Belantamab

Introduction to Belantamab

Belantamab mafodotin (trade name: Blenrep) is an antibody-drug conjugate (ADC) developed by GlaxoSmithKline. It received accelerated approval from the FDA in 2020 for the treatment of relapsed or refractory multiple myeloma. Belantamab mafodotin consists of three key components:

  1. A humanized monoclonal antibody targeting B-cell maturation antigen (BCMA), a protein highly expressed on multiple myeloma cells
  2. A protease-resistant maleimidocaproyl linker
  3. Monomethyl auristatin F (MMAF), a potent microtubule inhibitor

This innovative therapy represents a significant advancement in the treatment of multiple myeloma, particularly for patients who have exhausted other treatment options.

Mechanism of Action

Belantamab mafodotin works through a multi-faceted mechanism:

  1. Binding: The antibody portion of belantamab mafodotin selectively binds to BCMA on the surface of multiple myeloma cells.
  2. Internalization: Upon binding, the ADC-BCMA complex is internalized into the myeloma cell.
  3. Release of cytotoxic agent: Inside the cell, lysosomal enzymes cleave the linker, releasing the cytotoxic agent MMAF.
  4. Cell death: MMAF disrupts the microtubule network within the cell, leading to G2/M cell cycle arrest and apoptosis.
  5. Immunogenic cell death: The ADC also promotes immunogenic cell death, potentially enhancing the anti-tumor immune response.
  6. Antibody-dependent cellular cytotoxicity (ADCC): The antibody component can recruit immune effector cells to attack the myeloma cells.

This multi-modal approach allows for targeted delivery of a potent cytotoxic agent to myeloma cells expressing BCMA, while also engaging the immune system to enhance anti-tumor activity.

Indications

Belantamab mafodotin is indicated for:

  • 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
    • An immunomodulatory agent

This indication was approved under accelerated approval based on response rate. Continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials.

While initially approved for adult patients, research is ongoing to explore its potential use in pediatric populations with BCMA-expressing hematological malignancies.

Administration

Belantamab mafodotin is administered as an intravenous infusion. The typical dosing regimen is:

  • 2.5 mg/kg administered as an intravenous infusion over approximately 30 minutes once every 3 weeks
  • Treatment is continued until disease progression or unacceptable toxicity
  • Dose modifications may be necessary based on adverse reactions, particularly ocular toxicity

Important administration considerations:

  • Belantamab mafodotin must be reconstituted and diluted by a healthcare professional prior to administration
  • It should be administered by healthcare professionals experienced in the use of anti-cancer therapies
  • Patients should receive adequate hydration prior to administration to reduce the risk of tumor lysis syndrome

Adverse Effects

Common adverse effects of belantamab mafodotin include:

  • Keratopathy (corneal epithelium changes)
  • Decreased visual acuity
  • Nausea
  • Blurred vision
  • Pyrexia
  • Fatigue
  • Infusion-related reactions
  • Thrombocytopenia
  • Anemia
  • Neutropenia

Belantamab mafodotin carries a boxed warning for ocular toxicity. Keratopathy, changes in the corneal epithelium as seen on eye examination, can manifest with or without symptoms, can occur at any time during treatment, and can result in severe vision loss.

Due to the risk of ocular toxicity, belantamab mafodotin is only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the BLENREP REMS.

Monitoring

Patients receiving belantamab mafodotin should be closely monitored for:

  • Ocular toxicity:
    • Ophthalmic examinations, including visual acuity and slit lamp examinations, should be performed at baseline, prior to each dose, and promptly for worsening symptoms
    • Monitoring should continue during treatment and for at least 3 months after the last dose
  • Thrombocytopenia: Monitor complete blood counts at baseline and during treatment
  • Infusion-related reactions: Monitor patients during and after infusion
  • Embryo-fetal toxicity: Verify pregnancy status prior to initiating treatment in females of reproductive potential
  • Tumor lysis syndrome: Assess blood chemistry and hydration status at baseline and during treatment

Regular assessment of these parameters is crucial for early detection and management of adverse effects, ensuring optimal patient outcomes and quality of life during treatment.



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