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

Abstract

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.

Leukemic Stem Cells and Hematological Malignancies

“…Myeloma cells proliferate, leading to the formation of tumors, infiltration of the bone marrow, and subsequent depletion of red and white blood cells. Genetic anomalies in oncogenes such as CMYC , NRAS , and KRAS may affect the growth of plasma cells; however, the specific cause remains unclear [ 69 , 70 , 71 ]. Multiple myeloma stem cells, like cancer stem cells or leukemic stem cells, are functionally and phenotypically heterogeneous and induce resistance to chemotherapy and radiation therapy [ 72 ].…”

Liquid Biopsies as Non-Invasive Tools for Mutation Profiling in Multiple Myeloma: Application Potential, Challenges, and Opportunities

“…Mutations in the PSMB5 gene are implicated in resistance to proteasome inhibitors (PI, e.g., bortezomib), while mutations in CRBN and genes of the Cereblon pathway are associated with resistance to treatment with immunomodulatory agents (IMiDs) [36,37]. Only very recently, Perroud et al showed that mutations in the MAPK pathway are associated with unfavorable outcomes in patients treated with PI/IMiD combinations [15]. Furthermore, it has been reported that mutations in TP53, ATM, ATR, and CCND1 confer to an inferior prognosis, while IRF4 mutations have been associated with a favorable prognostic impact [12].…”

“…Although still far from clinical practice, circulating biomarkers could assess patient eligibility for these targeted treatments. More data relate to the way in which mutation profiling can be used to detect and predict therapy resistance [15,36,37]. Coffey et al (2021) recently performed the targeted sequencing of cfDNA in 16 patients with RRMM and linked these results to highthroughput screening of drug compounds to predict response to these treatments.…”

“…However, patients continue to relapse, and, in particular, those with high-risk disease characteristics including unfavorable cytogenetic abnormalities have inferior outcomes [7][8][9][10][11]. The increasing use of next-generation sequencing (NGS) technology over the last decade has shown that in many MM patients, a complex, dynamic tumor mutation profile occurs that affects prognosis and therapeutic response [12][13][14][15][16][17]. In addition, several studies have demonstrated a spatial genetic heterogeneity in the BM compartment of MM patients.…”

Multiple myeloma: signaling pathways and targeted therapy

“…The RAS/MAPK pathway plays a crucial role in MM by influencing cell proliferation, survival, and differentiation. The activation of this pathway in MM is often driven by mutations and increased levels of cytokines present in the tumor microenvironment, such as IL-6, insulin-like growth factor (IGF), and vascular endothelial growth factor (VEGF) [ 84 – 86 ]. The aberrant activation of RAS/MAPK pathway contributes to the development and progression of MM and other cancers [ 87 , 88 ].…”