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.

"The Long Journey of Unexplained Erythrocytosis": Erythrocytosis due to High-Oxygen Affinity Hemoglobinopathy - Hemoglobin Variant Little Rock (HBB: c.432C>A) - A Report of a Swiss Family and Review of the Literature.

The differential diagnosis of erythrocytosis is complex, involving a tailored algorithm. Congenital causes are rare and such patients commonly face a long journey looking for diagnosis. This diagnosis requires expertise and accessibility to modern diagnostic tools. We present the case of a young Swiss man with long-standing erythrocytosis of unknown origin and his family. The patient had an episode of malaise as he went skiing above 2,000 m altitude. In the blood gas analysis, p50 was low (16 mm Hg) and erythropoietin was normal. Using next-generation sequencing, a mutation in the hemoglobin subunit beta gene was found, a pathogenic variant known as hemoglobin Little Rock causing high oxygen affinity. Some family members also had unexplained erythrocytosis, therefore the mutational status of the family was analyzed, the grandmother and mother showed the presence of the same mutation. The use of modern technology finally offered a diagnosis to this family.