Phase I results of the LEGEND-2 trial: LCAR-B38M CAR-T therapy for patients with relapsed or refractory multiple myeloma

LCAR-B38M is a chimeric antigen receptor T-cell (CAR T-cell) therapy that dually binds two distinct B cell maturation antigen (BCMA) epitopes, making it distinct from the other BCMA directed CAR T-cell therapies currently in trials. LCAR-B38M is currently under investigation in the LEGEND-2 trial (NCT03090659); a single-arm, open-label, multicenter phase I study in patients with relapsed/refractory multiple myeloma (RRMM). Wan-Hong Zhao from the Second Affiliated Hospital of Xi’an Jiaotong University, ShaanXi, China, and colleagues published the phase I data in the Journal of Hematology & Oncology on 20^th December 2018. The primary outcome of the LEGEND-2 study was to evaluate the safety of LCAR-B38M CAR T cells and the secondary objective was to evaluate anti-myeloma response of the treatment.

Study design and baseline characteristics

• N = 57 patients with RRMM
• Median age: 54 years (range, 27–72)
• Median prior lines of therapy: 3 (range, 1–9) including proteasome inhibitor therapy (68%), immunomodulatory agents (86%), and both (60%)

Patients underwent leukapheresis. The CD3+ T cells were transduced with a LCAR-B38M lentiviral vector to express anti-BCMA CAR and were then expanded ex vivo with interleukin-2 stimulation. Lymphodepletion by cyclophosphamide, 300 mg/m², was given on days -5, -4 and -3. Total weight adjusted CAR+ T cell dose (median: 0.5 x 10⁶ cells/kg [0.07–2.1 x 10⁶]) was delivered as 3 infusions (20, 30 and 50%), 5 days after lymphodepleting chemotherapy started, over the course of 7 days.

Key findings

Data cut-off date was 6^th February 2018

Safety

• Patients experiencing ≥1 adverse event (AE): 100%
• Grade ≥3 AEs were reported in 65% of patients (n = 37)
• The most common (≥ 40%) AEs of any grade:
  • Pyrexia: 91% (52/57)
  • Cytokine release syndrome (CRS): 90% (51/57)
    • The majority of CRS events were grade 1 (47%) and grade 2 (35%)
    • Median time to onset of CRS was 9 days (range, 1–19)
    • Median time to resolution of CRS was 9 days (excluding the patient with grade 5 AE)
  • Thrombocytopenia: 49% (28/57)
  • Leukopenia: 47% (27/57)
• The most common (≥20%) grade ≥3 AEs:
  • Leukopenia: 30% (17/57)
  • Thrombocytopenia: 23% (13/57)
  • Aspartate aminotransferase increase: 21% (12/57)
• One patient experienced neurotoxicity of grade 1 aphasia, agitation, and seizure-like activity
• One patient experienced a grade 5 fatal AE

Efficacy

• Median follow-up of 8 months
• Overall response rate (ORR): 88% (95% CI, 76–95)
  • Complete response (CR): 68% (95% CI, 55–80)
  • Very good partial response (VGPR): 5% (95% CI, 1–15)
  • Partial response (PR): 14% (95% CI, 6–26)
• Minimal residual disease (MRD) was negative for 63% of patients (36/57)
• Median time to initial response: 1 month
• Median progression-free survival (PFS): 15 months (95% CI, 11–not estimable)
• Tumor mass decreases were observed in patients with extramedullary disease
• Estimated median duration of response (DoR): 14 months
• Median overall survival (OS) for all patients was not reached
• BCMA expression did not correlate with median PFS or OS
• LCAR-B38M CAR T cells were not detectable at 4 months in 71% of patients
• Only 5 patients showed persistence of LCAR-B38M cells up to 10 months

This phase I, first-in human clinical study of LCAR-B38M shows a manageable safety profile with durable responses in patients with RRMM. Efficacy was consistent across subgroups, including previous ASCT status, age, number of prior therapies and type or prior therapy. The analysis of the efficacy and safety of LCAR-B38M is ongoing in a phase Ib/II trial in the US (NCT03548207).