Carvykti
Carvykti
Generic Name
Carvykti
Mechanism
Carvykti utilizes a genetically engineered T‑cell that expresses a single‑chain variable fragment (scFv) against the B‑cell maturation antigen (BCMA).
• CAR components:
* scFv recognizing BCMA
* hinge and transmembrane domain for membrane anchorage
* intracellular signaling domains: CD3ζ and a co‑stimulatory domain (4‑1BB)
• Upon encountering a BCMA‑positive plasma cell, the CAR T‑cell is activated, secretes cytokines (IL‑2, IFN‑γ), and induces cytotoxic lysis via perforin/granzyme pathways.
• The therapy persists for weeks to months, providing sustained antigen‑specific surveillance.
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Pharmacokinetics
- Infusion: One dose of 0.25 × 10⁶ CAR‑positive T‑cells/kg (≈ 2 × 10⁶ cells total for a 70 kg patient).
- Cell expansion: Peak expansion occurs 7–14 days post‑infusion; serum levels decline after ~4–6 weeks but residual CAR T cells can persist for 12 months or longer.
- Clearance: No traditional elimination route; T‑cells are metabolized by apoptosis once antigen is cleared or immunomodulation occurs.
- Drug interactions: None applicable; careful monitoring during concomitant immunosuppressive or cytotoxic therapies required.
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Indications
Carvykti is approved for adults with *relapsed or refractory multiple myeloma* who have progressed after:
• ≥ 4 prior lines of therapy, including
• a proteasome inhibitor
• an immunomodulatory agent
• autologous stem‑cell transplant
• and a monoclonal antibody (ideally daratumumab).
The therapy demonstrates high overall response rates (≈ 70–80%) and durable remission in a heavily pre‑treated population.
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Contraindications
- Active, uncontrolled infection (viral, bacterial, fungal)
- Cytokine‑release syndrome (CRS) or neurotoxicity > grade 2 in prior CAR‑T treatments
- Severe organ dysfunction: uncontrolled hepatic, renal, or cardiac disease
- Pregnancy / lactation – teratogenic potential unknown
- High tumor burden (> 500 mL) or symptomatic CNS disease (risk of neurotoxicity)
- Prior CAR‑T therapy with documented severe reaction, unless disease progression warrants repeat therapy.
*Warnings:*
• CRS and immune‑related neurological events (ICANS).
• Potential for prolonged B‑cell aplasia → hypogammaglobulinemia.
• Myelosuppression and neutropenic infections.
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Dosing
1. Pre‑infusion conditioning (lymphodepletion)
• *Cyclophosphamide*: 260 mg/m² IV × 1 day
• *Fludarabine*: 30 mg/m² IV × 3 days
2. CAR T‑cell infusion:
• Single IV infusion over 1–2 h.
• Target dose: 0.25 × 10⁶ CAR‑positive T‑cells/kg.
3. Post‑infusion care
• Admit to high‑dependency unit for 5–7 days.
• Prophylactic steroids (dexamethasone 10 mg q12h) only if CRS > grade 3 or ICANS onset.
• Tocilizumab 8 mg/kg IV (max 800 mg) if CRS ≥ grade 3.
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Adverse Effects
| Adverse Event | Frequency | Notes |
| Cytokine‑release syndrome | 30–70% | Grade ≥ 3 in ~10–15% |
| Neurotoxicity (ICANS) | 10–40% | Grade ≥ 3 in ~5–8% |
| Anemia, neutropenia, thrombocytopenia | 30–50% | Grade ≥ 3 in ~20% |
| Hypogammaglobulinemia | Common | Monitor IgG; consider IVIG |
| Febrile neutropenia | 10–20% | Requires antibiotics |
| Secondary malignancy | Rare | Monitor long‑term |
| Myelosuppression | 20–30% | Prolonged cytopenias |
| Infusion reactions | 5–10% | Hypotension, bronchospasm |
*Serious events* include life‑threatening CRS, severe neurotoxicity, opportunistic infections, and organ failure.
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Monitoring
| Parameter | Timing | Rationale |
| CBC (WBC, Hgb, Plt) | Baseline, Day 1‑2, every 2 days for 21 days | Detect cytopenias, infection |
| CMP (liver/renal) | Baseline, Day 1‑2, weekly | Monitor organ function |
| CRP, ferritin, IL‑6 | Day 1‑2, then q2–4 days | Early CRS biomarkers |
| Neurological assessment | Baseline, q12 h | Detect ICANS |
| Serum IgG | Baseline, then q4 weeks | Identify hypogammaglobulinemia |
| Serum protein electrophoresis (SPEP) | Baseline, then monthly | Track MRD status |
| SARS‑CoV‑2 & bacterial cultures | As indicated | Infection surveillance |
| Tumor markers (M‑protein, free light chains) | Baseline, every 4 weeks | Response evaluation |
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Clinical Pearls
- Weight‑based dosing: Always calculate dose from actual body weight; errors lead to dose‑related toxicity.
- Lymphodepletion is critical: Insufficient pre‑conditioning reduces CAR‑T expansion and response.
- Early CRS recognition: Even mild fevers (≥ 38 °C) on Day 1 warrant close observation; pre‑emptive tocilizumab has decreased severe CRS rates.
- Neurotoxicity risk: Monitor for altered mental status, aphasia, or seizures; dexamethasone crosses the BBB and is first‑line for grade 3 ICANS.
- Immunoglobulin replacement: Consider IVIG for IgG < 400 mg/dL *or* persistent low B‑cell counts to reduce bacterial infections.
- Bridging therapy: Use non‑CAR‑T‑affecting agents (e.g., pomalidomide) to control disease if rapid progression is observed before infusion.
- Long‑term monitoring: Patients may develop B‑cell aplasia or secondary hematologic malignancies; annual CBC and immunophenotyping is advisable.
- Vaccinations: Post‑CAR‑T, live vaccines are contraindicated; inactivated vaccines can be administered once immune reconstitution is evident.
- Psychosocial support: CAR‑T often requires prolonged hospitalization; structured counseling improves adherence and outcomes.
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• Carvykti has transformed the therapeutic landscape for RRMM, offering durable remission for patients previously with limited options. Vigilant monitoring and prompt management of CRS and neurotoxicity are essential for maximizing benefit while mitigating risks.