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.