Loss of heterozygosity as a marker of homologous repair deficiency in multiple myeloma: a role for PARP inhibition?

Abstract

PARP inhibitors can induce synthetic lethality in tumors characterized by homologous recombination deficiency (HRD), which can be detected by evaluating genome-wide loss of heterozygosity (LOH). Multiple myeloma (MM) is a genetically unstable tumor and we hypothesized that HRD-related LOH (HRD-LOH) could be detected in patient samples, supporting a potential role for PARP inhibition in MM. Using results from targeted next-generation sequencing studies (FoundationOne® Heme), we analyzed HRD-LOH in patients 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)) using an algorithm to identify HRD-LOH segments. We demonstrated HRD-LOH in MM samples, increasing as disease progresses. The extent of genomic HRD-LOH correlated with high-risk disease markers. Outcome of RLMM patients, the biggest clinical group, was analyzed and patients with HRD-LOH above the third quartile (≥5% HRD-LOH) had significantly worse progression-free and overall survival than those with lower levels (p < 0.001). Mutations in key homologous recombination genes account for some, but not all, of the cases with an excess of HRD-LOH. 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.

Identification of novel mutational drivers reveals oncogene dependencies in multiple myeloma

“…45,46 We also previously showed in a separate data set that homologous recombination deficiency-associated LOH is more frequent in those with high-risk disease and is associated with worse outcomes. 47 In ovarian cancer, these mechanisms of genomic instability are used as key targets of PARP inhibitors, where sensitivity to PARP inhibition is induced either by chemically inhibiting the DNA damage response pathway or by inducing increased BRCAness with the proteasome inhibitor bortezomib. 48,49 Significant associations between mutations, translocations, and CNA clusters were seen, consistent with the molecular subgroups of NDMM being biologically distinct ( Figure 3C).…”

Microhomology-mediated end joining drives complex rearrangements and over-expression of MYC and PVT1 in multiple myeloma

“…42 We have previously shown that mutation of ATM, BRCA1 and other genes involved in DNA homologous recombination are associated with in increased levels of loss of heterozygosity in MM patients. 45 It is likely that disruption of this pathway is key in genomic instability and progression of disease.…”

Toward personalized treatment in multiple myeloma based on molecular characteristics

“…Mutational analysis of genomic instability can also predict for adverse outcomes with increases in genome-wide loss of heterozygosity associated with adverse outcomes. 46…”

“…Therapies in development Further targets have been identified that may predict response to therapeutic agents, although these are at earlier stages of development. Examples include IDH1/IDH2 mutations and IDH inhibitors, 79,80 loss of heterozygosity or ATM/ATR mutations and PARP inhibitors, 46 and FGFR3 mutations and FGFR3 inhibitors. 81 Several are being studied in large umbrella studies such as the Multiple Myeloma Research Foundation MyDRUG study and the Canadian "CAPTUR" study.…”