Introduction Functional high-risk MM (FHR) is currently defined as relapse within 18 month (mo) of induction therapy irrespective of initial risk assessment. In the pre-QUAD +ASCT era, this population experienced shorter and less frequent responses to subsequent therapy, with overall survival (OS) from first progression of < 2 years. With improved upfront therapy fewer patients (pts.) display early progression; however those who do progress quickly are expected to have even worse disease biology. Therefore, we studied a large cohort of patients treated with upfront QUAD + ASCT to determine the optimal cutpoint for the definition of FHR MM in this population, and describe outcomes of subsequent therapies.

Methods We analyzed newly diagnosed MM (NDMM) pts. who received QUAD induction followed by ASCT in the context of prospective clinical trials or an institutional database. Post ASCT consolidation and maintenance varied and were influenced by clinical trial design, cytogenetic risk and MRD status. We captured occurrence of IMWG-defined disease progression (2PFS, second progression-free survival) and OS from initiation of subsequent therapy to identify the optimal threshold for FHR based on post-progression OS less than 2 years. We tested definitions of FHR with cutpoints of 12 mos (FHR12), 18 mos (FHR18), 24 mos (FHR24), and 36 mos (FHR36) as candidates for optimal thresholds. We also described the outcomes of subsequent therapy, noting the application of T-cell redirecting therapy (TCRT, bispecific T-cell engagers and/or chimeric antigen receptor T-cells).

Results Overall, 312 patients received QUAD induction plus ASCT. Median age was 62 years (IQR 56-68), 171 were male (55%), 97 were of racial-ethnic minority (31%), 115 (37%) had 1 and 45 (15%) had 2 or more high-risk chromosome abnormalities [HRCA, del(17p); t(4;14), t(14;16), gain/amp(1q)]. Median duration of follow up was 41.5 mo. There were 64 pts with disease progression. The proportion of pts fitting in each FHR cutpoint, as estimated by cumulative incidence of progression was 3.6% for FHR12, 6.3% for FHR18, 10.3% for FHR24 and 16.5% for FHR36. There were no meaningful differences in patient and disease characteristics among different cutpoints. Next treatment included a TCRT in 10 (16%) patients. Median 2PFS was 3.3 mo (95% C.I. 2.2-4.4) for FHR12, 2.7 mo (95% C.I. 2.2-3.2) for FHR18, 3.3 mo (95% C.I. 2.0-4.6) for FHR24 and 5.8 mo (95% C.I. 2.4-9.2) for FHR36. Median OS was 9.8 mo (95% C.I. 6.2-13.3) for FHR12, 8.8 mo (95% C.I. 6.6-11.1) for FHR18, 11.5 mo (95% C.I. 3.4-19.7) for FHR24 and 18.8 mo (95% C.I. 10.4-27.3) for FHR36, pointing to 36 mo as the most inclusive timepoint to define the FHR population. Disease progression within 36 mo. (vs >36 mo.) of onset of therapy was associated with reduced 2PFS (HR 2.92, 95% C.I. 1.27-2,67, P=0.012) and OS (HR 6.66, 95% C.I. 1.56-28.47, P=0.011). Median 2PFS was N.R. for pts who did vs. 6.64 mo. (95% C.I.4.2-9.0) for those who did not receive TCRT in next line of therapy (P=0.002). Twelve-month 2PFS rate was 90% vs. 23% for pts treated with and without TCRT. In multivariable analysis the use of TCRT in next line therapy was associated with substantially improved 2PFS (HR 0.12, 95% C.I. 0.02-0.90, P=0.039) even when adjusted for FHR status.

Conclusion In the current era of QUAD + ASCT for the treatment of NDMM, the definition of FHR should encompass patients with disease progression in the first 36 months of therapy. TCRT should be considered the current standard salvage, as this approach is associated with the best outcomes for patients with FHR MM. This study provides benchmark data for clinical trials deploying agents with novel mechanisms of action in this difficult to treat population.

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2025
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