Introduction: Functional high-risk multiple myeloma (FHRMM) is defined through dynamic assessment of disease kinetics after treatment initiation and is generally associated with poor prognosis. When compared to traditional salvage chemotherapy, CAR T has shown superior efficacy as earlier line of therapy (LOT) (1-2) for FHRMM (CARTITUDE-4). However, outcomes with its use in later lines (3+) for FHR disease remain unknown. Here, we describe a single center experience of FHRMM patients (pts) receiving CAR T-cell therapy.

Methods: FHRMM was defined as with progressive disease (PD) <24 months of frontline therapy. Primary objective was to determine efficacy outcomes including best overall response (ORR), progression free survival (PFS), and overall survival (OS). Secondary objective was to determine safety outcomes including cytokine release syndrome (CRS), Immune effector associated neurotoxicity syndrome (ICANS), cytopenias, and infection rates within 90 days post CAR T. Cox regression analyses were performed to determine predictors of efficacy in multivariable analyses (MVA).

Results: The study included 177 pts treated with CAR T from 3/2018 until 10/2024 with 103 (58%) FHR and 74 (42%) non-FHR pts. Of these 103 FHR pts, 49 (48%) had PD <12 months of frontline therapy. Median pt age was 65 (range 39-86) years with 63 (36%) pts >70 years of age at time of CAR T infusion. A total of 102 (58%), 47 (27%), and 28 (16%) pts had received ciltacabtagene autoleucel (cilta-cel), idecabtagene viculeucel (ide-cel), and investigational B-cell maturation antigen (BCMA) directed autologous CAR T product, respectively. A total of 64 (36%) pts had extramedullary disease (EMD), 34 (19%) had high disease burden (>50% bone marrow involvement), and 94 (54%) had high-risk cytogenetics (HRCG) defined as presence of deletion 17p, t(4;14), t(14;16) on FISH at the time of CAR T. Median prior LOT was 5 (2-14) with 97% of pts having received 3+ LOT, all pts were triple class exposed, 150 (85%) were anti CD38 monoclonal antibody refractory, and 31 (18%) pts had received prior BCMA directed therapy. Baseline characteristics were balanced between the two groups except FHR pts had higher rates of EMD (42% vs 28%) and HRCG (58% vs 47) and shorter median time from autologous transplant to CAR T (31 vs 70 months) compared to the non-FHR pts. With the median follow-up of 16 (95% CI 15-20) months, no differences were seen in the best ORR (84% vs 80%, p=0.4) or CR or better rates (42% vs 47%, p=0.3) between the FHR and non-FHR groups, respectively. The median PFS were 9.2 and 13 months (p=0.3), with 12-month PFS of 42% and 52% in the FHR and non-FHR groups, respectively. Within the FHR group, pts with PD <12 months of frontline therapy had median PFS of 8.3 months vs 12 months in pts with PD 12-24 months post frontline therapy (p=0.5). On MVA stratified by CAR-T product, EMD (HR 2.38, 95% CI 1.52-3.74, p=<.001), high disease burden (HR 2.35, 95% CI 1.47-3.75, p=<.001), and prior BCMA therapy (HR 2.21, 95% CI 1.24-3.95, p=0.008) were associated with inferior PFS. At data cutoff, median OS were 29 and 55 months (p=0.038), with 12-month OS of 78% and 87% in the FHR and non-FHR groups, respectively. Within the FHR group, pts with PD <12 months of frontline therapy had median OS of 29 months vs 26 months in pts with PD 12-24 months post frontline therapy (p=0.1). On MVA stratified by CAR-T product, after adjusting for all significant covariates, only EMD (HR 2.41, 95% CI 1.32-4.42, p=.004) and high disease burden (HR 2.57, 95% CI 1.39-4.74, p=0.003) were associated with inferior OS.

There were no significant differences in the rates of CRS (all grade 76% vs 74%, grade 3+ 5% vs 3.6%), ICANS (all grade 12% vs 11%), cytopenias (all grade 51% vs 57%, grade 3+ 26% vs 19%) and infections within 90 days (all grade 43% vs 47%, grade 3+ 16% vs 15%) between FHR and non-FHR pts, respectively. However, patients with FHR disease had higher rates of grade 3 ICANS (5% vs 0%, p=.032).

Conclusion: FHRMM pts receiving CAR T as later LOT have inferior survival outcomes compared to those with non-FHR disease, underscoring the poor prognostic impact of PD <24 months from frontline therapy. This association was largely driven by active EMD and high disease burden at the time of CAR T, highlighting the potential benefit of utilizing CAR T as an early LOT for FHRMM. Our findings need to be confirmed with focus on outcomes of FHRMM with CAR T in clinical trials and real-world evidence.

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2025
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