Loss of heterozygosity in multiple myeloma: A role for PARP inhibition?
8026 Background: PARP inhibitors can induce synthetic lethality in tumors characterized by homologous recombination deficiency (HRD). Two PARP inhibitors are approved for the treatment of BRCA mutated ovarian cancer. HRD can be detected by evaluating genome-wide loss of heterozygosity (LOH), which is associated with response to PARP inhibition. Myeloma (MM) is a genetically unstable tumor and we hypothesized that LOH could be detected in patient samples, supporting a potential role for PARP inhibition in MM. Methods: We analyzed 406 cases at all disease stages: MGUS (n = 7), smoldering MM (SMM, n = 30) newly diagnosed MM (NDMM, n = 71), treated MM (TRMM, n = 64) and relapsed MM (RLMM, n = 234). CD138+ plasma cell DNA underwent targeted next generation sequencing (FoundationOne Heme) interrogating 405 cancer related genes and 3543 single nucleotide polymorphisms (SNPs) across the genome. An algorithm using the minor allele frequencies of the examined SNPs and copy number profile across the 22 autosomal chromosomes identified LOH segments. Events unlikely to be caused by HRD, e.g. whole chromosome or chromosome-arm loss, were excluded. The percentage of genomic LOH for each sample was calculated as the sum of the lengths of included LOH segments divided by the length of the interrogated genome. Results: We found evidence of HRD detected by LOH with higher LOH selecting for patients with poor outcome. LOH increases with advancing disease stage from a median of 0.3% in MGUS to 3.1% in RLMM. LOH was highest in the PR and MMSET molecular subgroups and correlated significantly with the gene expression defined risk score GEP70 (R = 0.4, p < 0.001) and proliferation index (R = 0.4, p < 0.001). Outcome of RLMM patients, the biggest clinical group, was analyzed and patients with LOH above the 3rdquartile (≥5%LOH) had significantly worse overall survival than those with lower levels (p < 0.001). LOH correlates and overlaps with other metrics of poor prognosis, suggesting it may be a prognostic marker itself. Conclusions: We demonstrated LOH in MM samples, increasing as disease progresses and associated with poor prognosis. These data support the further evaluation of PARP inhibitors in MM patients, particularly in the relapsed setting with a high unmet need for new treatments.