Co-Existent Hyperdiploidy Does Not Abrogate The Poor Prognosis Associated With Adverse Cytogenetics In Myeloma
Authors: Pawlyn Charlotte , Melchor Lorenzo , Boyle Eileen M , Brioli Annamaria , Kaiser Martin F , Gregory Walter , Drayson Mark T , Jackson Graham , Ross Fiona M , Child J. Anthony , Morgan Gareth J , Davies Faith E 
Published: October 2019

Abstract
The development of the cytogenetic abnormalities hyperdiploidy or a translocation involving the immunoglobulin heavy chain are initiating events in the pathogenesis of myeloma. Previous studies have shown that hyperdiploidy is associated with a more favorable outcome whilst the presence of specific translocations (4;14), (14;16) and (14;20) are associated with poor clinical outcomes especially when they occur in association with other high risk features such as del17p and 1q+. While it has been generally accepted that these events are mutually exclusive, review of a number of clinical datasets shows that they occur together in a significant proportion of cases. This raises the mechanistic issue of which cytogenetic abnormality occurs first as well as the more practical issue of what it means for prognosis. In order to address these important questions we have investigated these cases with interphase FISH (iFISH) as well as determining their outcome in the Myeloma IX study.
Myeloma IX is a large study (1960 newly diagnosed myeloma patients) that has been extensively described. iFISH results with a complete data set for hyperdiploidy, adverse IgH translocations, 1q+ and del17p were available for 847 patients with a median follow up of 5.9 years. 58% of patients (499/847) had hyperdiploidy and had a significantly improved survival compared with non-hyperdiploid patients (Median OS 49.7 vs 42.8 months, p=0.016 and PFS 18.8 vs 16.3 months, p=0.028).
Hyperdiploid patients were divided into those who had one or more of the adverse lesions t(4;14), t(14;16), t(14;20), del17p and 1q+ (61%, 304/499) and their outcome was compared to those with none (39%, 195/499). The overall and progression free survival was significantly worse for those with hyperdiploidy plus an adverse lesion compared to those with hyperdiploidy alone (Median OS 60.9 vs 35.7 months, p<0.001, median PFS 23 vs 15.4 months, p<0.001). These results remained significant on multivariate analysis. When subdivided into those patients with hyperdiploidy plus: del17p alone, 1q+ alone, an adverse translocation alone or >1 adverse lesion, there remained a significant detrimental effect on survival (OS and PFS) for the del17p, 1q+ and >1 lesion groups and a trend towards worse survival for those with an adverse translocation (numbers too small to prove significance) when compared to those with hyperdiploidy and no adverse lesion. (table 1)
Table 1 HD = Hyperdiploidy No. of patients PFS (months) OS (months) HD, no adverse lesions 304 23 60.9 HD plus del 17p 20 19.1 (p=0.019) 35.2 (p=0.003) HD plus 1q+ 142 15.4 (p<0.001) 38.1 (p<0.001) HD plus adverse translocation 9 15.4 (p=0.272) 40.1 (p=0.180) HD plus >1 lesion 24 12.1 (p<0.001) 19.9 (p<0.001)
The converse situation was also examined by taking each population with an abnormal lesion and dividing them by the presence or absence of hyperdiploidy. 409/847 (48%) of patients had at least one adverse lesion and they had a significantly worse outcome within the whole data set than those without any adverse lesions (OS 60.6 vs 33.7 months, p<0.001, PFS 23.3 vs 15 months, p<0.001). When the impact of hyperdiploidy within the high-risk population (195/409 hyperdiploid, 214/409 non-hyperdiploid) was examined there was no difference in survival, (OS 35.7 vs 33.6 months p=0.64, PFS 15.4 vs 14.5 months, p=0.58). This remained true across each adverse lesion when individually analysed.
A group of patients with hyperdiploidy and a (4;14) translocation were analysed at a single-cell level using iFISH. Within each case the percentage of cells with a translocation was consistently high, whereas the frequency of individual chromosomal trisomies varied. This suggests that the translocation event may occur earlier. Single cell genetic analysis using the Fluidigm technology is ongoing in order to confirm this finding.
In conclusion, patients with co-existent hyperdiploidy and adverse cytogenetics have worse outcomes than those with hyperdiploidy alone. The progression of their disease is not different to those patients with adverse cytogenetics alone and our data suggests that the presence of hyperdiploidy is not able to abrogate or even ameliorate this adverse prognostic feature. It is important that this is recognised when designing treatment strategies for this group of patients as they should be treated with more aggressive chemotherapy regimens to maximize their response and control disease.

Disclosures:
No relevant conflicts of interest to declare.