in Multiple Myeloma, High-Risk Features Are Modulated By Other Chromosomal changes : A Large Snparray IFM Study

In multiple myeloma, cytogenetic changes display important value for patients’ outcome. In this setting, the most important changes are the del(17p), and the t(4;14), conferring a poor outcome. However, a certain heterogeneity is observed in survival of these high-risk patients. We hypothesized that other chromosomal changes may impact the outcome. We retrospectively analyzed a large series of 242 patients displaying either the t(4;14) (157 patients), or the del(17p) (110 patients), 25 patients presenting both abnormalities, using SNP-array. The main advantage of SNParray analyses is that all the unbalanced chromosomal changes are analyzed, in contrast to FISH which informs only for the chosed probes. For t(4;14), 144 patients have relapsed, and 103 have died. The median PFS was 1.4 year, and the median OS was 3.5 years. The median beta2-microglobulin (b2m) level was 4.0 mg/L (range, 1.2-38.3). The distribution of ISS stages 1, 2, and 3 was 35.4%, 26.4%, and 38.2%, respectively. Based on FISH results, 31.2% of the patients presented the abnormal configuration with only one fused signal. In all these patients, SNP-array analysis showed a loss of the telomeric part of one chromosome 4. In contrast to previous reports on this particularity in which the explanation was a loss of the derivative chromosome 14,^17,18 we clearly show here that this configuration results from an unbalanced translocation. In patients with t(4;14), del(1p32) (p<0.001), del(16q) (p=0.03), del22q (p=0.04) and more than 30 chromosomal structural changes (p=0.02) negatively impacted PFS. For OS, del(13q14) (p=0.01), del(1p32) (p<0.001), and the number of chromosomal structural changes (p<0.05 and p=0.01 for [10;30[and more than 30 structural changes, respectively) worsened the prognosis of patients.

In patients with del(17p) (110 patients), 99 patients relapsed, and 83 died. The median PFS was 1.3 year and the median OS was 2.7 years. The median beta2-microglobulin (b2m) level was 4.4 mg/L (range, 1.4-32.1). The distribution of ISS stages 1, 2, and 3 was 28.4%, 26.9%, and 44.8%, respectively. For patients with del(17p), del(1p32) (p<0.001), del(16q)] (p=0.03), del22q (p=0.04) and more than 30 chromosomal structural changes (p=0.02) negatively impacted PFS. For OS, del(1p32) (p=0.004) worsened the prognosis of patients, whereas more than 8 trisomies (p=0.008) was found to have a protective effect on survival.

This study, which is the largest series of high-risk patients, analyzed with the most modern genomic technique, identified two main factors negatively impacting survival: del(1p32) and genomic complexity. Furthermore, we did show that 1/3 of patients with t(4;14) did not display upregulation of FGFR3 because of loss of the telomeric part of the chromosome 4. These patients do not present a better prognosis than those upregulating FGFR3, reinforcing the idea that FGFR3 activation is not important in the biology of the t(4;14).