Cilta-Cel Demonstrates Continued Robust and Long-Lasting Responses in Relapsed/Refractory Myeloma

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

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

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

“Cilta-cel is [currently] being investigated in the ongoing phase 2 CARTITUDE-2 trial [NCT04133636] and the phase 3 CARTITUDE-4 [NCT04181827] trial in earlier-line settings,” lead study author Saad Z. Usmani, MD, the Division Chief of Plasma Cell Disorders at Levine Cancer Institute, Atrium Health, said in a presentation of the data.

Cilta-cel is a CAR T-cell therapy with 2 BCMA-targeting single-domain antibodies. Earlier data from CARTITUDE-1 showed that at a median follow-up of 12.4 months, the agent induced an ORR of 97%, with a sCR 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 at a median follow-up of 18 months.

To be eligible for enrollment, patients had to have a confirmed diagnosis of progressive multiple myeloma, according to International Myeloma Working Group criteria; they also had to have received at least 3 prior therapies or be double refractory. Additionally, patients had to have measurable disease, an ECOG performance status of 0 or 1, and have received prior treatment with proteasome inhibitors, immunomodulatory drugs, or an anti-CD38 therapy.

Participants enrolled to the study underwent 28 days of screening prior to apheresis; this was followed by bridging therapy, as needed. Thereafter, 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 prior to infusion. On day 1, patients received infusion with cilta-cel at a target dose of 0.75 x 106 (range, 0.5-1.0 x 106) CAR-positive viable T cells/kg. The median administered dose was 0.71 x 106 CAR-positive viable T cells/kg.

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

The primary end point of the phase 1b portion of the study was to characterize the safety of cilta-cel and determine the recommended phase 2 dose. The primary end point of the phase 2 portion of the trial was efficacy, specifically ORR.²

In total, 113 patients were enrolled and underwent apheresis, 101 went on to receive lymphodepletion, and 97 were treated with cilta-cel. Among those who received the CAR T-cell therapy, 29 patients were enrolled to the phase 1b portion of the study (n = 23 ongoing), and 68 were enrolled to the phase 2 portion (n = 53 ongoing).

Overall, 73 patients received bridging therapy, and the median turnaround time for the CAR T-cell therapy was 29 days (range, 23-64). Notably, no patients discontinued due to a manufacturing failure, and just 1 patient received retreatment with cilta-cel.

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

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. Additionally, most patients had tumor BCMA expression of 50% or more (91.9%) and had received 5 or more prior lines of therapy (66.0%). The median number of prior therapies received was 6 (range, 3-18). Notably, 87.6% of patients were triple-class refractory, 42.3% were penta-drug refractory, and 99.0% were refractory to their last line of therapy 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]). An estimated 73% of patients did not experience disease progression or death at 12 months, and the median DOR was not reached in those who achieved a sCR. The median time to first response with the CAR T-cell therapy was 1 month (range, 0.9-10.7), and the median time to best response and to a CR or greater was 2.6 months (range, 0.9-15.2).

Among 61 patients evaluable for minimal residual disease (MRD), 91.8% had MRD-negative status at 10-5, compared with 57.5% of all patients (n = 97). In patients with a 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). Moreover, 18-month PFS rate in all patients was 66.0% (95% CI, 54.9%-75.0%) vs 75.9% (95% CI, 63.9-84.5%) in those who achieved a sCR. The 18-month OS rate 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 duration was 4 days (range, 1-97). Most of these cases were grades 1 or 2 in severity (94.6%), and most were resolved within 14 days of onset (98.9%). Additionally, 2.1% of patients experienced immune effector cell–associated neurotoxicity syndrome (ICANS) of grade 3 or higher, and 9.3% experienced other grade 3 or higher neurotoxicities.

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

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

References

1. Usmani S, Berdeja JG, Madduri D, et al. Updated results of ciltacabtagene autoleucel (cilta-cel), a b-cell maturation antigen (BCMA)-directed chimeric antigen receptor T (CAR-T) cell therapy in relapsed/refractory multiple myeloma (RRMM). Presented at: 2021 SOHO Annual Meeting; September 8-11, 2021; Virtual. Abstract MM-119.
2. A study of JNJ-68284528, a chimeric antigen receptor T cell (CAR-T) 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