Ciltacabtagene autoleucel (Carvykti®; Janssen Biotech/Legend Biotech, previously known as JNJ-68284528), a B cell maturation antigen (BCMA-) targeting CAR T-cell therapy, significantly slows or stops progression of multiple myeloma when compared with standard-of-care treatments among those for whom lenalidomide (Revlimid®; Celgene, a Bristol-Myers Squibb Company) no longer works.

This conclusion is based on the outcomes of the phase 3 CARTITUDE-4 study (ClinicalTrials.gov identifier: NCT04181827), funded by Janssen Research & Development and Legend Biotech. The results of the study were presented at the annual meeting of the American Society of Clinical Oncology (ASCO), held June 2 – 6, 2023, in Chicago, Illinois.

CAR -T-cell therapy
Currently approved and commercially available CAR T-cell immunotherapies are uniquely developed for each individual patient. In this process, some T-cells are removed from the patient’s own blood and are re-engineered/modified in a laboratory, so they have specific proteins called receptors on their surface.

In CAR T-cell therapy, these receptors allow the modified T-cells to recognize the cancer cells. When the modified T-cells are returned to the patient’s body, they seek out and destroy cancer cells.

In simple terms, Chimeric Antigen Receptors or CARs are recombinant receptor constructs composed of an extracellular single-chain variable fragment (scFv) derived from an antibody which are joined to a hinge/spacer peptide and a transmembrane domain and further linked to the intracellular T-cell signaling domains of the T-cell receptor. CAR T-cells combine the specificity of an antibody with the cytotoxic and memory functions of T cells.

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Now, after decades of painstaking research, CAR T-cell therapies, designed to modify T-cells to recognize cancer cells in order to more effectively target and destroy them, have entered the mainstream of cancer treatment. [1]

Ciltacabtagene autoleucel is a CAR T-cell therapy.

Study design
The global, phase 3 CARTITUDE-4 study enrolled participants from 16 countries, including the United States, Europe, Asia, and Australia. The study participants were around 61 years of age, 55% were men, and 75% were White.

The study is one of only two phase 3 clinical trials investigating CAR T-cell therapy in the early lines of therapy for multiple myeloma and the CARTITUDE-4 is the only phase 3 study to currently explore using CAR T-cell therapy after the first relapse of the disease.

Findings
The CARTITUDE-4 clinical trial included 419 people with multiple myeloma who had already received one to three lines of treatment, including lenalidomide, which was no longer effective. In this study there were 208 participants in the ciltacabtagene autoleucel arm and 211 participants in the standard-of-care treatment arm, which used either a combination of bortezomib (Velcade®; Takeda Pharmaceuticals), pomalidomide (Pomalyst®; Celgene, a Bristol-Myers Squibb Company), and dexamethasone or a combination of daratumumab (Darzalex®; Janssen Biotech), pomalidomide, and dexamethasone.

After a median follow-up of 16 months, the researchers found that ciltacabtagene autoleucel reduced the risk of disease progression by 74%, compared with the standard-of-care treatments. Objective response rates, which is the percentage of patients whose cancer responded to the treatment, were 84.6% in the group assigned to ciltacabtagene autoleucel, compared with 67.3% in the group assigned to standard-of-care treatment. Those assigned to the CAR T-cell therapy also had better minimal residual disease negativity (60.6%), compared with those assigned to standard of care (15.6%). Minimal residual disease negativity indicates the percentage of patients for whom testing did not find any cancer cells remaining after treatment.

“Lenalidomide-based therapies are used extensively as frontline treatments, in both young and elderly patients and including those who are transplant-eligible and transplant-ineligible. This causes an increase in the number of cases where the disease no longer responds to lenalidomide early in the course of the disease,” said lead study author Binod Dhakal, MD, of Medical College of Wisconsin, Milwaukee, WI.

“These findings show that ciltacabtagene autoleucel is highly effective in patients with lenalidomide-refractory multiple myeloma as early as after first relapse,” Dhakal added.

Most participants (97% receiving ciltacabtagene autoleucel and 94% receiving standard of care) experienced grade 3/4 adverse events, including infections (27% vs. 25%) and low blood cell counts (94% vs. 86%), including neutropenia, thrombocytopenia, and anemia. Cytokine release syndrome, which may arise as immune cells are sent into overdrive by the treatment, developed in 76% of participants who received ciltacabtagene autoleucel.

Around 5% of those receiving the CAR T-cell therapy developed immune effector cell-associated neurotoxicity syndrome (ICANS), a syndrome that affects a person’s nervous system.

What’s Next
The researchers will continue to follow the study participants to determine the long-term effects of ciltacabtagene autoleucel. Additional analyses of the data are ongoing, such as health-related quality of life, subgroup analyses, and biomarker analyses. The researchers hope to publish and present additional findings when they are available. Ciltacabtagene autoleucel is also being studied as frontline therapy in additional ongoing clinical trials.

Clinical trial
A Study Comparing JNJ-68284528, a CAR-T Therapy Directed Against B-cell Maturation Antigen (BCMA), Versus Pomalidomide, Bortezomib and Dexamethasone (PVd) or Daratumumab, Pomalidomide and Dexamethasone (DPd) in Participants With Relapsed and Lenalidomide-Refractory Multiple Myeloma (CARTITUDE-4) – NCT04181827

Highlights of prescribing Information
Ciltacabtagene autoleucel (Carvykti®; Janssen Biotech/Legend Biotech)[Prescribing Infromation]
Lenalidomide (Revlimid®; Celgene, a Bristol-Myers Squibb Company)[Prescribing Information]
Bortezomib (Velcade®; Takeda Pharmaceuticals)[Prescribing Information]
Pomalidomide (Pomalyst®; Celgene, a Bristol-Myers Squibb Company)[Prescribing information]
Daratumumab (Darzalex®; Janssen Biotech)[Prescribing Information]

Reference
[1] CAR T-cell Therapies. Frequently Asked Questions. International Journal of CAR t-cell therapy. Online. Last accesses on June 4, 2023.
[2] Dhakal B, Yong K, Harrison SJ, Mateos MV, Moreau P,  Van de Donk NWCJ, Sidana S, Popat R, et al. First phase 3 results from CARTITUDE-4: Cilta-cel versus standard of care (PVd or DPd) in lenalidomide-refractory multiple myeloma. J Clin Oncol 41, 2023 (suppl 17; abstr LBA106). DOI 10.1200/JCO.2023.41.17_suppl.LBA106.

Featured image:Attendees and presenters during the Plenary Session of the American Society of Clinical Oncology (ASCO), held June 2 – 6, 2023 in McCormick Place, Chicago, IL. Photo courtesy: © 2023 ASCO/Scott Morgan/

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