The legendary Bio-Citagiorencel reduces the risk of disease progression or death by 74%

On June 5, 2023, Legendary Biology announced data from Phase 3 of its CARTITUDE 4 study in Somerset, New Jersey, USA. Results showed that at a median follow-up of 16 months, Cedarkeorenzel reduced the risk of disease progression or death in adult patients with multiple myeloma who had previously received line 1 to 3 therapy and were lenalidomide-resistant by 74% compared with standard treatment (hazard ratio, 0.26, 95%CI, 0.18 -- 0.38, P < 0.0001). The research data in 2023, the American society of clinical oncology (ASCO) annual meeting in presentation and oral reports (paper # LBA106) form, and in the New England journal of medicine published (TheNewEnglandJournalofMedicine, NEJM). The results of the study will also be presented in full session at the European Society of Hematology (EHA) Hybrid Congress on 10 June (Abstract #S100).

Data from the first analysis of CARTITUDE 4 showed a statistically significant improvement in progression-free survival, with a hazard ratio of 0.26.

CARTITUDE 4 is the first randomized study to evaluate the efficacy of early use of cilta-cel cell therapy versus standard therapy (DPd or PVd) in relapsed lenadolan-resistant multiple myeloma patients.

Long-term data for CARTITUDE 1 and LEGEND 2 continue to show deep and lasting remission.

Eligible patients in the CARTITUDE 4 study were known to have received prior line therapy (including proteasome inhibitors and immunomodulators) of 1-3 and were resistant to lenalidomide. The study randomly assigned 419 patients to either cilta-cel (n=208) or SOC (n=211). Data from this study showed that at a median follow-up of 16 months, the SOC group had a median PFS of 11.8 months (95%CI, 9.7-13.8), while the cilta-cel group had not yet reached a median PFS (95%CI, 22.8-NE). There was a 65% reduction in the risk of disease progression or death among patients who had previously received first-line treatment (hazard ratio, 0.35, 95%CI, 0.19 -- 0.66, P < 0.0001). In secondary endpoints, the overall response rate (ORR) in the cilta-cel group was 85%, 73% achieved complete response (CR) or better, and the overall minimal residual disease (MRD) negative rate was 61%. Among patients treated with SOC, ORR was 67%, CR or better was 22%, and MRD negative rate was 33%.

In the study, 97% and 94% of patients in the cilta-cel and SOC groups had grade 3 or 4 adverse events, including infection (27% vs 25%) and hemocytopenia (94% vs 86%). Overall, 39 patients died in the cilta-cel group and 46 in the SOC group, including 10 and 5 patients died from treatment-related adverse events, respectively. Of the patients treated with cilta-cel (n=176), 76% had cytokine release syndrome (CRS) (grade 3 1%, no grade 4 or 5), 5% had immunoeffector cell-related neurotoxic syndrome (all grade 1 or 2), and 1 grade 1 motor and neurocognitive adverse event.

The final analysis of the CARTITUDE 1 study shows deep and lasting remission

Final analysis data from the Phase 1b/2 study of CARTITUDE 1 (NCT03548207) showed that patients with relapsed or refractory multiple myeloma who had been treated with multiple therapies continued to achieve deep and lasting responses after treatment with cilta-cel (Abstract#8009). At a median follow-up of 33.4 months (range 1.5-45.2), the median PFS was 34.9 months (95%CI, 25.2-NE), and about 47.5% of patients were still alive and progression-free at 36 months.

In the study, 97 patients who had previously received median sixth-line therapy were treated with cilta-cel, with 42% of patients having quad refractory, 88% having triple refractory, and 99% resistant to last-line therapy. Median duration of response at data cutoff was 33.9 months (95%CI, 25.5 -- NE). Median overall survival (OS) was not achieved in this study, with an OS rate of about 62.9% at 36 months. Of 49 patients with assessable minimal residual disease (MRD), 26 patients had MRD-negative rates lasting at least 12 months, 20 patients had MRD-negative rates consistently meeting (CR) or better, and 18 MRD-negative patients had CR or better at 24 months after infusion. No new safety signals and no new neurotoxic events were reported since a median follow-up of 27.7 months, and six new cases of secondary primary malignancies were reported, including two cases of basal cell carcinoma and one case of myelodysplastic syndrome, B-cell lymphoma, melanoma, and prostate cancer. 5 new deaths (3 disease progression; One case each of pneumonia and sepsis, both determined by the investigators to be unrelated to cilta-cel), and a total of 35 deaths (17 cases of disease progression, 12 cases determined by the investigators to be unrelated to cilta-cel, and 6 cases associated).

Five-year follow-up data from LEGEND-2 highlighted a deep and lasting response

The five-year follow-up of LEGEND-2 is the longest of any study targeting BCMACAR-T cell therapy. In this study, LCAR-B38M uses a CAR structure similar to cilta-cel. The results showed a median overall survival (OS) of 55.8 months, and 18% of patients with multiple myeloma treated with multiple therapies remained disease-free.

At data cut-off, the median follow-up time of the LEGEND 2 study was 65.4 months (range 0.4 to 78.8). 74 patients who had previously received median third-line therapy (range 1 to 9) were treated with LCAR-B38M. 35.7% of the patients had high risk cytogenetic characteristics, and the ORR was 87.8%. 73% of patients achieved CR, with a median duration of response of 23 months and a median PFS of 18 months, consistent with previously reported data. The MRD-negative CR rate was 67.6%. No new CAR T-cell-related toxicities were reported in the analysis.

About CARVYKTI® (ciltacabtageneautoleucel; cilta-cel, Cildaci Oroncel)

CARVYKTI® is a chimeric antigen receptor T cell (CAR) therapy targeting B cell maturation antigen (BCMA) that uses a transgenic chimeric antigen receptor (CAR) to modify a patient's own T cells to recognize and eliminate BCMa-expressing cells. BCMA is mainly expressed on the surface of malignant multiple myeloma B cells, advanced B cells and plasma cells. CARVYKTI® 's CAR protein has two single-domain antibodies targeting BCMA and has a high affinity for BCMa-expressing cells. Upon binding to BCMa-expressing cells, CAR promotes T cell activation, amplification, and subsequent elimination of target cells.

In December 2017, Janssen signed an exclusive worldwide license and cooperation agreement with Legendary Biology to develop and commercialize CARVYKTI®.

CARVYKTI® received marketing approval from the US FDA in February 2022, a conditional marketing authorization from the European Union EC in May, and MHLW approval in Japan in September for the treatment of adult patients with relapsed or refractory multiple myeloma. cilta-cel was certified as a breakthrough therapy in the US in December 2019 and in China in August 2020. In addition, cilta-cel was awarded priority drug status by the European Commission in April 2019. cilta-cel was granted orphan drug status by the US FDA, the European EMA and the Japanese PMDA in February 2019, February 2020 and June 2020 respectively. In March 2022, the European Medicines Agency's Committee for Orphan Medicinal Products unanimously recommended that the orphan designation of cilta-cel be maintained on the basis of clinical data showing an improved and sustained rate of complete response after treatment.

About CARTITUDE-4

CARTITUDE 4(NCT04181827) is the first Phase 3 study of international, randomised, open-labelling, We evaluated the efficacy and safety of CAR-T therapy versus pomeramide, bortezomib, and dexamethasone (PVd) or daleimumab, pomeramide, and dexamethasone (DPd) in adult patients with multiple myeloma who had relapsed and were resistant to linalidomide after previous first - to third-line therapy. After apherasation, patients randomly assigned to receive cilta-cel in the study received PVd or DPd as bridging therapy, and cilta-cel was transfused 5 to 7 days after lymphocyte exfoliation. A total of 176 patients received planned cilta-cel during bridging therapy and 20 patients received cilta-cel after disease progression. In the SOC group, 28 patients received PVd and 183 received DPd until disease progression. The primary endpoint of this study was PFS. Secondary endpoints included safety, overall survival (OS), minimal residual disease (MRD) negative rate, and overall response rate (ORR). As part of the CARTITUDE 4 study, patients will continue to be tracked for primary and secondary endpoints.

About CARTITUDE-1

CARTITUDE 1 (NCT03548207) is a Phase 1b/2, open-label, single-arm, multicenter trial, To evaluate the treatment of cilta-cel in adult patients with relapsed or refractory multiple myeloma who have previously received at least third-line therapy, including proteasome inhibitors [PI], immunomodulators [IMiD], and anti-CD38 monoclonal antibodies. Of the 97 patients enrolled in the trial, 99% were resistant to last-line therapy and 88% were triple resistant (i.e., their tumors did not respond or did not respond to IMiD, PI, and anti-CD38 monoclonal antibody).

About LEGEND-2

LEGEND-2 (NCT03090659) is a one-arm, open-label, phase 1/2 study conducted in China with four independent research institutions as participating hospitals. The study evaluated the efficacy and safety of LCAR-B38M in patients with relapsed or refractory multiple myeloma. LCAR-B38M, a product studied in China, and Ciltacabtageneautoleucel(cilta-cel), a product studied in the US/EU, represent the same CAR T therapy.

About multiple myeloma

MultipleMyeloma (MM) is considered as an incurable blood tumor, which is a malignant disease caused by excessive proliferation of plasma cells in bone marrow. More than 35,000 people in the United States are expected to be diagnosed with multiple myeloma in 2023, and more than 12,000 will die from the disease. Although some people with multiple myeloma have no obvious symptoms, they are diagnosed due to symptoms that may include bone disease, abnormal low blood counts, elevated blood calcium, kidney problems or infections. While there may be some relief with treatment, unfortunately, patients are likely to relapse. Patients who relapse after treatment with standard therapies, including protease inhibitors, immunomodulators, and anti-CD38 monoclonal antibodies, face a poor prognosis and limited treatment options.