Subclonal <i>TP53</i> copy number is associated with prognosis in multiple myeloma.

Abstract

Multiple myeloma (MM) is a genetically heterogeneous cancer of bone marrow plasma cells with variable outcome. To assess the prognostic relevance of clonal heterogeneity of <i>TP53</i> copy number, we profiled tumors from 1777 newly diagnosed Myeloma XI trial patients with multiplex ligation-dependent probe amplification (MLPA). Subclonal <i>TP53</i> deletions were independently associated with shorter overall survival, with a hazard ratio of 1.8 (95% confidence interval, 1.2-2.8; <i>P</i> = .01). Clonal, but not subclonal, <i>TP53</i> deletions were associated with clinical markers of advanced disease, specifically lower platelet counts (<i>P</i> < .001) and increased lactate dehydrogenase (<i>P</i> < .001), as well as a higher frequency of features indicative of genomic instability, del(13q) (<i>P</i> = .002) or del(1p) (<i>P</i> = .006). Biallelic <i>TP53</i> loss-of-function by mutation and deletion was rare (2.4%) and associated with advanced disease. We present a framework for identifying subclonal <i>TP53</i> deletions by MLPA, to improve patient stratification in MM and tailor therapy, enabling management strategies.