Autologous Bone Marrow Transplantation - Blog Science Connections

Myeloma Biology and Therapy 265
only 1 of 100 patients studied, but increased mi/c-RNA expression was noted
in about 25% of patients, including 1 with an abnormal transcript size. Bcl-\
was rearranged in 5% of 100 patients evaluated (8). These studies were
further complemented by analysis of muc-protein expression using flow
cytometry with DNA counterstaining, which demonstrated mt/c-protein
expression preferentially in aneuploid tumor cells (9).
To summarize our biologic studies: we found hyperdiploid abnormalities
in over 80% of patients. Often these were accompanied by complex
morphologic chromosome anomalies, which were associated with IgA
myeloma in the case of lymphoma-like translocation and with only Bence
Jones proteinuria in cases of hypodiploidy. As in some B-cell lymphomas, the
observations of CALLAand B4 expression and of translocations involving the
immunoglobulin heavy-chain gene locus on chromosome 14 suggest the
involvement of a pre-B precursor cell in the neoplastic disease process,
whereas the coexpression of early and well-differentiated B-cell phenotypes is
an example of differentiation infidelity. Clinically, drug resistance was
associated with a low plasma-cell RNA content and hypodiploid DNA stem
lines (10).
THERAPY
The relatively dismal outlook for patients with established resistance to
melphalan and prednisone results from the lack of effective salvage therapy.
Alkylating-agent combinations, interferon, and prednisone pulses induce
short remissions in about 15% of such patients. These results have been
substantially improved through use of the VAD (vincristine [Oncovin],
Adriamycin [doxorubicin], dexamethasone) regimen and of high-dose
melphalan.
VAD
In order to determine the relative therapeutic contribution of dexamethasone
to the success of VAD (11), we compared dexamethasone pulsing and
VAD in two successive clinical trials of patients refractory to standard
melphalan and prednisone and also, in 25% of patients, resistant to
Adriamycin (12). Responses to dexamethasone or VAD were defined by
greater than 75% tumor cytoreduction and occurred in about 60% of patients
with relapsing myeloma who received VAD. Dexamethasone alone induced
remission in 25% of patients regardless of prior responsiveness, and a third of
patients with primary resistance responded to VAD. There was a steep
incremental increase in response rate as the duration of primary resistance
decreased, from 16% for patients with resistance for greater than 1 year to
46% for those with primary refractory disease for less than 6 months
(combined dexamethasone and VAD groups). Responses occurred rapidly:
median tumor halving times were 1.4 months for dexamethasone and 0.7