Background: For patients with newly diagnosed multiple myeloma (NDMM) who are transplant eligible, daratumumab, bortezomib, lenalidomide, and dexamethasone (DVRd) is recommended by the National Comprehensive Cancer Network guidelines as induction therapy followed by autologous stem cell transplant (ASCT), consolidation, and maintenance therapy. Ciltacabtagene autoleucel (cilta-cel) is a chimeric antigen receptor (CAR)-T cell therapy with 2 B-cell maturation antigen (BCMA)-targeting single-domain antibodies. In the phase 1b/2 CARTITUDE-1 study, a single infusion of cilta-cel resulted in deep and durable responses with a manageable safety profile in heavily pretreated patients with relapsed/refractory MM. At a median follow-up of 27.7 months, the overall response rate (ORR) was 98%, 83% of patients achieved stringent complete response (CR), and median duration of response was not reached. The randomized, open-label, global, multicenter, phase 3 EMagine/CARTITUDE-6 study (EMN28/68284528MMY3005; NCT05257083) aims to compare the efficacy of DVRd followed by cilta-cel and lenalidomide versus DVRd followed by ASCT, DVRd, and lenalidomide. Study Design and Methods: Eligible patients are aged ≥18 years with NDMM per International Myeloma Working Group diagnostic criteria, have measurable disease at screening, and have high-dose therapy and ASCT as part of their intended initial treatment plan. Exclusion criteria are patients who have received any prior therapy for MM or smoldering myeloma (except a short course of corticosteroids). After giving informed consent, patients are randomized 1:1 into 2 treatment arms (target recruitment: N=750). In the cilta-cel arm, patients will undergo apheresis before receiving 6 cycles of DVRd induction. After induction, patients will receive lymphodepletion (intravenous cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2 daily for 3 days), followed by a single cilta-cel infusion (target dose 0.75×106 CAR+ viable T cells/kg) 5-7 days later. After the cilta-cel infusion, patients will receive lenalidomide post CAR-T therapy for 2 years (or longer, at investigator discretion). In the control arm, patients will receive 4 cycles of DVRd induction, followed by ASCT and 2 cycles of DVRd consolidation. Patients will then receive lenalidomide maintenance for 2 years (or longer at investigator discretion). The dual primary endpoints are progression-free survival (PFS) and minimal residual disease (MRD)-negative CR sustained for ≥12 months, with MRD status determined by next-generation sequencing at a sensitivity of at least 10-5. Secondary endpoints include ORR, ≥CR rate, overall MRD-negative CR rate, time to subsequent therapy, PFS on next-line therapy, overall survival, adverse events, pharmacokinetic/pharmacodynamic markers, and changes in health-related quality of life. Exploratory correlative biomarker analyses will also be performed. Enrollment opens in September 2022, with anticipated primary completion in June 2026. This study will investigate the efficacy and safety of a cellular therapy approach with cilta-cel versus standard of care ASCT in patients with NDMM who are transplant eligible. Figure: EMagine/CARTITUDE-6 Study Design Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Ciltacabtagene autoleucel (cilta-cel) consists of autologous T cells genetically modified to express a two-binding domain chimeric antigen receptor (CAR). The target antigen of the CAR is B-cell maturation antigen (BCMA), which is highly expressed on malignant plasma cells (PC) from multiple myeloma subjects. In the Phase 1b/2 CARTITUDE-1 study, cilta-cel led to early, deep, and durable responses and was approved for the treatment of patients with relapsed or refractory multiple myeloma (RRMM) after four or more prior lines of therapy by FDA. Despite cilta-cel's outstanding overall response rate (97.9%) and duration of response (DOR) in RRMM patients, relapse still occurs. Biomarkers associated with this durable response and acquired resistance remain to be elucidated. We present updated correlative data from the CARTITUDE-1 study. At the ~3 year follow-up (October 2022 data cutoff), 97 patients had received a single infusion of cilta-cel (median 0.71 x10 6 cells/kg [range 0.52 x10 6-0.94 x10 6]); the median follow up was 33.4 months (range 1.5-45.2), median DOR was 33.9 months (95% CI, 25.5-not estimable [NE]) and median PFS was 34.9 months (95% CI, 25.2-NE) (Lin Y et al, ASCO 2023). Drug product (DP), baseline and on-treatment whole blood and bone marrow samples from enrolled patients were analyzed by methods including flow cytometry, MSD immunoassays, Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq) and TCR sequencing. In CARTITUDE-1, the DP contained a mixture of transduced and non-transduced T cells; the median transduction efficiency was 16% (range 5-32%), with a balanced distribution of CAR+CD4+ and CAR+CD8+ cells, median frequency 12% (range 2-28%) and 6% (range 2-20%), respectively. Further, the DP T cell subset composition was variable but balanced between central (Tcm) and effector memory (Tem) phenotypes. CAR+ T cells expanded reaching a median peak concentration (C max of 730 cells/µL; range 3-13805 cells/µL) in blood between days 12-14 post-infusion and persisted in circulation for a median of 100 days (range 20-912 days). High efficacy (best response) and DOR were achieved despite variable CAR-T cell expansion and lack of detectable CAR-T cell persistence over time. At C max, the CD4:CD8 ratio (based on % of CAR+ cells) was 0.29, demonstrating a CAR+CD8+ T cell preferential expansion, and both CAR+CD4+ and CAR+CD8+ T cells were predominantly of a Tcm phenotype, median 95% (range 62-99.5%) and 96% (range 33-99.7%), respectively. Higher frequency of early-memory T cell phenotypes has been associated with clinical responses to CAR-T therapies in MM (Dancy et al., Blood 2018). CITE-seq analyses showed that DP characteristics such as a high CD8+ stem-like phenotype and a low CD4+ Treg-like phenotype in the CAR+ T cell compartment associated with longer DOR. Some of the most abundant clones in the DP single cell TCR data were CAR+CD8+ T cells expressing granzyme B, suggesting high cytotoxic potential. Additional bulk TCR sequencing data suggest both diversity and individual clonal expansion longitudinally after cilta-cel infusion. We also evaluated tumor and patient intrinsic characteristics at baseline. BCMA expression on bone marrow PC was prevalent and highly variable among RRMM patients; however, expression did not associate with best response or DOR. Further, high ORR was observed in patients with high-risk cytogenetics, high tumor burden (>= 60% bone marrow PC), or baseline plasmacytomas, although with a non-statistically significant shorter PFS. Sustained MRD negativity strongly associated with longer DOR. Conversely, patient-intrinsic characteristics associated with inflammation (CRP, ferritin, neutrophils, pro-inflammatory cytokines) correlated with shorter DOR. Treatment benefit of the magnitude seen with cilta-cel had not been reported with any other approved therapy in this setting. Correlative analyses suggest an emerging profile to help understand such outstanding clinical activity: a balanced CD4/CD8 ratio and Tcm/Tem phenotype of the manufactured DP and preferential expansion of CAR+CD8+ Tcm cells. Further, certain baseline patient-intrinsic and tumor characteristics may explain the longer DOR in the RRMM setting. These investigations help identify markers of response to cilta-cel and may lead to CAR-T cell design or manufacturing strategies that enhance drug product characteristics and thus clinical efficacy.

Background: Guidelines from the National Comprehensive Cancer Network recommend daratumumab, bortezomib, lenalidomide, and dexamethasone (DVRd) as induction therapy followed by autologous stem cell transplant (ASCT), consolidation, and maintenance therapy for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM). In the phase 1b/2 CARTITUDE-1 study, a single infusion of ciltacabtagene autoleucel (cilta-cel), a chimeric antigen receptor (CAR)-T cell therapy with two B-cell maturation antigen (BCMA)-targeting single-domain antibodies, resulted in deep and durable responses with manageable safety in heavily pretreated patients with relapsed/refractory multiple myeloma. The overall response rate (ORR) was 98% (median follow-up of 27.7 months), with 83% of patients achieving stringent complete response (CR); median duration of response was not reached. The aim of this open-label, multicenter, global, phase 3 EMagine/CARTITUDE-6 study (EMN28/68284528MMY3005; NCT05257083) is to evaluate the efficacy of DVRd followed by cilta-cel and lenalidomide versus DVRd followed by ASCT, DVRd, and lenalidomide. Study design and methods: Patients aged ≥18 years with NDMM (per International Myeloma Working Group criteria), measurable disease at screening, and high-dose therapy and ASCT as part of their intended initial treatment plan are eligible. Patients are excluded if they received any prior therapy for multiple myeloma or smoldering myeloma, except a short course of corticosteroids. After providing informed consent, patients are randomized (1:1) into 2 treatment arms, with target recruitment of N=750. In the cilta-cel arm, patients will undergo apheresis before receiving 6 cycles of DVRd induction treatment. After induction, patients will first receive lymphodepletion (intravenous cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2 daily for 3 days), and then a single infusion of cilta-cel (target dose 0.75×106 CAR+ viable T cells/kg) 5–7 days later. Following cilta-cel infusion, patients will be given lenalidomide post CAR-T therapy for 2 years (or longer, per investigator discretion). The patients in control arm will receive 4 cycles of DVRd induction, then ASCT and 2 cycles of DVRd consolidation, followed by lenalidomide maintenance therapy for 2 years (or longer, per investigator discretion). Dual primary endpoints are progression-free survival (PFS) and minimal residual disease (MRD)-negative CR sustained for ≥12 months. MRD status is assessed by next-generation sequencing at a sensitivity of at least 10-5. The secondary endpoints include ORR, ≥CR rate, overall MRD-negative CR rate, time to subsequent therapy, PFS on next-line therapy, overall survival, adverse events, pharmacokinetic/pharmacodynamic markers, and health-related quality of life. Exploratory correlative biomarker analyses will also be conducted. Enrollment began in September 2022, with expected primary completion in June 2026. This study will explore a cellular therapy approach with cilta-cel versus standard of care ASCT in transplant-eligible patients with NDMM.