General MM

Monoallelic deletion of the whole locus of immunoglobulin heavy chain gene confers better prognosis than t(4;14) and t(14;16) translocations in newly diagnosed patients with multiple myeloma

Initiating events in the pathogenesis of multiple myeloma (MM) include translocations involving the immunoglobulin heavy-chain gene (IGH) at 14q3. During disease progression, co-existing clones acquire additional chromosomal abnormalities (CAs). These CAs can have prognostic value; for example patients with t(4;14), t(14;16) and t(14;20) CAs in IGH have a poor prognosis and are considered high-risk by the International Myeloma Working Group.1 A deletion of the whole locus of the IGH gene, or its segments (w_del(IGH)), occurs in 14–27% of patients with MM, but little is known of the prognostic significance. Adrian Duek and Luba Trakhtenbrot, from The Chaim Sheba Medical Center, Israel, and colleagues conducted a retrospective analysis of 255 newly‑diagnosed patients with MM, to determine the prognostic significance of the monoallelic deletion of the whole locus of IGH when compared to t(4;14) and t(14;16) CAs.2

 

Patient Population and Study Design
  • N = 255 newly-diagnosed patients with MM carrying w_del(IGH), t(4;14) or t(14;16)
    • w_del(IGH): 45.8% (n = 117)
    • t(4;14): 38.8% (n = 99)
    • t(14;16): 15.3% (n = 39)
  • Mean age at diagnosis: 61.6 ± 11.6 years
  • Median follow-up: 3.5 years
  • International Staging System (ISS):
    • ISS I: 55% had w_del(IGH)
    • ISS III: highest proportion had t(14;16) (P = 0.05)
  • Analysis of demographic, clinical and laboratory data and overall survival (OS)
Key Findings

All data is given as w_del(IGH) vs t(4;14) vs t(14;16)

Overall Survival:

  • Estimated median OS: 9.5 years vs 4.2 years vs 3 years
  • Mortality odds ratios:
    • t(4;14) vs w_del(IGH): 2.08
    • t(14;16) vs w_del(IGH): 2.33
  • When adjusting for age, gender and staging (ISS), t(4;14) and t(14;16) showed an increased mortality risk:
    • t(4;14) vs w_del(IGH): 2.67 (95% CI, 1.39–5.09)
    • t(14;16) vs w_del(IGH): 4.61 (95% CI, 2.14–9.94)

Additional CAs:

  • In the entire cohort (n = 255): 0–4 additional CAs were identified
  • Mean number of CAs: 1.58 vs 2.13 vs 2.3 (P < 0.0001)
  • Additional CAs (≥1): 87.2%, 98%, 100%

In newly-diagnosed patients with MM, a monoallelic deletion of the entire IGH locus was associated with fewer additional CAs and a significantly longer OS when compared to patients with t(4;14) and t(14;16) CAs. This suggests it may have potential as a new prognostic factor, with further studies required to investigate this. It was also noted that a weakness of the current study was its retrospective nature and lack of data on response rate to therapy.

This study also provides evidence that w_del(IGH) is an early pathogenic event in MM. Fewer late chromosomal events, such as del(p53), del(1p) and multiple (1q) gains, were seen in the w_del(IGH) group compared to the t(4;14) and t(14;16) groups. Additionally, the improved OS in patients with w_del(IGH) may be due to a diagnosis at an earlier ISS stage, which could support the notion that w_del(IGH) occurs earlier in the pathogenesis of the disease.

The International Myeloma Working Group recently included chromosomal abnormalities in the risk-stratification of MM, therefore, it is paramount that MM risk groups are well defined in order to optimize treatment strategies.

References
  1. Sonneveld P. et al. Treatment of multiple myeloma with high-risk cytogenetics: a consensus of the International Myeloma Working Group. Blood. 2016 Jun 16. DOI: 10.1182/blood-2016-01-631200
  2. Duek A., Trakhtenbrot L. et al. Newly-diagnosed multiple myeloma patients carrying monoallelic deletion of the whole locus of immunoglobulin heavy chain gene have a better prognosis compared to those with t(4;14) and t(14;16). Genes, Chromosomes & Cancer. 2019 Jan 24. DOI: 10.1002/gcc.22738 [Epub ahead of print].
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