Corneal Epithelial Findings in Patients with Multiple Myeloma Treated with Antibody–Drug Conjugate Belantamab Mafodotin in the Pivotal, Randomized, DREAMM-2 Study
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Ophthalmol Ther https://doi.org/10.1007/s40123-020-00280-8 ORIGINAL RESEARCH Corneal Epithelial Findings in Patients with Multiple Myeloma Treated with Antibody–Drug Conjugate Belantamab Mafodotin in the Pivotal, Randomized, DREAMM-2 Study Asim V. Farooq . Simona Degli Esposti . Rakesh Popat . Praneetha Thulasi . Sagar Lonial . Ajay K. Nooka . Andrzej Jakubowiak . Douglas Sborov . Brian E. Zaugg . Ashraf Z. Badros . Bennie H. Jeng . Natalie S. Callander . Joanna Opalinska . January Baron . Trisha Piontek . Julie Byrne . Ira Gupta . Kathryn Colby Received: April 21, 2020 Ó The Author(s) 2020, corrected publication 2020 ABSTRACT monomethyl auristatin F (MMAF), to myeloma cells. In the phase II DREAMM-2 study Introduction: Patients with relapsed or refrac- (NCT03525678), single-agent belamaf (2.5 mg/kg) tory multiple myeloma (RRMM) represent an demonstrated clinically meaningful anti-mye- unmet clinical need. Belantamab mafodotin loma activity (overall response rate 32%) in (belamaf; GSK2857916) is a first-in-class anti- patients with heavily pretreated disease. Micro- body–drug conjugate (ADC; or immunoconju- cyst-like epithelial changes (MECs) were com- gate) that delivers a cytotoxic payload, mon, consistent with reports from other MMAF- containing ADCs. Methods: Corneal examination findings from Digital Features To view digital features for this article patients in DREAMM-2 were reviewed, and the go to https://doi.org/10.6084/m9.figshare.12326546. clinical descriptions and accompanying images The original version of this article was revised based upon recent changes to the FDA label and guidance on D. Sborov the use of belamaf. Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA A. V. Farooq (&) Á A. Jakubowiak Á K. Colby B. E. Zaugg University of Chicago Medical Center, Chicago, IL, Moran Eye Center, University of Utah, Salt Lake USA City, UT, USA e-mail: [email protected] A. Z. Badros S. Degli Esposti University of Maryland School of Medicine, NIHR Biomedical Research Centre at Moorfields Eye Baltimore, MD, USA Hospital NHS Foundation Trust, UCL Institute of Ophthalmology, London, UK B. H. Jeng Department of Ophthalmology and Visual Sciences, R. Popat University of Maryland School of Medicine, University College London Hospitals, NHS Baltimore, MD, USA Foundation Trust, London, UK N. S. Callander P. Thulasi University of Wisconsin, Carbone Cancer Center, Emory Eye Center, Emory University, Atlanta, GA, Madison, WI, USA USA J. Opalinska Á J. Baron Á T. Piontek Á J. Byrne Á S. Lonial Á A. K. Nooka I. Gupta Emory University, Winship Cancer Institute, GlaxoSmithKline, Upper Providence, PA, USA Atlanta, GA, USA Ophthalmol Ther (slit lamp microscopy and in vivo confocal microscopy [IVCM]) of representative events Key Summary Points were selected. A literature review on corneal events reported with other ADCs was Corneal microcyst-like epithelial changes performed. (MECs) are frequently associated with Results: In most patients receiving single-agent antibody–drug conjugates (ADCs) belamaf (72%; 68/95), MECs were observed by containing monomethyl auristatin F, slit lamp microscopy early in treatment (69% which have been studied in a variety of had their first event by dose 4). However, IVCM cancers, including belantamab mafodotin revealed hyperreflective material. Blurred vision (belamaf, GSK2857916) currently being (25%) and dry eye (15%) were commonly investigated for the treatment of relapsed reported symptoms. Management of MECs or refractory multiple myeloma. included dose delays (47%)/reductions (25%), with few patients discontinuing due to MECs In this report, the authors further (1%). The first event resolved in most patients characterize belamaf-associated MECs and (grade C2 MECs and visual acuity [each 77%], provide a representative case report. MECs blurred vision [67%], and dry eye [86%]), with typically are seen early in treatment, are no reports of permanent vision loss to date. A manageable with dose modifications, and literature review confirmed that similar MECs tend to resolve after completing were reported with other ADCs; however, event treatment. management strategies varied. The pathophys- Presented images demonstrate that MECs iology of MECs is unclear, though the ADC appear as bilateral, diffuse, microcyst-like cytotoxic payload may contribute to on- or off- lesions on slit lamp photography; target effects on corneal epithelial cells. however, on confocal microscopy the Conclusion: Single-agent belamaf represents a affected areas appear as hyperreflective new treatment option for patients with RRMM. material that is (at least predominantly) As with other ADCs, MECs were observed and intracellular. additional research is warranted to determine their pathophysiology. A multidisciplinary Available literature on corneal events with approach, involving close collaboration other ADCs supports the observations between eye care professionals and hematolo- with belamaf treatment and confirms the gist/oncologists, is needed to determine appro- need for additional research on the priate diagnosis and management of these underlying pathophysiology and optimal patients. management. Trial Registration: ClinicalTrials.gov Identifier, The authors propose a mechanism NCT03525678. whereby MECs represent an off-target effect of belamaf in the cornea leading to Keywords: Antibody–drug conjugate; apoptosis of epithelial cells, which are Belantamab mafodotin; Cornea; In vivo eventually replaced with new epithelial confocal microscopy; Microcyst-like epithelial cells, leading to the eventual resolution of changes; Monomethyl auristatin F; Multiple MECs and symptoms after completing myeloma; Oncology treatment. Ophthalmol Ther INTRODUCTION Multiple myeloma (MM) is an incurable hema- tologic cancer characterized by the uncon- trolled accumulation of malignant plasma cells in the bone marrow [1, 2]. It has an incidence rate of approximately 6.9 per 100,000 persons in the USA, with a median age at diagnosis of 69 years [3]. It typically has a poor prognosis; the median overall survival is less than 7 years Fig. 1 Belamaf structure and mechanism of action. ADC for patients with Revised International Staging antibody–drug conjugate, ADCC/ADCP antibody-di- System stage II disease, and 3.6 years for stage III rected cellular cytotoxicity/phagocytosis, BCMA B-cell disease [4]. Despite recent advances in the maturation antigen, IgG1 immunoglobulin G1, mAb management of MM, there are a substantial Monoclonal antibody, MM multiple myeloma, MMAF number of patients who develop relapsed or monomethyl auristatin F refractory MM (RRMM) and are resistant to current standard-of-care options (proteasome response was 11.0 months (95% CI 4.2–NR) inhibitors, immunomodulatory agents, and with a median follow-up of 12.4 months with monoclonal antibodies [mAbs]) [5]. Evidence belamaf 2.5 mg/kg, the recommended dose for suggests that this patient population has a par- future development [12]. ticularly unfavorable prognosis with currently Many patients who received belamaf in these available treatments (median progression-free clinical studies developed changes within the survival: 3.4 months and median overall sur- corneal epithelium (which, in this report, we vival: 9.3 months) and represents an unmet call microcyst-like epithelial changes, or MECs), medical need [6]. similar to those observed with other MMAF- Belantamab mafodotin (belamaf; containing ADC [7–9, 13]. Here, we report GSK2857916) is a first-in-class antibody–drug characteristics of these MECs and associated conjugate (ADC, also known as an immuno- examination results observed in patients conjugate) targeting B-cell maturation antigen receiving the 2.5-mg/kg dose of belamaf in (BCMA) that is currently under clinical devel- DREAMM-2 and provide a representative case. opment for RRMM [7–9]. It is composed of an We also report the findings of a literature review afucosylated humanized immunoglobulin G1 on corneal changes associated with ADCs. anti-BCMA mAb conjugated to a cytotoxic Finally, we provide a proposed mechanism payload, the microtubule-disrupting agent underlying these events, along with a screening known as monomethyl auristatin F (MMAF; and management paradigm for these patients. Fig. 1)[10]. BCMA is a cell membrane receptor that is expressed on all malignant plasma cells and is essential for their proliferation and sur- METHODS vival [2]. Belamaf binds to BCMA and kills MM cells via a multimodal mechanism involving, in The full methodological details of DREAMM-2 part, delivery of MMAF to BCMA-expressing were previously reported [7]. In brief, eligible MM cells, thereby inducing apoptosis [10, 11]. patients with RRMM were randomized (1:1) to In both phase I (DREAMM-1; NCT02064387) receive belamaf 2.5- or 3.4-mg/kg every 3 weeks and phase II (DREAMM-2; NCT03525678) by intravenous infusion over 30 min or longer studies, single-agent belamaf demonstrated on day 1 of each cycle. Patients received treat- clinically meaningful anti-myeloma activity in ment until disease progression or an unaccept- patients with heavily pretreated RRMM [7–9]. able toxicity occurred. Patients without current Specifically, in DREAMM-2, the overall response corneal epithelial disease, with the exception of rate was 32% and the median duration of mild dry eye disease, were permitted to enroll. Ophthalmol Ther Here, we report data for patients receiving the with baseline. For patient-reported symptoms, 2.5-mg/kg dose of belamaf (13-month follow- recovery was defined as full recovery or return