T-cell-redirecting therapies in early relapsed multiple myeloma: a systematic review and network meta-analysis.

backgroundChimeric antigen receptor T cells and bispecific antibodies, are moving from late-line salvage into early relapsed multiple myeloma. Indirect comparisons in heavily pretreated patients have favored cell therapy, but whether that hierarchy holds in early relapse is unknown.

methodsWe analyzed randomized phase 3 trials comparing a T-cell-redirecting therapy against a daratumumab-pomalidomide-dexamethasone-type control after at least one prior line. Pseudo-individual patient time-to-event data were reconstructed from published survival curves. Regimens were compared indirectly in Bayesian network meta-analyses reported under fixed-effect and random-effects assumptions, re-estimated in a frequentist graph-theoretical model. Control-arm dispersion was quantified by random-effects synthesis of median progression-free survival. Overall survival was additionally analyzed as restricted mean survival differences at 24 and 36 months. Safety and a cost-consequence analysis were assessed descriptively (PROSPERO: CRD420261431847).

resultsFour trials (2,174 patients) investigating ciltacabtagene autoleucel, teclistamab-daratumumab, and talquetamab-daratumumab with or without pomalidomide were included. Control-arm median progression-free survival spanned 9.9 to 24.4 months (I-squared 91%). Under fixed effects, teclistamab-daratumumab ranked first for progression-free survival (P-score 98%, the mean probability of outranking a competing treatment rather than the probability of being best) and separated from talquetamab-daratumumab (hazard ratio 0.55, 95% credible interval 0.34 to 0.88). Once between-trial heterogeneity was admitted, every contrast crossed unity (versus ciltacabtagene autoleucel 0.62, 0.21 to 1.81). Overall survival was concordant under both models (teclistamab-daratumumab versus ciltacabtagene autoleucel 0.94, 0.55 to 1.62), with restricted mean survival gains over control of 0.7 to 1.6 months at 24 months and rankings between 56% and 70%. Toxicity profiles differed across modalities, although their overall burden cannot be reliably compared across trials. Cost per progression-free month, computed against a population-standardized denominator, was lowest for cilta-cel and converged with the bispecific regimens only under short, fixed treatment durations.

conclusionsRandomized evidence in early relapse does not establish an efficacy hierarchy among these regimens. Progression-free survival estimates favored teclistamab-daratumumab, but no contrast was robust to plausible between-trial heterogeneity, and equivalence could not be demonstrated. Until comparative data exist, treatment selection cannot rest on efficacy data alone and will be informed by patient- and disease-related factors, toxicity, sequencing, access, and cost.