Acquired Loss of a Sex Chromosome Is a Positive Prognostic Factor for Patients with Multiple Myeloma Undergoing ASCT

Abstract

Introduction: In patients with multiple myeloma (MM), small somatic genetic lesions in non-malignant blood cells, i.e. clonal hematopoiesis, has been found to be associated with inferior survival and other adverse outcomes (Mouheddine T.H. et al. - Nature Comm. 2020). However, large-scale alterations on a chromosomal level are also acquired in ageing blood cells and may impact patient outcomes. Methods: Using a novel bioinformatic approach, we performed a genome-wide analyses of chromosomal aberrations in 998 patients with multiple myeloma before undergoing autologous stem cell transplant (ASCT) in a national population-based cohort. Post-induction harvest samples were analyzed with a custom Illumina deCODE Genetics SNP array and further processed using MoChA bioinformatic pipeline (Loh P., Genovese G. et al. - Nature 2020) to identify acquired mosaic chromosomal alterations (mCAs). Comprehensive clinical data was collected from nationwide registries with long-term follow-up (the Danish Multiple Myeloma Registry and the Danish Civil Registration System). Data included information on diagnostic criteria, peripheral blood counts, M protein, β-2 microglobulin, albumin, genetic myeloma aberrations by FISH, treatment, response to ASCT, progression, and death. Results: We identified 178 patients (17.8%) with acquired chromosomal alterations before undergoing ASCT. Autosomal mCAs were identified in 77 patients (7.7%), while 109 patients (10.9%) had loss of sex chromosomes (X or Y). Alterations were found on all chromosomes. Median cell fraction of autosomal mCA clones was 6.6% (IQR 2.7-20.4) in the analyzed harvest samples. Loss of sex chromosome was strongly associated with higher age (Wilcoxon P < 0.0001), while the age association was less robust for autosomal mCAs (Wilcoxon P = 0.094). There was no impact of type of induction regimen on frequency of mCAs. Full clinical annotation was available for 799 patients. Median follow-up was 6.4 years. Interestingly, at MM diagnosis, bone marrow plasma cell infiltration was significantly lower in patients with loss of chromosome X or Y (β coefficient -9.1%, P = 0.003). In accordance, hemoglobin level at diagnosis was also significantly higher in patients with sex chromosome loss (P = 0.027), despite these patients being older. In addition, the response to ASCT was superior in patients with loss of a sex chromosome. In patients that obtained at least a very good partial response after ASCT, 12.9% had sex chromosome loss, while only 4.7% of patients with poorer responses had sex chromosome loss (chi-square test P = 0.0017). In relation to these findings, overall survival was found to be superior in patients with loss of chromosome X, also when adjusted for age and sex (adj.P = 0.02). This survival difference was however only observed for long-term survivors (after more than four years of follow-up), indicating a possible interaction with later treatments. On the contrary, detection of multiple autosomal mCAs (n=14 patients) was associated with early age-independent inferior survival (adj.P = 0.005). A single autosomal mCA did not affect overall survival. To identify possible infiltration of malignant cells in the stem cell harvest, in a subset of patients (n=360) we were able to cross-check mCAs with FISH data on chromosomal variants identified in CD138+ sorted myeloma cells. We found no overlap between common myeloma chromosomal aberrations by FISH and identified mCAs. This indicates that the identified mCAs are from cells of the non-malignant hematopoietic system and not from myeloma plasma cells. Conclusion: In a longitudinal nationwide cohort of MM patients we examined the impact of acquired hematopoietic chromosomal alterations. Somatic mCAs or loss of sex chromosome was detected in stem cell harvest material in almost one fifth of patients undergoing ASCT. Sex chromosome loss was significantly associated with higher age, but surprisingly, it was also significantly associated with better response to ASCT and longer overall survival. The underlying biological causes of these findings remain to be elucidated. With regards to clonal origins, we did not identify any chromosomal variants to be present in both the myeloma clone (by diagnostic CD138+ FISH) and in the harvest product (by mCA analysis) in the same patient.