Early Responders (Time to Best Response ≤3 months) Predicts Functional High-Risk Multiple Myeloma

Introduction: Despite advancements in risk evaluation and management of multiple myeloma (MM), functional high-risk (FHR) MM often shows a suboptimal response to induction therapy or relapses early after initial treatment. Early recognition of FHRMM may help to tailor treatment approaches and improve survival outcomes. However, the characteristics of FHRMM is not fully understood, and the impact of current treatment on FHRMM remains unclear. Our objective is to identify baseline risk factors and treatment response kinetics associated with FHRMM.

Method: The patients with newly diagnosed multiple myeloma (NDMM) between January 2017 and December 2022 were included. The patients' characteristics, treatment protocols, best responses, and survival data were collected and analyzed. High-risk factors were defined based on the NCCN MM guideline 2024v4, which includes various cytogenetic abnormalities and disease characteristics (R-ISS III, extramedullary disease, circulating plasma cells, and cytogenetic abnormalities including Del(1p32), t(4;14), t(14;16), t(14;20), Del17p, 1q21 gain/1q21 amp, and MYC translocation). Among MM without baseline risk factors, those progressed or relapsed ≤18 months after treatment initiation were considered FHR, while those progressed or relapsed >18 months were classified as standard risk (SR). Cox regression analysis was used to assess the impact of multiple variables on prognosis, and log-rank test was performed to explore risk factors for FHRMM.

Results: Among 211 NDMM patients, there were 30 patients (14.2%) in the FHR group, 119 (56.4%) in the SR group, and 62 (29.4%) in the high-risk (HR) group. With a median follow-up of 44.0 months, the progression-free survival (PFS) and overall survival (OS) for FHR group were 14.0 months and 39.0 months, respectively. Notably, the FHR group had a significantly higher proportion of patients with time to best response (TBR) ≤3 months compared to the SR group, P=0.039. Furthermore, among non-HR groups stratified by TBR, there were significant differences in PFS and OS between TBR ≤3 months and TBR >3 months, with median PFS of 30.0 months and 56.0 months, and median OS of 58.0 months and 94.0 months, respectively, both P<0.001. Autologous stem cell transplantation (ASCT) significantly improved the PFS of FHRMM patients, P=0.033.

Conclusions: At present, it is not easy to differentiate FHR from SR patients based on the baseline characteristics of NDMM. Nevertheless, the analysis of response kinetics suggests that TBR ≤3 months could be a feasible indicator for early identification of FHRMM. ASCT has been found to improve the prognosis of FHRMM.