ACTIVATING MUTATIONS OF N-RAS AND K-RAS IN MULTIPLE-MYELOMA SHOW DIFFERENT CLINICAL ASSOCIATIONS - ANALYSIS OF THE EASTERN-COOPERATIVE-ONCOLOGY-GROUP PHASE-III TRIAL

Mutations of members of the ras family are among the most common oncog ene mutations found in multiple myeloma (MM). We have examined the mut ational status of the N- and K-ras genes at codons 12, 13, and 61 in 1 60 newly diagnosed MM patients enrolled on the Eastern Cooperative Onc ology Group (ECOG) phase III clinical trial E9486. The total incidence of ms mutations was found to be 39% of the samples analyzed. Five pat ients 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 ms mutation was identified at diagnosis. In all cases, the res mutation of the disease progression sample was identical to that f ound at diagnosis. In contrast, three of 25 patients who did not show any ms mutation at diagnosis acquired a res mutation at the time of di sease progression. No significant association was observed between any ras mutation and stage of disease, beta(2)-microglobulin levels. labe ling index, or protein type. The mean tumor burden and median survival for patients with mutations of N-ras was indistinguishable from patie nts 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 su rvival of patients with a K-ras mutation was significantly shorter (2. 0 v 3.7 years, P <.02). To determine if the status of ms mutations cou ld affect treatment response, we examined patient survival on the thre e treatment arms of E9486. Although the presence of a ms mutation in t he multidrug treatment, VBMCP alone, showed a marginal significance, n either the VBMCP, nor the addition of interferon-cr showed statistical ly significant survival differences between mutant and wildtype ms sta tus. Interestingly, there appeared to be a statistically significant d ifference in survival of patients treated with VBMCP and alternating h igh doses of cyclophosphamide + prednisone. Patients with ras mutation s had a median survival of 2.1 years; patients with wildtype ras had a median survival of 4.0 years (P <.01). (C) 1996 by The American Socie ty of Hematology.