FDA Grants Priority Review to Cilta-Cel for Relapsed/Refractory Multiple Myeloma


The FDA has granted priority review to the biologics license application for ciltacabtagene autoleucel for the treatment of patients with relapsed/refractory multiple myeloma.



The FDA has granted priority review to the biologics license application (BLA) for ciltacabtagene autoleucel (cilta-cel) for the treatment of patients with relapsed/refractory multiple myeloma.1

The BLA is supported by data from the phase 1b/2 CARTITUDE-1 trial (NCT03548207), which demonstrated that the investigational BCMA-directed CAR T-cell therapy induced an objective response rate (ORR) of 96.9%, when administered at the recommended phase 2 dose in this patient population.2 Among those who responded to treatment with cilta-cel, the stringent complete response (sCR) rate was 67.0%, the very good partial response (VGPR) rate was 25.8%, and the partial response (PR) rate was 4.1%.

The regulatory agency is expected to make a decision on the application by November 29, 2021, under the Prescription Drug User Fee Act.

“Cilta-cel has shown great promise in the treatment of patients with heavily pretreated multiple myeloma according to study findings reported to date,” Ying Huang, PhD, chief executive officer and chief financial officer of Legend Biotech, stated in a press release. “Today’s priority review designation marks another significant milestone for this cell therapy. We look forward to our continued collaborative efforts with Janssen and in working with the FDA to bring this transformative therapy to patients who are in need of new treatment options.”

In the open-label, multicenter phase 1b/2 trial, investigators set out to examine the safety and efficacy of cilta-cel in adult patients with relapsed and/or refractory multiple myeloma. To be eligible for enrollment, patients needed to be at least 18 years of age, have measurable disease, and an ECOG performance status of 0 or 1. They also needed to have previously received at least 3 regimens or were double refractory to a proteasome inhibitor and an immunomodulatory drug and had received an anti-CD38 antibody.

Following apheresis, bridging therapy was allowed for study participants. Patients received cyclophosphamide at 300 mg/m2 and fludarabine at 30 mg/m2 daily for 3 days as lymphodepletion. Investigators administered a single infusion of the CAR T-cell product at the target dose of 0.75 x 106 (range, 0.5-1.0 x 106) CAR+ viable T cells/kg on days 5 to 7 following the initiation of lymphodepletion. The median dose given was 0.71 x 106.

The primary objective of the phase 1b portion of the research was to characterize the safety of cilta-cel and to identify the recommended phase 2 dose. In the phase 2 portion, the objective was to examine the efficacy of the CAR T-cell product. Investigators evaluated response per International Myeloma Working Group criteria and assessed minimal residual disease (MRD) through the use of next-generation sequencing.

Additional findings previously presented at the 2020 ASH Annual Meeting showed that 97 participants were given the CAR T-cell therapy across both phases of the trial. Eighty-six percent were still on the trial at the time of data presentation. Cilta-cel had a median manufacturing time of 29 days, and no patients withdrew from the trial due to manufacturing failure.

The median progression-free survival (PFS) experience with the product had not yet been reached and the estimated 1-year PFS rate was 76.6%. In those who achieved a sCR with cilta-cel, the estimated PFS rate at 1 year was 84.5%, while it was 68.0% in those who experienced a VGPR. The median overall survival (OS) had also not yet been reached; the estimated 1-year OS rate was 88.5%.

Additional data from the trial presented during the Virtual 47th Annual Meeting of the EBMT indicated that among 57 evaluable patients, 93.0% (n = 53) experienced MRD 10-5 negativity; 57.9% achieved MRD negativity and a sCR, while 86.0% achieved MRD negativity and a VGPR or better.3 Moreover, the time to MRD 10-5 negativity was 1 month (range, 0.8-7.7). Of the participants who had 6 months of individual follow-up, most were found to have cilta-cel CAR+ T cells below the level of quantification in their peripheral blood.

Regarding safety, the majority of toxicities were found to be hematological. Grade 3 or higher neutropenia was reported in 94.8% of patients (n = 92), while grade 3 or higher thrombocytopenia was experienced by 59.8% of patients (n = 58). The median time to recovery was 2 weeks for those with neutropenia and 4 weeks for those with thrombocytopenia. Late recovery, defined as longer than 1 month from first onset, occurred in 10.3% and 25.8% of these patients, respectively.

Additionally, 57.7% of patients experienced any-grade infections with cilta-cel, but most of these effects were found to be grade 1 or 2 in severity; 19.6% of these effects were grade 3 or higher. The most frequent infection was pneumonia, and this was reported in 8.2% of patients. Sepsis was reported in 4.1% of study participants.

Cytokine release syndrome was reported in 94.8% of patients, although 94.6% of these cases were grade 1 or 2. Ninety-one of the 92 cases resolved within 2 weeks of onset and the majority of these participants were given tocilizumab (Actemra; 69.1%) or corticosteroids (21.6%). The median time to CRS onset was 1 week (range, 1-12 days). However, 89% of patients (n = 82) had CRS onset at day 4 or later and 73.9% (n = 68) at day 6 or later.

Updated data from the trial will be shared at the 2021 ASCO Annual Meeting and the 2021 EHA Virtual Congress.

In April 2021, a marketing authorization application was submitted to the European Medicines Agency for the approval of cilta-cel as treatment for patients with relapsed and/or refractory multiple myeloma based on findings from CARTITUDE-1.


  1. US Food and Drug Administration grants BCMA CAR-T cilta-cel priority review for the treatment for relapsed/refractory multiple myeloma. News release. Legend Biotech Corporation. May 26, 2021. Accessed May 27, 2021. https://bwnews.pr/3fNCQK8
  2. Madduri D, Berdeja JG, Usmani SZ, et al. CARTITUDE-1: phase 1b/2 study of ciltacabtagene autoleucel, a B-cell Maturation Antigen-directed chimeric antigen receptor T cell therapy, in relapsed/refractory multiple myeloma. Blood. 2020;136(suppl 1):22-25. doi:10.1182/blood-2020-136307
  3. Madduri D, Berdeja JG, Usmani SZ, et al. CARTITUDE-1: phase 1b/2 study of ciltacabtagene autoleucel, a B-cell maturation antigen–directed chimeric antigen receptor t cell therapy, in relapsed/refractory multiple myeloma. Presented at: 47th Annual Meeting of the European Society for Blood and Marrow Transplantation; March 14-17, 2021; Virtual. Accessed March 17, 2021.
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