Inhibiting MEK in MAPK pathway-activated myeloma.

Over the last decade, new drugs have significantly changed the paradigm for treating multiple myeloma (MM), resulting in improved outcomes and reduced toxicity. However, many patients with MM relapse, and those who are refractory to or relapse after therapy with an immune-modulatory drug and a proteasome inhibitor have a dismal prognosis.1 Improving the outcome of relapsed and refractory MM is a significant clinical challenge. Importantly, in this respect, recently published data have established the frequent mutation of the RAS/mitogen-activated protein kinase (MAPK) pathway,2, 3, 4, 5 with mutations in NRAS, KRAS or BRAF being present in up to 50% of newly diagnosed MM cases. We routinely perform comprehensive genomic profiling using the FoundationOne Heme assay (Supplementary Methods). Review of these data shows the majority of the NRAS, KRAS and BRAF mutations occur in hotspots causing constitutive activation of the corresponding proteins. This makes the MAPK pathway a significant therapeutic target in MM.