Belantamab Mafodotin-blmf: Management and Prevention of Ocular Toxicities

Jordan Snyder, PharmD, BCOP
Clinical Oncology Pharmacist
University of Kansas Health System
Kansas City, Kansas

Despite recent advances, multiple myeloma remains an incurable disease, which affects approximately 32,000 patients each year. Multiple myeloma is a plasma cell disorder largely characterized by bone pain, anemia, renal dysfunction, and hypercalcemia. The use of immunomodulatory agents, prote­asome inhibitors, monoclonal antibodies, and corticosteroids are the backbone of the management of multiple myeloma, including relapsed/refractory disease. However, the addition of novel agents has begun to change the outlook and management of multiple myeloma. One such agent is belantamab ma­fodotin-blmf.¹

Belantamab mafodotin-blmf received accelerated approval from the U.S. Food and Drug Administration (FDA) for use in relapsed or refractory multiple myeloma in patients who have received at least 4 prior therapies, including an anti-CD38 monoclo­nal antibody, an immunomodulatory agent, and a proteasome inhibitor.2 The approved dose is 2.5 mg/kg intravenously every three weeks until disease progression or unacceptable toxicity. Belantamab ma­fodotin-blmf is a B-cell maturation antigen (BCMA)-directed antibody with a microtubular inhibitor conjugate. BCMA is a cell-surface receptor that is expressed on myeloma cells but is largely absent on naïve and memory B-cells. Belantamab mafodotin-blmf is composed of three parts: an afucosylated, humanized immunoglobulin G1 antibody directed against BCMA; a microtubular inhibitor, microtubule-disrupting monomethyl auristatin F (MMAF) which is linked to the antibody via prote­ase-resistant maleimidocaproly linker. Upon binding to BCMA, belantamab mafodotin-blmf is internalized and MMAF is released. The release of MMAF disrupts the microtubules leading to cell cycle arrest and apoptosis. ^2-4

Clinical Trial
The accelerated approval of belantamab mafodotin-blmf was based on the Phase II trial, DREAMM-2, an open-label, two-arm, random­ized, Phase II study, which included 196 relapsed/refractory multi­ple myeloma patients. Patients were randomized to receive either belantamab mafodotin-blmf 2.5 mg/kg or 3.4 mg/kg intravenously once every three weeks until disease progression or unacceptable toxicity. Patients with corneal epithelial disease were excluded from the study. Additionally, corticosteroid eye drops and preservative free artificial tears were supportive care agents required throughout the study period; the addition of a cooling eye mask was optional during the infusion.

The median lines of therapy prior to study enrollment was 7 (3-21) in the 2.5 mg/kg dosing arm and 6 (3-21) in the 3.4 mg/kg dosing arm. The overall response rate (ORR) was 31% (97.5% con­fidence interval [CI]: 20.8-42.6) in the 2.5 mg/kg dosing cohort and 34% (97.5% CI: 23.9-46.0) in the 3.4 mg/ kg dosing cohort. The most common grade 3 and 4 adverse events were keratopathy (27% in 2.5 mg/kg dosing group and 21% in 3.4 mg/kg dosing group), thrombocytopenia (20% in 2.5 mg/kg group and 33% in 3.4 mg/ kg group), and anemia (20% in 2.5 mg/kg group and 25% in 3.4 mg/kg group).⁴

Safety
Dose reductions due to adverse events oc­curred in 28 (29%) patients in the 2.5 mg/ kg cohort and 41 (41%) in the 3.4 mg/kg cohort. In addition, dose delays occurred in 51 (54%) patients and 61 (62%) patients in the 2.5 mg/kg dosing cohort and 3.4 mg/ kg dosing cohort, respectively. Hematologic toxicity, most commonly thrombocytopenia, occurred frequently. All grade thrombocy­topenia occurred in 33 (34%) of patients receiving 2.5 mg/kg and 58 (59%) of patients receiving 3.4 mg/kg. Median time to onset of thrombocytopenia was 26.5 days. Dose adjustments and/or treat­ment delay for thrombocytopenia is recommended for platelets less than 50,000/mcL.^3-4

Infusion reactions occurred in 20 patients (21%) receiving 2.5 mg/kg and 16 patients (16%) receiving 3.4 mg/kg. Grade 1-2 infu­sion reactions were the most common and occurred with the first infusion, with the most commonly reported reactions being pyrexia and chills during or within 24 hours of infusion. Pre-medications are not required prior to the first infusion but should be adminis­tered for subsequent cycles if reactions occur. For infusion reactions less than or equal to grade 3, belantamab mafodotin-blmf may be paused and resumed at a 50% rate decrease once symptoms resolve. For those patients with grade 4 infusion reactions, belantamab mafodotin-blmf should be permanently discontinued.⁴

The most common adverse effect seen with belantamab ma­fodotin-blmf was keratopathy; this occurred in 67 patients (71%) in the 2.5 mg/kg dosing cohort and 74 patients (75%) in the 3.4 mg/kg dosing cohort. Keratopathy was the most common adverse event leading to treatment discontinuation and resulted in dose reductions in 22 patients (23%) and 27 patients (27%) in the 2.5 mg/kg dosing cohort and 3.4 mg/kg dosing cohort, respectively. The most common patient reported corneal symptoms were dry eye and blurred vision. Corneal changes often resolved following discontin­uation of treatment; median time to resolution was 71 days (inter­quartile range [IQR] 57-99) in the 2.5 mg/kg dosing cohort and 96 days (IQR 70-127) in the 3.4 mg/kg dosing cohort. No permanent vision loss was reported. Of note, those patients with a history of dry eye were more likely to develop corneal changes compared to those patients without a history of dry eye.⁴

Prevention and Management of Ocular Toxicities
The exact mechanism of ocular toxicity is not completely known; corneal events have been reported with other antibody drug conju­gates (ADCs) using MMAF or other microtu­bule-targeting agents. This toxicity might be related to off-target uptake of the ADC into actively dividing epithelial cells which reside in the basal epithelial layer of the cornea. This results in apoptosis of the epithelial cells which then begin to migrate to the cen­ter of the cornea resulting in blurred vision and dry eyes.4-5

Due to this, ophthalmic examinations should be performed at baseline and prior to each subsequent dose. Baseline exam should be completed within three weeks of begin­ning treatment. Subsequent examinations should be completed at least one week after the previous dose and within two week prior to the next dose. It is recommended to begin prophylactic preser­vative-free artificial tears at least 4 times per day beginning with the first infusion and continuing throughout treatment. Contact lenses should also be avoided during belantamab mafodotin-blmf treatment.3 During DREAMM-2, prophylactic corticosteroid eye drops were administered to a subset of patients in order to evaluate the efficacy in preventing corneal changes. Although it was a small subset of patients, it was found that corticosteroid eye drops were ineffective prophylaxis. There are no recommendations for cortico­steroid eye drops throughout treatment due to limited evidence in preventing corneal toxicity.4

Other than artificial tears, corneal toxicities can be managed with treatment delays or dose reductions. For those patients who develop grade 2 corneal changes, it is recommended to hold the dose and resume at the same dose once corneal changes resolve to at least grade 1. It is recommended to reduce the dose of belan­tamab mafodotin-blmf to 1.9 mg/kg upon resolution of toxicity for those patients that develop grade 3 ocular toxicity. For grade 4 toxicity, permanent discontinuation of belantamab mafodotin-blmf should be considered, but if treatment is continued, symptoms should resolve to at least grade 1 before resuming at a reduced dose. Belantamab mafodotin-blmf should be discontinued in patients unable to tolerate 1.9 mg/kg or those with grade 4 ocular toxicity. 3

Belantamab REMS Program
Due to the risk of ocular toxicity, a risk evaluation and mitigation strategy (REMS) program exists; belantamab mafodotin-blmf is only available through this REMS program. The goal of this pro­gram is to ensure safe use of belantamab and ensure healthcare providers and patients are informed of the risks associated with belantamab mafodotin-blmf.

In order for prescribers to prescribe belantamab ma­fodotin-blmf, the provider must review prescribing information and REMS program education. Following review, the provider must complete the knowledge assessment and complete the REMS en­rollment form. Prior to initiation of treatment, patients should be counseled on risks and monitoring require­ments using the patient guide. Following consent, enrollment of the patient should be completed using the patient enrollment form. Prior to each dose, the results of the ophthalmic exam should be reported via the patient status form. Not only do patients and providers need to be enrolled, but healthcare settings dispensing belantamab mafodotin-blmf must be enrolled as well. The authorized representative, which could be a pharmacist, nurse, advance practitioner, or director of the healthcare setting, should review education materials and submit the enrollment form.

Training of all relevant staff should take place prior to administration of first dose at the health system. Authorization should be obtained with each dose of belantamab ma­fodotin-blmf; the authorization should include ensuring prescriber is certified and the patient is enrolled and authorized. The dose in milligrams and date of administration should be reported to the REMS program within five days of administration. If the patient discontinues the treatment or transfers care, the REMS program should be notified.3,6-9

Patient Assistance Program
Co-pay assistance is available for commercially insured patients if eligible through the GlaxoSmithKline (GSK) Co-pay program. Eligi­ble uninsured or Medicare patients may receive medication free of charge through GSK’s Patient Assistance Program. No cost preser­vative-free lubricating eye drops are available via GSK’s Blenrep eye drop supportive care program after completion and submission of enrollment form.^{10, 11}

Future Directions
Belantamab mafodotin-blmf is currently being studied in com­bination with other anti-myeloma agents, including proteasome inhibitors and immunomodulatory agents. Due to responses in the relapse/refractory setting, belantamab mafodotin-blmf is also being evaluated for use in upfront, transplant ineligible patients. These studies are also evaluating various dosing intervals in hopes to decrease toxicity. In order to expand access and provide addition­al real-world data, belantamab mafodotin-blmf is being studied in renal and hepatic impairment.¹²

REFERENCES

1. National Comprehensive Cancer Network. Multiple Myeloma. Version 4.2021. Available at https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf. Accessed March 1, 2021.
2. FDA granted accelerated approval for belantamab mafodotin-blmf for multiple myeloma. August 6, 2020. Available at https://www.fda.gov/ drugs/drug-approvals-and-databases/fda-granted-accelerated-approval-belantamab-mafodotin-blmf-multiple-myeloma. Accessed March 1, 2021.
3. Blenrep (Belantmamb mafodotin-blmf) [package insert]. Research Triangle Park, NC: GlaxoSmithKline.
4. Lonial S, Lee HC, Badros A, et al. Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomized, open-label, Phase II study. Lancet Oncol. 2020 Feb;21(2):207-221.
5. Farooq AV, Esposti SD, Popat R, et al. Corneal Epithelial Findings in Patients with Multiple Myeloma Treated with Antibody–Drug Conjugate Belantamab Mafodotin in the Pivotal, Randomized, DREAMM-2 Study. Ophthalmol Ther. 2020;9:889-911.
6. Blenrep REMS (risk evaluation and mitigation strategy). Available at https://www.blenreprems.com/#Main. Accessed March 1, 2021.
7. Blenrep REMS Prescribers. Available at https://www.blenreprems.com/#Main/Prescribers. Accessed March 17, 2021.
8. Blenrep REMS Patients. Available at https://www.blenreprems.com/#Main/Patients. Accessed March 17, 2021.
9. Blenrep REMS Healthcare Settings. Available at https://www.blenreprems.com/#Main/HealthcareSetting. Accessed March 17, 2021.
10. Blenrep (belantamab mafodotin-blmf). Available at https://www. togetherwithgskoncology.com/patient-information/blenrep/. Accessed March 17, 2021.
11. Blenrep (belantamab mafodotin-blmf). Available at https://www. blenrephcp.com/initiation-and-resources/hcp-resources/. Accessed March 1, 2021.
12. U.S. National Library of Medicine. ClinicalTrials.gov. Available at https:// www.clinicaltrials.gov/. Accessed March 1, 2021.