Despite advances and significant improvement in survival, multiple myeloma (MM) remains incurable and nearly all patients relapse after treatment. In order to gain insights into the genomic lesions associated with acquisition of drug resistance and progression of disease, we performed high resolution genome-wide single nucleotide polymorphism and copy number analyses on matched diagnostic and relapse samples from 24 MM patients either treated with proteasome inhibitor (bortezomib)-based induction regimen (n=12) or conventional chemotherapeutic agents (n= 12). All relapse samples have a clear relationship to the diagnosis clone. The vast majority of patients (92%) acquired additional copy number abnormalities (CNAs) or uniparental disomy (UPD) at relapse or exhibited change in the pattern of lesions present at diagnosis. Of these, 45% acquired new lesions and 41% both acquired new lesions and lost lesions present at diagnosis. Remarkably, loss of lesions at relapse was significantly associated with initial bortezomib treatment (8 out of 12 versus 1 out of 12; P = 0.009). Moreover, in 75% of the bortezomib-treated MM, the lesions lost at relapse included either UPD or deletion providing direct evidences that the relapse clone arose from a common prediagnosis clone present as a minor population at diagnosis that acquired additional abnormalities before emerging as the relapse clone. These results suggest that resistance to novel therapeutic agent known to target MM cells in the bone marrow milieu preferentially goes through with selection of minor prediagnosis clone while escape to conventional chemotherapeutic agents is almost exclusively associated with clonal evolution from diagnosis clone. These data support the proposal to combine several anti-myeloma drug upfront in order to obtain long-term remissions.
Anderson:Millennium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Munshi:Millennium Pharmaceuticals: Honoraria, Speakers Bureau.
Asterisk with author names denotes non-ASH members.