Effect of MAPK activation via mutations in NRAS, KRAS and BRAF on clinical outcome in newly diagnosed multiple myeloma.

Until now, next generation sequencing (NGS) data has not been incorporated into any prognostic stratification of multiple myeloma (MM) and no therapeutic considerations are based upon it. In this work, we correlated NGS data with (1) therapy response and survival parameters in newly diagnosed multiple myeloma, treated by VRd * and (2) MM disease stage: newly diagnosed multiple myeloma (ndMM) versus relapsed and/or refractory (relapsed/refractory multiple myeloma). We analyzed 126 patients, with ndMM and relapsed refractory multiple myeloma (rrMM), treated at the University Hospital of Bern (Inselspital). Next generation sequencing was performed on bone marrow, as part of routine diagnostics. The NGS panel comprised eight genes CCND1, DIS3, EGR1, FAM46C (TENT5C), FGFR3, PRDM1, TP53, TRAF3 and seven hotspots in BRAF, IDH1, IDH2, IRF4, KRAS, NRAS. The primary endpoint was complete remission (CR) after VRd in ndMM, in correlation with mutational profile. Mutational load was generally higher in rrMM, with more frequently mutated TP53: 11/87 (13%) in ndMM versus 9/11 (81%) in rrMM (OR 0.0857, p = 0.0007). In ndMM, treated by VRd, mutations in MAPK-pathway members (NRAS, KRAS or BRAF) were associated with reduced probability of CR (21/38, 55%), as compared with wild type NRAS, KRAS or BRAF (34/40, 85%; OR 0.2225, p = 0.006). NRAS c.181C > A (p.Q61K) as a single mutation event showed a trend to reduced probability of achieving CR (OR 0.0912, p = 0.0247). Activation of MAPK pathway via mutated NRAS, KRAS and BRAF genes seems to have a negative impact on outcome in ndMM patients receiving VRd therapy. VRd* - bortezomib (Velcade®), lenalidomide (Revlimid®) and dexamethasone.

Drug-induced, mixed-type hepatitis following ingestion of Cordyceps sinensis.

The use of herbal and dietary supplements is increasing worldwide. Consumers consider it as a natural, and therefore safe and healthy alternative to conventional synthetic drugs and do not expect adverse effects. However, numerous herbal and dietary supplements have been associated with adverse hepatic reactions of variable severity. Recognition of adverse hepatic reactions following the ingestion of herbal and dietary supplements is sometimes difficult since clinical presentation can resemble that of other etiologies unrelated to xenobiotics. Pharmacovigilance is based on spontaneous reporting and, thus, many incidents probably remain unrecorded due to lack of awareness among users and prescribers. The present report describes the first case of cholestatic hepatitis after the intake of an herbal supplement containing Cordyceps sinensis. Causality was considered probable after exclusion of alternative causes, a close temporal relationship, and an immediate dechallenge response with a full remission.