PS1346 CLONAL EVOLUTION IN MULTIPLE MYELOMA PATIENTS RECEIVING MAINTENANCE THERAPY
Authors: C. Terragna, V. Solli, A. Poletti, M. Martello, E. Borsi, L. Pantani, E. Zamagni, R. Termini, E. Lakpo Agboyi, K. Mancuso, L. Cifarelli, S. Rocchi, I. Rizzello, P. Tacchetti, G. Martinelli, M. Cavo
Journal: HemaSphere (2019)

Background: Multiple Myeloma (MM) disease progression is often coupled to radical changes of the genomic sub‐clonal architecture, which in turn might impact the tumor‐specific aggressiveness and invasiveness over time. Therefore, MM patients (pts) are unlikely to maintain sustained MRD negativity status and the disease typically recurs. It is assumed that therapy bears a major role as selective driver to induce genomic changes within pts’ clonal architecture; nevertheless the identification of specific therapy‐driven genomic changes has been so far prevented by the scarce number of homogeneously‐treated cohorts of pts with paired samples (diagnosis and relapse). Aims: In the present study we estimated the role of maintenance therapy in eliciting genomic changes in a cohort of MM pts, up‐front treated with bortezomib‐based regimens. Methods: Whole genome Copy Number Alterations (CNAs) landscape was obtained by analyzing SNPs array with dedicated R packages. The study included 43 pts, whose BM‐CD138+ cell fractions were collected both at diagnosis and at first relapse. 25 pts received maintenance therapy (19 lenalidomide, 6 proteasome inhibitor) and 18 did not. Median times to progression (TTP) were 30,5 (range 15–100) and 30 months (range 14–117) for pts who did or did not receive maintenance, respectively. Results: We first aimed at defining pts evolution patterns. To this purpose, an analysis algorithm was first developed to assess the CNAs changes between diagnosis and relapse of any functional genomic region (i.e. coding genes and miRNA). Results were than bi‐clustered, by employing three linkage‐methods, hence revealing common subgroups of genes and pts showing similar behaviors, under the same therapeutic selective pressure: overall, 20 and 23 pts relapsed with branching and stable pattern, respectively. Pts who received maintenance where more likely to relapse with changes in their genomic background (64% branched), as compared to pts who did not receive maintenance (39% were stable); nevertheless, any differences in overall survivals (OS) post first relapse were observed among pts with branching evolution pattern and pts whose genomic background remained stable between diagnosis and relapse. We than focused on CN changes of specific genomic regions, whose prognostic role has been already established in MM, i.e. CN losses of TP53 on chromosome (chr) 17p, Rb1 on chr13q, WWOX on chr16p, cdkn1c and FAM46C on chr1p; CN gain of CKS1B on chr1q. When present at diagnosis, these CNAs tended to persist throughout pts’ clinical follow up, regardless of whether pts received or not maintenance. The emersion of any of these CNAs at relapse was more likely in pts receiving maintenance (40% vs 17% of cases), even if maintenance seemed to favor a better disease control both in pts carrying durably any of these CNAs and in pts where any of them emerged at relapse. Pts with branching evolution pattern of any of the above mentioned CNAs particularly benefitted of maintenance therapy, with OS post first relapse significantly longer than pts who did not received maintenance therapy (50 vs 14 months, p = 0.004). Summary/Conclusion: Genomic changes caused by the selective pressure of maintenance therapy and provoking the emersion of branched clones at relapse are likely to require time to take place. This might explain the extended survival observed in pts who received maintenance and relapsed with branching evolution patterns, as compared to that of pts whose genomic landscape tended to remain stable. ACKNOWLEDGEMENTS: AIRC (MC), Fondazione Berlucchi (CT)