CKS1B/CDKN2C Copy Number Ratio : A New Predictor of Survival in Transplant- and Non Transplant-Eligible Multiple Myeloma Patients

BACKGROUND

Current molecular risk stratification of multiple myeloma (MM), based on the presence of t(4 ;14) and 17p deletion, cannot fully explain treatment outcome heterogeneity, as other features also predict prognosis. About 30% of genetic events map to chromosome 1 : most upregulated genes to 1q and most downregulated ones to 1p. CKS1B gains on 1q21 and CDKN2C loss on 1p32, both favoring cell cycle progression, portended impaired outcome in many but not all studies. Based on their recurrence and considering their functional convergence, we hypothesized CKS1B/CDKN2C copy number ratio to be a risk factor fitter than each aberration alone.

METHODS

This single-center retrospective study, enrolled 104 newly diagnosed adult patients aged ≥18 years, 48 transplant-eligible and 56 not. All patients were routinely tested for CKS1B and CDKN2C and treated according to consensus guidelines. Data were collected from 2012 to May 31, 2018. For each subject, we calculated a FISH-based ratio by CKS1B on CDKN2C copy number : it was equal to 1 with no change in copy number and >1 in case of CKS1B gains, CDKN2C loss or both. In patients with CDKN2C biallelic loss, the ratio was not equal to 0, but to CKS1B copy number, as functional consequence should prevail over arithmetic result. We, then, analyzed separately the impact of CKS1B gains, CDKN2C loss and CKS1B/CDKN2C ratio on PFS and OS.

RESULTS

In the transplant subgroup, the median follow-up was 22.9 (1.4-71.9) months. By FISH analysis, 15 patients had variable gains of CKS1B, 6 monoallelic and 1 biallelic CDKN2C loss ; CKS1B/CNKN2C copy number ratio was ≥1.5 in 17, ≥2 in 9 and ≥3 in 2. ROC curves evaluating the relevance of the ratio were statistically significant for PFS (p=0.008) and OS (p=0.049). Median PFS from diagnosis, overall and for patients with CKS1B gains, CDKN2C loss and ratio ≥1.5 was 21.6 (1.4-68.4), 24.8 (vs 41.5 with no CKS1B gains), 28.7 (vs 37.7 with no 1p deletion) and 25 (vs 42 with normal ratio) months, respectively. By Kaplan-Meier log-rank analyses, PFS was significantly impaired by CKS1B gains (p=0.014) and ratio ≥1.5 (p=0.007), but not by CDKN2C loss (p=0.339). Median OS from diagnosis, overall and for patients with CKS1B gains, CDKN2C loss and ratio ≥1.5 was 22.9 (1.4-71.9), 24.2 (vs 64.2 with no CKS1B gains), 44.9 (vs 54.8 with no 1p deletion) and 32 (vs 64 with normal ratio) months, respectively. By Kaplan-Meier log-rank analyses, OS was also significantly impaired by CKS1B gains (p=0.001) and ratio ≥1.5 (p=0.004), but not CDKN2C loss (p=0.339). In multivariate analyses, parameters negatively influencing PFS were age >65 years (p=0.005), CKS1B gains (p=0.001), ratio ≥1.5 (p=0.006) and ISS3 status (p=0.019) ; factors unfavorably affecting OS were age >65 years (p=0.044), ratio ≥1.5 (p=0.049) and non secretory status (p=0.018), but not CKS1B gains (p=0.174).

In the non transplant subgroup, the median follow-up was 26.4 (0.2-87.3) months. By FISH analysis 30 patients had variable gains of CKS1B and 10 hemizygous loss of CDKN2C ; CKS1B/CDKN2C ratio was ≥1.5 in 34, ≥2 in 21 and ≥3 in 7. ROC curves evaluating the relevance of the ratio showed only a trend toward statistical significance for PFS (p=0.065), but not for OS (p=0.137). Median PFS from diagnosis, overall and for patients with CKS1B gains, CDKN2C loss, ratio ≥2 and ≥3 was 17.5 (0.2-79.9), 20.9 (vs 26.7 with no CKS1B gains), 15.9 (vs 24.9 with no CDKN2C loss), 16.6 (vs 26.9 for ratio <2) and 11.1 (vs 25.6 for ratio <3) months, respectively. In Kaplan-Meier log-rank analyses, PFS was significantly impaired by ratio ≥3 (p=0.000), but not by CKS1B gains (p=0.204) or CDKN2C loss (p=0.273). Median OS from diagnosis, overall and for patients with CKS1B gains, CDKN2C loss, ratio ≥2 and ≥3 was 26.4 (0.2-87.3), 34 (vs 40 with no CKS1B gains), 24 (vs 43.6 with no 1p loss), 31.2 (vs 44.6 with ratio <2) and 13 (vs 45.2 with ratio <3) months, respectively. By Kaplan-Meier log-rank analyses, OS was also negatively affected by ratio ≥3 (p<0.0001), but not by CKS1B gains (p=0.476) or CDKN2C loss (p=0.207). In multivariate analyses, factors negatively impacting PFS were platelet count <150 G/L (p=0.020) and ratio ≥3 (p=0.031) ; parameters unfavorably affecting OS were bone marrow plasma cells ≥60% (p=0.018) and ratio ≥3 (p=0.026).

CONCLUSIONS

Even with few patients, these results provide proof of the concept of CKS1B/CDKN2C ratio as an outcome predictor. Of note, the ratio indicated worse post-transplant PFS and OS in patients over 65 years.