Longitudinal fluorescence in situ hybridization reveals cytogenetic evolution in myeloma relapsing after autologous transplantation

Abstract

To investigate cytogenetic evolution after upfront autologous stem cell transplantation for newly diagnosed myeloma we retrospectively analyzed fluorescence in situ hybridization results of 128 patients with paired bone marrow samples from the time of primary diagnosis and at relapse. High-risk cytogenetic abnormalities (deletion 17p and/or gain 1q21) occurred more frequently after relapse (odds ratio: 6.33; 95% confidence interval: 1.86-33.42; P<0.001). No significant changes were observed for defined IGH translocations [t(4;14); t(11;14); t(14;16)] or hyperdiploid karyotypes between primary diagnosis and relapse. IGH translocations with unknown partners occurred more frequently at relapse. New deletion 17p and/or gain 1q21 were associated with cytogenetic heterogeneity, since some de novo lesions with different copy numbers were present only in subclones. No distinct baseline characteristics were associated with the occurrence of new high-risk cytogenetic abnormalities after progression. Patients who relapsed after novel agent-based induction therapy had an increased risk of developing high-risk aberrations (odds ratio 10.82; 95% confidence interval: 1.65-127.66; P=0.03) compared to those who were treated with conventional chemotherapy. Survival analysis revealed dismal outcomes regardless of whether high-risk aberrations were present at baseline (hazard ratio, 3.53; 95% confidence interval: 1.53-8.14; P=0.003) or developed at relapse only (hazard ratio, 3.06; 95% confidence interval: 1.09-8.59; P=0.03). Our results demonstrate cytogenetic evolution towards high-risk disease after autologous transplantation and underline the importance of repeated genetic testing in relapsed myeloma (EudraCT number of the HD4 trial: 2004-000944-26).

Figure 1.

Clonal evolution in patients with gain of 1q21 and del17p. (A) Distribution of copy numbers of chromosome 1q21. Patients with increasing copy numbers after relapse are represented in red, patients with decreasing copy numbers in blue. (B–D) Examples of clonal evolution in three patients with de novo del17p. Panel B illustrates cause of the disease in a patient with minimal response (MR) after autologous transplantation (TPL). After relapse (PD), the second FISH analysis showed a new del17p present in 60% of analyzed plasma cells and no significant changes of the abnormalities already present at initial diagnosis. The patient represented in panel C achieved a very good partial remission (VGPR). The initially present hyperdiploid clone harboring a del13 and del8 was detected in a smaller subset of analyzed plasma cells with a new, subclonal del17p. In panel D, the patient relapsed after tandem TPL and partial remission with a new del17p and MYC translocation. Compared to the patient in panel C the maternal clone could be detected in a larger proportion of plasma cells after relapse.

Figure 2.

Multivariate survival analysis from different landmarks. Kaplan-Meier plots and multivariate analyses for overall survival in patients without high-risk cytogenetic abnormalities (CA) at both time points (black line), high-risk CA only at first (red line), only at second (green line) or at both (blue line) FISH analyses. Different landmarks were used: (A) from start of chemotherapy, (B) from progressive disease, (C) from second FISH analysis.