Efficacy and safety of cilta-cel in patients with progressive multiple myeloma after exposure to other BCMA-targeting agents

Abstract

B-cell maturation antigen (BCMA)-targeting therapies, including bispecific antibodies (BsAbs) and antibody-drug conjugates (ADC), are promising treatments for multiple myeloma (MM), but disease may progress after their use. CARTITUDE-2 is a phase 2, multicohort study evaluating the safety and efficacy of cilta-cel, an anti-BCMA chimeric antigen receptor T therapy, in various myeloma patient populations. Patients in cohort C progressed despite treatment with a proteasome inhibitor, immunomodulatory drug, anti-CD38 antibody, and non‑cellular anti-BCMA immunotherapy. A single cilta-cel infusion was given after lymphodepletion. The primary end point was minimal residual disease (MRD) negativity at 10−5. Overall, 20 patients were treated (13 ADC-exposed; 7 BsAb-exposed; 1 in the ADC group also had prior BsAb exposure); 16 (80%) were refractory to prior anti-BCMA therapy. At a median follow-up of 11.3 months (range, 0.6-16.0), 7/20 (35%) patients were MRD-negative (7/10 [70.0%] in the MRD-evaluable subset). Overall response rate (95% CI) was 60.0% (36.1-80.9). Median duration of response and progression-free survival (95% CI) were 11.5 (7.9-not estimable) and 9.1 (1.5-not estimable) months, respectively. The most common adverse events were hematologic. Cytokine release syndrome occurred in 12 (60%) patients (all grade 1/2); 4 had immune effector cell-associated neurotoxicity syndrome (2 grade 3/4); none had parkinsonism. Seven (35%) patients died (3 of progressive disease, 4 of adverse events [1 treatment-related, 3 unrelated]). Cilta-cel induced favorable responses in patients with relapsed/refractory MM and prior exposure to anti-BCMA treatment who have exhausted other therapies. This trial was registered at www.clinicaltrials.gov as #NCT04133636.

Eight‐color multiparameter flow cytometry (EuroFlow‐NGF) is as sensitive as next‐generation sequencing in detecting minimal/measurable residual disease in autografts of patients with multiple myeloma

“…Because MRD levels can be greatly reduced by the development of novel agents such as proteasome inhibitors, IMiDs, monoclonal antibodies [ 17 ], BiTEs [ 18 ], and CAR‐T [ 19 , 20 ], innovative high‐sensitivity MRD detection methods have become increasingly important. Conventional MRD detection methods such as NGS and NGF have been applied to BM because MM has a strong effect on BM.…”

“…Even if MRD negativity in the BM was achieved, relapses may originate from extramedullary lesions [ 24 ]. On the other hand, MRD levels in peripheral blood cells reflect the tumor burden in the whole body of patients with MM [ 25 , 26 ], although only a few studies focused on the usefulness of MRD levels detected in peripheral blood, including autografts [ 6 , 7 , 20 ] using highly sensitive MRD detection methods.…”

Current Main Topics in Multiple Myeloma

“…The observation of disease relapses during anti-BCMA therapies and the lack of effective therapeutic strategies afterwards have fostered some research on the efficacy of re-treating patients with the same class of drugs. Currently, a definitive rule of optimal sequence cannot be given, but when CART are used after BsAbs or ADC, the length of exposure to anti-BCMA and the free interval from BsAb/ADC to CART could be considered the most important predictive factors of response to re-treatment [ 230 ]. ADC followed by BsAbs-CART is the most frequent utilized anti-BCMA sequence because ADC were available all over the world before than BsAbs/CART.…”

Noninfectious causes of fever in hematologic malignancies. Are antibiotics still indicated?

“…Fever frequently occurs after CAR-T therapy. The frequency of fever varies by specific CAR-T product, ranging from 25% of patients treated with idecabtagene vicleucel for relapsed/refractory multiple myeloma (in the KarMMa trial) to 94% of patients treated with brexucabtagene autoleucel for relapsed/refractory mantle cell lymphoma (in the ZUMA-2 trial) [6][7][8][9][10][11] (Table 1). CRS, which occurs in most patients receiving CAR-T therapy, is almost always associated with fever [6][7][8][9][10][11].…”

“…The frequency of fever varies by specific CAR-T product, ranging from 25% of patients treated with idecabtagene vicleucel for relapsed/refractory multiple myeloma (in the KarMMa trial) to 94% of patients treated with brexucabtagene autoleucel for relapsed/refractory mantle cell lymphoma (in the ZUMA-2 trial) [6][7][8][9][10][11] (Table 1). CRS, which occurs in most patients receiving CAR-T therapy, is almost always associated with fever [6][7][8][9][10][11]. Details on infections are not reported in many clinical trials for CAR-T therapies, though in the aforementioned ZUMA-2 trial, 56% of patients had an infection, so clearly, fever and other manifestations of CRS were often unrelated to infection [11].…”