Isoform-specific shRNA-mediated RAS knockdown reduces cell viability specifically in MM cell lines harboring the respective oncogenic isoform. MM cells were transiently transfected with shRNA expression vectors (20 μg/mL) targeting K- or N-RAS and cell viability was measured after 5 days in culture. N-RAS mutated cell lines INA-6 (G12D) and JJN-3 (Q61K) were specifically sensitive to N-RAS knockdown, whereas K-RAS mutated MM.1S cells (G12A) were most sensitive to K-RAS knockdown. The viability of MM cell lines AMO-1 and U266 (wild-type RAS) remained unaffected by knockdown of either RAS isoform.