Response Rate Hits 100% for bb2121 in Multiple Myeloma

Yi Lin, MD, PhD

All patients with multiple myeloma showed a response following treatment with an active dose of bb2121, an investigational anti—B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell construct, according to findings from a small phase I study presented during the 22nd Annual European Hematology Association (EHA) Congress in Madrid, Spain.

The objective response rate (ORR) was 100% (95% CI, 78.2-100) in 9 evaluable patients that had been infused with bb2121 at a dose of 5.0 x 10⁷ CAR-positive T cells or higher; 27% of patients achieved complete response (CR) and 75% of patients demonstrated a very good partial response (VGPR) or better. The evaluable patients at this dose level were minimal residual disease (MRD)-negative.

“All patients in the active dose cohorts achieved an objective response that was durable up to 54 weeks,” commented Yi Lin, MD, PhD, assistant professor of medicine and oncology at the Mayo Clinic in Rochester, NY.

The bb2121 construct contains autologous T cells that are transduced with a lentiviral vector encoding a novel CAR with an anti-BCMA single-chain variable fragment, a 4-1BB costimulatory motif, and a CD3-zeta T-cell activation domain. It targets the TNF receptor superfamily member, BCMA, which is expressed nearly universally on multiple myeloma cells, and restricted to plasma cells and some mature B cells. A feature of the construct is that its potent activity is accompanied by low tonic signaling, thereby decreasing the risk of CRS seen with other therapies that target BCMA, according to Lin.

Lin presented findings from the CRB-401 phase I study, which is currently ongoing, in heavily pretreated patients with multiple myeloma. The CRB-401 is enrolling at 7 sites to an anticipated total enrollment of 50 patients. The primary endpoint of the trial is the incidence of adverse events (AEs) and abnormal laboratory test results, which include dose-limiting toxicities (DLTs).

To be included in the study, patients were required to have undergone at least 3 prior treatments, including a proteasome inhibitor and an immunomodulatory agent, or who were double-refractory with ≥50% BCMA expression. Of the 21 patients treated thus far, all had undergone autologous stem cell transplant, and had a median of 7 (range, 3-14) prior therapies; 71% of the patients had received daratumumab (Darzalex), 100% had lenalidomide (Revlimid), 91% pomalidomide (Pomalyst), 100% bortezomib (Velcade), and 91% of patients had received carfilzomib (Kyprolis). The median patient age was 58 years, and 62% were male. High-risk cytogenetic changes were reported at baseline in 67% of patients.

Patients underwent leukapheresis and a lymphodepletion conditioning chemotherapy regimen consisting of cyclophosphamide and fludarabine for 3 days followed by 2 days of rest before the CAR T-cell infusion. Their mononuclear cells were then shipped to a central facility for manufacturing. This was the first multicenter myeloma CAR T-cell study with central manufacturing. “In part we are also testing the feasibility of making CAR T cells available to more patients,” Lin pointed out.

A total of 21 patients in the study have been dosed in 5 dose cohorts: 5.0 x 10⁷ (cohort 1), 15.0 x 10⁷ (cohort 2), 45.0 x 10⁷ (cohort 3), 80 x 10⁷ (cohort 4), and at a dose of 120 x 10⁷ CAR-positive T cells (cohort 5), which has not been carried forward. The first response evaluation was done at 1 month post treatment.

“These are incredible data,” session chair Tobias Haas, MD, professor of medicine at Medizinische Klinik Klinikum, Technische Universität, Munich, Germany remarked.

The ORR across all dose levels was 89% (95% CI, 65-99). The median time to first response was 31 days, and the median time to best response was 50.5 days. The duration of response was 134 days and longer (95% CI, 7-361).

“We also have not seen any dose limiting toxicities to date, and the safety profile of bb2121 has been manageable through doses as high as 800 x 10⁶ cells, making this a very promising treatment regimen in myeloma,” Lin said.

Fifteen (71%) patients experienced cytokine release syndrome (CRS), 2 patients had grade 3 CRS that resolved within 24 hours, and 4 patients had grade 1/2 CRS; 4 patients received tocilizumab (Actemra) and one grade 1 CRS was treated with steroids. Two patients had pyrexia. Importantly, no cases of grade 3/4 neurotoxicity were reported.

In addition, M-protein was rapidly cleared from the serum in most patients as early as 4 weeks post infusion, as was free light chain, which was reduced from baseline by 100% by the time of the data cutoff in all but 2 patients. The change from baseline in serum BCMA by 4 weeks post infusion ranged from 80% to 100%.

“Bb2121 has induced durable and deepening responses in a heavily pretreated population of patients with relapsed or refractory multiple myeloma,” Lin said.

“No patients have relapsed to date; 1 patient has now survived for more than a year,” Lin commented. She also noted that responses in the bone marrow have been observed with resolution of extramedial bone marrow lesions observed in 2 patients.

Lin Y, Berdeja J, Raje N, et al. First-in-human multicenter study of bb2121 anti-BCMA CAR T cell therapy for relapsed/refractory multiple myeloma: updated results. Abstract presented at: 22nd Annual European Hematology Association Congress; June 22-25, 2017; Madrid, Spain. Abstract S142.

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Lin said, “bb2121 was successfully manufactured in all patients.” All patients consistently demonstrated CAR-positive T-cell expansion. CAR T cells persisted in the blood up to 24 weeks and 68% were also detected in the bone marrow by flow cytometry.