Reference: January 2026 | Issue 1 | Vol 12 | Page 35
Ciltacabtagene autoleucel (cilta-cel) has demonstrated unprecedented response rates and progression-free survival (PFS) in relapsed/refractory multiple myeloma (RRMM), but a proportion of patients experience early relapse. Identifying these patients is essential to guide future therapeutic strategies, such as enhanced bridging therapy or consolidation, while avoiding overtreatment in those likely to achieve durable disease control.
A multi-centre study of patients treated at 15 US academic centres evaluated outcomes based on high-risk (HR) features, while adjusting for baseline ferritin, prior BCMA, and ECOG performance status (PS ≥2).
HR features included functional HR disease (FHR), defined as relapse within 18 months of first-line therapy initiation; true extramedullary disease (EMD); traditional HR cytogenetics as defined in CARTITUDE-1, ie, deletion 17p, t(4;14), t(14;16); and a 2024 IMS-IMWG-adapted HR definition (deletion 17p; t(4;14) or t(14;16) with gain 1q or deletion 1p; and gain 1q with deletion 1p).
The cohort included 598 patients treated with cilta-cel between May 2022 and December 2024 who had available data on all HR features. The median age was 65 years, with a range of 33 to 83 years.
The median number of prior lines of therapy (pLOT) was five, ranging from one to 18. Eight per cent had received prior BCMA-directed therapy, and 27 per cent were penta-refractory. Most patients (88 per cent) received bridging therapy and 30 per cent achieved at least partial response.
One in three participants had FHR, 43 per cent had traditional HR cytogenetics, 42 per cent had adapted IMS-IMWG HR disease, and 11 per cent had EMD.
Median follow-up was 10.6 months. Overall response rate (ORR) and complete response (CR) rates were lower in patients with vs without HR features. In the FHR group, ORRs were 89 per cent vs 94 per cent, and CR rates were 61 per cent vs 75 per cent.
With traditional HR features, ORRs were 90 per cent vs 94 per cent, and CR rates were 65 per cent vs 74 per cent. Those with adapted IMS-IMWG HR had ORRs of 91 per cent vs 94 per cent, with CR rates of 64 per cent vs 75 per cent. In patients with EMD, ORRs were 77 per cent and 94 per cent, while CR rates were 61 per cent vs 71 per cent.
Corresponding 12-month PFS was also lower in patients with versus without HR features: FHR (55% vs 79%), traditional HR (63% vs 78%), adapted IMS-IMWG HR (61% vs 80%) and EMD (59% vs 73%).
ORR, CR rate, and 12-month PFS in patients without any HR features compared to those with ≥1 HR feature were 96 per cent vs 90 per cent, 81 per cent vs 64 per cent, and 83 per cent vs 65 per cent, respectively.
In multivariable models, each HR feature was independently associated with inferior PFS after adjusting for baseline ferritin, prior BCMA, and ECOG PS ≥2.
While FHR (OR 3.04; 95% CI 1.59-5.89) and adapted IMS-IMWG HR (OR 2.07; 95% CI 1.10-3.89) were independently associated with odds of relapse within 18 months, EMD was not (OR 0.90; 95% CI 0.32-2.40) when accounting for prior BCMA, ECOG PS ≥2, and baseline ferritin.
These findings may inform risk-adapted therapeutic strategies and interventional trials, including bridging, consolidation, or maintenance approaches, to improve outcomes in the highest RRMM patients.
The researchers noted that Tec-Dara could be more accessible than other second-line therapies for MM as it could be delivered in community settings, not just academic centres.
Tec-Dara outperformed DPd and DVd in terms of quality of life outcomes and had a safety profile comparable to the control arm.
Prof Mateos noted that future studies could determine which patients would benefit most from the Tec-Dara combination in comparison to other therapies. Trials involving other bispecific antibody combinations are also underway and could shed additional light on the optimal use of such combinations as early as the first relapse.
