Understanding the role of hyperdiploidy in myeloma prognosis: which trisomies really matter?

Abstract

Key Points• In myeloma patients, trisomy 3 improved time to progression and trisomies 3 and/or 5 improved overall survival. • In contrast, trisomy 21 significantly worsened overall survival.The prognosis of multiple myeloma is mainly dependent upon chromosomal changes. The 2 major abnormalities driving poor outcome are del(17p) and t(4;14). However, the outcome of these high-risk patients is not absolutely uniform, with some patients presenting long survival. We hypothesized that these better outcomes might be related to concomitant "good-risk" chromosomal changes exploring hyperdiploidy. We analyzed a large series of 965 myeloma patients, including 168 patients with t(4;14) and 126 patients with del(17p), using high-throughput single-nucleotide polymorphism arrays after plasma cell sorting. As expected, trisomic chromosomes were highly associated. Using the LASSO model, we found that only chromosome 3, when trisomic, was associated with a longer progression-free survival and that 3 trisomies modulated overall survival (OS) in myeloma patients: trisomies 3 and 5 significantly improved OS, whereas trisomy 21 worsened OS. In patients with t(4;14), trisomies 3 and/or 5 seemed to overcome the poor prognosis. For the first time, using a specific modeling approach, we show that not all trisomies display the same prognostic impact. This finding could be important for routine assessment of prognosis in myeloma, and some highrisk patients with a traditional evaluation could in fact be standard-risk patients. (Blood. 2015;126(25):2713-2719

Prognostic significance of cytogenetic heterogeneity in patients with newly diagnosed multiple myeloma

“…The presence of subclonal CA in patients with a HD karyotype is most likely because gains of odd-numbered chromosomes are highly associated with each other (supplemental Figure 3). 16 The events leading to trisomies in MM are not fully understood. Preclinical studies in Wilms tumor cells demonstrated that bipolar mitosis with missegregation of chromosomes during anaphase causes trisomies.…”

Ixazomib significantly prolongs progression-free survival in high-risk relapsed/refractory myeloma patients

“…The individual abnormalities t(4;14), 16,17 t(14;16), 17,18 and del(17p) 17,19 have been shown to be independent poor prognostic markers in MM. The findings from our analyses showed a consistent PFS benefit with IRd vs placebo-Rd across the different markers, with a HR of 0.596 (95% CI, 0.286-1.243) in patients with del(17p) and 0.645 (95% CI, 0.250-1.663) in patients with t(4;14).…”

“…[16][17][18][19] Additionally, gain of 1q21 on FISH has been shown to confer poor prognosis 17,20,21 ; in some reports, 1q21 amplification is considered a high-risk abnormality, 21,22 including in a 2016 consensus paper from the International Myeloma Working Group, 10 whereas other reports classify it as conferring intermediate or standard risk. 23,24 To date, although data on the use of novel agent-based treatments have demonstrated that these regimens improve outcomes in patients with MM vs previous or existing standards of care, progression-free survival The online version of this article contains a data supplement.…”

Deregulated expression of long non‐coding RNA UCA1 in multiple myeloma

“…Moreover, patients with UCA1 “high” expression levels were associated with presence of gain 1q21 or t(4;14), which have been previously described as unfavorable prognostic factors for MM . This observation was further supported via opposite, however not significant, association with UCA1 “low” expression group of patients and HY status standing as a favorable factor for MM prognosis . The “low/high” UCA1 groups of MM patients were further heterogeneous in biochemical parameters.…”