Synthetic lethal model for dual inhibition of single-stranded and double-stranded DNA repair. Cells that have some degree of genomic instability acquire genomic complexity that allows for favorable clonal selection and emergence of favorable genetic traits that confer proliferation, survival, or drug-resistant phenotypes. In a random stochastic process some of these cells suffer irreparable damage and cannot divide further. If this genomic instability is further increased such as the “BRCAness” induced in myeloma cells by bortezomib, it creates further challenges to myeloma cells. If subsequent inhibition of single-stranded DNA repair is inhibited by PARP inhibitors, Neri and colleagues are able to induce cell death.