-2 study. However, IRRs were typically mild-to-moderate in severity and most were considered resolved at 13-month follow-up. Importantly, IRRs resulted in few dose modifications or discontinuations, allowing patients to continue active belamaf treatment, which has been associated with durable responses in patients with RRMM. Funding: GSK (Study 205678; drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. Disclosures Nooka: Karyopharm Therapeutics, Adaptive technologies: Consultancy, Honoraria, Research Funding; Spectrum Pharmaceuticals: Consultancy; Adaptive Technologies: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria, Other: Personal Fees: Travel/accomodations/expenses, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding. Lee:Celgene: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Genentech: Consultancy; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Sanofi: Consultancy; Daiichi Sankyo: Research Funding; Regeneron: Research Funding; Genentech: Consultancy; GlaxoSmithKline: Consultancy, Research Funding. Badros:Amgen: Consultancy; University of Maryland: Current Employment. Voorhees:TeneBio: Honoraria, Other: Other relationship; Janssen: Honoraria, Other: Other relationship; Adaptive Biotechnologies: Honoraria, Other: Other relationship; Oncopeptides: Honoraria, Other: Other relationship; Novartis: Honoraria, Other: Other relationship; GSK: Honoraria, Other: Other relationship; BMS/Celgene: Honoraria, Other: Other relationship. Hultcrantz:Intellisphere LLC: Consultancy; Amgen: Research Funding; Daiichi Sankyo: Research Funding; GSK: Research Funding. Karlin:Sanofi: Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Celgene: Other: Personal fees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees. Arnulf:BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria; Celgene: Research Funding. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. Zhi:GSK: Current Employment, Current equity holder in publicly-traded company. Baron:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Piontek:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Lewis:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Opalinska:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Gupta:Novartis: Current equity holder in publicly-traded company; GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Cohen:Novartis: Other: Patents/Intellectual property licensed, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda,: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees. Lonial:Karyopharm: Consultancy; Sanofi: Consultancy; Amgen: Consultancy, Honoraria, Other: Personal fees; Takeda: Consultancy, Other: Personal fees, Research Funding; Novartis: Consultancy, Honoraria, Other: Personal fees; Janssen: Consultancy, Honoraria, Other: Personal fees, Research Funding; BMS: Consultancy, Honoraria, Other: Personal fees, Research Funding; GSK: Consultancy, Honoraria, Other: Personal fees; Abbvie: Consultancy; Merck: Consultancy, Honoraria, Other: Personal fees; JUNO Therapeutics: Consultancy; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Honoraria; Genentech: Consultancy; Onyx: Honoraria.

Introduction: Patients with heavily pretreated RRMM have a poor prognosis (median overall survival [OS]: 6-9 months) and a need for novel, well-tolerated treatments that induce lasting responses (Gandhi Leukemia 2019; Chari NEJM 2019). Belamaf (GSK2857916) is a first-in-class, B-cell maturation antigen-targeting, antibody-drug conjugate (ADC) containing monomethyl auristatin F (MMAF). In DREAMM-2 (NCT03525678), patients with heavily pretreated RRMM who responded to single-agent belamaf maintained deep and durable responses at 13-month follow-up (median OS: >13 months) with a manageable safety profile (Lonial ASCO 2020, Poster 436). Consistent with other MMAF-containing ADCs, ocular events were common (Farooq et al. Ophthal Ther 2020). These events included keratopathy (microcyst-like epithelial changes [MECs]: an eye exam finding with/without symptoms), best-corrected visual acuity (BCVA) changes, and symptoms (blurred vision and dry eye). Longer-term recovery data will help inform management strategies. Methods: In DREAMM-2, eye exams were conducted at baseline and prior to each dose in patients received single-agent belamaf (2.5 or 3.4 mg/kg Q3W) and included a corneal exam and assessment of BCVA change from baseline (Snellen visual acuity [VA]). Dose modifications (delays/reductions) were permitted to manage these events. The corneal events were graded per the Keratopathy and Visual Acuity (KVA) scale, which combined corneal exam findings and BCVA changes from baseline. Dose modifications were determined based on the most severe KVA scale grade. These events were followed until recovery, defined as any Grade 1 exam findings/no exam findings, and ≤1-line decline in Snellen VA compared with baseline. A change to a BCVA 20/50 or worse (ie, limiting driving ability) in the better-seeing eye (in patients with BCVA better than 20/50 at baseline) was considered one definition of clinically meaningful VA decrease. Recovery of these events was defined as BCVA improvement to better than 20/50 (better-seeing eye). We report ocular event outcomes for patients receiving belamaf 2.5 mg/kg (recommended dose for future clinical development) from a 13-month follow-up post-hoc analysis. Results: In patients receiving single-agent belamaf 2.5 mg/kg, 72% (68/95) experienced a treatment-related eye exam finding of keratopathy (MECs) (Farooq Ophthal Ther 2020).Fewer patients (56%; 53/95) had symptoms (eg, blurred vision or dry eye) and/or a ≥2-line BCVA decline (better-seeing eye). Treatment discontinuations due to ocular events were rare (3% [3/95] total; 1% [1/95] each due to keratopathy [MECs], blurred vision, and reduced BCVA (Farooq Ophthal Ther 2020). In patients with keratopathy (MEC) events Grade ≥2 per KVA, 48% (29/60) had >1 event. The first event recovered in 77% (46/60; Table; Farooq Ophthal Ther 2020). At last follow-up, 48% (29/60) had documented recovery of their most recent event (Farooq Ophthal Ther 2020). In patients with unrecovered events at last follow-up, 45% (14/31) are receiving treatment or in follow-up. The remaining 55% (17/31) are no longer in follow-up (9 died; 4 withdrew from study; 4 lost to follow-up). 84% (37/44) of patients with Grade 3/4 events were improving or had recovered events at last follow-up. Seventeen (18%) patients had a clinically meaningful BCVA decline, with no reports of complete permanent vision loss (Farooq Ophthal Ther 2020). Of these patients, 76% (13/17) had 1 event and 24% (4/17) had 2 events (no patients had >2 events). 82% (14/17) had recovery of their first event and 82% (14/17) had recovery at last follow-up (Farooq Ophthal Ther 2020). Of the remaining 3 patients with unrecovered events, 1 patient is receiving treatment and 2 patients are no longer in follow-up (1 died due to disease progression; 1 withdrew from study). Conclusions: Though keratopathy (MECs) were frequently observed on eye exam, the majority of patients did not experience a clinically meaningful BCVA decline, and events rarely led to treatment discontinuation. The first keratopathy (MEC) event or clinically meaningful BCVA decline recovered in the majority of patients with events. In this ongoing study, patients are being followed for recovery. Based on experience, it is anticipated these events will likely recover over time. Funding: GSK (205678); drug linker technology licensed from Seattle Genetics; mAb produced using POTELLIGENT Technology licensed from BioWa. Disclosures Lonial: Karyopharm: Consultancy; Sanofi: Consultancy; Amgen: Consultancy, Honoraria, Other: Personal fees; Onyx: Honoraria; Takeda: Consultancy, Other: Personal fees, Research Funding; Novartis: Consultancy, Honoraria, Other: Personal fees; Janssen: Consultancy, Honoraria, Other: Personal fees, Research Funding; BMS: Consultancy, Honoraria, Other: Personal fees, Research Funding; GSK: Consultancy, Honoraria, Other: Personal fees; Abbvie: Consultancy; Merck: Consultancy, Honoraria, Other: Personal fees; JUNO Therapeutics: Consultancy; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Honoraria; Genentech: Consultancy. Nooka:Spectrum Pharmaceuticals: Consultancy; Oncopeptides: Consultancy, Honoraria; Adaptive Technologies: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria, Other: Personal Fees: Travel/accomodations/expenses, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Karyopharm Therapeutics, Adaptive technologies: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding. Thulasi:Emory University: Current Employment. Badros:University of Maryland: Current Employment; Amgen: Consultancy. Jeng:Kedrion, Merck, GSK: Consultancy; University of Maryland: Current Employment; EyeGate: Current equity holder in publicly-traded company. Callander:University of Wisconsin: Current Employment; Cellectar: Research Funding. Sborov:University of Utah: Current Employment; Celgene, Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees. Zaugg:University of Utah: Current Employment. Popat:Celgene: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other: Travel support, Research Funding; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); GSK: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); AbbVie: Consultancy, Honoraria. Degli Esposti:GlaxoSmithKline: Consultancy, Honoraria; Moorfields Eye Hospital: Current Employment. Byrne:Adaptimmune, Novartis: Current equity holder in publicly-traded company; GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Opalinska:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Baron:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Piontek:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Gupta:Novartis: Current equity holder in publicly-traded company; GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Dana:Kala: Consultancy; Alcon: Consultancy; GSK: Consultancy; Aramis Biosciences, Claris Biotherapeutics, GelMEDIX: Current equity holder in private company; Novartis: Consultancy; Dompe: Consultancy; Massachusetts Eye and Ear; Harvard Medical School Department of Ophthalmology: Current Employment; NIH, DOD, Allegan: Current equity holder in publicly-traded company. Farooq:GlaxoSmithKline: Consultancy; University of Chicago: Current Employment. Jakubowiak:Adaptive, Juno: Consultancy, Honoraria; AbbVie, Amgen, BMS/Celgene, GSK, Janssen, Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Context: Single-agent belamaf demonstrated deep and durable responses in the DREAMM-2 ( NCT03525678 ) primary analysis (1) and long-term follow-up (2,3). Keratopathy (microcyst-like epithelial changes [MECs] observed on eye examination with/without symptoms) were managed through dose delays and reductions. Objective: To provide an update on the impact of dose delays on responses in patients receiving single-agent belamaf 2.5-mg/kg in DREAMM-2 (13-month follow-up). Methods: In the DREAMM-2 study (single-agent belamaf 2.5 mg/kg [n=97] or 3.4 mg/kg [n=99] Q3W), dose modifications were permitted to manage adverse events (AEs), including keratopathy (MECs), an eye examination finding that may/may not be associated with symptoms. Objective response (IMWG criteria 2016) was assessed by an independent review committee Q3W, regardless of treatment delays. Here, we report a post-hoc analysis on the impact of dose delays >63 days on clinical response in the 2.5-mg/kg arm (the selected dose for future clinical development based on risk–benefit assessment). Results: In patients receiving single-agent belamaf (2.5 mg/kg), dose delays (54%) and reductions (35%) due to AEs were common (2,3). Keratopathy (MECs) was the most frequent reason for dose delays (47%) and reductions (25%), leading to only 1 patient (1%) discontinuing treatment (2,3). Of 31 patients with ≥partial response, 16 had prolonged treatment interruptions (>63 days). Of these 16 patients, 14 (88%) continued experiencing a clinical benefit during the first prolonged delay: 6 (38%) deepened their response during delay (1 SD to MR; 2 PR to VGPR; 2 MR to VGPR; 1 VGPR to CR); 6 (38%) maintained the same response category as that of the last evaluable assessment during delay/first evaluable assessment after delay; 2 (13%) had increasing paraproteins during the delay but did not meet progression criteria. Two (13%) developed disease progression (1 patient 6 weeks into delay; 1 patient 3 weeks after delay). Conclusions: Despite dose delays lasting for several cycles to manage AEs, most responses were sustained throughout the delay, thus maintaining clinical benefit for the majority of patients. Funding: GlaxoSmithKline (205678). Drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. References: [1] Lonial Lancet Oncol 2020. [2] Lonial ASCO 2020, EP436. [3] Lonial EHA 2020, EP970.

Context: Belamaf showed deep and durable single-agent activity in the pivotal DREAMM-2 study primary analysis ( NCT03525678 ) (1–7) in a patient population that historically has a poor prognosis (overall survival [OS] 6–9 months). Objective: To present longer-term efficacy/safety outcomes (13-month follow-up) with single-agent belamaf in DREAMM-2 in the overall patient population and patients with HR cytogenetics and RI, subgroups with poor outcomes. Methods: DREAMM-2 is an ongoing study of belamaf 2.5 mg/kg (n=97) or 3.4 mg/kg (n=99). Primary outcome: overall response rate (ORR; ≥partial response). In post-hoc analyses, HR-cytogenetics included t(4;14), t(14;16), 17p13del, or 1q21 + . RI was based on eGFR (mild: ≥60– Results: Overall population ORRs in the 2.5 mg/kg and 3.4 mg/kg groups were 32% (97.5% CI: 21.7–43.6) and 35% (97.5% CI: 24.8–47.0); 19% and 23% of patients (58% and 66% of responders) achieved very good partial response or better. Median duration of response was 11.0 (95% CI: 4.2–not reached [NR]) and 6.2 months (95% CI: 4.8–NR). Median progression-free survival was 2.8 (95% CI: 1.6–3.6) and 3.9 months (95% CI: 2.0–5.8); median estimated OS was 13.7 (95% CI: 9.9–NR) and 13.8 months (95% CI: 10.0–NR). Most common Grade ≥3 adverse events (AEs) were keratopathy (microcyst-like epithelial changes [MECs] observed on eye examination; 2.5 mg/kg: 46%; 3.4 mg/kg: 42%), thrombocytopenia (2.5 mg/kg: 22%; 3.4 mg/kg: 32%), and anemia (2.5 mg/kg: 21%; 3.4 mg/kg: 27%). AE-related permanent discontinuation occurred in 9% and 12%; discontinuation due to MECs was rare (2.5 mg/kg: 1%; 3.4 mg/kg: 3%). HR cytogenetics and RI subgroup analyses will be presented at the conference. Conclusions: Deep and durable responses to single-agent belamaf were sustained and no new safety signals identified with longer follow-up in this heavily pretreated RRMM population. Funding: GSK (205678). Drug linker technology licensed from Seattle Genetics; mAb produced using POTELLIGENT Technology licensed from BioWa. References: [1] Lonial et al. Lancet Oncol. 2020. [2] Lonial et al. ASCO 2020. EP436. [3] Lonial et al. EHA 2020. EP970. [4] Cohen et al. ASCO 2020. EP441. [5] Trudel et al. EHA 2020. EP1037. [6] Lee et al. ASCO 2020. EP419. [7] Lee et al. EHA 2020. EP1006.

8536 Background: Single-agent belantamab mafodotin (B-cell maturation antigen targeting immunoconjugate) showed clinically meaningful activity and manageable safety in patients with heavily pre-treated RRMM (DREAMM-2, NCT03525678, Lancet Oncol.2020). We report updated results (median follow-up 9 months). Methods: DREAMM-2 is an ongoing single-agent belantamab mafodotin (2.5 or 3.4 mg/kg) study in patients with RRMM after ≥3 prior therapy lines and refractory to an immunomodulatory agent, a PI, and refractory and/or intolerant to an anti-CD38 mAb. Primary endpoint: overall response rate (ORR; ≥partial response per independent review committee). Results: ORR was 31% in the 2.5 mg/kg (19% with ≥very good partial responses [VGPR]) and 35% (24% with ≥VGPR) in the 3.4 mg/kg groups (Table). Duration of response (DoR) was not reached (NR) in the 2.5 mg/kg and 6.2 months in the 3.4 mg/kg groups; 1-year overall survival (OS) estimate was 53%. Common Grade 3/4 AEs ( > 10% in either group) were keratopathy (2.5: 29%; 3.5: 24%), thrombocytopenia (2.5: 21%; 3.4: 32%), anemia (2.5: 20%; 3.4: 27%), pneumonia (2.5: 6%; 3.4: 13%), and neutropenia (2.5: 11%; 3.4: 16%). AEs were managed with dose delays (2.5: 54%; 3.4: 62%) and reductions (2.5: 34%; 3.4: 43%); discontinuations due to AEs were uncommon (2.5: 9%; 3.4: 12%). Conclusions: Single-agent belantamab mafodotin was well-tolerated, and clinically meaningful responses were sustained despite dose modifications with longer follow-up. Funding: GlaxoSmithKline (205678). Drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. Clinical trial information: NCT03525678 . [Table: see text]

Background: Bromodomains (BRDs) are domains found in a variety of proteins that recognize and bind to acetylated lysine residues in histone and other target proteins. The BRD and extra-terminal (BET) family of BRD-containing proteins bind to acetylated histone tails, alters chromatin structure and facilitates transcriptional complex localization to specific genes, thereby regulating gene transcription. The investigational agent GSK525762 is a potent small molecule inhibitor of the BET family of proteins that prevents assembly of macromolecular complexes and transcriptional response. GSK525762 inhibits growth in a broad spectrum of human hematological cancer cell lines, including cell lines derived from human patients with acute myeloid leukemia (AML), non-Hodgkin's lymphoma (NHL), and multiple myeloma (MM). GSK525762 is orally bio-available and can cause tumor reduction and improved animal survival in in vivo xenograft models of hematologic malignancies. Methods: This is a Phase I/II, open-label, 2-part study. Part 1 is a dose-escalation phase to determine the safety, tolerability, and recommended Phase 2 dose (RP2D) of GSK525762 in adult subjects with relapsed/refractory AML, NHL, and MM. Dose escalation is performed independently for each of these three cohorts. An accelerated dose titration was employed with one subject per dose level until the occurrence of a ≥Grade 2 drug-related toxicity or dose-limiting toxicity; thereafter, subjects have been enrolled in a standard 3+3 design. A Neuenschwander continual reassessment method (N-CRM) model is used at each dose escalation decision to provide guidance for the next dose escalation level. Starting dose is 5 mg GSK525762 orally once daily and dose escalation continues until the MTD is identified. All data, including safety, tolerability, pharmacokinetics (PK), and efficacy, are used to identify the RP2D. In Part 1, approximately 60-70 subjects will be enrolled (approximately 20 in each of three disease-specific cohorts); no hypothesis is being tested, and all analysis will be descriptive and exploratory. In Part 2, the clinical activity of GSK525762 (overall response rate) will be evaluated in expansion cohorts of subjects with AML, NHL, and MM. Up to 32 subjects may be enrolled into the AML and NHL cohorts, and up to 37 subjects may be enrolled in the MM cohort. Cohorts may be closed early if they do not exceed futility assessment. In addition, an exploratory cohort of subjects with double-hit lymphoma (DHL) and triple-hit lymphoma (THL) will be enrolled to evaluate clinical activity in this patient population. Additional study objectives include analysis of PK after single and repeat dosing, evaluation of pharmacodynamics (PD) and the relationship between GSK525762 exposure and safety/efficacy/PD parameters. Recruitment is ongoing across five centers (USA, UK, and Australia). Currently, 40 subjects have been enrolled (29 AML, 8 NHL, and 3 with MM). Study funded by GSK. Disclosures Stein: Seattle Genetics: Research Funding; Agios Pharmaceuticals: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding; Novartis: Consultancy. Huntly:Novartis: Speakers Bureau; BMS: Speakers Bureau; Ariad: Speakers Bureau; Pfizer: Speakers Bureau. Dickinson:GlaxoSmithKline: Consultancy, Research Funding. Horner:GlaxoSmithKline: Employment. Brennan:GlaxoSmithKline: Employment. Baron:GlaxoSmithKline: Employment. Kremer:GlaxoSmithKline: Employment, Equity Ownership. Dhar:GlaxoSmithKline: Employment.