Key Takeaways:

• A US multicenter analysis found that functional high-risk (FHR) disease, adapted International Myeloma Society-International Myeloma Working Group (IMS-IMWG) cytogenetic risk features, and extramedullary disease (EMD) each correlated with inferior progression-free survival after ciltacabtagene autoleucel (cilta-cel) in patients with relapsed or refractory multiple myeloma (RRMM).
• FHR and adapted IMS-IMWG high-risk features independently predicted relapse within 18 months, whereas EMD did not.
• Patients without any high-risk features achieved superior outcomes, including 12-month PFS of 83% vs 65% for those with ≥ 1 high-risk factor.

Cilta-cel continues to deliver high response rates in RRMM, yet early relapse remains a critical challenge. A multicenter analysis across 15 US academic institutions evaluated high-risk disease biology to identify predictors of suboptimal outcomes. The study provides one of the largest real-world assessments of cilta-cel performance to date and outlines key risk factors for clinicians and oncology pathway leaders.

Study Findings

The cohort included 598 patients treated between May 2022 and December 2024, with a median age of 65 years and a median of 5 prior lines of therapy. High-risk (HR) features were common: 33% had FHR disease, 43% had traditional high-risk cytogenetics, 42% met the adapted IMS-IMWG high-risk definition, and 11% had EMD.

Overall response rates (ORR) and complete response (CR) rates were consistently lower in patients with HR features. ORR ranged from 77% in those with EMD to 94% in those without HR markers. CR rates also declined across HR subgroups. Twelve-month progression-free survival (PFS) was similarly reduced: patients with FHR achieved 55% vs 79% without FHR; those with adapted IMS-IMWG HR disease had 61% vs 80%.

Multivariable Cox regression demonstrated that FHR, adapted IMS-IMWG HR disease, and EMD were each independently associated with inferior PFS after adjustment for prior B-cell maturation antigen (BCMA) therapy, baseline ferritin, and Eastern Cooperative Oncology Group (ECOG) performance status ≥ 2.

A subset analysis of 247 patients with ≥18 months follow-up identified predictors of early relapse. FHR (OR 3.04; 95% CI 1.59-5.89) and adapted IMS-IMWG HR (OR 2.07; 95% CI 1.10-3.89) significantly increased odds of relapse within 18 months, while EMD did not. Time-varying Cox modeling showed these same HR features predicted relapse only in the <18-month period, suggesting early disease biology rather than long-term relapse risk drives outcomes.

Clinical Implications

These findings highlight the importance of refined risk stratification for patients treated with cilta-cel. FHR disease and adapted IMS-IMWG cytogenetic abnormalities identify a subgroup that benefits less from single-agent CAR T and may require intensified strategies. For oncology payers and clinical pathway leaders, risk-adapted approaches—such as optimized bridging therapy, post-CAR T consolidation, or maintenance—may improve durability of response.

The observation that EMD impacts PFS but not early relapse risk suggests differing relapse kinetics across HR phenotypes, supporting tailored interventions. Patients without any HR markers demonstrated excellent outcomes, reinforcing cilta-cel’s strong efficacy in standard-risk RRMM.

“While cilta-cel leads to high response rates and durable PFS in RRMM, a subset of patients with FHR and adapted IMS-IMWG HR remains at increased risk for early relapse,” the investigators concluded. “These findings inform risk-adapted therapeutic strategies and interventional trials, including bridging, consolidation, or maintenance approaches, to improve outcomes in the highest-risk RRMM patients.”

Conclusion

This large US real-world analysis identifies key predictors of early relapse following cilta-cel therapy. Incorporating FHR and adapted IMS-IMWG HR disease into CAR T treatment planning may help optimize outcomes and guide future interventional trial design.

Reference

Hansen D, Peres L, Dima D, et al. Predictors of early relapse following ciltacabtagene autoleucel: Informing risk-adapted therapy in relapsed/refractory multiple myeloma. Presented at: ASH 2025; December 6-9; Orlando, FL.