Prognostic significance of copy-number alterations in multiple myeloma

Abstract

Purpose: Chromosomal aberrations are a hallmark of multiple myeloma but their global prognostic impact is largely unknown.

Patients and methods: We performed a genome-wide analysis of malignant plasma cells from 192 newly diagnosed patients with myeloma using high-density, single-nucleotide polymorphism (SNP) arrays to identify genetic lesions associated with prognosis.

Results: Our analyses revealed deletions and amplifications in 98% of patients. Amplifications in 1q and deletions in 1p, 12p, 14q, 16q, and 22q were the most frequent lesions associated with adverse prognosis, whereas recurrent amplifications of chromosomes 5, 9, 11, 15, and 19 conferred a favorable prognosis. Multivariate analysis retained three independent lesions: amp(1q23.3), amp(5q31.3), and del(12p13.31). When adjusted to the established prognostic variables (ie, t(4;14), del(17p), and serum beta(2)-microglobulin [Sbeta(2)M]), del(12p13.31) remained the most powerful independent adverse marker (P < .0001; hazard ratio [HR], 3.17) followed by Sbeta(2)M (P < .0001; HR, 2.78) and the favorable marker amp(5q31.3) (P = .0005; HR, 0.37). Patients with amp(5q31.3) alone and low Sbeta(2)M had an excellent prognosis (5-year overall survival, 87%); conversely, patients with del(12p13.31) alone or amp(5q31.3) and del(12p13.31) and high Sbeta(2)M had a very poor outcome (5-year overall survival, 20%). This prognostic model was validated in an independent validation cohort of 273 patients with myeloma.

Conclusion: These findings demonstrate the power and accessibility of molecular karyotyping to predict outcome in myeloma. In addition, integration of expression of genes residing in the lesions of interest revealed putative features of the disease driving short survival.

Fig 1.

Prognostic impact of copy-number abnormality–based model in initial and validation cohorts. (A) Initial cohort stratified according to amp(1q23.3), amp(5q31.3), del(12p13.31) by single nucleotide polymorphism (SNP) array. (B) Initial cohort stratified according to amp(5q31.3), del(12p13.31) by SNP array and serum β₂-microglobulin (Sβ₂M) ≥ 5.5 mg/L. (C) Validation cohort stratified according to amp(5q31.3), del(12p13.31) by fluorescent in situ hybridization and Sβ₂M ≥ 5.5 mg/L.

Fig 2.

Prognostic impact of (A) hyperdiploidy and (B) amp(5q31.3) within hyperdiploid patients.

Fig A1.

(A) Recurrence of copy-number abnormalities (CNAs) across 192 multiple myeloma (MM) in chromosomal order. Red or blue bars denote gain or loss of chromosome material. (B) dChip median-smoothed log ratio copy number heatmap showing all chromosomes. Each column represents a case and SNPs are arranged from 1p(tel) to Xq(tel) from top to the bottom. Blue represents deletion and red amplification. (C) Recurrence of uniparental disomy across the samples.