FDA Approves Janssen and Legend Biotech’s Carvykti for Expanded Indication in Earlier Line Multiple Myeloma

This is a developing story and will be updated with new information as it becomes available.

The FDA has approved Janssen’s and Legend Biotech's ciltacabtagene autoleucel (cilta-cel; marketed as Carvykti) for an expanded indication in adult patients with relapsed and lenalidomide-refractory multiple myeloma (MM) who have been treated with at least 1 prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent.¹

The decision was based on data from the CARTITUDE-4 clinical trial (NCT04181827), a phase 3, randomized, open-label study evaluating cilta-cel against standard of care (SOC) therapy in patients who received 1 to 3 prior lines of therapy.² The most recent data from CARTITUDE-4 were presented at the American Society of Clinical Oncology (ASCO) 2023 Annual Meeting, held June 2-6, in Chicago, Illinois, by Binod Dhakal, MD, associate professor, Medical College of Wisconsin.³

“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, Medical College of Wisconsin, Division of Hematology and Oncology, said in a statement.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.”

CARTITUDE-4 randomly assigned 206 patients to receive cilta-cel and 211 to receive SOC. The SOC therapy consisted of pomalidomide, bortezomib, and dexamethasone (PVd) or daratumumab, pomalidomide, and dexamethasone (DPd).

As of June 2023, 176 received cilta-cel as study treatment with 143 continuing to be followed posttreatment phase and 77 patients were ongoing with SOC therapy.³ It was reported that patients in the cilta-cel arm had a 12-month progression-free survival (PFS) rate of 76%, versus 49% in the SOC arm. Cilta-cel improved PFS in patients that had 1 or 2-3 prior lines of treatment. Patients with only 1 prior therapy may have experienced a stronger treatment benefit, but it was noted at the time that more data would be needed to confirm this trend. Dhakal, while presenting the data at ASCO, noted that cilta-cel's safety profile in CARTITUDE-4 was similar to other studies evaluating cilta-cel, but with lower rates of neurotoxicity when compared with CARTITUDE-1.

Johnson & Johnson noted in the press release announcing today's FDA decision that in CARTITUDE-4 cilta-cel decreased the risk of disease progression or death by 59% versus the SOC therapies. In terms of safety, the press release also stated that cilta-cel includes a boxed warning for cytokine release syndrome; immune effector cell-associated neurotoxicity syndrome; Parkinsonism and Guillain-Barre syndrome and associated complications; hemophagocytic lymphohistiocytosis/macrophage activation syndrome; prolonged and recurrent cytopenias; and secondary malignancies including myelodysplastic syndrome, acute myeloid leukemia, and T-cell malignancies. Furthermore, the Warnings and Precautions list mentions increased early mortality; hypogammaglobulinemia; infections; hypersensitivity reactions; and effects on ability to drive and use machines.

“This milestone underscores our commitment to improve outcomes for patients and transform the treatment of multiple myeloma with CARVYKTI,” Jordan Schecter, MD, Vice President, Disease Area Leader, Multiple Myeloma, Johnson & Johnson Innovative Medicine, added.¹ “We are proud to bring an important, highly effective immunotherapy that has demonstrated a favorable benefit/risk profile to physicians and patients for the earlier treatment of relapsed/refractory multiple myeloma, and we look forward to building on this latest milestone as we continue to focus on our ultimate goal of delivering a cure for multiple myeloma.”

Legend Biotech submitted the supplemental biologics license application (BLA) leading to today’s decision in June 2023.² In a United States Securities and Exchange Commission (SEC) filing dated to January 23, 2024, it was revealed that the supplemental BLA would be put in front of the FDA’s Oncologic Drugs Advisory Committee (AdComm).⁴ The AdComm meeting ultimately took place on March 15, 2024.⁵

The committee members unanimously voted (11 yes, 0 no, 0 abstain) in favor of cilta-cel's benefit-risk profile for patients with relapsed and lenalidomide-refractory MM after at least 1 prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent.

The FDA’s concerns around cilta-cel revolved around overall survival (OS), as there was an increased rate of early deaths in patients treated with cilta-cel compared with standard of care, which appears to be inherent to autologous CAR-T therapy. The agency acknowledged that the increased upfront hazard rate is similar to that seen with treatments such as hematopoietic stem cell transplant, but since data are immature and the causes of the early deaths are not fully understood, it cannot yet definitively be said that survival will be better overall with cilta-cel.

The sponsor responded by providing a restricted mean survival time analysis on PFS which showed a difference of 4.7 months (95% CI, 3.1-6.1) and a difference of 2.3 months (95% CI, 0.1-4.5), and stated that early deaths are due to disease progression before cilta-cel, COVID-19, and cilta-cel as subsequent therapy.

Cilta-cel was originally approved by the FDA in February 2022 for the treatment of adult patients with relapsed/refractory MM following 4 or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.⁶ Cilta-cel functions by targeting B-cell maturation antigen.

Notably, cilta-cel's expanded approval today was just 1 of 2 major CAR-T approvals that the FDA announced in the past 24 hours. Early in the day on April 5, 2024, the FDA approved Bristol Myers Squibb and 2seventy bio’s supplemental biologics license application for idecabtagene vicleucel's (ide-cel; Abecma), expanding the indication for that CAR-T product to patients with relapsed or refractory MM after 2 or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an antiCD38 monoclonal antibody.

REFERENCES
1. 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. News release. Johnson & Johnson. April 6, 2024. Accessed April 6, 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. Legend Biotech announces submission of supplemental application to the U.S. FDA for expanded use of CARVYKTI® (ciltacabtagene autoleucel). News release. Legend Biotech. June 6, 2023. Accessed April 5, 2024. https://www.businesswire.com/news/home/20230606005760/en/Legend-Biotech-Announces-Submission-of-Supplemental-Application-to-the-U.S.-FDA-for-Expanded-Use-of-CARVYKTI%C2%AE-ciltacabtagene-autoleucel
3. Dhakal B, Yong K, Harrison SJ, et al. First phase 3 results from CARTITUDE-4: Cilta-cel versus standard of care (PVd or DPd) in lenalidomide-refractory multiple myeloma. Presented at: ASCO 2023 Annual Meeting; June 2-6; Chicago, Illinois. Abstract #LBA106
4. Legend Biotech provides update on US FDA and EMA applications for expanded use of CARVYKTI® (ciltacabtagene autoleucel) in earlier lines of treatment for relapsed/refractory multiple myeloma; FDA label update for CAR-T cell immunotherapies. United States SEC Form 6-K. January 23, 2024. Accessed April 5, 2024. https://investors.legendbiotech.com/static-files/0e1a1a5f-2b96-4cf7-9003-e188fa6fba79
5. March 15, 2024: Meeting of the Oncologic Drugs Advisory Committee Meeting Announcement. News release. FDA. March 15, 2024. Accessed April 5, 2024. https://www.fda.gov/advisory-committees/advisory-committee-calendar/march-15-2024-meeting-oncologic-drugs-advisory-committee-meeting-announcement-03152024
6. 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 April 5, 2024. https://bit.ly/35yWwjv