On August 5, 2020, the antibody-drug conjugate belantamab mafodotin-blmf was granted accelerated approval for treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent.^1,2 The agent is a conjugate of a B-cell maturation antigen–directed antibody and a microtubule inhibitor. Due to the risks of ocular toxicity, belantamab mafodotin-blmf is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS), called the Blenrep REMS.

Supporting Efficacy Data

Approvalwas based on findings in the phase II, multi-center DREAMM-2 trial (ClinicalTrials.gov identifier NCT03525678).^2,3 In the trial, patients (n = 218) received belantamab -mafodotin-blmf at 2.5 mg/kg or at 3.4 mg/kg intravenously (IV) once every 3 weeks until disease progression or unacceptable toxicity. Eligible patients had relapsed or refractory multiple myeloma, had previously received three or more prior therapies (including an anti-CD38 monoclonal antibody), and were refractory to an immunomodulatory agent and a proteasome inhibitor. Patients had measurable disease by International Myeloma Working Group criteria. Patients at baseline with corneal epithelial disease, except for mild punctate keratopathy, were excluded from the study.

The major efficacy outcome measures were overall response rate and response duration assessed by an independent review committee using International Myeloma Working Group Uniform Response Criteria for Multiple Myeloma. Efficacy data are from the 97 patients who received the recommended dosage of 2.5 mg/kg.

A response was observed in 30 patients (31%, 97.5% confidence interval = 21%–43%), including a stringent complete response in 2 (2%), a complete response in 1 (1%), a very good partial response in 15 (15%), and a partial response in 12 (12%). Median duration of response was not reached, with 73% of responders having a response duration of at least 6 months. Median time to the first response was 1.4 months.

How It Works

Belantamab mafodotin-blmf is an antibody-drug conjugate. The antibody component is an afucosylated IgG1 directed against B-cell maturation antigen, a protein expressed on normal B lymphocytes and multiple myeloma cells. The small-molecule component is MMAF, a microtubule inhibitor. Upon binding to B-cell maturation antigen, belantamab mafodotin-blmf is internalized followed by release of MMAF via proteolytic cleavage. The released MMAF intracellularly disrupts the microtubule network, leading to cell-cycle arrest and apoptosis.

Belantamab mafodotin-blmf showed antitumor activity in multiple myeloma cells and mediated killing of tumor cells through MMAF-induced apoptosis, as well as by tumor cell lysis through antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis.

How It Is Used

The recommended dose of belantamab mafodotin-blmf is 2.5 mg/kg as an IV infusion over approximately 30 minutes once every 3 weeks. The recommended dose reduction for adverse reactions is to 1.9 mg/kg IV once every 3 weeks. Treatment should be discontinued in patients who are unable to tolerate a dose of 1.9 mg/kg.

Patients should have ophthalmic exams prior to initiation of and during treatment. They should also be advised to use preservative-free lubricant eye drops and avoid contact lenses unless directed by an ophthalmologist.

Product labeling provides detailed instructions on dosage modification, including withholding of treatment; reducing the dose; slowing of infusion; and discontinuing of treatment for corneal adverse reactions, thrombocytopenia, infusion-related reactions, and grade 3 and 4 adverse reactions.

Safety Profile

Among patients receiving belantamab mafodotin-blmf at 2.5 mg/kg in the DREAMM-2 trial, 22% were exposed for at least 6 months. The most common adverse events of any grade (≥ 20%) were keratopathy (71%), decreased visual acuity (53%), nausea (24%), blurred vision (22%), pyrexia (22%), infusion-related reactions (21%), and fatigue (20%). The most common grade 3 or 4 adverse events included keratopathy (44%), decreased visual acuity (28%), and blurred vision (4%). The most common grade 3 or 4 laboratory abnormalities were decreased lymphocytes (22%), decreased platelets (21%), decreased hemoglobin (18%), and decreased neutrophils (9%).

Serious adverse events occurred in 40% of patients, the most common being pneumonia (7%), pyrexia (6%), renal impairment (4.2%), sepsis (4.2%), hypercalcemia (4.2%), and infusion-related reactions (3.2%). Adverse events led to dosage interruption in 54% of patients, the most common causes being keratopathy (47%), blurred vision (5%), dry eye (3.2%), and pneumonia (3.2%). Dose reduction due to adverse events occurred in 29% of patients, the most common causes being keratopathy (23%) and thrombocytopenia (5%). Adverse events led to treatment discontinuation in 8%, the most common cause being keratopathy (2.1%). Fatal adverse events occurred in 3.2% of patients, including sepsis (1%), cardiac arrest (1%), and lung infection (1%).

Belantamab mafodotin-blmf has a boxed warning for ocular toxicity. Treatment has caused changes in the corneal epithelium resulting in changes in vision, including severe vision loss and corneal ulcer, and symptoms such as blurred vision and dry eyes. Ophthalmic exams should be conducted at baseline, prior to each dose, and promptly for worsening symptoms. Treatment should be withheld until improvement and resumed or permanently discontinued, based on severity.

Belantamab mafodotin-blmf has warnings/precautions for thrombocytopenia, infusion-related reactions, and embryofetal toxicity. Complete blood cell counts should be performed at baseline and during treatment as clinically indicated. Patients should be advised not to breastfeed while receiving belantamab mafodotin-blmf. 

REFERENCES

1. U.S. Food and Drug Administration: FDA granted accelerated approval to belantamab mafodotin-blmf for multiple myeloma. Available at fda.gov/drugs/drug-approvals-and-databases/fda-granted-accelerated-approval-belantamab-mafodotin-blmf-multiple-myeloma. Accessed August 19, 2020.

2. Blenrep (belantamab mafodotin-blmf) for injection, for intravenous use, GlaxoSmithKline, August 2020. Available at accessdata.fda.gov/drugsatfda_docs/label/2020/761158s000lbl.pdf. Accessed August 27, 2020.

3. Lonial S, Lee HC, Badros A, et al: Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): A two-arm, randomised, open-label, phase II study. Lancet Oncol 21:207-221, 2020.