Among 310 newly diagnosed multiple myeloma (MM) patients treated with quadruplet therapy (QUAD) + autologous stem cell transplantation (ASCT), this study tested four FHR cutoff points (12, 18, 24, and 36 months from treatment start) to find the best definition of functional high-risk (FHR) MM, and assessed the impact of T-cell–redirecting therapy (TCRT) on second-line outcomes (median follow-up 41.8 months, 66 progression events).
The 36-month cutoff (FHR36) best matched the historical FHR benchmark of ~2-year post-progression OS: median OS was 23.8 months for FHR36 vs. 8.1 months for FHR18. FHR36 captured 16.4% of patients. Among those who progressed, 12-month second PFS (2PFS) was 80% with TCRT vs. 23% without TCRT; overall response rate was 91% vs. 47% (p = .009). On multivariable analysis, TCRT independently improved 2PFS (HR 0.17; 95% CI, 0.04–0.71; p = .02).
- Only 11 patients (17% of progressors) received TCRT, limiting statistical power and external validity. - Combined prospective trial (MASTER) and institutional database patients introduce heterogeneity in induction/consolidation regimens. - TCRT use was driven by trial availability and fitness, introducing possible selection bias.
In the QUAD + ASCT era, clinicians should redefine FHR MM as progression within **36 months** of starting therapy (not the older 18-month cutoff), which captures ~1 in 6 patients with poor conventional outcomes. Patients meeting FHR36 criteria should be prioritized for early TCRT (CAR T-cell or bispecific), given markedly better 2PFS and response rates.
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