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Abstract
Multiple myeloma (MM) patients with suboptimal response to induction therapy or early relapse, classified as the functional high-risk (FHR) patients, have been shown to have poor outcomes. We evaluated newly-diagnosed MM patients in the CoMMpass dataset and divided them into three groups: genomic high-risk (GHR) group for patients with t(4;14) or t(14;16) or complete loss of functional TP53 (bi-allelic deletion of TP53 or mono-allelic deletion of 17p13 (del17p13) and TP53 mutation) or 1q21 gain and International Staging System (ISS) stage 3; FHR group for patients who had no markers of GHR group but were refractory to induction therapy or had early relapse within 12 months; and standard-risk (SR) group for patients who did not fulfill any of the criteria for GHR or FHR. FHR patients had the worst survival. FHR patients are characterized by increased mutations affecting the IL-6/JAK/STAT3 pathway, and a gene expression profile associated with aberrant mitosis and DNA damage response. This is also corroborated by the association with the mutational signature associated with abnormal DNA damage response. We have also developed a machine learning based classifier that can identify most of these patients at diagnosis.
Highlights
There is an increasing appreciation that risk stratification is important in the management of multiple myeloma (MM) [1]
We divided the patients into three groups: genomic high-risk (GHR) group for patients with t(4;14) or t(14;16) or complete loss of functional TP53 (bi-allelic deletion of TP53 or mono-allelic deletion of 17p13 and TP53 mutation) or 1q21 gain and International Staging System (ISS) stage 3; functional highrisk (FHR) group for patients who had no markers of GHR group but were refractory to induction therapy or had early relapse within 12 months; and standard-risk (SR) group for patients who did not fulfill any of the criteria for GHR or FHR
FHR patients had the worst survival Of the 512 evaluable patients, there were 345 patients in the SR group, 106 patients in the GHR group, and 61 patients in the FHR group
Summary
There is an increasing appreciation that risk stratification is important in the management of multiple myeloma (MM) [1]. A real-world outcome study of 1320 newly diagnosed patients by Australian and New Zealand Myeloma and Related Diseases Registry (MRDR) showed that 40% of patients with suboptimal response to induction therapy died within 3 years of diagnosis, and patients who had early disease progression within 12 months of starting induction therapy had median OS of only 20.2 months [13]. These patients are categorized as the functional high-risk (FHR) MM patients. We comprehensively compare their genomic profiles (DNA mutations, mutational signatures (MS), transcriptional signatures, copy number abnormalities) with other MM patients to gain insights into what may drive this phenotype of extremely poor outcome
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