Redefining functional high‐risk multiple myeloma in the context of upfront quadruplet therapy and autologous stem cell transplantation

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BACKGROUND: Functional high-risk (FHR) multiple myeloma (MM) was historically defined as progression within 18 months of starting therapy, with expected subsequent overall survival (OS) <2 years. The optimal definition of FHR in the era of combined quadruplet therapy (QUAD) + autologous stem cell transplantation (ASCT) is unknown. METHODS: The authors analyzed 310 patients with newly diagnosed MM who received QUAD + ASCT and had with a median follow up of 41.8 months, with 66 progression events, to identify the optimal definition of FHR MM and to explore the factors associated with outcomes of subsequent therapy. RESULTS: The cumulative incidence of progression with FHR cutoff points of within 12 months (FHR12), 18 months (FHR18), 24 months (FHR24), and 36 months (FHR36) of treatment initiation were 2.6%, 6.2%, 10.1%, and 16.4%, respectively. The median second PFS (2PFS) and OS from the onset of second-line therapy were 3.0 and 8.1 months, respectively, for FHR12; 2.7 and 8.1 months, respectively, for FHR18; 3.3 and 15.7 months, respectively, for FHR24; and 5.8 and 23.8 months, respectively, for FHR36, pointing to 36 months as the optimal cutoff point to define FHR MM. The 12-month 2PFS rate was 80% versus 23% for patients treated with versus without T-cell-redirecting therapy, respectively. In multivariable analysis, T-cell-redirecting therapy was associated with a substantially improved 2PFS even when adjusted for FHR status. CONCLUSIONS: In the current era of QUAD + ASCT, the definition of FHR MM should encompass patients who have MM with disease progression in the first 36 months of therapy. This study provides benchmark data for clinical trials deploying agents with novel mechanisms of action in this difficult-to-treat population (ClinicalTrtials.gov identifier NCT03224507).

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