James N. Kochenderfer, MD
Treatment with the BCMA-directed CAR T-cell therapy bb2121 induced complete remissions (CRs) for 56% of patients with relapsed/refractory multiple myeloma, according to updated findings from a dose escalation trial presented at the 2017 ASH Annual Meeting.
The objective response rate (ORR) for bb2121 was 94%, which consisted of a very good partial response or better for 89% of patients. After 40 weeks of follow-up, the median progression-free survival (PFS) had not yet been reached. The 9-month PFS rate was 71%. The treatment was generally well-tolerated and the manufacturing success rate was 100%, according to the senior study author James N. Kochenderfer, MD.
“We are excited about the early results in a patient population with very advanced myeloma for whom previous therapies have failed,” Kochenderfer, of the Center for Cancer Research at the National Cancer Institute in Bethesda, said in a statement. “We have patients who have a sustained response and have been able to go for over a year with no additional myeloma therapy and tolerable adverse effects.”
The second-generation CAR T-cell therapy bb2121 consists of a 4-1BB costimulatory domain with an anti-BCMA scFv and CD3 zeta T cell activation domain. Based on an earlier assessment of the dose escalation trial, bb2121 was granted a breakthrough therapy designation in November 2017.
The study utilized a variety of doses, with a range of 150 to 300 × 106
CAR+ T cells identified for future study. The lowest dose (50 x 106
) was not shown to have clinical activity. Prior to infusion of the CAR T-cell therapy, patients received conditioning with fludarabine (30 mg/m2
) and cyclophosphamide (300 mg/m2
The trial enrolled 21 patients at a median age of 58 years (range, 37-74) following a median of 7 prior lines of therapy, with 29% of patients being refractory to bortezomib, lenalidomide, carfilzomib, pomalidomide, and daratumumab. The time since diagnosis was 4 years and patients had an ECOG performance status of 0 (48%) or 1 (52%). Forty-three percent of patients had high-risk cytogenetics. All patients had received prior autologous stem cell transplantation.
Activity was reported for those treated with an active dose of bb2121. At the median follow-up of 40 weeks, 9 of 10 evaluable patients tested negative for minimal residual disease. The duration of response was not yet reached but durable responses were seen, some of which lasted over 1 year. In general, the responses continued to improve as late as month 15, Kochenderfer said.
The median time to first response was 1.02 months and the median time to best response was 3.74 months. The median time to CR was 3.84 months.
"To see these types of responses after one treatment with bb2121 in a heavily pretreated patient population is very promising, and we are hopeful that CAR T therapy with bb2121 may become an important therapy in the fight against multiple myeloma, which remains an insidious and incurable disease," said Kochenderfer.
Fourteen of the 21 patients experienced at least 1 serious adverse event. Cytokine release syndrome (CRS) was experienced by 71% of patients, with 2 having a grade ≥3 event. Neurotoxicity was experienced by 21% of patients, with 1 having a grade 4 event associated with tumor lysis syndrome and CRS. Grade ≥3 neutropenia was experienced by 86% of patients, and grade ≥3 thrombocytopenia and anemia were experienced by 43% and 57% of patients, respectively.
Cytopenias seen in the trial were mostly associated with the conditioning chemotherapy, Kochenderfer said. Most grade 1 or 2 cytopenias resolved 2 months following infusion. There were 5 deaths in the trial, 3 due to disease progression, 1 from cardiac arrest, and 1 from myelodysplastic syndrome following treatment discontinuation.
"To date, the safety profile of bb2121 has been manageable," said Kochenderfer. "The 2 reported events of grade 3 CRS resolved within 24 hours."
A global phase II KarMMa trial is currently open for enrollment, and will serve as the basis for a regulatory submission for bb2121. The trial plans to enroll 94 patients with relapsed/refractory multiple myeloma. The primary endpoint of the study is response. The estimated primary completion date for the trial is November 2023.
Berdeja JG, Lin Y, Raje N, et al. Durable Clinical Responses in Heavily Pretreated Patients with Relapsed/Refractory Multiple Myeloma: Updated Results from a Multicenter Study of bb2121 Anti-Bcma CAR T Cell Therapy. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta. Abstract 740.