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The cilta-cel adverse event (AE) profile was consistent with that of the CAR-T class, which includes immune-related toxicities like cytokine release syndrome (CRS) and neurologic events like immune effector cell–associated neurotoxicity syndrome (ICANS) [6, 7]. Patients Infused With Cilta-cel as Study Treatment, N Patients With CNP, n (%) Maximum CNP Severity, n (%) Cranial Nerve Involvement in Addition to Cranial Nerve VII, n (% [Nerve, Grade]) Grade 2 Grade 3 CARTITUDE-1 97 3 (3.1) 2 (2.1) 1 (1.0) 1 (1.0 [V, 3]) CARTITUDE-2, cohort A/initial group 20 1 (5.0) 1 (5.0) 0 0 CARTITUDE-2, cohort B 19 1 (5.3) 1 (5.3) 0 0 CARTITUDE-2, cohort C 20 0 – – – CARTITUDE-4 176 16 (9.1) 14 (8.0) 2 (1.1) 2 (1.1 [III, 3; V, 3]) Total 332 21 (6.3) 18 (5.4) 3 (0.9) 3 (0.9) Cilta-cel ciltacabtagene autoleucel, CNP cranial nerve palsy. Ad hoc correlative analyses of drug product characteristics, CAR-T dose, and immunophenotypes of samples from CARTITUDE-4 are summarized in Supplementary Results. Pharmacokinetics showed significantly higher CAR-T peak expansion and exposure levels in patients with versus without CNP (Fig.

ABSTRACT Background Early (often continuous) treatment of multiple myeloma (MM) with lenalidomide has become common practice, leading to an increase in lenalidomide‐refractory disease. Methods We report real‐world treatment patterns, health care resource utilization (HCRU), and outcomes for patients with lenalidomide‐refractory MM using data from Optum US Claims and Optum electronic health record (EHR) databases with index date from January 2016 to March 2022 (Claims) or December 2021 (EHR). Eligible patients had received 1–3 prior lines of therapy (LOT), including a proteasome inhibitor. Results A total of 1383 and 1597 patients with lenalidomide‐refractory disease were included from the Claims and EHR databases, respectively, with median ages of 72 and 68 years and mean Charlson Comorbidity Index scores of 4.0 and 3.1. The most common treatment combinations were daratumumab–pomalidomide–dexamethasone, daratumumab–bortezomib–dexamethasone, and pomalidomide–dexamethasone (~5% each). From LOT 2 to LOT 6, treatment attrition (patients who died or received no further treatment) was 95.2% to 95.9%. Median time to next treatment was 5.4 (Claims) and 5.9 months (EHR). Median OS was 35.2 (Claims) and 41.2 months (EHR). HCRU was consistent across LOT. Conclusions Patients with lenalidomide‐refractory MM who received 1–3 prior LOT had poor outcomes and moved quickly through available therapies, demonstrating an unmet need to improve outcomes in this difficult‐to‐treat patient population.

Ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen (BCMA)-directed CAR T-cell therapy, is effective in heavily pretreated patients with relapsed or refractory multiple myeloma. We investigated cilta-cel in earlier treatment lines in patients with lenalidomide-refractory disease. In this phase 3, randomized, open-label trial, we assigned patients with lenalidomide-refractory multiple myeloma to receive cilta-cel or the physician's choice of effective standard care. All the patients had received one to three previous lines of treatment. The primary outcome was progression-free survival. A total of 419 patients underwent randomization (208 to receive cilta-cel and 211 to receive standard care). At a median follow-up of 15.9 months (range, 0.1 to 27.3), the median progression-free survival was not reached in the cilta-cel group and was 11.8 months in the standard-care group (hazard ratio, 0.26; 95% confidence interval [CI], 0.18 to 0.38; P<0.001). Progression-free survival at 12 months was 75.9% (95% CI, 69.4 to 81.1) in the cilta-cel group and 48.6% (95% CI, 41.5 to 55.3) in the standard-care group. More patients in the cilta-cel group than in the standard-care group had an overall response (84.6% vs. 67.3%), a complete response or better (73.1% vs. 21.8%), and an absence of minimal residual disease (60.6% vs. 15.6%). Death from any cause was reported in 39 patients and 46 patients, respectively (hazard ratio, 0.78; 95% CI, 0.5 to 1.2). Most patients reported grade 3 or 4 adverse events during treatment. Among the 176 patients who received cilta-cel in the as-treated population, 134 (76.1%) had cytokine release syndrome (grade 3 or 4, 1.1%; no grade 5), 8 (4.5%) had immune effector cell-associated neurotoxicity syndrome (all grade 1 or 2), 1 had movement and neurocognitive symptoms (grade 1), 16 (9.1%) had cranial nerve palsy (grade 2, 8.0%; grade 3, 1.1%), and 5 (2.8%) had CAR-T-related peripheral neuropathy (grade 1 or 2, 2.3%; grade 3, 0.6%). A single cilta-cel infusion resulted in a lower risk of disease progression or death than standard care in lenalidomide-refractory patients with multiple myeloma who had received one to three previous therapies. (Funded by Janssen and Legend Biotech; CARTITUDE-4 ClinicalTrials.gov number, NCT04181827.).

Minimal residual disease (MRD) negativity is an important predictor of long-term treatment outcomes in multiple myeloma. In CARTITUDE-1, treatment with the chimeric antigen receptor-T cell (CAR-T) therapy ciltacabtagene autoleucel (cilta-cel) resulted in MRD negativity in 92% of evaluable patients with relapsed/ refractory multiple myeloma (RRMM). Although MRD negativity is generally associated with longer progression-free survival (PFS), the relationship between sustained MRD negativity and other efficacy outcomes in CARTITUDE-1 has not been established. We describe how MRD-negativity status was assessed in CARTITUDE-1 and 1report CARTITUDE-1 efficacy outcomes of patients with sustained MRD negativity. Patients (N=97) with RRMM and prior treatment with >3 lines of therapy, including a proteosome inhibitor, immunomodulatory drug, and anti-CD38 monoclonal antibody, received a single infusion of cilta-cel. Using next-generation sequencing (NGS), MRD negativity was assessed (Figure). Bone marrow aspirate was collected from patients at baseline to identify cells with gene mutations, known as myeloma clones, and then collected at day 28 and months 6, 12, 18, and 24 posttreatment to assess frequency of these clones. Calibration and quality-control testing were used to verify that samples had sufficient cells to detect MRD negativity, defined as <1 myeloma cell in 105 nucleated cells. Patients were characterized by length of MRD negativity (<6 months, 6-12 months, ≥12 months); patients with 2 MRD-negative results ≥6 months apart (before progression or subsequent treatment) were considered to have sustained MRD negativity. Duration of response (DOR) and PFS were compared between patients with versus without sustained MRD negativity. Of 61 patients whose samples passed calibration and quality-control standards for MRD evaluation via NGS, 56 (92%) achieved MRD negativity; sustained MRD negativity was observed for <6 months in 22 patients, 6 to 12 months in 10 patients, and >12 months in 24 patients. Patients with sustained MRD negativity had longer median (95% CI) DOR (612 months: NE [12.5 mo, NE]; >12 months: NE [NE, NE]) and PFS (6-12 months: NE [13.4 months, NE]; >12 months: NE [NE, NE]) compared with patients with sustained MRD negativity for <6 months (DOR: 10.3 months [5.1, 15.6]; PFS: 11.0 months [5.4, 16.6]). Discussion: Sustained MRD negativity was a meaningful measure of response in CARTITUDE-1 and was associated with favorable outcomes. Nurse practitioners should understand the importance of baseline sampling for MRD assessments and the significance of this outcome for clinical practice.