Bortezomib-Associated Optic Atrophy in Two Patients With Multiple Myeloma

Clinical Correspondence Bortezomib-Associated Optic Atrophy in Two Patients With Multiple Myeloma Joseph G. Chacko, MD, Raed Behbehani, MD, Kelsey N. Hundley, MD, Yazan Al-Fanek, BS B ortezomib (Velcade) is a proteasome inhibitor and a relatively new antineoplastic agent indicated for the treatment of multiple myeloma and mantle cell lymphoma. Optic neuropathy with severe vision impairment has been reported in postmarketing experience for this medication but, to our knowledge, has never been reported in the literature. We present 2 cases where bortezomib is the likely cause of optic neuropathy. CASE 1 A 54-year-old woman was referred for vision loss in her left eye. She reported that a "smudge" appeared in her vision 2 months previously and progressed to a "grey film." She denied associated eye pain. She had a history of headaches and primary open-angle glaucoma for 7 years treated with bimatoprost, brimonidine and timolol ophthalmic drops, and selective laser trabeculoplasty, with well-controlled intraocular pressures. Eleven years ago, the patient had been diagnosed with multiple myeloma and was in remission after VDT-PACE chemotherapy and 2 bone marrow transplantations (BMTs). She has been receiving weekly maintenance infusions of bortezomib (0.8 mg/m2) and dexamethasone (8 mg) for 8 years and daily thalidomide. She also was taking acyclovir, zolpidem, aripiprazole, aspirin, buspirone, clotrimazole, sertraline, estradiol, fenofibrate, levothyroxine, pantoprazole, and pravastatin. On examination, visual acuity was 20/30 in the right eye and 20/200 with a left relative afferent pupillary deficit. Two months prior, acuity was 20/25, right eye, and 20/40, Department of Ophthalmology (JGC, KNH, YA-F), Harvey and Bernice Jones Eye Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas; and Department of Ophthalmology (RB), Al-Bahar Eye Center, Sabah Medical Area, Kuwait City, Kuwait. The authors report no conflicts of interest. Address correspondence to Yazan Al-Fanek, BS, Jones Eye Institute, University of Arkansas for Medical Sciences, 4301 W. Markham #523, Little Rock, AR 72205; E-mail: [e-mail] Chacko et al: J Neuro-Ophthalmol 2018; 38: 473-475 left eye with normal pupillary reactions. Ophthalmoscopy revealed optic disc pallor and inferior rim thinning bilaterally with C/D ratio 0.6/0.7. Optical coherence tomography demonstrated retinal nerve fiber layer (RNFL) thickness of 44 mm, right eye, and 54 mm, left eye (Fig. 1). The right visual field showed a superior arcuate defect and the left field was severely constricted (Fig. 2). MRI of the brain was unremarkable, as was the analysis of cerebrospinal fluid. Bortezomib infusions were promptly stopped and 1 year later visual acuity was 20/25, right eye, and 20/100, left eye. Visual field testing was unchanged while RNFL measurements were 41 mm, right eye, and 43 mm, left eye. CASE 2 A 61-year-old man noted progressive loss of vision in his right eye for 8 months and more recently in the left eye for 3 months. He had undergone chemotherapy for multiple myeloma for approximately 18 months with bortezomib and BMT 6 months ago. He recalled that his visual symptoms started after receiving a dose of bortezomib. His only medication history was that he had been given intravenous immunoglobulin for multiple myeloma. Visual acuity was 20/30, right eye, and 20/25, left eye, with normal color vision and pupillary testing. He had right optic disc pallor. Optical coherence tomography revealed thinning of the papillomacular bundle in the right eye with RNFL thickness of 97 mm, right eye, and 101 mm, left eye. Visual field testing documented bilateral superior arcuate defects (Fig. 3). No abnormalities were detected on MRI of the brain and orbits. On further questioning, the patient reported a tingling sensation in both arms and legs, which started after bortezomib treatment. On follow-up 1 month after stopping bortezomib, the patient reported improved vision and a repeat visual field showed improvement in the superior arcuate defects. 473 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 1. Case 1. Spectral domain optical coherence tomography shows severe thinning of the RNFL in both eyes. OD, right eye; OS, left eye. Blurred vision was reported in 11% of patients with multiple myeloma in the phase II clinical trial of bortezomib (1). A review of the Food and Drug Administration's adverse events reporting system (FAERS) revealed 41 reports of "blindness," 22 reports of "unilateral blindness," 57 cases of "reduced visual acuity," and 71 cases of "visual impairment" where bortezomib is prime suspect (2). Although the number of these reports may seem high, they are in line with adverse events in the FAERS database (2,3). It is believed that bortezomib inhibits protein degradation through proteasome inhibition thereby leading to toxic build-up of protein. This toxicity can be detrimental to any cell type with high protein turnover including retinal ganglion cells. The long-term use of bortezomib, the progressive nature of the vision loss, the presence of optic disc pallor, and normal neuroimaging studies are consistent with a toxic optic neuropathy. In our first patient (Case 1), we believe that bortezomib caused a gradual bilateral optic neuropathy over 8 years that became visually symptomatic when central vision was affected in the patient's left eye. In our second patient (Case 2), use of bortezomib had been used for only 18 months, so there was less visual impairment. This patient also experienced symptoms of peripheral neuropathy, a known side effect of bortezomib (4). Multiple myeloma relapse has been described with vitritis and optic disc edema (5). However, both of our patients had normal cerebrospinal fluid analysis and no evidence on brain MRI of myeloma invasion of the central nervous system. We considered other possible causes of optic neuropathy in our 2 patients. Graft vs host (GVH) disease has been associated with an inflammatory optic neuropathy leading to profound vision loss and signal abnormalities of the optic nerves on MRI (6). Neither patient developed GVH disease, and the clinical profile and normal neuroimaging results did not support this diagnosis. FIG. 2. Case 1. Automated visual fields reveal superior and inferior arcuate defects in the right eye and marked constriction in the left eye. FIG. 3. Case 2. Automated visual fields demonstrate superior arcuate defects bilaterally. 474 Chacko et al: J Neuro-Ophthalmol 2018; 38: 473-475 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence This report documents an association of optic neuropathy and bortezomib. Visual function stabilized in our 2 patients when the medication was discontinued. Additional reports are needed to better delineate the association of bortezomib with optic nerve dysfunction. REFERENCES 1. Millennium Pharmaceuticals, Inc. Velcade: highlights of prescribing information. 2017. Available at: http://www.velcadehcp.com/pdf/VELCADE_PRESCRIBING_INFORMATION.pdf. Accessed September 25, 2017. 2. OpenFDA. Silver Springs, MD: U.S. Food and Drug Administration, 2014. Updated March 31, 2017. Available at: https://open.fda.gov/. Accessed September 25, 2017. 3. US Department of Health and Human Services. Food and Drug Administration. Guidance for Industry: Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment. 2005. Chacko et al: J Neuro-Ophthalmol 2018; 38: 473-475 Available at: https://www.fda.gov/downloads/drugs/ guidancecomplianceregulatoryinformation/guidances/ ucm071696.pdf. Accessed September 25, 2017. 4. Tacchetti P, Terragra C, Galli M, Zamagni E, Petrucci MT, Pezzi A, Montefusco V, Martello M, Posi P, Baldini L, Peccatori J, Ruggieri M, Pantani L, Lazzaro A, Elice F, Rocchi E, Gozzetti A, Cavaletti G, Palumbo A, Cavo M. Bortezomib-and thalidomideinduced peripheral neuropathy in multiple myeloma: clinical and molecular analyses of a phase 3 study. Am J Hematol. 2014;89:1085-1091. 5. Nugent AK, Paulus YM, Chan A, Kim JW, Schwartz EJ, Moshfeghi DM. Multiple myeloma recurrence with optic nerve infiltration diagnosed by vitrectomy, immunohistochemistry, and in situ hybridization. Eur J Ophthalmol. 2014;24:446- 448. 6. Moesen I, Kidd DP. Bilateral inflammatory optic neuropathy related to graft versus host disease following allogeneic bone marrow transplantation for Hodgkin disease. Neuroophthalmology. 2014;38:224-229. 475 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.