Cilta-cel Produces Durable Responses in Relapsed/Refractory Multiple Myeloma

A single infusion of the CAR T-cell therapy ciltacabtagene autoleucel (cilta-cel; Carvykti) produced deep and durable responses in patients with relapsed/refractory multiple myeloma with a manageable toxicity profile, according to long-term follow-up data of the phase 1b/2 CARTITUDE-1 trial (NCT03548207) presented at the 2022 ASCO Annual Meeting.¹

At a median follow-up of 27.7 months, cilta-cel produced an overall response rate (ORR) of 97.9% (95% CI, 92.7%-99.7%) among 97 evaluable patients, which included a stringent complete response (sCR) rate of 82.5% (95% CI, 73.4%-89.4%). Moreover, 94.8% of patients experienced a very good partial response or better. Responses achieved with cilta-cel were noted to deepen over time.

“Most patients in the high-risk subgroups responded, including [those] with high-risk cytogenetics, high tumor burden, or baseline plasmacytomas,” Saad Z. Usmani, MD, MBA, FACP, lead study author and hematologic oncologist and chief of the Myeloma Service at Memorial Sloan Kettering Cancer Center, said in a presentation of the data. “However, duration of response [DOR], progression-free survival [PFS], and overall survival [OS] were shorter in those subgroups.”

The single-arm, open-label trial enrolled patients who had progressive multiple myeloma per International Myeloma Working Group criteria and measurable disease at screening. These patients were at least 18 years of age, had an ECOG performance status of 0 or 1, and received at least 3 prior lines of systemic therapy or were double refractory. To participate, they must have had prior exposure to a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 monoclonal antibody.

After the screening period, patients underwent apheresis, and then went on to receive bridging therapy, as needed. Prior to infusion, patients underwent lymphodepletion, where they received 300 mg/m² of cyclophosphamide and 30 mg/m² of fludarabine from day -5 to day -3. On day 1, patients received a single infusion of cilta-cel at a target dose of 0.75 x 10⁶ CAR+ viable T cells/kg. The median administered dose of the CAR T-cell product was 0.71 x 10⁶ (range, 0.51 x 10⁶ to 0.95 x 10⁶) CAR+ viable T cells/kg.

The primary end point of the phase 1b portion of the trial was to assess the safety of cilta-cel and to establish the recommended phase 2 dose. In the phase 2 portion of the research, the primary objective was to evaluate the efficacy of the CAR T-cell therapy.

Previous data from CARTITUDE-1 showed that at a median follow-up of 21.7 months, patients achieved an ORR of 98%, with a sCR rate of 82.5%.2 In February 2022, the FDA approved cilta-cel for the treatment of adult patients with relapsed/refractory multiple myeloma following 4 or more prior lines of therapy, including a PI, an IMiD, and an anti-CD38 monoclonal antibody, based on prior findings from the trial.³

At the 2022 ASCO Annual Meeting, investigators reported landmark 2 years post last-patient-in data from the trial. As of January 11, 2022, a total of 97 patients received treatment with cilta-cel. Notably, these patients had received a median of 6 prior lines of therapy (range, 3-18).

Additional data showed that the median DOR with the CAR T-cell therapy among all patients was not estimable (NE; 95% CI, 23.3-NE).

Among patients in high-risk subgroups, including those with high-risk cytogenetics, high tumor burden, or baseline plasmacytomas, ORRs ranged from 95.1% to 100%. Notably, DOR, PFS, and/or OS were all lower in the subgroups of patients with high-risk cytogenetics, ISS stage III disease, high tumor burden, and the presence of plasmacytomas. Despite the lack of detectable CAR T-cell persistence in peripheral blood in patients at 6 months of follow-up, high efficacy response rates were reported with the agent.

In 61 patients determined to be evaluable for minimal residual disease (MRD), 91.8% had negativity at 27.7 months of follow-up. Those with sustained MRD negativity of at least 6 and 12 months experienced improved PFS compared with the overall population.

Notably, the overall median PFS was still not reached (NR; 95% CI, 24.5-NE). The PFS rate at 27 months was 54.9% (95% CI, 44.0%-64.6%). In patients with MRD negativity of at least 12 months, the 27-month PFS rate was 78.8% (95% CI, 51.5%-91.8%); this rate was 73.0% (95% CI, 52.1%-85.9%) in those with MRD negativity of at least 6 months, and 64.2% (95% CI, 51.9%-74.1%) in those who achieved a sCR.

Overall, the median OS was NR (95% CI, NE-NE) with the CAR T-cell therapy. The 27-month OS rate for all patients was 70.4% (95% CI, 60.1%-78.6%). Patients who achieved MRD negativity for more than 12 months and more than 6 months had 27-month OS rates of 93.5% (95% CI, 76.1%-98.3%) and 90.8% (95% CI, 67.7%-97.6%), respectively.

No new treatment-related deaths were reported with extended follow-up. Overall, 30 patients died during the study following cilta-cel infusion, although no deaths occurred in the first 30 days of treatment. Two deaths occurred within 100 days of treatment, and the remaining 28 deaths happened more than 100 days after infusion. The most common causes of death (in more than 1 patient) were progressive disease (n = 14), acute myeloid leukemia (AML; n = 3), respiratory failure (n = 3), and sepsis and/or shock (n = 2).

Twenty secondary primary malignancies were reported in 16 patients. Nine patients had hematologic malignancies, including low-grade B-cell lymphoma (n = 1), myelodysplastic syndrome (MDS; n = 6), and fatal AML (n = 3). Notably, 1 patient had both MDS and fatal AML. Furthermore, 6 patients had non-melanoma skin cancers; 1 patient each experienced malignant melanoma, adenocarcinoma, myxofibrosarcoma, and prostate cancer.

Further safety data showed 1 new case of signs and symptoms of parkinsonism, which equates to 6 total cases reported to date. The implementation of patient management strategies has reduced the incidence of parkinsonism from 6% in CARTITUDE-1 to less than 0.5% across the CARTITUDE clinical trial program. In CARTITUDE-1, 3 of the 6 patients with parkinsonism have died, 2 of whom due to underlying causes and 1 related to parkinsonism. At the time of data cutoff, 1 other patient has recovered from parkinsonism, and 1 is recovering with ongoing grade 2 symptoms.

Cilta-cel is currently under additional investigation in earlier lines of treatment in patients with multiple myeloma in the phase 2 CARTITUDE-2 trial (NCT04133636), as well as the phase 3 CARTITUDE-4 (NCT04181827), CARTITUDE-5 (NCT04923893), and EMagine/CARTITUDE-6 (NCT05257083) trials.

References

1. Usmani SZ, Martin TG, Berdeja JG, et al. Phase 1b/2 study of ciltacabtagene autoleucel, a BCMA-directed CAR-T cell therapy, in patients with relapsed/refractory multiple myeloma (CARTITUDE-1): two years post LPI. J Clin Oncol. 2022;40(suppl 16):8028. doi:10.1200/JCO.2022.40.16_suppl.8028
2. Martin T, Usmani SZ, Berdeja JG, et al. Updated results from CARTITUDE-1: phase 1b/2 study of ciltacabtagene autoleucel, a B-cell Maturation Antigen-directed Chimeric Antigen Receptor T-cell therapy, in patients with relapsed/refractory multiple myeloma. Blood. 2021;138(suppl 1):549. doi:10.1182/blood-2021-146060
3. US FDA approves Carvykti (ciltacabtagene autoleucel), Janssen’s first cell therapy, a BCMA-directed CAR-T immunotherapy for the treatment of patients with relapsed or refractory multiple myeloma. News release. Janssen. February 28, 2022. Accessed June 16, 2022. https://bit.ly/35yWwjv