Four-year follow-up of LCAR-B38M in relapsed or refractory multiple myeloma: a phase 1, single-arm, open-label, multicenter study in China (LEGEND-2)

Abstract

Background LCAR-B38M is a chimeric antigen receptor T cell product with two binding domains targeting B cell maturation antigen. Our previous reports showed a remarkable efficacy of LCAR-B38M in patients with relapsed/refractory multiple myeloma (RRMM) at a median follow-up of 2 years. Here, we report long-term safety and efficacy data from a median follow-up of 4 years. Methods LEGEND-2 was a phase 1, single-arm, open-label study conducted in four registered sites in China. Seventy-four participants with RRMM received LCAR-B38M treatment. Lymphodepletion was performed using cyclophosphamide or cyclophosphamide plus fludarabine. LCAR-B38M, at a median dose of 0.513 × 106 cells/kg, was intravenously administered either in three split infusions or in a single infusion. The primary objective was the safety of LCAR-B38M, and the secondary objective was efficacy. Results As of May 25, 2021, the median follow-up was 47.8 months. All patients experienced ≥ 1 adverse events (AEs). Grade ≥ 3 AEs were observed in 45/74 (60.8%) patients. Cytokine release syndrome (CRS) occurred in 68/74 (91.9%) cases; 7 (9.5%) had grade ≥ 3 CRS. One patient experienced grade 1 central nervous system toxicity. The overall response rate was 87.8%. Fifty-four out of 74 (73.0%) patients achieved complete response. The median progression-free survival was 18.0 months, and the median overall survival for all patients was not reached. The median duration of response was 23.3 months. Four patients experienced viral infection more than 6 months post-infusion, and four patients developed second primary non-hematological malignancies at a median time of 11.5 months post-CAR-T cell transfer. Conclusions The 4-year follow-up data of LCAR-B38M therapy demonstrated a favorable long-term safety profile and a durable response in patients with RRMM. Trial registration Clinicaltrials.gov NCT03090659 (retrospectively registered on March 27, 2017); ChiCTR-ONH-17012285.

N6-methyladenosine reader YTHDF2 promotes multiple myeloma cell proliferation through EGR1/p21cip1/waf1/CDK2-Cyclin E1 axis-mediated cell cycle transition

“…Initiation of MM is characterized by monoclonal gammopathy of unknown significance (MGUS) and smoldering MM (SMM), finally developing into the extramedullary MM (EMM) and plasma cell leukemia (PCL). Treatment of MM involves the use of proteasome inhibitor-based regimen, and is supplemented with immunotherapy, including monoclonal antibodies and chimeric antigen receptor-engineered T cells [ 2 ]. However, MM remains incurable with high mortality rate.…”

Challenges and optimal strategies of CAR T therapy for hematological malignancies

“…Munshi NC [56] II Single arm 128 CAR T-BCMA MM ORR was 73%, with a CR of 33%; the median PFS was 8.8 months Martin T [58] I/II Single arm 97 CAR T-BCMA MM ORR was 97.9%, with a CR of 82.5%; 27-month PFS and OS rates were 54.9% and 70.4% Zhao WH [59] I CAR-T platform enabling 22-36 h manufacturing. [74] A multicenter first-in-human study of GC012F enrolled 28 R/R MM patients, including 89.3% (25/28) high-risk MM, at a median 6.3-month follow-up, the ORR was 89.3% (25/28), and MRD negativity plus sCR was achieved in 75.0% (21/28) of patients.…”

“…The median PFS was 18.0 months and the OS was still not reached. The median DOR was 23.3 months [59] …”

“…The median DOR was 23.3 months. [59] Despite high response rates, up to 30% of patients with R/R lymphoma or myeloma did not respond well to CAR T therapy. [60] In recent years, many studies have revealed various intrinsic resistance mechanisms of cancer cells against CAR T cell therapy, providing an important reference for developing new CAR T strategies [Table 1].…”

A comprehensive analysis of coagulopathy during anti‐B cell maturation antigen chimeric antigen receptor‐T therapy in multiple myeloma, a retrospective study based on LEGEND‐2

“…We conducted this retrospective analysis upon the LEGEND-2 (NCT03090659), 9,13 a phase one, single-arm, open-label study in China. Six patients with DIC prior to CAR-T cell infusion were excluded from this retrospective study.…”