April 2018 VOL 9, NO 4

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ASH Conference Highlights

CAR T-Cell Therapy Targeting B-Cell Maturation Antigen Shows “Impressive” Results in Multiple Myeloma

Although chimeric antigen receptor (CAR) T-cell therapies directed against the CD19 protein garnered much attention at ASH 2017, CAR T cells targeting B-cell maturation antigen (BCMA), a protein expressed nearly universally on multiple myeloma cells, were found to be remarkably effective in patients with heavily pretreated multiple myeloma.

In the phase 1, dose-escalation clinical trial CRB-401 of 21 patients with multiple myeloma that relapsed after a median of 7 lines of therapy, the response to a single infusion of the CAR T-cell therapy called bb2121, which was engineered to target BCMA, was 86%. The response rate increased to 94% in 18 patients who had received higher active doses of the infused CAR T cells, reported James N. Kochenderfer, MD, Center for Cancer Research, National Cancer Institute, Bethesda, MD.

The dose-escalation clinical trial of bb2121 was conducted in patients with relapsed or refractory multiple myeloma who had received at least 3 previous lines of therapy, including a proteasome inhibitor and an immunomodulatory drug, or who were double-refractory, and who had at least 50% BCMA expression on plasma cells.

Study Details

The study enrolled 24 patients, 21 of whom had received bb2121. The study’s objective was to identify the maximum tolerated dose. Overall, 29% of patients had disease refractory to 5 common multiple myeloma therapies, including bortezomib (Velcade), lenalidomide (Revlimid), carfilzomib (Kyprolis), pomalidomide (Pomalyst), and daratumumab (Darzalex).

After lymphodepletion with fludarabine and cyclophosphamide, patients received from 50 × 106 to 800 × 106 CAR T cells. The median follow-up was 35 weeks, with the first response assessment at week 4.

Overall, 43% of the study cohort had high-risk cyto­genetics. All patients had received previous autologous stem cell transplantation.

“Generally, this was a very well-tolerated CAR T-cell product,” said Dr Kochenderfer. A total of 71% of patients had cytokine release syndrome (CRS), with 10% being grade ≥3. The 2 reported grade 3 CRS events resolved within 24 hours. Overall, 24% of patients had neurologic toxicity, but no grade ≥3 neurotoxicity or dose-limiting toxicities were observed. Five deaths occurred during the study, 3 because of disease progression at the 50 × 106 dose, which was deemed not to have clinical activity. Overall, 14 patients had ≥1 serious adverse events.

Prolonged Duration of Response

Among the 18 patients who received active doses of bb2121 (150 × 106 to 800 × 106 CAR T cells), 17 (94%) had an objective response, with a complete response rate that improved from 27% in May 2017 to 56% at data lock in October 2017. After 40 weeks of follow-up, 9 of 10 evaluable patients had no minimal residual disease. Some responses have been ongoing for more than 1 year.

“Our longest response has been going on 68 weeks at this point. In general, very impressive responses when compared to my previous experience treating multiple myeloma,” said Dr Kochenderfer. Responses continued to improve as late as month 15, and the duration of response has not yet been reached. Overall, 2 patients who received active doses of bb2121 were in complete remission at the time of their deaths.

The median time to first response was 1.02 months, the median time to best response was 3.74 months, and the median time to complete response was 3.84 months. The median progression-free survival has not been reached in the active-dose cohorts. At 9 months, progression-free survival was 71%.

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