FDA Approves Cilta-Cel for R/R Multiple Myeloma After at Least One Prior Line of Therapy


The FDA has approved cilta-cel for select patients with relapsed/refractory multiple myeloma who have received at least 1 line of therapy, and who are lenalidomide refractory.



The FDA has approved ciltacabtagene autoleucel (Carvykti; cilta-cel) for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least one prior line of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), and who are refractory to lenalidomide (Revlimid).1

The regulatory decision was supported by findings from the phase 3 CARTITUDE-4 study (NCT04181827) in which the CAR T-cell therapy (n = 208) reduced the risk of disease progression or death by 59% vs standard care regimens (n = 211) in those with relapsed and lenalidomide-refractory multiple myeloma who previously received one to three lines of therapy, according to the press release issued by Johnson & Johnson.

Data published in the New England Journal of Medicine indicated that at a median follow-up of 15.9 months (range, 0.1-27.3), the median PFS was not yet reached with cilta-cel vs 11.8 months with standard regimens (HR, 0.26; 95%[CI, 0.18-0.38; P <.001).2

"Carvykti demonstrated remarkable efficacy as a personalized, one-time infusion in the earlier treatment of relapsed/refractory multiple myeloma as shown through the CARTITUDE-4 study results," Binod Dhakal, MD, associate professor in Division of Hematology and Oncology at Medical College of Wisconsin, stated in a press release.1 "With this approval, I'm excited for patients who may have the opportunity for a treatment-free period for their multiple myeloma as early as first relapse, with the hope of eliminating the burden of having to be on continuous treatment while living with this challenging disease."

About CARTITUDE-4: Eligibility, Treatment, Objectives

The open-label, randomized trial enrolled patients who had received one to 3 prior lines of therapy, including a PI and an IMiD, who were resistant to lenalidomide. They did not have prior exposure to a CAR T-cell therapy or BCMA-targeted therapy.

Study participants were randomly assigned 1:1 to receive a single infusion of cilta-cel following physician's choice of bridging therapy or standard regimens that were physician's choice of pomalidomide (Pomalyst), bortezomib (Velcade), and dexamethasone (PVd) or daratumumab (Darzalex), pomalidomide, and dexamethasone (DPd).

Those assigned to the standard-care arm received PVd in 21-day cycles or DPd in 28-day cycles until progressive disease (PD). Those who experienced PD were not permitted to crossover to receive the CAR T-cell therapy. Those in the CAR T-cell therapy arm first underwent apheresis, had at least one cycle of bridging therapy, and received lymphodepletion in the form of cyclophosphamide at 300 mg/m2 plus fludarabine at 30 mg/m2. Cilta-cel was infused 5 to 7 days after the chemotherapy regimen was completed; the target dose was 0.75 × 106 CAR-positive viable T cells per kg of body weight.

Stratification factors included regimen selection (PVd vs DPd), disease severity at screening per International Staging System (I vs II vs III), and number of prior lines of treatment (1 vs 2 or 3).

In the standard-regimen arm, 183 received DPd and 28 were given PVd. All patients in the cilta-cel arm received bridging therapy, with 182 receiving DPd and 26 receiving PVd.

The primary objective of the trial was PFS and important secondary objectives included complete response (CR) or better, overall response rate (ORR), minimal residual disease negativity, overall survival (OS), and worsening of patient-reported symptoms—all of which were assessed sequentially. Investigators also examined the safety and pharmacokinetic profile of the drug.

Baseline Demographic and Disease Characteristics

The baseline characteristics of the patients were well balanced between the cilta-cel and standard-regimen arms. The median patient age was 61.5 years (range, 27-80), more than half of patients were male (55.8% vs 58.8%), most were White (75.5% vs 74.4%) and from Europe (61.5%. vs 61.1%).

In the cilta-cel arm, 54.8% had an ECOG performance status of 0, 44.7% had a status of 1, and 0.5% had a status of 2; in the standard-regimen arm, these rates were 57.3%, 42.2%, and 0.5%, respectively. Regarding disease stage in the CAR T-cell therapy arm, 65.4% had stage I disease, 28.8% had stage II disease, and 5.8% had stage III disease; these respective rates were 62.6%, 30.8%, and 6.6% in the standard-regimen arm. Moreover, 59.4% of those in the cilta-cel arm had high-risk cytogenetics, as did 62.9% of those in the standard-regimen arm.

In the CAR T-cell therapy arm, the number of prior lines of therapy received was 1 for 32.7% of patients, 2 for 39.9% of patients, and 3 for 27.4% of patients; these respective rates were 32.2%, 41.2%, and 26.5% in the standard-regimen arm. All patients had received prior lenalidomide; 3.8% and 4.7% of patients had prior exposure to pomalidomide. In terms of anti-CD38 antibodies 24.5% and 25.6% of patients had prior daratumumab and 1.0% and 0.9% of patients had prior isatuximab-irfc (Sarclisa). In the cilta-cel arm, 97.6% of patients had prior bortezomib, 37.0% had carfilzomib, and 10.1% had ixazomib; these respective rates were 97.2%, 31.3%, and 10.0% in the standard-regimen arm.

All patients were refractory to lenalidomide. In the cilta-cel arm, patients were also refractory to bortezomib (26.4%), carfilzomib (24.5%), any anti-CD38 antibody (24.0%), daratumumab (23.1%), ixazomib (7.2%), pomalidomide (3.8%), triple-class (14.4%), and penta-drug (1.0%); in the standard-regimen arm, these rates were 22.7%, 21.3%, 21.8%, 21.3%, 8.1%, 4.3%, 15.6%, and 0.5%, respectively.

Additional Efficacy Data

In the intention-to-treat population, the 12-month PFS rate with cilta-cel was 75.9% (95% CI, 69.4%-81.1%) vs 48.6% (95% CI, 41.5%-55.3%) with standard care regimens.

The CR or better rate in the cilta-cel arm was 73.1% vs 21.8% with standard regimens (odds ratio [OR], 10.3; 95% CI, 6.5-16.4). The ORRs in the cilta-cel and standard-regimen arms were 84.6% and 67.3%, respectively (OR, 3.0; 95% CI, 1.8-5.0). Moreover, 60.6% of those in the cilta-cel arm and 15.6% of those in the standard-regimen regimens achieved MRD negativity at any time during the study (OR, 8.7; 95% CI, 5.4-13.9).

OS data were still immature at the data cutoff date of November 1, 2022 (HR, 0.78; 95% CI, 0.5-1.2; P = .26).

Lastly, the median time to symptom worsening in the cilta-cel and standard-regimen arms was 23.7 months (95% CI, 22.1-not estimable [NE]) vs 18.9 months (95% CI, 16.8-NE), respectively (HR, 0.42; 95% CI, 0.26-0.68).

Safety Data

A total of 208 patients in each arm comprised the safety population. Grade 3 or 4 toxicities were experienced by 96.6% of those who received cilta-cel vs 94.2% of those who were given standard regimens. Serious toxicities were observed in 44.2% and 38.9% of patients, respectively. Second primary cancers occurred in 4.3% of those in the cilta-cel arm and 6.7% of those in the standard-regimen arm.

In the CAR T-cell therapy arm, the most common grade 3 or 4 toxicities included neutropenia (89.9%), thrombocytopenia (41.3%), anemia (35.6%), lymphopenia (20.7%), upper respiratory tract infection (1.9%), COVID-19 (2.9%), lower respiratory tract or lung infection (4.3%), hypogammaglobulinemia (7.2%), diarrhea (3.8%), fatigue (1.9%), constipation (0.5%), hypokalemia (3.8%), asthenia (0.5%), reduced appetite (1.0%), back pain (1.0%), arthralgia (1.0%), dyspnea (0.5%), insomnia (1.0%), cytokine release syndrome (CRS; 1.1%), neurotoxicity (2.8%), and immune effector cell–associated neurotoxicity syndrome (ICANS) and associated symptoms (0.1%).

The toxicity profile comes with a boxed warning for CRS, ICANS, Parkinsonism, and Guillain-Barre syndrome and their affiliated complications such as hemophagocytic lymphohistiocytosis/macrophage activation syndrome, cytopenias that are prolonged and recurrent, and secondary malignancies such as acute myeloid leukemia, myelodysplastic syndrome, and T-cell malignancies.1


  1. Carvykti is the first and only BCMA-targeted treatment approved by the US FDA for patients with relapsed or refractory multiple myeloma who have received at lease one prior line of therapy. News release. Johnson & Johnson. April 5, 2024. Accessed April 5, 2024. https://www.jnj.com/media-center/press-releases/carvykti-is-the-first-and-only-bcma-targeted-treatment-approved-by-the-u-s-fda-for-patients-with-relapsed-or-refractory-multiple-myeloma-who-have-received-at-least-one-prior-line-of-therapy
  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
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