A phase I study of anti-BCMA CAR T cell therapy in relapsed/refractory multiple myeloma and plasma cell leukemia

Abstract

Background: Relapsed/refractory (R/R) multiple myeloma (MM) patients and primary plasma cell leukemia (PCL) have an unfavorable prognosis and no effective treatment. This study was designed to assess the safety and preliminary efficacy of a novel anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cell in R/R MM and PCL.

Methods: Between February 22, 2017, and June 25, 2018, 28 R/R and two R/R primary PCL patients received a median dose of 11.2 × 10⁶ CAR+ cells/kg. The subjects were refractory to a proteasome inhibitor and/or an immunomodulatory agent. Fludarabine and cyclophosphamide were given as lymphodepletion chemotherapy.

Results: Results for these 30 consecutive patients who received an anti-BCMA CAR T cell infusion are reported. The patients had received a median of four prior lines of therapy. A total of 44 different types of adverse events were recorded, and hematologic toxic effects were the most common events of any grade during treatment. Hematologic toxic effects were also the most common events of grade 3 or higher. A total of 29 patients (96.7%) had cytokine release syndrome, which was of grade 1 or 2 in 24 patients (80%) and grade 3 in five patients (16.7%). Neurologic toxic effects only occurred in one patient (3.3%) and were of grade 1. The objective response rate was 90%, and the complete response rate was 43.3%. With a median follow-up of 12.6 months, the median progression-free survival (PFS) and overall survival were 5.2 months and 14.0 months. One of the two primary PCL achieved a complete response with a PFS of 307 days. The other patients achieved a very good partial response with a PFS of 117 days.

Conclusions: Anti-BCMA CAR T cell treatment is safe and highly active in R/R multiple myeloma.

Keywords: anti-BCMA CAR T cell; multiple myeloma; plasma cell leukemia; relapsed/refractory.

FIGURE 1

Consort diagram

FIGURE 2

Schematic diagrams of lentiviral vector and CAR constructs. Upper, schematic diagram of lentiviral vector. Lower, schematic diagram of anti‐BCMA CAR. The second‐generation CAR utilized in this trial was composed of a single‐chain variable fragment (scFv) derived from a murine monoclonal antibody against human BCMA, the costimulatory domain from CD28, and the CD3ζ chain as an activation domain Abbreviations: L, linker; SP, signal peptide; VH, variable H chain; VL, variable L chain.

FIGURE 3

Follow‐up of 30 patients treated with anti‐BCMA CAR T cells. Duration corresponding to different response statuses was represented as the length of colored bars for each patient. Time points of status, change, death, and censoring were also marked Abbreviations: CR, complete response; PD, progressive disease; PR, partial response; sCR, stringent complete response; SD, stable disease; VGPR, very good partial response.

FIGURE 4

Response profile of 30 patients treated with anti‐BCMA CAR T cells. (A) Response distribution in the 30 patients. Ninety percent of them were responders, including 56.7% showing ≥VGPR. (B) Left: C _max of transgenic vector copy level between responder and non‐responders; Right: Comparison of Cmax between patients with achieved ≥VGPR and DOR > median (148 days) and other responders (≤PR and DOR ≤148 days). Responders had significantly higher C _max than non‐responders, and there was a trend that deep responders were having higher C _max

FIGURE 5

Representative images are showing the anti‐myeloma activity of anti‐BCMA CAR T cells. (A) Patient 1, plasma cells were evaluated in bone marrow smear and core biopsies by CD138 and BCMA IHC staining before CAR‐BCMA treatment (baseline) and 6 months after anti‐BCMA CAR T cells infusion (post‐infusion). (B) Patient 1, longitudinal dynamics of the serum M spike after anti‐BCMA CAR T cell infusion. (C) Patient 16, computerized tomography imaging of the extramedullary disease. The sizeable soft tissue plasmacytoma in the left chest was significantly reduced in size after anti‐BCMA CAR T cell infusion. (D) Patient 28, positron emission tomography imaging of the multiple lesions of this patient with primary plasma cell leukemia and numerous extramedullary involvements (grey arrows, and white arrows 1–7). At day 60 post‐CAR T infusion, the masses on the skin (white arrow 3), abdominal cavity (white arrow 4), next to the left ischial bone (white arrows 5 and 6), and pancreas (white arrow 7) had nearly all disappeared

FIGURE 6

Prognostic factors in 30 patients treated with anti‐BCMA CAR T cells. (A) Patients with previous SCTs showed poorer PFS compared to those without; (B) Patients with EMM/PCL showed worse OS compared to those without