Cellular and T cell engager Immunotherapy

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

P-011: Impact of Daratumumab Refractoriness on Clinical Outcomes Following CAR T-cell Therapy for Relapsed/Refractory Multiple Myeloma

Friday, September 27, 2024

Bruno A. Costa, MD (he/him/his)

Myeloma Research Affiliate
Icahn School of Medicine at Mount Sinai & Memorial Sloan Kettering Cancer Center
New York, New York, United States

Introduction: Ciltacabtagene autoleucel (cilta-cel) and idecabtagene vicleucel (ide-cel) are two chimeric antigen receptor T-cell (CAR T) products recently approved for the treatment of relapsed/refractory multiple myeloma (RRMM) with 1-2 prior lines of therapy (LOT) 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 (pts) enrolled in these pivotal trials were dara refractory. We conducted a single-center retrospective analysis to compare the outcomes of RRMM pts who received BCMA-directed CAR T-cell therapy based on dara refractoriness status.

Methods: Our analysis included all pts with RRMM who received ide-cel, cilta-cel, or orvacabtagene autoleucel (orva-cel) between April 2018 and November 2023. All pts were dara exposed and divided into two groups according to their dara refractoriness status: dara refractory (DR) and dara non-refractory (DN). 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). Response categories were determined per IMWG consensus definitions. CRS/ICANS were graded based on ASTCT criteria.

Results: Of 127 pts included (age range: 37-86 years) in the analysis, 28 (22%) were DN at the time of cell infusion. The analyzed groups (DR vs DN) had comparable rates of pts 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). 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%) and prior LOT (6 vs 4). With a median follow-up of 12 months (range: 1-72) 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.

Conclusions: A majority of pts treated with BCMA-directed CAR T for RRMM in this single-center experience were dara refractory. Despite more prior LOT, higher rates of EMD, and higher rates of prior BCMA-directed therapy, the DR group showed similar 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.