Efficacy and Safety Study of bb2121 in Subjects With Relapsed and Refractory Multiple Myeloma

Rationale

Idecabtagene vicleucel (ide-cel, bb2121) is made from the patient's own T cells, transduced with a lentiviral vector that encodes a chimeric antigen receptor (CAR) against B-cell maturation antigen (BCMA, TNFRSF17), and given as one intravenous infusion of up to 450 × 10^6 CAR+ T cells after fludarabine and cyclophosphamide lymphodepletion. BCMA is expressed mainly on plasma cells and late B cells, including myeloma cells. The CAR lets T cells recognize BCMA without HLA restriction, expand and kill myeloma cells that no longer respond to proteasome inhibitors, immunomodulatory drugs and anti-CD38 antibodies.

Results

In the 137 treated patients (ClinicalTrials.gov posted results, follow-up up to about 5 years), the overall response rate (partial response or better, independent committee) was 74.5% (95% CI 67.1-81.8) and the complete or stringent complete response rate was 34.3% (26.4-42.3). In 102 responders, median time to response was 1.0 month and median duration of response was 11.04 months (9.92-12.52). Median progression-free survival was 8.90 months (6.01-11.86) and median overall survival was 28.25 months (20.21-38.08). MRD negativity at 10^-5 with at least very good partial response was 40.9% (32.6-49.6). Grade 3 or 4 adverse events occurred in 136 of 137 patients; cytokine release syndrome in 116 (serious in 22 of 137; non-serious in 110 of 137), neurotoxicity in 53 and infections in 95. Serious adverse events occurred in 108 of 137 (adverse-event table); 82 of 137 died.

• In 137 treated patients with triple-class exposed relapsed and refractory multiple myeloma, a single infusion of the anti-BCMA CAR T-cell therapy idecabtagene vicleucel (bb2121; 150 to 450 × 10^6 CAR+ T cells after fludarabine and cyclophosphamide) produced an overall response rate (partial response or better, independent response committee) of 74.5% (95% CI 67.1-81.8) and a complete or stringent complete response rate of 34.3% (95% CI 26.4-42.3) in the phase 2 KarMMa trial (ClinicalTrials.gov posted results, follow-up up to 24 months for response). (Registry results)
• In 102 responders among 137 patients with relapsed and refractory multiple myeloma treated with idecabtagene vicleucel in the phase 2 KarMMa trial, median time to first response was 1.0 month (range 0.5-8.8) and median duration of response was 11.04 months (95% CI 9.92-12.52); in all 137 treated patients, median progression-free survival was 8.90 months (95% CI 6.01-11.86) and median overall survival was 28.25 months (95% CI 20.21-38.08), with follow-up of about 5 years (ClinicalTrials.gov posted results). (Registry results)
• In 137 patients with relapsed and refractory multiple myeloma treated with idecabtagene vicleucel in the phase 2 KarMMa trial, 41.6% (95% CI 33.3-50.3) reached very good partial response or better with minimal residual disease negativity at a sensitivity of 10^-4, 40.9% (95% CI 32.6-49.6) at 10^-5 and 24.8% (95% CI 17.8-32.9) at 10^-6 (ClinicalTrials.gov posted results). (Registry results)
• In 137 patients with relapsed and refractory multiple myeloma treated with idecabtagene vicleucel in the phase 2 KarMMa trial, any-grade adverse events occurred in 137, grade 3 or 4 adverse events in 136, cytokine release syndrome in 116, neurotoxicity in 53 and infections in 95 (safety outcome measure, follow-up about 5 years); cytokine release syndrome was a serious adverse event in 22 of 137 and haemophagocytic lymphohistiocytosis in 2 of 137 (ClinicalTrials.gov posted results). (Registry results)
• In 137 patients with relapsed and refractory multiple myeloma treated with idecabtagene vicleucel in the phase 2 KarMMa trial, serious adverse events were reported in 108 of 137 and death from any cause in 82 of 137 over follow-up of about 5 years (adverse-event table; the safety outcome measure lists 98 patients with serious adverse events), and neutropenia of any grade occurred in 130 of 137 and thrombocytopenia in 95 of 137 among non-serious events (ClinicalTrials.gov posted results). (Registry results)
• In 136 pharmacokinetic-evaluable patients with relapsed and refractory multiple myeloma treated with idecabtagene vicleucel in the phase 2 KarMMa trial, mean peak (Cmax) transgene level was 388,151 copies/µg genomic DNA (SD 372,281) at a mean Tmax of 12.1 days, with similar means across dose levels (449,827 at 450 × 10^6, 335,916 at 300 × 10^6 and 317,794 at 150 × 10^6 CAR+ T cells) and large variability within each level (ClinicalTrials.gov posted results). (Registry results)
• In 127 patients with relapsed and refractory multiple myeloma treated with idecabtagene vicleucel at 150, 300 or 450 × 10^6 CAR+ T cells in the phase 2 KarMMa trial, higher CAR T-cell exposure (transgene AUC 0-28 days and Cmax) was associated with higher overall and complete response rates and with cytokine release syndrome requiring tocilizumab or corticosteroids, while exposures overlapped widely across the three dose levels. (Connarn 2023)
• In 126 of 128 patients with relapsed and refractory multiple myeloma treated with idecabtagene vicleucel in the phase 2 KarMMa trial (EORTC QLQ-C30, QLQ-MY20 and EQ-5D-5L analysis), statistically significant and clinically meaningful improvements from baseline were seen by month 1 for pain (-8.9) and disease symptoms (-10.2) and by month 2 for fatigue (-7.2), physical functioning (6.1), cognitive functioning (6.7) and global health status (8.0), and were sustained through 15 to 18 months. (Delforge 2021)
• In the phase 2 KarMMa trial of idecabtagene vicleucel, a patient with relapsed and refractory multiple myeloma who progressed after anti-BCMA CAR T-cell therapy had selection of a tumor clone with a homozygous deletion of the BCMA gene (TNFRSF17), identified as the mechanism of immune escape. (Da 2021)
• In 137 patients with relapsed and refractory multiple myeloma treated with idecabtagene vicleucel in the phase 2 KarMMa trial, 69 patients who were negative for anti-CAR antibodies before infusion became positive afterwards, 60 stayed negative, and 6 were positive both before and after infusion (ClinicalTrials.gov posted results). (Registry results)

Design implications

A single infusion of autologous anti-BCMA CAR T cells after lymphodepletion produces responses in most heavily pretreated myeloma patients, but few are durable: median duration of response was about 11 months and median progression-free survival 8.9 months, so BCMA targeting alone needs a way to extend CAR T-cell persistence or prevent relapse. Antigen loss is one escape route: a KarMMa participant relapsed with a clone carrying a homozygous deletion of the BCMA gene (TNFRSF17), which argues for a second target or screening for BCMA loss. Higher CAR T-cell exposure was associated with higher response rates, but exposure overlapped widely across the 150, 300 and 450 × 10^6 dose levels, so dose is a weak control of expansion. Cytokine release syndrome (116 of 137), neurotoxicity (53), prolonged cytopenias and infections are the main liabilities to design against.

Limitations

Single-arm, open-label phase 2 with no control arm; 137 of 149 enrolled patients were treated and response rates use the treated patients as denominator. No success criterion for the overall response rate appears in the sources used (posted results and abstracts of secondary analyses; no results paper is linked in the registry), so the primary endpoint is not judged. Counts differ between registry tables (serious adverse events 98 in the safety outcome, 108 in the adverse-event table).