Copy number evolution and its relationship with patient outcome—an analysis of 178 matched presentation-relapse tumor pairs from the Myeloma XI trial

Abstract

Structural chromosomal changes including copy number aberrations (CNAs) are a major feature of multiple myeloma (MM), however their evolution in context of modern biological therapy is not well characterized. To investigate acquisition of CNAs and their prognostic relevance in context of first-line therapy, we profiled tumor diagnosis–relapse pairs from 178 NCRI Myeloma XI (ISRCTN49407852) trial patients using digital multiplex ligation-dependent probe amplification. CNA profiles acquired at relapse differed substantially between MM subtypes: hyperdiploid (HRD) tumors evolved predominantly in branching pattern vs. linear pattern in t(4;14) vs. stable pattern in t(11;14). CNA acquisition also differed between subtypes based on CCND expression, with a marked enrichment of acquired del(17p) in CCND2 over CCND1 tumors. Acquired CNAs were not influenced by high-dose melphalan or lenalidomide maintenance randomization. A branching evolution pattern was significantly associated with inferior overall survival (OS; hazard ratio (HR) 2.61, P = 0.0048). As an individual lesion, acquisition of gain(1q) at relapse was associated with shorter OS, independent of other risk markers or time of relapse (HR = 2.00; P = 0.021). There is an increasing need for rational therapy sequencing in MM. Our data supports the value of repeat molecular profiling to characterize disease evolution and inform management of MM relapse.

Chromosome 1q21 abnormalities refine outcome prediction in patients with multiple myeloma - a meta-analysis of 2,596 trial patients

“…While several studies showed that 1q21 gain is an independent poor prognostic factor, other studies have failed to support a relationship. [2][3][4][5][6][7] Previous studies have often been small or conducted outside of clinical trials, thus having limited power to demonstrate a relationship, especially as assays can be complicated by heterogeneity in terms of copy number (gain vs. amp(1q)). 6 In contrast to t(4;14) or del(17p), 1q21 status is not included among the high-risk markers listed by the International Myeloma Working Group (IMWG) Revised International Staging System (R-ISS), 8 and as a result it has invariably not been reported in most clinical trials over the past decade.…”

“…This is in line with the ongoing evolution of 1q aberrations, which have been shown to be of clinical significance. 3,14 Of note, the recent study describing significant differences between amp(1q) and gain(1q) only had median follow-up of less than 2 years, which is short for exploratory survival analyses in NDMM. 6 To examine the impact of different therapies on 1q CNAs, we performed landmark analyses from start of maintenance (Supplemental Fig.…”

Systems medicine dissection of chr1q-amp reveals a novel PBX1-FOXM1 axis for targeted therapy in multiple myeloma

“…Genetic amplification of chr1q (chr1q-amp), one of the most frequent copy number aberrations (CNA), confers adverse prognosis in cancer [1][2][3] . In multiple myeloma (MM), an incurable cancer of the B lineage plasma cells (PC), chr1q-amp is a secondary genetic event present in 30-40% of patients at diagnosis and is associated with adverse prognosis, high-burden proliferative disease and drug resistance [4][5][6][7][8][9] . In addition, along with t(4;14) and del(17p), chr1q-amp is one of the top three genetic markers conferring adverse overall and progression free survival in MM 10,11 .…”

Multiple Myeloma: Molecular Pathogenesis and Disease Evolution

“…Consolidation and maintenance therapy can then control more indolent clones, which persist after induction therapy, leading to a longer survival [66]. Mutations in known MM-driving genes (e.g., KRAS ), segmental copy number alterations, and inactivation of tumor suppressors, such as TP53 , drive disease progression by Darwinian clonal evolution, and both mutations in such genes, as well as branched evolution itself, have been associated with an adverse prognosis [67-69]. Another complexity arises from intrapatient spatial heterogeneity, which was shown to be present in 75% of patients analyzed by multiregion sequencing [70].…”