FDA ODAC Committee Votes Unanimously in Favor of Benefit-Risk Profile of Cilta-Cel in Early R/R Myeloma


The FDA’s Oncologic Drugs Advisory Committee voted in favor of ciltacabtagene autoleucel for patients with early relapsed/refractory myeloma.



The FDA’s Oncologic Drugs Advisory Committee voted 11 to 0 that the benefits of ciltacabtagene autoleucel (cilta-cel; Carvykti) do outweigh its risks for the treatment of adult patients with relapsed/refractory multiple myeloma who have received at least 1 prior line of therapy, including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), and are refractory to lenalidomide (Revlimid).1

The vote followed a discussion of results from the phase 3 CARTITUDE-4 trial (NCT04181827), which demonstrated that in the intent-to-treat (ITT) population, cilta-cel (n = 208) elicited a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with pomalidomide (Pomalyst) plus bortezomib (Velcade) and dexamethasone (PVd) or daratumumab (Darzalez) plus pomalidomide and dexamethasone (DPd; n = 211; HR, 0.26; 95% CI, 0.18-0.38; P < .0001). Patients in the cilta-cel arm experienced a median PFS that was not estimable (NE; 95% CI, 22.8-NE) vs 11.8 months (95% CI, 9.7-13.8) for patients in the standard-of-care (SOC) arm.2

Regarding the key secondary end point of overall survival (OS), the median OS was NE (95% CI, NE-NE) for cilta-cel vs NE (95% CI, 33.97-NE) for the SOC arm (HR, 0.57; 95% CI, 0.40-0.83). The 24-month OS rates were 79% and 66%, respectively.

However, the FDA raised concerns regarding the OS rates during the first 10 months of treatment in the ITT population. In the first 10 months, 14% of patients in the cilta-cel arm died compared with 12% of patients in the SOC arm. Specifically, 4.8% of patients in the cilta-cel arm died due to progressive disease (PD) prior to receiving the CAR T-cell therapy, whereas 0.5% of patients in the SOC arm died due to PD prior to treatment. After treatment, 9.1% of patients in the cilta-cel arm died in the first 10 months, including 1.4% due to PD and 7.7% due to adverse effects (AEs). In the SOC arm, 11.3% of patients died within the first 10 months after starting treatment, including 7.1% due to PD and 4.2% due to AEs.3

“Although we [are aware of] the difference in early deaths in patients who did not go on to receive cilta-cel…these patients started the process to [receive] cilta-cel and had received leukapheresis and bridging therapy. These [outcomes] are still relevant in the benefit-risk of cilta-cel,” Helkha Peredo-Pinto, MD, MPH, a clinical reviewer with the FDA’s Center for Drug Evaluation and Research, said during the meeting.

Janssen, the sponsor for cilta-cel, attributed the early OS imbalance to patients who experienced PD or death prior to receiving the CAR T-cell therapy.

Previously, 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.4

CARTITUDE-4 was an open-label, randomized study that enrolled patients at least 18 years of age with multiple myeloma who had received 1 to 3 prior lines of therapy, including a PI and an IMiD, who were refractory to lenalidomide. Patients were required to have an ECOG performance status of 0 or 1, and prior treatment with CAR T-cell therapy or a BCMA-targeted therapy was not allowed.2

Patients were randomly assigned 1:1 to receive cilta-cel or SOC with physician’s choice of PVd or DPd. Those in the CAR T-cell therapy arm received at least 1 cycle of bridging therapy with PVd or DPd following apheresis. Five to 7 days following lymphodepletion with 300 mg/m2 of cyclophosphamide and 30 mg/m2 of fludarabine per day for 3 days, cilta-cel was administered as a single infusion at a target dose of 0.75 x 106 CAR+ T cells/kg.

PFS served as the trial’s primary end point. Secondary end points included stringent complete response (sCR) sCR/CR rate, objective response rate (ORR), minimal residual disease (MRD) negativity rate, and OS.

Additional data showed a PFS benefit was observed with cilta-cel across all prespecified subgroups.

Furthermore, cilta-cel elicited an ORR of 85%, including a sCR rate of 58%, a CR rate of 15%, a very good partial response (VGPR) rate of 8%, and a partial response (PR) rate of 3%. In the PVd/DPd arm, the ORR was 67%, comprised of sCR, CR, VGPR, and PR rates of 15%, 7%, 24%, and 22%, respectively (odds ratio [OR] for sCR/CR, 10.3; 95% CI, 6.5-16.4; P <.0001).

Responders in the cilta-cel arm (n = 176) experienced a median duration of response that was NE compared with 16.6 months (95% CI, 12.9-NE) for responders in the SOC arm (n = 142). The 12-month event-free rates were 84.7% (95% CI, 78.1%-89.4%) and 63.0% (95% CI, 54.2%-70.6%) for cilta-cel and PVd/DPd, respectively.

In the ITT population, the MRD negativity rate was 60.6% for cilta-cel and 15.6% for SOC (OR, 8.7; 95% CI, 5.4-13.9). In patients who were evaluable for MRD, those treated with cilta-cel (n = 144) achieved a MRD negativity rate of 87.5% compared with 32.7% for those treated with PVd/DPd (n = 101).

Regarding safety, any-grade AEs occurred in 100% of patients in both arms, and the rates of grade 3/4 AEs were 84% for cilta-cel and 91% for SOC. The rates of non-fatal serious AEs were 35% for cilta-cel and 38% for SOC. AEs leading to death occurred in 11% of patients in the cilta-cel arm vs 8% of patients in the PVd/DPd arm, as of the November 2022 data cutoff. At the December 2023 data cutoff, those rates were 12% and 13%, respectively.

In the cilta-cel arm, any-grade cytokine release syndrome (CRS) was reported in 78% of patients, and 3% experienced grade 3/4 CRS. CRS events resolved in 99% of patients who experienced the AE. Additionally, any-grade immune effector cell–associated neurotoxicity syndrome (ICANS) occurred in 7% of patients in the cilta-cel arm, including 0.5% who experienced grade 3/4 events. ICANS resolved in 93% of patients who experienced the toxicity.

Notably, second primary malignancies were reported in 9% of evaluable patients in the cilta-cel arm (n = 188) compared with 8% of evaluable patients in the control arm (n = 208). Secondary primary malignancies in the experimental arm included cutaneous/non-invasive malignancies (5%); hematologic malignancies (3%), including acute myeloid leukemia or myelodysplastic syndrome (2%) and T-cell lymphoma (0.5%); and non-cutaneous/invasive malignancies (2%). Secondary primary malignancies in the SOC arm included cutaneous/non-invasive malignancies (6%) and non-cutaneous/invasive malignancies (2%); however, no second primary hematologic malignancies occurred in the control arm.


  1. March 15, 2024, Meeting of the Oncologic Drugs Advisory Committee (ODAC). FDA.
  2. San-Miguel J, Dhakal B, Yong K, et al. Cilta-cel or standard care in lenalidomide-refractory multiple myeloma. N Engl J Med. 2023;389(4):335-347. doi:10.1056/NEJMoa2303379
  3. Oncologic Drugs Advisory Committee meeting introductory comments. FDA. March 15, 2024. Accessed March 15, 2024.
  4. FDA approves ciltacabtagene autoleucel for relapsed or refractory multiple myeloma. FDA. February 28, 2022. Accessed March 15, 2024.
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