Activating mutations of N- and K-ras in multiple myeloma show different clinical associations: analysis of the Eastern Cooperative Oncology Group Phase III Trial

Abstract

Mutations of members of the ras family are among the most common oncogene mutations found in multiple myeloma (MM). We have examined the mutational status of the N- and K-ras genes at codons 12, 13, and 61 in 160 newly diagnosed MM patients enrolled on the Eastern Cooperative Oncology Group (ECOG) phase III clinical trial E9486. The total incidence of ras mutations was found to be 39% of the samples analyzed. Five patients showed evidence of more than one mutation. We obtained 22 marrow samples from patients at the time of disease progression or relapse, for whom a ras mutation was identified at diagnosis. In all cases, the ras mutation of the disease progression sample was identical to that found at diagnosis. In contrast, three of 25 patients who did not show any ras mutation at diagnosis acquired a ras mutation at the time of disease progression. No significant association was observed between any ras mutation and stage of disease, beta 2-microglobulin levels, labelling index, or protein type. The mean tumor burden and median survival for patients with mutations of N-ras was indistinguishable from patients with no ras mutations. However, patients with K-ras mutations had a significantly higher mean bone marrow tumor burden at diagnosis than patients with no ras mutations (57% v 36%, P ‼ .02); and the median survival of patients with a K-ras mutation was significantly shorter (2.0 v 3.7 years, P ‼ .02). To determine if the status of ras mutations could affect treatment response, we examined patient survival on the three treatment arms of E9486. Although the presence of a ras mutation in the multidrug treatment, VBMCP alone, showed a marginal significance, neither the VBMCP, nor the addition of interferon-alpha showed statistically significant survival differences between mutant and wildtype ras status. Interestingly, there appeared to be a statistically significant difference in survival of patients treated with VBMCP and alternating high doses of cyclophosphamide + prednisone. Patients with ras mutations had a median survival of 2.1 years; patients with wild-type ras had a median survival of 4.0 years (P ‼ .01).

Expression profile of telomere‐associated genes in multiple myeloma

“…Also, along with hTERT, in MM permitted bypass of senescence, a substantial extension of lifespan, and possibly immortalization. KRAS is an oncogene involved in various malignancies, including MM [84]. It is implicated in telomere maintenance by the stimulation of telomere-telomere fusions (T-TFs) [85], demonstrating a high degree of genomic instability [86].…”

Blockade of the MEK/ERK signalling cascade by AS703026, a novel selective MEK1/2 inhibitor, induces pleiotropic anti‐myeloma activity in vitro and in vivo

“…In parallel, the MEK/ ERK signalling cascade tightly regulates cytokine and growth factor secretion within the BM milieu, which can further augment MM growth, survival, and drug resistance (Giuliani et al, 2004;Menu et al, 2004;Hideshima et al, 2007). Importantly, the key components of the Ras/Raf/MEK/ERK signalling pathway frequently mediate constitutive activation of downstream effectors in late stage MM and plasma cell leukaemia (PCL) (Corradini et al, 1993;Liu et al, 1996;Bezieau et al, 2002;Intini et al, 2007;Tiedemann et al, 2008).…”

“…In these indications, the presence of the BRAF V600E mutation was suggested to predict responses to MEK inhibition (Davies et al, 2002;Solit et al, 2006;Pratilas & Solit, 2007;Friday & Adjei, 2008). RAS mutations, either NRAS or KRAS but not HRAS, were found in MM patients with increasing frequency in relapsed (45-67%) versus newly diagnosed (25%) diseases, correlating with more aggressive disease features (Portier et al, 1992;Liu et al, 1996;Rasmussen et al, 2005;Chng et al, 2008). RAS mutations have been rarely detected (<7%) in pre-malignant monoclonal gammopathy of undetermined significance (MGUS) (Rasmussen et al, 2005;Chng et al, 2008), suggesting an important role of mutated RAS in malignant transformation of clonal plasma cells and MM pathogenesis.…”

Alterations of RAS signalling in Chinese multiple myeloma patients: absent BRAF and rare RAS mutations, but frequent inactivation of RASSF1A by transcriptional silencing or expression of a non‐functional variant transcript

“…Activation of RAS is a common feature in a wide spectrum of tumours. In multiple myeloma (MM), RAS mutations have been observed at variable incidences with most of them >40% and showing generally more common N-than K-RAS mutations in western studies (Neri et al, 1989;Portier et al, 1992;Corradini et al, 1993;Liu et al, 1996;Feinman et al, 1997;Bezieau et al, 2001). However, data on Chinese patients with MM have been lacking.…”