What is Blenrep (belantamab mafodotin)?

Blenrep (Belantamab Mafodotin): A BCMA-Targeted Therapy for Relapsed/Refractory Multiple Myeloma

Blenrep (belantamab mafodotin-blmf) is a first-in-class B-cell maturation antigen (BCMA)-directed antibody-drug conjugate that combines an anti-BCMA monoclonal antibody with the cytotoxic agent monomethyl auristatin F (MMAF), indicated for heavily pretreated multiple myeloma patients who have received at least four prior therapies including a proteasome inhibitor, immunomodulatory agent, and anti-CD38 monoclonal antibody. 1, 2

Mechanism of Action and Structure

Belantamab mafodotin consists of three key components:

• An afucosylated, humanized IgG1 monoclonal antibody that targets BCMA
• The microtubule inhibitor MMAF
• A protease-resistant maleimidocaproyl linker connecting the two 2

The mechanism of action involves:

1. Binding to BCMA, a protein expressed on multiple myeloma cells
2. Internalization of the antibody-drug complex
3. Release of MMAF via proteolytic cleavage
4. Disruption of the microtubule network, leading to cell cycle arrest and apoptosis
5. Additional tumor cell killing through antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP) 2

Clinical Efficacy

Blenrep demonstrated efficacy in the DREAMM-2 phase II trial:

• Response rate of approximately 31% in patients with triple-class refractory multiple myeloma at the 2.5 mg/kg dose 1, 3
• Median progression-free survival of 2.9 months at the 2.5 mg/kg dose 1
• Durable responses with median duration of response of 11 months 4

Administration and Dosing

• Administered as an intravenous infusion at 2.5 mg/kg once every 3 weeks until disease progression or unacceptable toxicity 2
• Available as a sterile, preservative-free, white to yellow lyophilized powder in 100-mg single-dose vials for reconstitution 2

Safety Profile and Adverse Events

The most significant adverse events include:

1. Ocular Toxicity (Boxed Warning):

   • Keratopathy occurs in 71-80% of patients, with grade 3-4 events in 27-31% 1, 3
   • Changes in visual acuity, blurred vision, and dry eye are common 3
   • Requires enrollment in a Risk Evaluation and Mitigation Strategy (REMS) program 2, 3
   • Regular ophthalmic examinations are mandatory for early detection and management 4

2. Hematologic Toxicities:

   • Thrombocytopenia (73% of patients)
   • Anemia (67% of patients) 1

3. Other Common Adverse Events:

   • Fatigue (73%)
   • Nausea (72%) 1

Current Status and Availability

In November 2022, belantamab mafodotin was withdrawn from the market after failing to meet the primary endpoint in the DREAMM-3 trial, which compared it to pomalidomide plus dexamethasone. However, patients already receiving the drug can continue treatment through a compassionate use program, and clinical trials with belantamab mafodotin are ongoing. 1

Patient Selection and Monitoring

Optimal candidates for Blenrep therapy:

• Patients with relapsed/refractory multiple myeloma who have received at least 4 prior therapies
• Prior exposure to a proteasome inhibitor, immunomodulatory agent, and anti-CD38 monoclonal antibody 1

Required monitoring:

• Baseline and regular ophthalmic examinations before each dose
• Complete blood count monitoring for hematologic toxicities
• Renal and hepatic function tests 2, 4

Special Populations

• Geriatric Use: No significant differences in effectiveness between patients aged <65 years and ≥65 years, though keratopathy patterns may differ slightly 2
• Renal Impairment: No dose adjustment needed for mild to moderate impairment; not established for severe impairment 2
• Hepatic Impairment: No dose adjustment needed for mild impairment; not established for moderate or severe impairment 2

Blenrep represents an important treatment option for heavily pretreated multiple myeloma patients with limited alternatives, though careful management of its unique toxicity profile, particularly ocular events, is essential for optimal outcomes.