Cytogenetic high-risk abnormalities reveal poor prognosis in newly diagnosed MM

Cytogenetic High Risk Abnormalities (HRA) are thought to be responsible for poor prognosis in Multiple Myeloma (MM) and patients with these factors are considered to be high-risk for more aggressive disease. On 1^st September 2017, Moritz Binder and Shaji Kumar, from the Division of Hematology at the Mayo Clinic in Minnesota, along with colleagues, published the results of their study investigating the cumulative effect of multiple HRA in newly diagnosed MM in the Blood Cancer Journal.   

Newly diagnosed patients at the Mayo Clinic (n = 1181) between July 2005 and July 2015 who had received first-line therapy with novel agents were included in the study. Patients also had cytogenetic evaluation in the first six months of diagnosis using fluorescence in situ hybridization (FISH) for risk stratification. Significance was determined after adjusting for prognostic factors such as age, sex, International Staging System (ISS) stage and first-line therapy.

Study

• HRA types included: t(4;14), t(14;16), t(14;20) and del(17p)
• Patients (pts) with no HRA: n = 884 (75%)
• Pts with HRA: n = 297 (25%)
  • one HRA: n = 262 (22%) (vs zero, HR = 1.65, 95% CI: 1.32 – 2.05, P < 0.001)
  • two HRA: n = 35 (3%) (vs zero, HR = 3.15, 95% CI: 2.00 – 4.96, P < 0.001)
• Median age = 65 years (28–95)
• Pts were treated with at least one first-line novel agent; proteasome inhibitor (PI) (n= 590, 50%), immunomodulatory drug (IMiD) (n = 416, 35%), both PI and IMiD (n = 175, 15%) and some pts had autologous hematopoietic stem cell transplantation (AHSCT) as part of first-line treatment (n = 450, 38%) 

Key Findings

• Median Overall Survival (OS) = 6.6 years (6.0–8.0)
• Median OS was significantly shorter in patients with one or two HRA (compared to zero):
  • One HRA = 4.9 vs3 years, P < 0.001
  • Two HRA = 2.7 vs3 years, P < 0.001
• Median Progression-Free Survival (PFS) was also significantly shorter in patients with one or two HRA (compared to zero):
  • One HRA = 1.5 vs1 years, P < 0.001
  • Two HRA = 1.2 vs1 years, P = 0.007
• Del(17p) and High-Risk Translocation (HRT) were associated with increased hazard
• Pts with monosomy of chromosome 13 had significantly shorter median OS: 5.5 vs3 years, P < 0.001 and PFS = 1.75 vs 2.00 years, P = 0.013
  • HR = 1.27, 95% CI 1.04–1.56, P = 0.022
• Pts with del(13q) had significantly longer OS: median not reached vs 4 years, P = 0.006 but not PFS
  • HR = 0.48, 95% CI 0.28–0.81, P = 0.006

Conclusion

This study revealed that patients with multiple and cumulative HRA had negatively affected OS and PFS. Hazard ratios of patients with two HRAs were two-fold, compared to patients with a single HRA, and three-fold compared to patients with no HRA. Patients undergoing ASCT showed better OS results despite their HRA status, suggesting that this may be a more useful treatment for high-risk groups. Patients with both del(17p) and another HRA had a two-fold increase in hazard compared to patients with one of the two or none. Interestingly, patients with monosomy of chromosome 13 had significantly shorter OS and PFS, although presence of del(13q) was considered ‘protective’ as patients had longer OS. The authors also concluded that further research was required to show the isolated effects of different HRA on the overall outcomes for MM patients. This would help to predict the risk associated with their individual disease and also improvement of care.