Carvykti - Drug Monograph

Introduction

Carvykti (ciltacabtagene autoleucel) is a revolutionary chimeric antigen receptor (CAR) T-cell therapy approved for the treatment of relapsed or refractory multiple myeloma. As a genetically modified autologous T-cell immunotherapy, it represents a significant advancement in hematologic malignancy treatment, offering new hope for patients who have exhausted multiple prior lines of therapy.

Mechanism of Action

Carvykti is a B-cell maturation antigen (BCMA)-directed genetically modified autologous T-cell immunotherapy. The mechanism involves:

• Collection of patient's T-cells via leukapheresis
• Genetic modification to express CARs targeting BCMA
• CAR T-cells recognize and bind to BCMA on multiple myeloma cells
• Upon binding, CAR T-cells become activated and proliferate
• Activated CAR T-cells induce cytotoxic effects on BCMA-expressing cells through:

- Release of perforin and granzyme B - Activation of caspase pathways - Secretion of inflammatory cytokines

This results in targeted lysis of malignant plasma cells expressing BCMA.

Indications

Carvykti 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:

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

Dosage and Administration

• Target dose: 0.5-1.0 × 10⁶ CAR-positive viable T cells per kg body weight
• Minimum dose: 0.1 × 10⁶ CAR-positive viable T cells per kg

1. Leukapheresis for T-cell collection 2. Manufacturing period (approximately 4 weeks) 3. Lymphodepleting chemotherapy: - Fludarabine 30 mg/m²/day × 3 days - Cyclophosphamide 300 mg/m²/day × 3 days - Administered 2-14 days before Carvykti infusion 4. Carvykti infusion: - Premedicate with acetaminophen and diphenhydramine - Administer via intravenous infusion over 30 minutes

• Renal impairment: No specific dosage adjustments recommended
• Hepatic impairment: No specific dosage adjustments recommended
• Elderly: No specific dosage adjustments recommended

Pharmacokinetics

• CAR T-cells expand rapidly post-infusion
• Peak expansion typically occurs within 10-14 days
• CAR T-cells may persist for months to years

• Primarily distributes to bone marrow and sites of disease
• Can cross the blood-brain barrier in minimal amounts

• Elimination kinetics not fully characterized
• CAR T-cells may undergo apoptosis or immune-mediated clearance

Contraindications

• Hypersensitivity to ciltacabtagene autoleucel or any component of the formulation
• Active uncontrolled infection
• Pregnancy (based on mechanism of action)

Warnings and Precautions

• Occurred in 95% of patients in clinical trials
• May be life-threatening or fatal
• Monitor for fever, hypoxia, hypotension, and organ dysfunction
• Requires prompt management with tocilizumab and/or corticosteroids

• Occurred in 21% of patients
• Includes immune effector cell-associated neurotoxicity syndrome (ICANS)
• Monitor for encephalopathy, seizures, cerebral edema

• May be life-threatening
• Monitor for febrile illness, cytopenias, and organ dysfunction

• May persist for several weeks post-infusion
• Monitor blood counts regularly

• Monitor immunoglobulin levels
• May require immunoglobulin replacement

• Theoretical risk of insertional oncogenesis
• Monitor patients long-term for secondary malignancies

Drug Interactions

• Avoid concomitant use with:

- Live vaccines during treatment and until immune recovery - Cytotoxic chemotherapy during CAR T-cell expansion phase

• Caution with:

- Corticosteroids (may interfere with CAR T-cell function) - Other immunosuppressive therapies

Adverse Effects

• Cytokine release syndrome (95%)
• Fatigue (76%)
• Musculoskeletal pain (70%)
• Nausea (67%)
• Pyrexia (57%)
• Hypogammaglobulinemia (52%)
• Headache (45%)
• Diarrhea (38%)
• Cough (35%)
• Constipation (33%)
• Anorexia (32%)
• Edema (32%)
• Vomiting (30%)
• Neurotoxicity (21%)

• Severe CRS (5%)
• Severe neurotoxicity (3%)
• Infections (28%)
• Prolonged cytopenias
• Tumor lysis syndrome

Monitoring Parameters

• Complete blood count with differential
• Comprehensive metabolic panel
• Immunoglobulin levels
• Infectious disease screening

• Daily monitoring for CRS and neurotoxicity for first 10-14 days
• Temperature and vital signs every 4-8 hours
• Neurological assessments
• CBC with differential (at least 3 times weekly for first month)
• Metabolic panel (weekly for first month)
• CRP and ferritin levels
• Immunoglobulin levels (monthly)
• CAR T-cell expansion monitoring (as clinically indicated)

• Blood counts until recovery
• Immunoglobulin levels
• Surveillance for secondary malignancies
• Monitoring for late effects

Patient Education

• Understand the multi-step process and time commitment
• Arrange for a caregiver to assist during recovery period
• Plan to stay within 2 hours of treatment center for at least 4 weeks post-infusion

• Report any fever (temperature ≥38°C) immediately
• Monitor for signs of CRS: fever, chills, fatigue, dizziness
• Watch for neurological symptoms: confusion, difficulty speaking, seizures
• Avoid driving or operating heavy machinery for 8 weeks post-infusion

• Avoid live vaccines until advised by healthcare provider
• Practice infection prevention measures
• Attend all follow-up appointments
• Use reliable contraception for at least 1 year post-treatment
• Report any new or worsening symptoms promptly

• Keep wallet card with emergency contact information
• Ensure local emergency department is aware of CAR T-cell therapy
• Have tocilizumab access plan in place

References

1. US Food and Drug Administration. (2022). Carvykti prescribing information. 2. Berdeja, J. G., et al. (2021). Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. The Lancet, 398(10297), 314-324. 3. Martin, T., et al. (2023). CARTITUDE-2: Efficacy and safety of ciltacabtagene autoleucel in patients with relapsed/refractory multiple myeloma. Journal of Clinical Oncology, 41(12), 1323-1334. 4. National Comprehensive Cancer Network. (2023). Multiple myeloma guidelines version 3.2023. 5. Brudno, J. N., & Kochenderfer, J. N. (2019). Recent advances in CAR T-cell toxicity: Mechanisms, manifestations and management. Blood Reviews, 34, 45-55. 6. American Society for Transplantation and Cellular Therapy. (2021). ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biology of Blood and Marrow Transplantation, 25(4), 625-638.