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8019 Background: Preclinical data demonstrate that nirogacestat, a gamma-secretase inhibitor, may increase cell-surface levels of a B-cell maturation antigen (BCMA) and reduce soluble BCMA levels, which could enhance anti-BCMA agent activity in multiple myeloma. In the DREAMM-5 (NCT04126200) Phase I/II platform trial belantamab mafodotin (belamaf; BLENREP), a BCMA-targeting antibody-drug conjugate, is being evaluated in combination with nirogacestat to determine if the combination can result in similar efficacy and an improved ocular safety profile compared to the currently approved belamaf schedule (single agent dose 2.5 mg/kg Q3W) in patients with RRMM which showed a 31% overall response rate (ORR) and 44.5% Gr3/4 keratopathy (BLENREP US prescribing information). Methods: This cohort within the DREAMM-5 nirogacestat combination sub-study has a sequential dose-exploration (DE) phase evaluating 0.95 mg/kg Q3W belamaf with 100 mg BID nirogacestat continuously, followed by a randomized cohort expansion (CE) comparing the combination to a belamaf 2.5 mg/kg Q3W arm. Results: Preliminary results from the 10 patients (pts) in the DE cohort with low-dose belamaf + nirogacestat are presented in this abstract. Pts had a median (range) of 4.5 (3–10) prior lines of therapy. At time of data cut-off (Nov 15, 2021), pts received a median (range) of 7 cycles (1–26). The ORR was 60% (n=6/10) and 20% (n=2) achieved a very good partial response (Table). The key emergent adverse events (AEs) included ocular events (n=7 [70%]; ≥Grade [Gr] 3, n=2 [20%] of which Gr 3 keratopathy was reported in 1 pt [10%]), diarrhea (n=7 [70%]; Gr 3, n=1 [10%]) and hypophosphatemia (n=7 [70%]; Gr 3, n=1, [10%]). There were 2 Grade 5 AEs, neither of which were related to study treatment. No pt permanently discontinued study due to treatment related AEs. Conclusions: Encouraging clinical activity and a manageable safety profile is observed with low dose belamaf (0.95 mg/kg Q3W) + nirogacestat (100 mg BID continuously) in pts with RRMM. This ongoing sub-study is actively recruiting patients and will continue to evaluate belamaf + nirogacestat efficacy and safety. Updated results will be reported at the congress. Funding: GSK (208887); drug linker technology licensed from Seagen Inc.; mAb produced using POTELLIGENT Technology licensed from BioWa. Clinical trial information: NCT04126200. [Table: see text]

8033 Background: Belantamab mafodotin (GSK2857916; belamaf; BLENREP) is a B-cell maturation antigen (BCMA)-targeting antibody–drug conjugate approved in the US and EU as a monotherapy for the treatment of adult patients with RRMM. Ocular events (OEs) during the pivotal DREAMM-2 trial (NCT03525678) included corneal exam findings (punctate keratopathy and microcyst-like epithelial changes), BCVA changes, and ocular symptoms. Dose reductions or delays based on corneal exam findings and BCVA were used to manage OEs. Here we performed a post hoc investigation of relationships between corneal exam findings, BCVA changes, and patient-reported ocular symptoms to explore if BCVA changes and symptoms could guide dosing, rather than corneal exams. Methods: Eye evaluations (including a corneal exam and BCVA assessment of Snellen visual acuity) were performed on all patients receiving single-agent belamaf (2.5 mg/kg) by ophthalmologists at baseline and prior to each belamaf dose. Changes in the corneal epithelium (Ker) and BCVA were both assessed as per protocol-defined criteria and assessment of grade (Gr) was based on the worse eye. BCVA grading was relative to baseline. Patient-reported ocular symptoms were reported as per the Common Terminology Criteria for Adverse Events. Results: In 12.5% of eye evaluations Gr 3–4 Ker was associated with minimal or no (Gr ≤1) BCVA changes. When patient-reported ocular symptoms were also considered, only 7.5% of evaluations found Gr 3–4 Ker with Gr ≤1 BCVA changes or ocular symptoms. Mild or no (Gr ≤2) Ker was associated with Gr ≤1 BCVA changes in 59.5% of evaluations, or in 38.8% of evaluations with no ocular symptoms reported. Overall, Gr 3–4 Ker were found in 24.9% of evaluations; by contrast, patients had Gr 2–4 BCVA changes or ocular symptoms in 53.7% of evaluations. Association of corneal epithelium changes (Ker) with BCVA changes and ocular symptoms. Conclusions: These findings highlight that BCVA changes and ocular symptoms should be further investigated to determine if they can be used as alternatives (eg, frequency of eye examinations based on symptoms) for the management of belamaf dosing to potentially reduce the burden on patients and healthcare professionals. Clinical trial information: NCT03525678. [Table: see text]

8541 Background: Patients with RRMM and HR cytogenetics have a poor prognosis and need effective therapies. In DREAMM-2 (NCT03525678), single-agent belantamab mafodotin (an immunoconjugate targeting B-cell maturation antigen) demonstrated clinically meaningful activity and a manageable safety profile in patients with heavily pretreated RRMM ( Lancet Oncol.2020). We present outcomes in patients with HR-cytogenetics (9-month follow-up). Methods: Patients with RRMM received single-agent belantamab mafodotin (2.5 or 3.4 mg/kg). For this post hoc analysis, HR-cytogenetics included t(4;14), t(14;16), 17p13del, or 1q21+ (tested locally). Results: The median number of cycles was 3 (2.5: range: 1–15) and 4 (3.4: range: 1–14). Overall response rate (ORR; ≥partial response [PR] per independent review committee) was 27% in the 2.5 mg/kg group (22% with ≥very good partial response [VGPR]) and 40% in the 3.4 mg/kg group (27% with ≥VGPR). The median duration of response (DoR) was not reached in the 2.5 mg/kg group and was 6.2 months in the 3.4 mg/kg group. The most common adverse events ( > 30% in either group) were consistent with the overall population ( Lancet Oncol.2020): keratopathy (2.5: 59%;3.4: 79%), thrombocytopenia (2.5: 44%; 3.4: 65%), nausea (2.5: 27%; 3.4: 33%), anemia (2.5: 24%; 3.4: 42%), and blurred vision (2.5: 20%; 3.4: 42%). Conclusions: Patients with HR-cytogenetics maintain deep and durable clinical responses with single-agent belantamab mafodotin, comparable to that reported in the overall population. The safety profile remained consistent with previous reports. 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]

TPS8552 Background: Single-agent belantamab mafodotin (GSK2857916), a B-cell maturation antigen targeting immunoconjugate, induced deep and durable responses in patients with RRMM, with a manageable safety profile (DREAMM-2, NCT03525678, Lancet Oncol.2020). A platform trial design allows efficient evaluation of belantamab mafodotin in combination with other anti-myeloma agents, such as a humanized wild-type IgG1 anti-OX40 agonist, an IgG4 inducible T-cell costimulatory (ICOS) agonist, and a gamma-secretase inhibitor. The unique, multimodal mechanisms of action (MoAs) of belantamab mafodotin, in combination with MoAs of these agents, has the potential to achieve synergistic effects in MM, to further enhance anti-myeloma activity without compromising safety. Methods: DREAMM-5 (NCT04162210) utilizes a master protocol with separate sub-studies comprised of sequential dose exploration (DE) and cohort expansion (CE) phases, to identify promising, effective belantamab mafodotin combinations when compared with a shared belantamab mafodotin monotherapy control arm (CE phase only). DE phases consist of multiple dosing cohorts with belantamab mafodotin combinations where patients are assigned to treatment slots by predetermined algorithmic approach (modified toxicity probability interval; N≤10 per cohort). Recommended phase 2 doses (RP2D) will be based on dose-limiting toxicities, safety, and pharmacokinetics. Interim analyses, based on overall response rate (ORR), determine if a RP2D is moved forward to a CE phase (N≥35 per cohort). Patients in the CE (stratified by number of prior therapies) will be randomized equally to open sub-studies. Eligible patients will have received ≥3 prior therapy lines which must include ≥1 immunomodulatory agent, proteasome inhibitor, and anti-CD38 antibody. The primary objectives are to identify RP2D for each combination (DE phase) and ORR (≥partial response, CE phase). Sub-studies 1 (combination with GSK3174998, OX40 agonist antibody) and 2 (combination with GSK3359609, ICOS agonist antibody) are currently enrolling. Sub-study 3 (combination with nirogacestat [PF-03084014; SpringWorks Therapeutics]) is projected to begin enrollment in the first half of 2020. Additional sub-studies will be explored based on scientific rationale and/or preclinical combination study results. Funding: GlaxoSmithKline (207495). Drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. Clinical trial information: NCT04162210 .

8502 Background: Belantamab mafodotin, a B-cell maturation antigen targeting immunoconjugate, demonstrated clinically meaningful, single-agent activity in patients with heavily pre-treated RRMM refractory to an immunomodulatory agent, a proteasome inhibitor, and refractory and/or intolerant to an anti-CD38 monoclonal antibody (DREAMM-2, NCT03525678, Lancet Oncol.2020). The multimodal mechanism of action and manageable safety profile make belantamab mafodotin a promising candidate for use in different RRMM combination regimens. Methods: DREAMM-6 (NCT03544281) is an ongoing, two-part, two-arm, study evaluating the safety, tolerability, and clinical activity of belantamab mafodotin in combination with bortezomib/dexamethasone (BorDex) and lenalidomide/dexamethasone in patients previously treated with ≥1 prior therapy line. Here, we present data for belantamab mafodotin in combination with BorDex. Part 1 (dose escalation) and Part 2 (dose expansion) evaluated belantamab mafodotin (2.5 and 3.4 mg/kg) administered as SINGLE (Day 1) or SPLIT dose (divided equally on Days 1 and 8) in combination with BorDex. Results: As of February 6, 2020, 52 patients were enrolled: 6 patients were enrolled at 2.5 mg/kg single dose and 7 at 3.4 mg/kg single dosing in Part 1, and 45 patients in Part 2. No dose-limiting toxicities were observed. Corneal events (including keratopathy, blurred vision, and dry eye) and thrombocytopenia were the most frequently reported AEs and were clinically manageable. Conclusions: In DREAMM-6, preliminary data demonstrate that the combination of belantamab mafodotin and BorDex has an acceptable safety profile, with no new safety signals identified. Funding: GlaxoSmithKline (207497). Drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. Clinical trial information: NCT03544281 .

8519 Background: Renal impairment, a frequent complication and poor prognostic factor in RRMM, often leads to poor tolerability of standard regimens. We report outcomes in patients with renal impairment receiving single-agent belantamab mafodotin (2.5 or 3.4 mg/kg; B-cell maturation antigen targeting immunoconjugate not renally metabolized) from the DREAMM-2 post-hoc analysis (NCT03525678). Methods: Eligible patients with RRMM had no active renal conditions and adequate renal function (based on albumin/creatinine ratio [2]: normal [≥90], mild impairment [mild, ≥60≤90], moderate impairment [mod, ≥30≤60]). Results: Overall response rates (95% CI) in patients with mild/mod impairment (2.5 mg/kg: 32% [21.4–44.0]; 3.4 mg/kg: 36% [25.6–48.5]) were similar to those in the overall population ( Lancet Oncol.2020). The median duration of response (DoR) was not reached (NR) in 2.5 mg/kg mild/mod subgroup (95% CI estimate: 4.2 months–NR); median DoR was 7.5 months (4.9–NR) in 3.4 mg/kg mild/mod subgroup. Rates of keratopathy and albuminuria were similar regardless of renal function; rates of anemia, pyrexia, and thrombocytopenia were more frequent in patients with impaired renal function (Table). eGFR did not change or changed to normal in most patients. Conclusions: Following treatment with single-agent belantamab mafodotin, patients with mild/mod renal impairment achieved a similar efficacy and safety profile as patients with normal renal function. 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]

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]

7015 Background: Enasidenib (AG-221), an oral mIDH2 inhibitor, promotes myeloid differentiation of leukemic blasts. Enasidenib treatment (Tx) can result in IDH-inhibitor-associated differentiation syndrome (IDH-DS), with manifestations akin to retinoic acid syndrome seen during acute promyelocytic leukemia Tx. Methods: A phase 1 dose-escalation/expansion study (N = 239) (NCT01915498) included 109 pts with relapsed/refractory AML who received enasidenib 100 mg /day. An independent Differentiation Syndrome Review Committee (DSRC) was formed to review potential IDH-DS cases. The DSRC identified and agreed on signs and symptoms possibly characteristic of IDH-DS, including fever, lung infiltrates, pleural or pericardial effusions, rapid weight gain, edema, and azotemia. Of the 109 pts, the DSRC identified and retrospectively reviewed 27 cases (8 investigator reported IDH-DS cases and 19 cases suggestive of IDH-DS) to determine consistency with IDH-DS. Results: The DSRC found 13 of the 27 cases to be consistent with IDH-DS (11.9% of 109 pts). Median time to onset was 30 days (range 7-116). Manifestations of IDH-DS in > 2 pts were dyspnea (n = 10), pyrexia (9), lung infiltrates (8), pleural effusion (5), and kidney injury (3). IDH-DS was effectively managed with systemic corticosteroids in 12/13 cases. Leukocytosis accompanied 4 cases and hydroxyurea was used for cytoreduction. Enasidenib was interrupted for 9 pts (median 7 days) but dose reductions or discontinuation were not required. Six of 13 pts had clinical responses (2 complete remission [CR], 2 CR with incomplete hematologic recovery, 1 partial remission, 1 morphologic leukemia-free state), 6 had stable disease and 1 had progressive disease. Conclusions: Systemic corticosteroids, close hemodynamic management, and hydroxyurea (in the presence of leukocytosis) are effective management strategies, should be administered promptly when IDH-DS is suspected, and continued until improvement. Enasidenib interruption can be considered if initial intervention is unsuccessful. IDH-DS represents a novel clinical finding in m IDH2 AML treated with enasidenib, and is likely due to its suggested mechanism of action, differentiation. Clinical trial information: NCT01915498.

e22085 Background: Ofatumumab is an anti-CD20 monoclonal antibody that induces cell lysis primarily through complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity (ADCC). Gi...