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


The Oncologic Drugs Advisory Committee of the FDA unanimously voted in favor of ciltacabtagene autoleucel for the treatment of early relapsed/refractory myeloma.

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

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

In an 11-0 vote, the Oncologic Drugs Advisory Committee of the FDA agreed that the benefits of ciltacabtagene autoleucel (cilta-cel; Carvykti) outweigh its risks for 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. https://www.youtube.com/watch?v=VSjdGeeXb40
  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. https://www.fda.gov/media/177057/download
  4. FDA approves ciltacabtagene autoleucel for relapsed or refractory multiple myeloma. FDA. February 28, 2022. Accessed March 15, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ciltacabtagene-autoleucel-relapsed-or-refractory-multiple-myeloma
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