bb21217, enriched T-cell therapy on KAR, improved responses, and prolonged response time (DOR) compared with unenricated CAR cells in patients with recurrent / refractory multiple myeloma, according to the results of the Phase I escalation and dilation study ( NCT03274219) which were presented during the ACA Annual Meeting in 2020.
Additionally, the percentage of aging CAR T cells decreased in the presence of an enriched CAR molecule (CAR +) called bb21217, according to the researchers.
The study included 74 highly treated patients with relapsed / refractory multiple myeloma who underwent ≥ 3 previous lines of treatment. The escalation dose of the study used a standard 3 + 3 regimen, with CAR + T-cell doses of 150 × 106 (n = 12), 300 × 106 (n = 6), and 450 × 106 (n = 6). In the study expansion phase, patients received doses of CAR + T cells of 300 × 106 (n = 8) and 450 × 106 (n = 37).
The primary endpoint was safety and the secondary endpoints were response, progression-free survival (PFS), minimal residual disease (MRD), and CAR + TA cell proliferation and persistence. In the presentation, lead researcher Melissa Alsina, PhD, presented data on 69 patients who had an average follow-up of 5.8 months.
The mean age was 62 years (range, 33-76), the majority were men (61%), and the majority had ECOG 1 performance statuses (59%). Prior to enrollment, 26% were Phase I of the International Stage System, 25% were Phase 2, and 19% were Phase III. Thirty-three per cent of patients were found to have risk cytogenetics, including fraction (17p), t (4; 14) or t (14; 16).
The mean number of previous regimens was 6, including 97% receiving lenalidomide (Revlimid), 94% receiving CD38 antibodies, 93% receiving less malidomide (Lesser), and 91% receiving bortezomib (Velcad). Eighty percent of the patients were doubly refractory and 64% were triple refractory.
“In terms of safety and tolerance, the most common side effect [AE] “It was 3/4 degree cytopenia,” said Alsina, an associate professor of medicine in the Blood and Marrow Transplant Program and head of the Multiple Myeloma Transplant Program, both at the Moffit Cancer Center in Tampa, Florida. “These were not dose-related,” she added.
The median recovery time for grade 3/4 neutropenia and grade 3/4 thrombocytopenia was 2.0 months and 2.2 months, respectively. Grade 3/4 infection has been reported in 26% of patients, with 1 death from infection reported within 6 months but in the absence of disease progression.
Two deaths have been reported within 8 weeks of bb21217 infusion, both attributed to cytokine release syndrome (CRS).
Regarding CRS, the mean time to onset was 2 days (range, 1-20) with 70% of patients reporting CRS of any grade. The majority of patients reported 65% of the 1/2 CRS grade, 1% reported grade 3, and 3% reported grade 5. To alleviate CRS symptoms, 31 patients received tocilizumab (Aktemra) and 10 patients received a combination of tocilizumab and corticosteroid.
The onset time of neurotoxicity was 7 days (range, 1-24) and the mean duration was 2 days (range, 1-188). “Cases of neurotoxicity were rare and were seen in 16% of patients with neurotoxicity in any ward,” Alsina said. Two grade 3 events have been reported: 1 case of grade 5 encephalopathy and 1 case of vertigo / vertigo resolving within 48 hours. A grade 4 encephalopathy has been reported. The patient was treated with tocilizumab, corticosteroid and cyclophosphamide.
The Objective Response Rate (ORR) is reported as 68% with a Strict Complete Response (sCR) / CR of 29% and a Very Good Partial Response (VGPR) of 25%. The median time of the first response was 1 month.
“We tested for MRD by next-generation sequencing, and the majority of patients who had PR were also MRD negative,” Alsina said. “Furthermore, all the patients in the CR were MRD negative,” she said.
Alsina noted that in the middle of enrolling patients for the 450 × 106 dose level, there was an update in the T cell production process. The update required an additional 29 patients to be enrolled in the expansion phase of the trial. “When these patients were evaluated, we observed an ORR of 84% and an sCR / CR rate of 32%. “Before this change, ENT was 68%,” she said. The incidence of AE, including all grades and CR grade 3 CRS and neurotoxicity, were similar between the two production processes.
When looking at DOR, even after only an average follow-up of 7 months, the average DOR was 17 months for the whole group. When stratified by dose, the 150 × 106 dose had an 11.5-month DOR, while the mean DOR for 300 × 106 and 450 × 106 doses was not estimated.
The researchers noted that memory-like T cell enrichment was associated with peak expansion and TAP T response. In particular, patients exhibited significantly better peak expansion because a higher percentage of memory-like T cells was observed. It is believed that this large part was related to the use of the product bb21217. This is useful because most memory-like T cells are associated with a smaller number of disease progression.
The phase I studied ended with enrollment and follow-up is ongoing.
“The negative rates of ORR, CR and MRD promise throughout the study and in the recommended phase 2 dose,” Alsina said. “Long-term persistence of T cells in KAR has been observed in 6 out of 11 patients who can be assessed at 12 months and 3 out of 6 patients who can be assessed at 18 months,” she concluded.
Alsina M, Shah N, Raje NS and others. Updated results from the Phase I CRB-402 study of anti-BCMA car-T-cell therapy bb21217 in patients with relapsed and refractory multiple myeloma: correlation of dilation and duration of response with T-cell phenotypes. Presented at: Annual Meeting of ASH 2020; December 5-8, 2020; Virtually. Abstract 130.