Chromosome 1q21 Gains Confer Inferior Outcomes In Multiple Myeloma Treated With Bortezomib But Copy Number Variation and Percentage Of Plasma Cells Involved Have No Additional Prognostic Value

Chromosome 1q21 aberrations have not been implemented into the routine clinical test yet, and their effect in multiple myeloma is still under investigation. Heterogeneity exists among patients presenting 1q21 gains, e.g., variation in the copy numbers and the size of clone carrying 1q21 gains. The prognostic value of copy number variation and percentage of plasma cells involved remained unclear.

In the present study, we analyzed the prognostic value of 1q21 in a in a series of 290 cases of newly diagnosed multiple myeloma treated in a prospective, nonrandomized clinical trial (BDH 2008/02).

The incidence of patients carrying at least three copies of 1q21 was significantly higher in relapsed MM than in newly diagnosed MM (73 out of 107 [68.2%] vs. 142 out of 290 [48.9%], p=0.001). Among the whole cohort, 278 newly diagnosed MM and 102 relapsed MM had copy number variation information. No statistical difference in the frequency of three, four, or at least five copies copies of 1q21 was found between relapsed and initially diagnosed cases.

1q21 gains showed a profoundly negative impact on survival in patients receiving bortezomib treatment. Patients with 1q21 gains had a significantly shortened PFS (13.5 months vs. 43.0 months, p<0.001) and OS (24.0 months vs. 54.0 months, p<0.001) than patients with two copies of 1q21. Further investigation of the impact of copy number variation on survival indicated that the median PFS of patients who had three, four, or at least five copies of 1q21 were 14.0 months (95% CI: 8.07-19.93), 14.0 months (95% CI: 5.47-22.53), and 10.0 months (95% CI: 4.12-15.88), respectively. The median OS of patients who had three and four copies were 24.0 months (95% CI: 11.85-36.14) and 30.0 months (95% CI: 18.14-41.85) respectively, while the OS of patients with at least five copies was not obtained due to the small sample size; no statistically significant differences were found. When the patients with four and five copies were analyzed as a whole, i.e., as one group of patients with at least four copies, patients with at least four copies of 1q21 also exhibited a comparable PFS (14.0 months vs.10.0 months, p=0.737) and OS (24.0 months vs. 30.0 months, p=0.382), compared with patients harboring three copies of 1q21.

Patients with 1q21 gains were divided into two groups according to the percentage of plasma cells involved, i.e., 20%-50% and >50%, which were seen respectively in 28/290 (9.7%) and 114/290 (43.8%) patients with newly diagnosed MM. The median PFS was 6.0 months (95% CI: 1.00-21.5) and 13.5 months (95% CI: 8.87-18.14) respectively, and median OS was 6.0 months (95% CI: 1.00-21.49) and 24.0 months (95% CI: 18.94-29.05) respectively. The difference in PFS and OS were not statistically significant between the two groups (p=0.753 and 0.273 respectively;).

No statistically significant differences were found in patients harboring 1q21 gains between bortezomib-based and thalidomide-based chemotherapy groups, and the median PFS and OS in patients receiving bortezomib-based regimens were 13.5 months (vs. 20.0 months; p=0.176) and 24.0 months (vs. 21.0 months; p=0.773) respectively. Therefore, bortezomib was unable to overcome the negative impact of 1q21 gains on survival, and to significantly improve the survival of these patients.

Our data demonstrated that copy numbers of 1q21 increased with progression of myeloma and predicted a poor prognosis in MM patients treated with bortezomib-based therapy. Our results also indicate that three copies of 1q21 gains and 20% of plasma cells with this abnormality were enough to confer bortezomib resistance. Chromosome 1q21 gains should be considered a high-risk feature in MM, and 1q21 analysis should be added to the diagnostic panel of FISH probes used in routine assessment of prognosis in patients with MM, especially those receiving bortezomib-based regimens.

No relevant conflicts of interest to declare.