Background:

 

CARTITUDE-4 is a global, phase 3, randomized, controlled trial (NCT04181827) of ciltacabtagene autoleucel (cilta-cel), a dual-binding, B-cell maturation antigen-targeting chimeric antigen receptor (CAR)-T cell therapy, versus (vs) standard of care (SOC; pomalidomide, bortezomib, and dexamethasone [PVd] or daratumumab, pomalidomide, and dexamethasone [DPd]) in lenalidomide-refractory patients.

 

Aims:

 

To report results of the first phase 3 study evaluating efficacy and safety of cilta-cel vs SOC in lenalidomide-refractory patients treated with 1-3 prior lines of therapy (LOT).

 

Methods:

 

Eligible patients had 1–3 prior LOT, including proteasome inhibitors (PI) and immunomodulatory drugs, and were lenalidomide-refractory. After apheresis, patients randomized to cilta-cel received PVd or DPd (physician’s choice) bridging therapy, then 1 cilta-cel infusion (target dose 0.75×106 CAR+ viable T cells/kg) 5–7 days after lymphodepletion. In the SOC group, patients received PVd or DPd (physician’s choice) until disease progression. The primary endpoint was progression-free survival (PFS), analyzed in the intent-to-treat (randomized) population. Informed consent was obtained prior to study entry.

 

Results:

 

419 patients were randomized (cilta-cel, n=208; SOC, n=211 [PVd, n=28; DPd, n=183]). 176 patients received planned cilta-cel treatment, 20 more received cilta-cel after progressive disease (PD) during bridging therapy, and 208 received SOC treatment. There were no manufacturing failures. Baseline characteristics were balanced (cilta-cel vs SOC: 59% vs 63% cytogenetic high risk [including gain/amp 1q]; 50% vs 46% PI refractory; 24% vs 22% anti-CD38 refractory; 33% vs 32% had 1 prior LOT). Median dose of cilta-cel was 0.71×106 CAR+ viable T cells/kg. At Nov 1, 2022, data cut-off, median follow-up was 16 months (range, 0.1–27). The primary endpoint was met; cilta-cel reduced risk of progression/death by 74% (Hazard ratio [HR]=0.26; P-value [P] <0.0001). Patients in the cilta-cel group had significantly improved overall response rate, rate of complete response (CR) or better, and overall minimal residual disease (MRD) negativity rate compared to the SOC group (Table), with a positive trend in overall survival (HR, 0.78; 95% CI, 0.5–1.2). 97% and 94% of patients treated in the cilta-cel and SOC groups, respectively, had grade 3/4 adverse events, including infections (27% vs 25%) and cytopenias (94% vs 86%). In the cilta-cel and SOC groups, respectively, 39 and 46 patients died (14 and 30 due to PD). In patients who received cilta-cel as study treatment (n=176), 76% had cytokine release syndrome (1% grade 3; no grade 4/5) and 5% had immune effector cell associated neurotoxicity syndrome (all grade 1/2). A single case of movement and neurocognitive treatment-emergent adverse event was reported (grade 1).

 

Summary/Conclusion:

 

A single cilta-cel infusion significantly improved PFS vs SOC in lenalidomide-refractory patients with 1–3 prior LOT, with a favorable benefit/risk profile across patient populations. The 74% reduction in progression/death and high rates of CR and MRD-negativity highlight the potential for cilta-cel to become a key therapy for patients with multiple myeloma after first relapse.

   Copyright © 2023.  All rights reserved.

 

Background:

 

Heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM) treated with standard of care therapy have median overall survival (OS) of ~12 months. In the single- arm, phase 1b/2 CARTITUDE-1 study (NCT03548207), patients received a single infusion of ciltacabtagene autoleucel (cilta-cel), a chimeric antigen receptor-T cell therapy targeting B- cell maturation antigen. At the final protocol-specified analysis (27.7-month median follow- up), overall response rate (ORR) was 98%, with 83% stringent complete response; 27- month rates of progression-free survival (PFS) and OS were 55% and 70%, respectively.

 

Aims:

 

To report CARTITUDE-1 study close out efficacy and safety results.

 

Methods:

 

Informed consent was obtained prior to study entry. Enrolled patients had received ≥3 prior lines of therapy (LOT) or were double refractory to a proteasome inhibitor (PI) and immunomodulatory drug (IMiD); and had received prior PI, IMiD, and anti-CD38 antibody therapy. Primary endpoint was ORR and safety; secondary endpoints included PFS, OS, and minimal residual disease (MRD)-negativity at 10-5.

 

Results:

 

97 patients received cilta-cel (59% male; median age 61 years; median of 6 prior LOT; 42% penta-drug refractory; 88% triple-class refractory; 99% refractory to last LOT). As of October 14, 2022, median follow-up was 33.4 months (range, 1.5−45.2). Median duration of response was 33.9 month (95% CI, 25.5–not estimable [NE]). Median PFS was 34.9 months (95% CI, 25.2–NE), with an estimated 47.5% of patients progression free and alive at 36 months. Median OS was not reached, with an estimated 62.9% survival at 36 months. Of 49 MRD-evaluable patients, 26 had MRD-negativity sustained for ≥12 months, of which 20 had sustained MRD-negative complete response (CR) or better. Median PFS was not reached in these subgroups (Table). Eighteen patients were MRD-negative with ≥CR at 24-months post infusion. No new safety signals and no new neurotoxicity events were reported since the 27.7-month median follow-up. Six new cases of second primary malignancy were reported, including 2 cases of basal cell carcinoma and 1 case each of myelodysplastic syndrome, B- cell lymphoma, melanoma, and prostate cancer. Five additional deaths occurred (progressive disease [PD], n=3; pneumonia and sepsis, n=1 each [both unrelated to cilta- cel]), for a total of 35 deaths (PD, n=17; unrelated to cilta-cel, n=12; related, n=6).

 

Summary/Conclusion:

 

Longer median PFS was observed after a single infusion of cilta-cel than any previously reported therapy in heavily pretreated patients with RRMM. Achieving CR and/or sustained MRD-negativity was associated with prolonged PFS. Patients continue to be followed for safety and survival in the 15-year CARTINUE long-term study (NCT05201781; MMY4002).

   Copyright © 2023.  All rights reserved.

   

 

Background:

 

LCAR-B38M CAR-T cells express a structurally differentiated chimeric antigen receptor (CAR) construct containing a 4-1BB costimulatory domain and 2 BCMA-targeting single-domain antibodies designed to confer avidity. LEGEND-2 was a first-in-human phase 1 study of LCAR-B38M conducted in China, which showed encouraging efficacy and manageable safety in 74 patients with relapsed or refractory multiple myeloma (RRMM). The US phase 1b/2 CARTITUDE-1 and Chinese phase 2 CARTIFAN-1 trials of ciltacabtagene autoleucel, which expresses the same CAR as LCAR-B38M, confirmed the efficacy observed in LEGEND-2. Here, we present ≥5-year follow-up data from LEGEND-2, the longest follow-up for any BCMA-targeted CAR-T cell therapy study.

 

Aims:

 

To report the efficacy and safety of LCAR-B38M after at least 5 years of follow-up in LEGEND-2.

 

Methods:

 

Study design was previously published. All patients in the trial provided informed consent. Patients underwent lymphodepletion with cyclophosphamide 300 mg/m2 (n=66) or cyclophosphamide 250 mg/ m2 plus fludarabine 25 mg/m2 (n=8) prior to receiving LCAR-B38M at a median dose of 0.51 × 106 (range, 0.07-2.10 × 106) CAR-positive T cells/kg in a single (n=9) or 3 split (n=65) infusions.

 

Results:

 

Patients were enrolled from 30 March 2016 to 26 November 2017. As of 30 November 2022, median follow-up was 65.4 months (range, 0.4-78.8). 74 patients had received LCAR-B38M (median age, 54.5 years; 60.8% male; median [range] 3 [1-9] prior lines of therapy [LOT]; 44.6% ISS stage I; 28.4% ISS stage III; 29.7% with extramedullary disease (EMD); 35.7% cytogenetic high risk). No new CAR-T cell-related toxicities were reported in the analysis. Overall response rate (87.8%), complete response (CR) rate (73.0%), minimal residual disease-negative CR rate (67.6%), median duration of response (23 months), and median progression-free survival (18 months) were mature and the same as previously reported; median overall survival (OS) was previously not reached. At 65.4-month median follow-up, median OS was 55.8 months, with 33 (44.6%) patients alive and 13 (17.6%) still disease- free. Compared with patients with progressive disease (PD) or who died, patients without PD were more likely to have baseline ECOG performance status (PS) 0, IgG type MM, ISS stage I MM, numerically shorter time from diagnosis, fewer prior LOT, no light chain MM, and no EMD (Table).

 

Summary/Conclusion:

 

At ≥5-year follow-up in LEGEND-2, median OS was 55.8 months and 18% of patients with RRMM were disease-free, raising the possibility of a cure in this heavily pretreated patient population. Our data suggest that patients who are less heavily pretreated or have good functional status may experience greater benefit, potentially being cured, from LCAR-B38M CAR-T cell therapy.

  Copyright © 2023.  All rights reserved.