Abstract
Daratumumab-containing regimens are an effective treatment for advanced cases of multiple myeloma. Overall, daratumumab has a favourable safety profile, although rare side effects can occur. Rare side effects of daratumumab include choroidal effusion. Patients who begin to experience symptoms such as eye swelling, vision changes, eye discharge and blurry vision should undergo urgent ophthalmological evaluation and their daratumumab infusions held.
Keywords: Haematology (drugs and medicines), Immunological products and vaccines, Eye, Drugs and medicines, Cancer - see Oncology
Background
Multiple myeloma is a haematological disorder characterised by clonal plasma cell proliferation and is treated with multiagent chemoimmunotherapy. Treatment of multiple myeloma has evolved over the last decade with several new agents of remarkable potential.1 Daratumumab is an anti-CD38 monoclonal antibody approved for its use in multiple myeloma in recent years. It has also recently been under investigation for first-line treatment, maintenance treatment post autologous stem cell transplant in high-risk multiple myeloma cases and treatment of light chain amyloidosis.2 Overall, daratumumab has a favourable safety profile, with typical adverse effects such as infusion reactions and haematological toxicity.3 Herein, we report a rare complication of choroidal effusion from daratumumab use in a patient with multiple myeloma. Choroidal effusion is an abnormal fluid collection between the sclera and the choroid and the ciliary body of the eye. The condition can be asymptomatic but can cause blurry vision and ocular pain and can even threaten vision in some cases.
Case presentation
A Caucasian woman in her 80s was referred to haematology clinic with an 8-week history of progressive shortness of breath and fatigue. She had been recently diagnosed with anaemia by her primary care physician. She did not complain of haematuria, vaginal bleeding, melaena or haematochezia. Her medical history was significant for atrial fibrillation, essential hypertension, hyperlipidaemia, osteoarthritis and bilateral cataract surgery. Her medications included apixaban. Physical examination revealed normal vitals. Auscultation of the chest and heart revealed no adventitious sounds. Laboratory work-up revealed low haemoglobin and haematocrit levels (96 g/Land 29.8, respectively). Serum ferritin (307 ng/mL), vitamin B12 (928 pg/mL) and folate (21.3 ng/mL) levels were found to be within normal limits. Immunoglobulin studies showed IgG lambda monoclonal gammopathy at 3140 mg/dL. The kappa to lambda ratio was 0.01. Iliac bone marrow biopsy showed hypercellular marrow with 70% involvement by monoclonal plasma cells. A diagnosis of IgG lambda multiple myeloma was established. Fluorescence in situ hybridisation revealed duplication of the long arm of chromosome 1 and monosomy of chromosome 13. The Revised Multiple Myeloma International Staging System stage was III in the setting of low albumin, elevated serum β2 microglobulin and lactate dehydrogenase (LDH).
Skeletal survey shows degenerative changes in the spine and multiple lucencies throughout the calvarium. The patient was started on triplet regimen using daratumumab 16 mg/kg intravenously on days 1, 8, 15 and 22 (cycles 1 and 2), then 16 mg/kg on days 1 and 15 (cycles 3–6), followed by 16 mg/kg on day 1, lenalidomide 15 mg per oral daily on days 1–21, and dexamethasone 20 mg per oral on days 1, 8, 15 and 22 (DRd) of a 28-day cycle. The first dose of daratumumab was given as split dose of 8 mg/kg on days 1 and 2 of cycle 1.
After two cycles of the DRd regimen, the patient achieved a very good partial response. Following cycle 3, she developed swelling, conjunctival redness and watery discharge of the right eye. The left eye was asymptomatic. The patient was initially diagnosed with conjunctivitis and tobramycin with dexamethasone eye-drops were started. Over the course of the next few weeks, the symptoms in her right eye persisted and she developed similar symptoms and floaters in her left eye.
Investigations
On ocular examination performed at the time of onset of right eye symptoms, her visual acuity was 20/125 in the right eye and 20/20 in the left eye. On slit lamp examination, there was mild diffuse conjunctival hyperaemia and chemosis. Fundus examination showed choroidal effusion temporally. B-scan ultrasonography of the right eye showed localised serous choroidal effusion superotemporally with a maximum elevation of 2.5 mm. She had an epiretinal membrane, causing decreased vision in the right eye. Her inflammatory systemic work-up was normal. Intraocular pressure of the right eye was 21 mm Hg and of the left eye 19 mm Hg.
Treatment and outcome
Daratumumab was discontinued when the patient developed similar symptoms in her left eye. She was continued on lenalidomide and dexamethasone. Her symptoms of conjunctival hyperaemia and chemosis significantly improved at 2-week follow-up. Her choroidal effusion was noted to have resolved at 3-month ophthalmological examination (figure 1). Her epiretinal membrane and vision remained stable.
Figure 1.
B-scan ultrasonography at presentation and at 3 months (8 weeks post discontinuation of daratumumab).
Discussion
Daratumumab-associated ophthalmic toxicities are uncommon but have been reported in the literature. Conjunctival oedema of any grade on the Common Terminology Criteria for Adverse Events was reported in three patients while one patient experienced grade 3 conjunctival oedema in the phase III trial reported by Palumbo et al.4 In addition to the conjunctival oedema, there have been rare case reports of choroidal effusions leading to myopic shift and angle closure glaucoma.5–9 Choroidal effusions must be on the differential of patients who begin to experience eye symptoms such as swelling, discharge, blurry vision or pressure in the eyes while using daratumumab. Urgent ophthalmological referral is warranted for these patients.
Review of the literature showed onset of symptoms is usually acute and does not seem to be related to the number of daratumumab infusions.5–9 In our case, the patient developed acute onset of symptoms after two cycles. In all the reported cases including ours, daratumumab was administered intravenously and symptoms are usually bilateral. In our case, there were retinal pigment epithelial changes at the temporal periphery of the left eye, suggesting possible resolved choroidal effusion. The exact pathophysiology of how daratumumab causes choroidal effusion remains unclear. Daratumumab is an IgG1k monoclonal antibody that binds to CD38 expressing cells. Studies in vertebrate eyes have found CD38 expression in several locations in the retina, including the Müller cell, ganglion cell layer, inner nuclear layer and retinal pigment epithelium. CD38 was also expressed in rat ciliary body in both pigmented and non-pigmented epithelium. It is speculated that daratumumab may interact with CD38 glycoprotein on the ciliary body, which potentially leads to ciliary body/choroidal effusion.10 11 As seen in topiramate-induced choroidal effusion, a spectrum of diseases ranging from simple choroidal effusion to myopic shift and acute angle closure glaucoma can be seen due to accumulation of fluid in the supraciliary space.12 This can lead to anteriorisation of the lens-iris diaphragm, thereby occluding the angle.
Outcomes are generally good and resolve within a few weeks spontaneously after discontinuation of daratumumab. In some cases, use of steroids has been found to be effective. In our case, eye symptoms completely resolved following discontinuation of daratumumab.
The event was reported to the Federal Drug Administration. We also solicited daratumumab-associated choroidal effusion cases from the Food and Drug Administration Adverse Event Reporting System (FAERS) and the WHO database (VigiBase) of reported potential medicinal side effects. There have been 300 eye disorders reported from the use of daratumumab and daratumumab/hyaluronidase in FAERS, of which 5 cases were choroidal effusion. In the VigiBase, 224 eye disorders were reported with daratumumab, of which 3 cases were choroidal effusion. No choroidal effusion event has been reported with daratumumab/vorhyaluronidase so far.
Learning points.
Daratumumab is an anti-CD38 monoclonal antibody used in the treatment of multiple myeloma in all phases of treatment and is usually safe with typical side effects including infusion-related reactions.
Daratumumab has been associated with ophthalmological side effects such as choroidal effusion, myopic shift and acute angle closure glaucoma; however, based on a single case report, causation cannot be established and firm conclusions cannot be drawn.
These side effects should be kept in mind if a patient develops ocular symptoms.
Daratumumab infusion should be stopped and the patient should be referred to an ophthalmologist.
Acknowledgments
We would like to acknowledge our patient who has given us the permission to report this case very enthusiastically with the hope to enhance information about the subject matter.
Footnotes
Contributors: All of the listed authors have substantially contributed to revising the manuscript critically for important intellectual content. All authors have approved the manuscript that has been submitted for publication and agree to be accountable for all the aspects of the work reported in the case report. AS: conception of the idea, analysis and interpretation of the labs and imaging, and drafting the manuscript and literature review. TB: literature review and drafting the report. DL: analysis and interpretation of the labs and critical review of the draft. HD: conception of the idea, analysis and review of the ophthalmology examination and imaging, and critical review of the report.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
Competing interests: None declared.
Provenance and peer review: Not commissioned; externally peer reviewed.
Ethics statements
Patient consent for publication
Obtained.
References
- 1.van de Donk NWCJ, Pawlyn C, Yong KL, et al. Multiple myeloma. The Lancet 2021;397:410–27. 10.1016/S0140-6736(21)00135-5 [DOI] [PubMed] [Google Scholar]
- 2.Ludwig H. Daratumumab: a game changer in myeloma therapy. Lancet Haematol 2020;7:e426–7. 10.1016/S2352-3026(20)30105-8 [DOI] [PubMed] [Google Scholar]
- 3.Nooka AK, Gleason C, Sargeant MO, et al. Managing infusion reactions to new monoclonal antibodies in multiple myeloma: Daratumumab and Elotuzumab. J Oncol Pract 2018;14:414–22. 10.1200/JOP.18.00143 [DOI] [PubMed] [Google Scholar]
- 4.Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med 2016;375:754–66. 10.1056/NEJMoa1606038 [DOI] [PubMed] [Google Scholar]
- 5.Saengsirinavin A-O, Wutthayakorn W, Chansangpetch S, et al. Acute bilateral angle closure induced by monoclonal antibody (Daratumumab) infusion. Am J Ophthalmol Case Rep 2021;22:101079. 10.1016/j.ajoc.2021.101079 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Rasmussen PK, Kiilgaard JF, Salomo M. Association of choroidal effusion and infusion of Daratumumab. JAMA Ophthalmol 2019;137:853–4. 10.1001/jamaophthalmol.2019.1427 [DOI] [PubMed] [Google Scholar]
- 7.Edwards RG, Vanderhoof S, Palestine A, et al. Bilateral secondary angle closure during Daratumumab infusion: a case report and review of the literature. J Glaucoma 2020;29:e83–6. 10.1097/IJG.0000000000001562 [DOI] [PubMed] [Google Scholar]
- 8.Strong A, Huvard M, Olson JL, et al. Daratumumab-induced choroidal effusion: a case report and review of the literature. Clin Lymphoma Myeloma Leuk 2020;20:e994–7. 10.1016/j.clml.2020.08.030 [DOI] [PubMed] [Google Scholar]
- 9.Mavrommatis MA, Jung H, Chari A, et al. Daratumumab-induced transient myopic shift. Am J Ophthalmol Case Rep 2019;13:116–8. 10.1016/j.ajoc.2018.12.017 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Horenstein AL, Sizzano F, Lusso R, et al. Cd38 and CD157 ectoenzymes mark cell subsets in the human corneal limbus. Mol Med 2009;15:76–84. 10.2119/molmed.2008.00108 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Khoo KM, Chang CF. Characterization and localization of CD38 in the vertebrate eye. Brain Res 1999;821:17–25. 10.1016/S0006-8993(98)01347-X [DOI] [PubMed] [Google Scholar]
- 12.Craig JE, Ong TJ, Louis DL, et al. Mechanism of topiramate-induced acute-onset myopia and angle closure glaucoma. Am J Ophthalmol 2004;137:193–5. 10.1016/S0002-9394(03)00774-8 [DOI] [PubMed] [Google Scholar]