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
Pc. Liu et al., 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, Blood, 88(7), 1996, pp. 2699-2706
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.