The clinical course and management of a patient with BRAF^V600E-mutant MM developing resistance to treatment with vemurafenib. Schematic dynamic overview of the myeloma cell populations, according to their mutational status, in relation to treatment with vemurafenib (Vem), bortezomib and dexamethasone (BTZ/DEX), and the combination regimen (A). The monoclonal proteins were monitored over time by serum and urine electrophoresis, respectively (B). Representative MRI images of intramedullary BRAF^V600E-mutant lesions of the proximal right tibia (C), initially responding to vemurafenib (NRAS^WT, month 5) acquiring a de novo NRAS^G12A mutation associated with resistance to vemurafenib (month 15), responding to BTZ/DEX as well as to the combination Vem-BTZ/DEX (month 25). (D) Immunohistochemistry denotes proliferation (by MIB1 expression) and activation status of ERK signaling (by phosphorylation of ERK [pERK]). Serial biopsies were taken from BRAF^V600E-mutant extramedullary lesions with a concomitant NRAS^G13R mutation (top row) or a NRAS^WT background (bottom row) at the time of relapse while on intermittent low-dose vemurafenib (month 10), on full-dose vemurafenib (month 15), and on bortezomib/dexamethasone (month 20). Although full-dose vemurafenib abrogates proliferation and ERK activation in the NRAS^WT tumor, no changes are seen in NRAS^G13R. In contrast, the opposite effects are seen on treatment with bortezomib/dexamethasone, confirming the contradictory responses seen to each regimen. wt, wild type.