FDA Approves Cilta-Cel for Relapsed/Refractory Multiple Myeloma


The FDA has approved ciltacabtagene autoleucel for the treatment of adult patients with relapsed and/or refractory multiple myeloma following 4 or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.



The FDA has approved ciltacabtagene autoleucel (cilta-cel; Carvykti) for the treatment of adult patients with relapsed/refractory multiple myeloma following 4 or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.1

The approval for cilta-cel was based on findings from the phase 1b/2 CARTITUDE-1 trial (NCT03548207), in which cilta-cel elicited an objective response rate (ORR) of 98% (95% CI, 92.7%-99.7%) in this patient population.2 Additionally, the stringent complete response rate (sCR) was 78% (95% CI, 68.8%-86.1%). The median duration of response (DOR) was 21.8 months at a median 18 months of follow-up.

“The responses in the CARTITUDE-1 study showed durability over time and resulted in the majority of heavily pretreated patients achieving deep responses after 18-month follow-up,” principal investigator Sundar Jagannath, MD, director of the Center of Excellence for Multiple Myeloma and professor of medicine, hematology and medical oncology, at The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai, stated in a press release. “The approval of cilta-cel provides physicians an immunotherapy treatment option that offers patients an opportunity to be free from anti-myeloma therapies for a period of time.”

In November 2021, the FDA had extended the Prescription Drug User Fee Act target date for the biologics license application (BLA) seeking the approval of cilta-cel for use in adult patients with relapsed and/or refractory multiple myeloma.3

On October 28, 2021, Janssen was alerted of the extension to allow for adequate time to review recently submitted data associated with an updated analytical method following an information request issued by the regulatory agency. Shortly after, on November 1, 2021, Janssen and Legend Biotech Corporation met with the FDA, and no additional clinical data were requested.

Due to the FDA's requests, the new decision date for the application had been moved to February 28, 2022.

The single-arm, open-label, phase 1b/2 trial enrolled patients with multiple myeloma who were at least 18 years of age, had measurable disease at screening, and an ECOG performance status of 0 or 1.4 Patients needed to have previously received 3 or more prior lines of therapy or become double refractory to a proteasome inhibitor and an immunomodulatory drug, and have received a proteasome inhibitor, immunomodulatory drug, and an anti-CD38 antibody, with documented progressive disease.

If patients previously received treatment with a CAR T-cell– or BCMA-targeted therapy, they were excluded.

Patients’ blood was apheresed in accordance with institutional standards. Between apheresis and CAR T-cell infusion, patients were permitted to receive bridging therapy if clinically indicated. After the successful manufacturing of cilta-cel, patients underwent lymphodepletion with cyclophosphamide at 300 mg/m2 and fludarabine at 30 mg/m2, both administered daily for 3 days. Five to 7 days following the initiation of lymphodepletion, patients were administered a single infusion at a target dose of 0.75 x 106 CAR-positive viable T cells/kg (range, 0.5 x 106-1.0 x 106).

The primary end point of the phase 1b portion of trial was to examine the incidence and severity of adverse effects (AEs). The primary end point of the phase 2 portion was ORR. Secondary end points in both phases included sCR, complete response (CR), very good partial response (VGPR), DOR, rate of minimal residual disease negativity, PFS, and OS. Investigators also evaluated pharmacokinetic and pharmacodynamic markers.

A total of 113 patients were enrolled to the trial and all underwent apheresis. Fourteen percent of patients did not receive the CAR T-cell therapy because of progressive disease (n = 2), study withdrawal (n = 2), or death (n = 8). A total of 101 patients underwent lymphodepletion; of these patients, 4 discontinued.

A total of 97 patients received cilta-cel; 29 of these patients received the product in the phase 1b portion and 68 did so in the phase 2 portion. Twenty-four patients in the phase 1b portion were still receiving treatment, as were 59 patients in the phase 2 portion.

The median age of patients was 61.0 years (IQR, 56.0-68.0), and 59% of patients were male. Moreover, most patients were White and non-Hispanic or non-Latino. Additionally, 24% of patients had a high-risk cytogenetic profile based on the presence of del(17p), t(14;16), or t(4;14), and 13% had extramedullary plasmacytomas at screening.

The median time from diagnosis was 5.9 years (IQR, 4.4-8.4), and patients received a median of 6 prior therapies (IQR, 4.0-8.0). Eighty-four percent of patients had been exposed to 5 drugs. Moreover, 84% were refractory to pomalidomide (Pomalyst), 65% to carfilzomib (Kyprolis), and 99% to anti-CD38 antibody treatment. Eighty-eight percent of patients were triple-class refractory, 42% were penta-drug refractory, and 99% were refractory to their last lane of therapy received.

Additional data showed that among those who achieved a CR or better, the 12-month PFS rate was 85% (95% CI, 72.0%-91.8%). In those who achieved a VGPR, this rate was 62% (95% CI, 42.1%-76.9%). Moreover, response rates were noted to be similar across the prespecified subsets analyzed.

Regarding safety, all patients experienced toxicities, including grade 3 or 4 effects. The most common AEs reported were hematologic in nature; grade 3 or 4 hematologic toxicities included neutropenia (95%), anemia (68%), leukopenia (61%), thrombocytopenia (60%), and lymphopenia (50%).

Those who had grade 3 or 4 cytopenic events following day 1 of CAR T-cell infusion recovered to grade 2 or less by day 30 for lymphopenia (88%), neutropenia (70%), and thrombocytopenia (59%).

Longer follow-up from the CARTITUDE-1 trial was presented during the 2021 ASH Annual Meeting and Exposition.5 Data from a 2-year follow-up analysis of the study demonstrated that all patient subgroups had achieved a consistently high ORR comparable with that of the overall patient population, with a range from 95.1% to 100%. Additionally, in all subgroups, 80% to 100% of minimal residual disease (MRD)-evaluable patients achieved MRD negativity at a 10-5 threshold.

In patients who were aged 65 years and older (n = 35), 8 of whom were 75 years and older, the ORR was 97.1% (95% CI, 85.1%-99.9%) and the MRD negativity rate was 91.3% (95% CI, 72%-98.9%).

Cilta-cel is available through the restricted CARVYKTI™ Risk Evaluation and Mitigation Strategy Program. There is also a boxed warning for this treatment regarding cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, Parkinsonism and Guillain-Barré syndrome, hemophagocytic lymphohistiocytosis/macrophage activation syndrome, and prolonged and/or recurrent cytopenias.

“We are committed to harnessing our science, deep disease understanding and capabilities to bring forward cell therapies like Carvykti as we continue to focus on our ultimate goal of delivering a cure for multiple myeloma,” Peter Lebowitz, MD, PhD, global therapeutic area head, oncology, Janssen Research & Development, LLC, which develops cilta-cel with Legend Biotech, stated in a press release. “We extend our sincere gratitude to the patients, their families and the teams of researchers and study centers who have participated in the clinical study of Carvykti and enabled today’s approval.”


  1. U.S. 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 February 28, 2022. https://bit.ly/35yWwjv
  2. Carvykti (ciltacabtagene autoleucel) suspension for intravenous infusion. Prescribing information. Janssen Biotech and Legend Biotech Corporation; 2022. Accessed February 28, 2022.
  3. Legend Biotech announces extension of PDUFA date for cilta-cel. News release. Legend Biotech Corporation. November 1, 2021. Accessed November 2, 2021. https://bit.ly/3GNZcIm
  4. Berdeja JG, Madduri D, Usmani SZ, et al. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. Lancet. 2021;398(10297):314-324. doi:10.1016/S0140-6736(21)00933-8
  5. Jakubowiak A, Usmani SZ, Berdeja JG, et al. Efficacy and safety of ciltacabtagene autoleucel in patients With relapsed/refractory multiple myeloma: CARTITUDE-1 subgroup analysis. Blood. 2021;138(suppl_1):3938. doi:10.1182/blood-2021-146069
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