Abecma - Drug Monograph

Introduction

Abecma (idecabtagene vicleucel; ide-cel) is a groundbreaking chimeric antigen receptor (CAR) T-cell therapy approved by the FDA in March 2021. It represents a novel class of immunocellular therapy that genetically modifies a patient's own T-cells to target and eliminate malignant plasma cells expressing B-cell maturation antigen (BCMA). Abecma is manufactured specifically for each patient through a complex cellular processing procedure, marking a significant advancement in the treatment of relapsed or refractory multiple myeloma.

Mechanism of Action

Abecma is an autologous, genetically modified CAR T-cell therapy. The mechanism involves:

• CAR T-cell Engineering: Patient's T-cells are collected via leukapheresis and genetically modified to express a CAR specific for BCMA
• Target Recognition: The CAR consists of an anti-BCMA single-chain variable fragment (scFv) domain that recognizes BCMA on myeloma cells
• T-cell Activation: Upon BCMA binding, the CD3ζ and 4-1BB costimulatory domains activate T-cell signaling pathways
• Cytotoxic Response: Activated CAR T-cells proliferate and induce apoptosis of BCMA-expressing cells through:

- Perforin/granzyme-mediated cytotoxicity - Cytokine release (IFN-γ, TNF-α, IL-2) - Fas/FasL pathway activation

This results in targeted elimination of malignant plasma cells while sparing BCMA-negative healthy cells.

Indications

Abecma is FDA-approved for the treatment of adult patients with relapsed or refractory multiple myeloma who have received:

• At least four prior lines of therapy, including:

- An immunomodulatory agent - A proteasome inhibitor - An anti-CD38 monoclonal antibody

This indication was approved under accelerated approval based on response rate from the KarMMa trial (NCT03361748). Continued approval may be contingent upon verification of clinical benefit in confirmatory trials.

Dosage and Administration

• Recommended dose: 300-460 × 10⁶ CAR-positive T cells
• Administered as a single intravenous infusion

1. Leukapheresis: T-cell collection 5-7 days prior to lymphodepletion 2. Lymphodepletion Chemotherapy: - Fludarabine 30 mg/m²/day × 3 days - Cyclophosphamide 300 mg/m²/day × 3 days - Administered 2-14 days before Abecma infusion 3. Abecma Infusion: - Premedicate with acetaminophen and diphenhydramine - Administer via intravenous infusion over 30 minutes - Do not use a leukocyte depletion filter

• Renal Impairment: No specific dosage adjustment recommended
• Hepatic Impairment: No specific dosage adjustment recommended
• Elderly: No dosage adjustment required based on age alone

Pharmacokinetics

• CAR T-cells expand rapidly post-infusion, peaking at 10-14 days
• Persistence detectable for up to 12 months in some patients
• Expansion correlates with response and toxicity severity

• Migrates to bone marrow, spleen, and tumor sites
• Crosses blood-brain barrier in minimal amounts

• Cellular elimination through apoptosis and immune-mediated clearance
• Half-life varies based on expansion and persistence characteristics

Contraindications

• Hypersensitivity to any component of Abecma or to fludarabine or cyclophosphamide
• Active uncontrolled infection
• Pregnancy (based on lymphodepletion chemotherapy contraindications)

Warnings and Precautions

• Cytokine Release Syndrome (CRS): May be life-threatening or fatal
• Neurologic Toxicities: May be life-threatening or fatal
• Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome (HLH/MAS): May be life-threatening or fatal
• Prolonged Cytopenias: May require supportive care

• Hypogammaglobulinemia: Monitor immunoglobulin levels and manage with replacement therapy
• Secondary Malignancies: Theoretical risk of insertional oncogenesis
• Effects on Ability to Drive: May impair consciousness and coordination
• Reproductive Risks: Based on lymphodepletion chemotherapy

Drug Interactions

• Corticosteroids: May interfere with CAR T-cell expansion and persistence
• Cytotoxic chemotherapy: May enhance myelosuppression
• Immunosuppressants: May reduce CAR T-cell efficacy
• Live vaccines: Contraindicated during and after treatment
• BCMA-directed therapies: Potential interference with target expression

Adverse Effects

• Cytokine release syndrome (85%)
• Fatigue (66%)
• Neutropenia (91%)
• Anemia (68%)
• Thrombocytopenia (63%)
• Infections (47%)
• Hypogammaglobulinemia (41%)

• Grade ≥3 CRS (6%)
• Grade ≥3 neurologic events (3%)
• Grade 3-4 cytopenias (89%)
• Grade 3-4 infections (20%)
• Tumor lysis syndrome (<1%)

Monitoring Parameters

• Complete blood count with differential
• Comprehensive metabolic panel
• Immunoglobulin levels
• Infection screening
• Cardiac function assessment

• Daily for first 7-10 days:

- Vital signs (temperature, blood pressure, oxygen saturation) - CRS assessment using ASTCT criteria - Neurologic assessment - CBC with differential

• Weekly for first month:

- Comprehensive metabolic panel - Inflammatory markers (CRP, ferritin) - Immunoglobulin levels

• Long-term monitoring:

- Minimal residual disease assessment - B-cell and plasma cell recovery - Immunoglobulin levels every 3-6 months

Patient Education

• Understand the multi-step process involving leukapheresis, chemotherapy, and infusion
• Recognize early symptoms of CRS (fever, fatigue, hypotension) and neurologic toxicity
• Report any signs of infection promptly
• Avoid driving or operating machinery for 8 weeks post-infusion
• Practice strict infection prevention measures
• Understand the need for immunoglobulin replacement if indicated
• Use effective contraception for at least 1 year post-treatment
• Carry patient wallet card and seek immediate medical attention for concerning symptoms
• Attend all scheduled follow-up appointments for long-term monitoring

References

1. Munshi NC, Anderson LD Jr, Shah N, et al. Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma. N Engl J Med. 2021;384(8):705-716. 2. FDA prescribing information: Abecma (idecabtagene vicleucel). March 2021. 3. Raje N, Berdeja J, Lin Y, et al. Anti-BCMA CAR T-Cell Therapy bb2121 in Relapsed or Refractory Multiple Myeloma. N Engl J Med. 2019;380(18):1726-1737. 4. NCCN Guidelines Version 3.2022 Multiple Myeloma. 5. Lee DW, Santomasso BD, Locke FL, et al. ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol Blood Marrow Transplant. 2019;25(4):625-638. 6. Brudno JN, Kochenderfer JN. Recent advances in CAR T-cell toxicity: Mechanisms, manifestations and management. Blood Rev. 2019;34:45-55.