CARVYKTI Dispersion for infusion Ref.[50034] Active ingredients: Ciltacabtagene autoleucel

Pharmacotherapeutic group: Other antineoplastic agents
ATC code: L0XX

Mechanism of action

CARVYKTI is a BCMA-directed, genetically modified autologous T cell immunotherapy, which involves reprogramming a patient’s own T cells with a transgene encoding a chimeric antigen receptor (CAR) that identifies and eliminates cells that express BCMA. BCMA is primarily expressed on the surface of malignant multiple myeloma B-lineage cells, as well as late-stage B cells and plasma cells. The CARVYKTI CAR protein features two BCMA-targeting single domain antibodies designed to confer high avidity against human BCMA, a 4-1BB co-stimulatory domain and a CD3-zeta (CD3ζ) signaling cytoplasmic domain. Upon binding to BCMA expressing cells, the CAR promotes T cell activation, expansion, and elimination of target cells.

Pharmacodynamic effects

In vitro co-culture experiments demonstrated that ciltacabtagene autoleucel-mediated cytotoxicity and cytokine release (interferon-gamma, [IFN-γ], tumour necrosis factor alpha [TNF-α], interleukin [IL]-2) were BCMA-dependent.

Clinical efficacy and safety

MMY2001 was an open label, single-arm, multicentre, Phase 1b/2 study evaluating the efficacy and safety of CARVYKTI for the treatment of adult patients with relapsed and refractory multiple myeloma who had received at least 3 prior lines of antimyeloma therapies, including a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 antibody and who had disease progression on or within 12 months after the last regimen. Patients with known active, or prior history of significant central nervous system (CNS) disease including CNS multiple myeloma, patients previously exposed to other anti-BCMA treatments, allogeneic stem cell transplant within 6 months before apheresis or ongoing treatment with immunosuppressants, creatinine clearance <40mL/min, absolute lymphocyte concentration <300/µL, hepatic transaminases >3 times the upper limit of normal, cardiac ejection fraction <45%, or with active serious infection were excluded from the trial.

In total, 113 patients underwent leukapheresis; CARVYKTI was manufactured for all patients. The median time from the day after receipt of leukapheresis material at manufacturing facility to release of medicinal product for infusion was 29 days (range: 23 to 64 days) and the median time from initial leukapheresis to CARVYKTI infusion was 47 days (range: 41 to 167 days).

Following leukapheresis and prior to administration of CARVYKTI, 73 of the 97 patients (75%) received bridging therapy. The most commonly used agents as bridging therapies (≥20% of patients) included dexamethasone: 62 patients (63.9%), bortezomib: 26 patients (26.8%), cyclophosphamide: 22 patients (22.7%), and pomalidomide: 21 patients (21.6%).

CARVYKTI was administered as a single IV infusion 5 to 7 days after the start of a lymphodepleting chemotherapy (cyclophosphamide 300 mg/m² intravenously daily and fludarabine 30 mg/m² intravenously daily for 3 days). Ninety-seven patients received CARVYKTI at a median dose of 0.71 × 10⁶ CAR-positive viable T cells/kg (range: 0.51 to 0.95 × 10⁶ cells/kg). All patients were hospitalised for the CARVYKTI infusion and for a minimum of 10 days afterward. Sixteen patients were not treated with CARVYKTI (n=12 after leukapheresis and n=4 after lymphodepleting therapy), due to either withdrawal by patient (n=5), progressive disease (n=2) or death (n=9).

Table 6. Summary of patient demographic and baseline characteristics:

ECOG= Eastern Cooperative Oncology Group; ISS= International Staging System; PI= Proteasome inhibitor; IMiD= Immunomodulatory drug; SCT= Stem cell transplant; NA= not applicable.
^a Plasmacytomas were not assessed until prior to lymphodepletion.

Efficacy results were based on overall response rate as determined by the Independent Review Committee assessment using IMWG criteria (see Table 7).

<bTable 7. Efficacy results for Study MMY2001:

CI=confidence interval; MRD= Minimal Residual Disease; NE= not estimable
Notes: Based on a median duration of follow up of 18 months
^a All complete responses were stringent CRs.
^b Only MRD assessments (10-5 testing threshold) within 3 months of achieving CR/sCR until death / progression / subsequent therapy (exclusive) are considered. All complete responses were stringent CRs. MRD negativity rate [() 95 CI] in evaluable patients (n=61) was 91.8% (81.9%, 97.3%).

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with CARVYKTI in all subsets of the paediatric population in multiple myeloma (see section 4.2 for information on paediatric use).

This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. This means that further evidence on this medicinal product is awaited. The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.