Impact of Daratumumab Refractoriness on Clinical Outcomes Following CAR T-Cell Therapy for Relapsed/Refractory Multiple Myeloma

Introduction: Ciltacabtagene autoleucel (cilta-cel) and idecabtagene vicleucel (ide-cel) are two chimeric antigen receptor (CAR) T-cell products targeting B-cell maturation antigen (BCMA) that have recently been approved for the treatment of relapsed/refractory multiple myeloma (RRMM) with 1-2 prior lines of therapy, based on the results of CARTITUDE-4 and KarMMa-3 trials. While daratumumab (dara) refractoriness is predictive of inferior outcomes with subsequent therapies, not all patients enrolled in these pivotal trials were refractory to this anti-CD38 monoclonal antibody. Therefore, we conducted a single-center retrospective cohort study comparing the clinical outcomes of RRMM patients who received BCMA-directed CAR T-cell therapy based on their dara refractoriness status.

Methods: Our analysis included all patients with RRMM who received ide-cel, cilta-cel, or orvacabtagene autoleucel (orva-cel) between April 2018 and November 2023. All patients were dara exposed and divided into two groups according to their dara refractoriness status: dara refractory (DR) and dara non-refractory (DN). Refractory disease was defined according to IMWG criteria as disease that did not respond to therapy (failing to achieve a partial response or better) or as progressive disease within 60 days of the last administered dose. Key outcomes of interest included progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and incidence of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Survival outcomes were calculated from the date of infusion. Response categories were determined per IMWG consensus definitions. CRS/ICANS were graded based on ASTCT criteria.

Results: Of 127 patients included (41% female, age range: 37-86 years) in the analysis, 28 (22%) were considered DN at the time of CAR T-cell infusion. In the DR group (n=99), 41.4% patients received cilta-cel, 31.3% patients received ide-cel, and 27.3% patients received orva-cel. In the DN group (n=28), 50% patients received cilta-cel, 32.1% patients received ide-cel, and 17.9% patients received orva-cel. All patients except one in the DN group were triple class exposed. The analyzed groups (DR vs DN) had comparable rates of patients with ECOG performance status >0 (68.7% vs 60.7%) and high-risk cytogenetic abnormalities (70.7% vs 71.4%), including del(17p)/TP53 mutation, t(4;14), t(14;16), t(14;20), 1q gain/amp and/or del(1p) by FISH analysis. In contrast, the DR group had higher rates of extramedullary disease (EMD) (46.5% vs 28.6%), prior BCMA-directed therapy (24.2% vs 7.1%), prior T-cell-redirecting therapy (13.1% vs 3.6%), high tumor burden (defined as ≥50% bone marrow plasma cells) (28.3% vs 14.3%), and a higher median number of prior lines of therapy (6 vs 4).

With a median follow-up of 12 months (range: 1-72 months) for the entire population, best ORR was 77.7% (40% sCR/CR, 22% VGPR, 15% PR) in the DR group vs 85.7% (50% sCR/CR, 14% VGPR, 21% PR) in the DN group. The 12-month PFS was 38% (95% CI: 28-not reached [NR]) in the DR group vs 57% (95% CI: 37-NR) in the DN group (HR: 0.6, p=0.08). The 12-month OS was 74% (95% CI: 64-NR) in the DR group and 86% (95% CI: 68-NR) in the DN group (HR: 0.56, p=0.18). CRS and ICANS rates were similar between the two groups: 74.7% (4% grade ≥3) and 13.1% (2% grade ≥3), respectively, in the DR group, and 78.6% (4% grade ≥3) and 21.4% (0% grade ≥3), respectively, in the DN group.

Conclusion: A majority of patients treated with BCMA-directed CAR T for RRMM in this single-center experience were dara refractory. Despite more prior lines of therapy and higher rates of EMD, high tumor burden, prior BCMA-directed therapy, and prior T-cell-redirecting therapy; the DR group showed comparable efficacy outcomes to DN group. Longer follow up with more patients, as well as details of efficacy and safety outcomes with univariate and multivariate analysis will be presented at the meeting.

Lesokhin:Memorial Sloan Kettering Cancer Center: Current Employment; Arcellx: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Serametrix, Inc.: Patents & Royalties; F. Hoffmann-La Roche Ltd, Janssen, SVB Leerink: Consultancy, Honoraria. Shah:Janssen, Amgen, Beyond Spring, BMS, GPCR, DSMB with ArcellX.: Research Funding. Korde:Remedy Health 8/2022: Other: part of (Patient Power); Amgen, Janssen, Epizyme, and AbbVie: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; CCO, OncLive, and Intellisphere: Consultancy. Tan:Takeda: Research Funding; Sanofi: Honoraria; Janssen: Honoraria, Research Funding. Landau:Abbvie, Immix Biopharma, Legend Biotech, Alexion, Prothena: Consultancy; Janssen, Alexion, Protego, Prothena: Research Funding. Scordo:Amgen: Research Funding; Omeros Corporation: Consultancy, Research Funding; IDEOlogy: Honoraria; Kite - A Gilead Company: Consultancy; MJH Life Sciences (Cancer Network): Honoraria; Angiocrine Biosciences, Inc.: Research Funding; Sanofi: Research Funding; Miltenyi Biotec: Consultancy; Medscape: Honoraria. Hassoun:Janssen, Takeda: Research Funding. Shah:Janssen: Honoraria, Research Funding; Bristol Myers Squibb: Research Funding; Sanofi: Honoraria. Hultcrantz:Abbvie, GlaxoSmithKline, SpringWorks Therapeutics, Daiichi Sankyo, Cosette Pharmaceuticals: Research Funding; Curio Science LLC, Intellisphere LLC, Janssen, Bristol Myers Squibb, and GlaxoSmithKline: Consultancy, Honoraria. Mailankody:BMS, J&J, GSK, Springworks Therapeutics: Research Funding. Usmani:Sanofi: Consultancy, Research Funding; Gracell: Consultancy; EdoPharma: Consultancy; Array Biopharma: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Genentech: Consultancy; Merck: Research Funding; Pharmacyclics: Research Funding; Oncopeptides: Consultancy; Sanofi: Consultancy, Research Funding; SeaGen: Consultancy, Research Funding; SecuraBio: Consultancy; SkylineDX: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Gilead: Research Funding; Amgen: Consultancy, Research Funding; Bristol-Myers Squibb - Celgene:: Consultancy, Research Funding; GSK: Consultancy, Research Funding; Pfizer: Consultancy; Abbvie: Consultancy, Research Funding; TeneoBio: Consultancy; Bristol-Myers Squibb - Celgene: Consultancy, Research Funding; Johnson & Johnson - Janssen: Consultancy, Research Funding.