Locally Produced CAR T-Cell Therapy Elicits 92% ORR in Relapsed/Refractory Myeloma

Treatment with the academically sourced and produced, second-generation, BCMA-directed CAR T-cell therapy HBI0101 led to an objective response rate (ORR) of 92% in patients with relapsed/refractory multiple myeloma, according to updated data from a phase 1 trial (NCT04720313) that were presented at the 21st International Myeloma Society Annual Meeting.¹

Results indicated that the stringent complete response (CR)/CR rate was 55%, the very good partial response (VGPR) rate was 21%, the partial response (PR) rate was 16%, and the rate of progressive disease (PD) was 8%. The rate of minimal residual disease (MRD) negativity at a sensitivity of 10–5 via flow cytometry was 74%.

“HBI0101, an anti-BCMA CAR T-cell therapy demonstrates high efficacy and manageable safety in a frailer and higher-risk population as compared with the registrational studies with commercial products,” lead study author Eyal Lebel, MD, of the Department of Bone Marrow Transplantation and Cancer Immunotherapy at Hadassah Medical Center in Jerusalem, Israel, said in a presentation of the data.

There are presently two FDA-approved BCMA-directed CAR T-cell therapies indicated for the treatment of patients with multiple myeloma: ciltacabtagene autoleucel (Carvykti) and idecabtagene vicleucel (Abecma). Despite showing unprecedented activity in the relapsed/refractory setting, there is limited applicability because of limited availability, long vein-to-vein waiting periods, and financial toxicity, Lebel explained.

Therefore, this study sought to evaluable the efficacy of a CAR T-cell therapy developed in-house that had been designed to offset some of these challenges. Within the phase 1a portion, patients received the product at 1 of 3 doses: 150 x 106 CAR T cells (n = 6); 450 x 106 CAR T cells; or 800 x 106 CAR T cells (n = 7). In phase 1b, 77 patients received the higher dose of HBI0101 CAR T cells. The present analysis pooled data from the third cohort of patients in phase 1a with those from phase 1b.¹

Prior findings from the phase 1 trial demonstrated manageable safety and high efficacy, Lebel reported. At the time of the first analysis, results of which were published in Haematologica, the ORR was 75% among 20 evaluable patients. Subsequent data published in Blood Advances in 2024 indicated that the ORR among the 50 patients who received the agent at the higher dose was 90%. ^2,3

To be eligible for inclusion patients had to have relapsed/refractory multiple myeloma following 3 prior lines of therapy, including a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody. Additional enrollment criteria included a platelet count of at least 30 x 109/L, creatinine clearance of at least 20 mL/min, ECOG performance status of 2 or less, and an ejection fraction of at least 40%.¹ Those with non-secretory disease were also permitted. “The inclusion criteria were relatively permissive relative to pharmaceutical trials,” Lebel said.

Patients received fludarabine and cyclophosphamide for lymphodepletion and bendamustine if creatinine clearance was below 30 mL/min.

Regarding baseline characteristics the median age was 64.5 years (range, 35-84) and most patients were female (n = 43). The breakdown for Revised International Staging System was 1 (n = 23), 2 (n = 38), 3 (n = 20), and was missing for 3 patients. Most patients (71%) had high-risk disease per fluorescence immunohistochemistry including 1q gain, and 41% had high-risk disease with translocations in 4:14 or 14:16 or 17p deletion. Additionally, 26% of patients had extramedullary disease, 87% were triple-refractory, and 38% were penta-refractory. The median number of prior lines of therapy was 4 (range, 3-13) and 17% and 14% of patients were BCMA-exposed and -refractory, respectively. Notably, 48% of patients were not eligible for the phase 2 KarMMa (NCT03361748) and CARTITUDE-1 (NCT03548207) trials.

Manufacturing and bridging occurred from September 12, 2021, to the data cutoff of April 11, 2024, during which time 95 patients were enrolled, 89 patients’ cells were collected, and 84 patients underwent infusion. Manufacturing was successful for all patients and 80 of the 84 received the optimal planned dose. The first 57 patients received fresh product and the remaining 27 received it cryopreserved. Of the 24% of patients who received bridging therapy (n = 20), 60% (n = 12) experienced SD/PD and 40% (n = 8) achieved PR or better.

Efficacy was also analyzed among the patients who received the fresh (n = 57) vs frozen (n = 27) product. Within the former population the ORR was 91% and the MRD-negativity rate was 72%. The sCR/CR, VGPR, PR, and PD rates were 58%, 21%, 12%, and 9%, respectively. For the latter population the ORR was 48% and the rates of sCR/CR, VGPR, PR, and PD were 48%, 22%, 22%, and 8%, respectively. “When we compare the cryopreserved product with the fresh product, there seem to be no differences,” Lebel said.

In the overall population the median progression-free survival (PFS) was 11.6 months (95% CI, 8.6-14.6) and the median overall survival (OS) was not reached ([NR] 95% CI, 19.6-NR). “There seems to be a trend in favor of the cryopreserved product [in terms of PFS], perhaps because these patients also got more bridging [therapy],” Lebel stated.

Lebel also presented data showcasing the difference in survival outcomes among patients within the trial who would and would not have been eligible for the KarMMa and CARTITUDE-1 trials. For PFS, the median value was 354 days (range, 193-not reached) in the eligible population vs 200 days (116-377) in the ineligible population. For OS the median length was NR (382-NR) and 565 days (223-NR) in the eligible and ineligible populations, respectively.

“We also found that responses were better in those patients who did not have high-risk cytogenetics, and patients with extramedullary disease did worse, as did the patients who had a larger proportion of effector memory T cells,” Lebel said.

Regarding safety, hematological adverse effects (AEs) included anemia (grade 3/4, 62%) thrombocytopenia (grade 3/4, 42%), and neutropenia (grade 3/4, 99%). Grade 3 or greater thrombocytopenia and neutropenia persisted after day 28 in 6% and 1% of cases, respectively. Immunoglobulin levels fell below 400 mg/dL in 74% of patients, and intravenous immunoglobulin replacement was needed in 38% of patients. Infections were also common (all grade, 43%; grade ≥3, 8%). Other grade 3 or greater AEs occurred in 11% of patients and 6% of patients developed secondary cancers of the lung, thyroid, bladder, bile duct, and skin.

Cytokine release syndrome occurred in 95% patients and although most events were grade 1/2 (76%), 19% were grade 3. Tocilizumab (Actemra) was used in 90% of cases and steroids were administered in 20% of cases. Only 4% of patients experienced immune effector cell–associated neurotoxicity syndrome, all of which were grade 1/2, and there were no treatment-related deaths.

“This data not only supports further utilization of HBI0101 CAR T-cell therapy, but also of CAR T production at an academic setting in general, ensuring a sufficient CAR T supply in light of the increasing demand” Lebel concluded.

Updated results with the agent in 16 patients with amyloid light chain amyloidosis are expected to be presented at the 2024 ASH Annual Meeting and Exposition.

References

1. Lebel E, Asherie N, Erenfeld SK, et al. HBI0101, an anti-BCMA chimeric antigen receptor T-cell (CART) for relapsed/refractory multiple myeloma. Presented at: 21st International Myeloma Society Annual Meeting; September 25-28, 2024; Rio de Janeiro, Brazil. Abstract OA-34.
2. Asherie N, Kfir-Erenfeld S, Avni B, et al. Development and manufacture of novel locally produced anti-BCMA CAR T cells for the treatment of relapsed/refractory multiple myeloma: results from a phase I clinical trial. Haematologica. 2023;108(7):1827-1839. doi:10.3324/haematol.2022.281628
3. Kfir-Erenfeld S, Asherie N, Lebel Eyal, et al. Clinical evaluation and determinants of response to HBI0101 (BCMA CART) therapy in relapsed/refractory multiple myeloma. Blood Adv. 2024;13(8):4077-4088. doi:10.1182/bloodadvances.2024012967