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CAR T-Cell Therapy for Relapsed/Refractory Multiple Myeloma: Comprehensive Overview

CAR T-cell therapy engineers a patient's own T cells to express a chimeric antigen receptor (CAR) targeting B-cell maturation antigen (BCMA), uniformly expressed on myeloma cells. Two products are FDA-approved for RRMM after ≥4 prior lines (including PI, IMiD, anti-CD38): idecabtagene vicleucel (Abecma/ide-cel) and ciltacabtagene autoleucel (Carvykti/cilta-cel).

Manufacturing & Infusion Workflow

  1. Leukapheresis: 3–6 L blood processed; T cells enriched (CD3+ selection).
  2. Genetic modification: Lentiviral (ide-cel) or gamma-retroviral (cilta-cel) vector transduces CAR construct (anti-BCMA scFv + CD28/4-1BB costim + CD3ζ signaling).
  3. Expansion & QC: 2–3 weeks; sterility, potency, viability, replication-competent virus testing.
  4. Lymphodepletion: Fludarabine 30 mg/m² + cyclophosphamide 300 mg/m² × 3 days — creates cytokine space, depletes Tregs.
  5. Infusion: Target dose: ide-cel 300–460M CAR+ T cells; cilta-cel 0.75M/kg (max 100M). Single IV infusion.

Mechanism of Action

  • CAR binds BCMA → immunological synapse → LCK/ZAP70 phosphorylation → cytotoxic granule release (perforin/granzymes) + Fas/FasL apoptosis + cytokine storm (IL-6, IFN-γ, TNF-α).
  • In vivo expansion peaks at 7–14 days; persistence correlates with depth/duration of response.
  • Memory phenotype (TSCM, TCM) enables long-term surveillance.

Efficacy (Pivotal Trials)

MetricIde-cel (KarMMa)Cilta-cel (CARTITUDE-1)
ORR73%98%
≥CR/sCR33%83%
Median PFS8.8 mo34.9 mo
MRD negativity (10-5)26%61%

Key Toxicities

  • CRS (Cytokine Release Syndrome): >90% any grade; Grade ≥3 ~5–10%. Tocilizumab ± steroids.
  • ICANS (Neurotoxicity): ~10–20% any grade; unique to cilta-cel: delayed parkinsonism, cranial neuropathies.
  • Cytopenias: Prolonged neutropenia/thrombocytopenia (30–50% Grade 3–4 at 1 mo); G-CSF support.
  • Infections: Bacterial, viral (HSV/VZV reactivation), fungal — prophylaxis mandated.
  • Secondary malignancies: T-cell lymphomas reported (rare); FDA boxed warning.

Future Directions

  • Earlier lines (1–3), BCMA-targeting bispecifics (teclistamab, elranatamab), allogeneic/off-the-shelf CAR-T, dual-target (BCMA × GPRC5D), armored CARs (IL-15, CCR2).

CAR T-cell therapy represents a paradigm shift—living drug, durable responses, but complex toxicity management. Specialized centers and multidisciplinary teams are essential.

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