Cilta-cel or Standard Care in Lenalidomide-Refractory Multiple Myeloma.

BACKGROUND: 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. METHODS: 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. RESULTS: 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%). CONCLUSIONS: 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.).

Real-world treatment patterns and outcomes in relapsed/refractory multiple myeloma (1-3 prior lines): Flatiron database.

In multiple myeloma (MM), early use of the immunomodulatory drug lenalidomide has led to an increased population of patients with lenalidomide-refractory MM in early-line settings, but their outcomes are not well characterized. Here, we report treatment patterns, survival outcomes, prognostic variables, and attrition rates for patients with proteasome inhibitor-exposed, lenalidomide-refractory MM, treated with 1-3 prior lines of therapy (LOT). From 12 767 patients with MM in the Flatiron Health database between January 2016 and April 2022, 1455 met the inclusion criteria. The most common subsequent treatments were triplet combinations (41.6% of patients); daratumumab/pomalidomide/dexamethasone was the most common treatment regimen (13.2%). Median real-world progression-free survival (RW-PFS) and overall survival (OS) were 6.5 months and 44.4 months, respectively. RW-PFS was similar in patients with 1, 2, or 3 prior LOT. International Staging System stage III, Eastern Cooperative Oncology Group performance status of 1, hemoglobin <12 g/dL, high-risk cytogenetics, and refractoriness to anti-CD38 antibody at baseline were associated with worse RW-PFS and OS. Outcomes remained similar for patients who received National Comprehensive Cancer Network-preferred treatments and those who received treatments after 2020. In 561 patients with 1 prior LOT at inclusion, cumulative attrition rate from LOT 2-5 was 85%, which included 25% patients who died and 60% with no further treatment. Patients with lenalidomide-refractory MM who have received 1-3 prior LOT have poor outcomes and progress rapidly through available therapies, highlighting the need for more effective treatments early in the disease course, before patients are lost to attrition.