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Activating mutations of N- and K-ras in multiple myeloma show different
clinical associations: analysis of the Eastern Cooperative Oncology Group
Phase III Trial
P Liu, T Leong, L Quam, D Billadeau, NE Kay, P Greipp, RA Kyle, MM Oken and B Van Ness
University of Minnesota, Minneapolis, USA.
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).
Volume 88,
Issue 7,
pp. 2699-2706,
10/01/1996
Copyright © 1996 by The American Society of Hematology
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