Cilta-Cel Demonstrates Strong, Lasting Responses In Relapsed / Refractory Myeloma

Ciltacabtagene autoleucel (cilta-cel) demonstrated robust and durable early responses after a single dose in a population of heavily pretreated multiple myeloma patients, according to updated results from the Phase 1b / 2 CARTITUDE-1 trial (NCT03548207) presented during the SOHO 2021 Annual Meeting.1

At a median follow-up of 18 months, CAR T cell therapy elicited an overall response rate (ORR) of 97.9%, with a strict complete response rate (CRs) of 80.4%, a very good response partial or better of 94.8%, and a partial response of 3.1%. Notably, response rates with cilta-cel were found to be comparable across different subgroups examined, including previous lines of treatment, resistance, extramedullary plasmacytomas, and cytogenetic risk.

In addition, the safety profile of the agent has remained consistent with its mechanism of action. No new safety signals were reported with longer follow-up, underscoring the success of the new patient management approaches that were implemented in the study to mitigate the incidence of neurotoxicity.

“Cilta-cel is [currently] under investigation in the CARTITUDE-2 phase 2 trial in progress [NCT04133636] and phase 3 CARTITUDE-4 [NCT04181827] trial in first-line settings, ”said lead author of the study, Saad Z. Usmani, MD, division chief of plasma cell disorders at Levine Cancer Institute, Atrium Health, in a data presentation.

Cilta-cel is a CAR T cell therapy with 2 single domain antibodies targeting BCMA. Previous data from CARTITUDE-1 have shown that at a median follow-up of 12.4 months, the agent induces an ORR of 97%, with a CRs of 67%. The 12-month progression-free survival (PFS) rate was 77% and the 12-month overall survival (OS) rate was 89%. At the meeting, investigators presented updated results with a median follow-up of 18 months.

To be eligible for recruitment, patients had to have a confirmed diagnosis of progressive multiple myeloma, according to the criteria of the International Myeloma Working Group; they must also have received at least 3 previous treatments or be doubly refractory. In addition, patients had to have measurable disease, an ECOG performance index of 0 or 1, and have received prior treatment with proteasome inhibitors, immunomodulatory drugs, or anti-CD38 therapy.

Participants enrolled in the study underwent 28 days of screening prior to apheresis; this was followed by bridging therapy as needed. Subsequently, patients underwent lymphodepletion with cyclophosphamide at a dose of 300 mg / m2 and fludarabine at a dose of 30 mg / m2 on days -5 to -3 before the infusion. On day 1, patients were infused with cilta-cel at a target dose of 0.75 x 106 (range, 0.5-1.0 x 106) viable CAR-positive T cells / kg. The median dose administered was 0.71 x 106 viable CAR-positive T cells / kg.

Post-infusion evaluations focused on examining the safety, efficacy, pharmacokinetics and pharmacodynamics of the agent, as well as biomarker testing.

The primary endpoint of the phase 1b part of the study was to characterize the safety of cilta-cel and to determine the recommended phase 2 dose. The primary endpoint of the phase 2 part of the trial was efficacy, in particular ORR.2

A total of 113 patients were included and underwent apheresis, 101 underwent lymphodepletion and 97 were treated with cilta-cel. Among those who received CAR T-cell therapy, 29 patients were included in the phase 1b part of the study (n = 23 in progress) and 68 were included in the phase 2 part (n = 53 in Classes).

Overall, 73 patients received transition therapy, and the median turnaround time for CAR T cell therapy was 29 days (range, 23-64). Notably, no patient discontinued due to manufacturing failure, and only one patient received retreatment with cilta-cel.

The median age of the patients included in the study was 61.0 years (range, 43-78), 58.8% were male, and 17.5% were Black / African American. Additionally, 13.4% had extramedullary plasmacytomas and 6.2% had bone plasmacytomas. Just over 20% (21.9%) had 60% or greater bone marrow plasma cells.

The median number of years since diagnosis was 5.9 (range, 1.6-18.2), and 23.7% of patients had a high-risk cytogenetic profile. In addition, most patients had tumor BCMA expression of 50% or greater (91.9%) and had received at least 5 prior lines of treatment (66.0%). The median number of previous treatments received was 6 (range, 3-18). In particular, 87.6% of patients were refractory to the triple class, 42.3% were refractory to penta-drugs and 99.0% were refractory to their last line of treatment received.

Additional data showed that the median duration of response (DOR) with cilta-cel was 21.8 months (95% CI, 21.8 – not evaluable [NE]). It is estimated that 73% of patients did not experience disease progression or death at 12 months, and the median DOR was not reached in those who achieved CRs. The median time to first response with CAR T-cell therapy was 1 month (range: 0.9-10.7), and the median time to best response and CR or greater was 2.6 months (range, 0.9-15.2).

Among 61 patients evaluable for minimal residual disease (MRD), 91.8% had negative MRD status at 10-5, compared to 57.5% of all patients (n = 97). In patients with CR or better, these rates were 89.4% and 43.3%, respectively. The median time to MRD 10-5 negativity was 1 month (range 0.8-7.7).

The median PFS with cilta-cel was 22.8 months (95% CI: 22.8 – NE). In addition, the rate of PFS at 18 months in all patients was 66.0% (95% CI, 54.9% to 75.0%) versus 75.9% (95% CI, 63.9%). at 84.5%) among those who obtained CRs. The OS rate at 18 months in all patients was 80.9% (95% CI: 71.4% -87.6%).

In terms of safety, 94.8% of patients experienced a cytokine release syndrome (CR) event; the median time to onset was 7 days (range, 1-12) and the median time was 4 days (range, 1-97). Most of these cases were grade 1 or 2 (94.6%) severity and most resolved within 14 days of onset (98.9%). In addition, 2.1% of patients developed immune effector cell-associated neurotoxicity syndrome (ICANS) grade 3 or higher, and 9.3% developed other neurotoxicity grade 3 or higher.

The most common grade 3/4 hematologic adverse reactions (AEs) with CAR T cell therapy included neutropenia (94.8%), anemia (68.0%) and leukopenia (60.8%) . The most common grade 3 or higher non-haematologic AEs were hypophosphatemia (7.2%), fatigue (5.2%), and increased aspartate transaminase (5.2%).

Mitigation strategies employed in this study to reduce the incidence of neurotoxicity included: improved transition therapy to reduce tumor burden; early and aggressive treatment of CRS and ICANS; and an extended monitor, including handwriting assessments.

The references

  1. Usmani S, Berdeja JG, Madduri D, et al. Updated results of ciltacabtagene autoleucel (cilta-cel), a b-cell maturing antigen (BCMA) directed by chimeric antigen T receptor (CAR-T) cell therapy in relapsed / refractory multiple myeloma ( RRMM). Presented at: SOHO 2021 Annual Meeting; from September 8 to 11, 2021; Virtual. Abstract MM-119.
  2. A study of JNJ-68284528, a chimeric antigen receptor (CAR-T) T cell therapy directed against B cell maturation antigen (BCMA) in participants with relapsed or refractory multiple myeloma (CARTITUDE- 1). ClinicalTrials.gov. Updated December 31, 2020. Accessed September 10, 2021. https://clinicaltrials.gov/ct2/show/NCT03548207


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