Clinical and genomic characterization of Chinese patients with functional high-risk multiple myeloma: A real-world validation study

OBJECTIVE: Precise risk stratification is increasingly essential in the management of multiple myeloma (MM) as some standard-risk (SR) patients still exhibit similar poor outcomes as genetically high-risk (GHR) patients in the era of novel agents. It has recently been demonstrated that functional high-risk (FHR) patients, those with suboptimal response to first-line induction therapy or early relapse within 12 months, have identifiable molecular characteristics from the SR group in the CoMMpass dataset. However, these findings lack practical validation in the real world. METHODS: MM cells purified by CD138 microbeads from newly diagnosed MM (NDMM) patients received fluorescence in situ hybridization and sequencing with a 92-gene Panel. Cytogenetic abnormalities defined GHR patients with t(4;14) or t(14;16) or complete loss of functional P53 or 1q21 gain and International Staging System (ISS) stage 3. SR group was patients who did not fulfill any criteria for GHR or FHR. RESULTS: There were 145 patients with NDMM, 78 in the SR group, 56 in the GHR group, and 11 in the FHR group. In the FHR group, eight patients were suboptimal responses to induction therapy, and three relapsed within 12 months. We found that male patients, patients with extra-medullary plasmacytoma (EMD), circulating clonal plasma cells (CPC) ≥0.05%, and P53 mono-allelic inactivation were significantly higher in the FHR group compared to the SR group. After a median follow-up of 21.0 months, the median progression-free survival (PFS) and overall survival (OS) were 5.0 months, 19.1 months and 36.6 months in the FHR, GHR, and SR groups, respectively. Compared to the SR group, FHR patients had a higher frequency of mutations in MKI67, ERN1, and EML4. GO analysis showed that mutations in FHR were enriched for oxidative stress, chromosomal segregation, and hypoxia tolerance. CONCLUSION: The FHR found in the SR NDMM patient group has unique clinical features, including being male, with EMD and CPC, and genetic characteristics of mutations affecting oxidative stress, chromosome segregation, and hypoxia tolerance. In contrast to previous reports, our data suggested that patients with P53 mono-allelic inactivation should be classified in the GHR group rather than the FHR group.