Abstract 3936: A branching evolution model at relapse characterizes multiple myeloma patients who responded to upfront combination therapy including new drugs
Authors: Terragna Carolina , Martello Marina , Santacroce Barbara , Solli Vincenza , Pantani Lucia , Zamagni Elena , Tacchetti Paola , Zannetti Beatrice , Mancuso Katia , Marzocchi Giulia , Testoni Nicoletta , Ameli Gaia , Termini Rosalinda , Dico Angela Flores , Borsi Enrica , Martinelli Giovanni , Cavo Michele 
Published: July 2017

Abstract
Intro: Multiple Myeloma (MM) is a biologically complex disease, whose genetic plasticity favors the coexistence of genetically heterogeneous subclones, selected in a Darwinian fashion throughout the disease course. Therapy might represent a major selective pressure over the different subclones, thus supporting an evolutionary model of the disease.
Aim: To explore the existence of different clonal evolution patterns in MM, eventually driven by therapeutic selective pressure.
P&M The study included 33 pts with symptomatic MM, up-front treated either with combination regimens including a proteasome inhibitor (28), or with cyclophosphamide. For each pts, paired BM samples were collected both at diagnosis and at relapse. SNPs array analyses were performed on the CD138+ enriched cell fractions.
Results: Two approaches were applied: a) monitoring the variations of macro CNAs; b) focusing on changes of CNAs frequencies, as observed in 27 genes of interest. Both approaches were consistent in highlighting three major evolution patterns: in 7/33 (21%) pts, the genomic background at relapse was almost identical to that of diagnosis. In 13/33 (39%) pts, an overall increase in the frequencies of the same CNAs as observed at diagnosis was detected at relapse. Finally, in 13/33 (39%) pts, either increased or decreased frequencies of several CNAs, as well as several differences in the CNAs type’s prevalence were observed at relapse, as compared to diagnosis. Of interest, even if an overall CNAs median number increase was observed from diagnosis to relapse (226 vs 507, respectively) - supported by acquisition of CNAs either commonly described as secondary genomic events (i.e. del17p13, amp1q21, del1p23), or associated to the resistance to bortezomib (i.e. del8p21) - any peculiar CNAs resulted significantly prevalent in the 3 identified subgroups of pts.
A high rate (92%) of achievement of VGPR or better quality of response to upfront therapy characterized the third subgroup of pts, whereas the rate of VGPR in the remaining pts was only 20% and PR or SD were observed in 9 and 7 pts, respectively. Finally, the median time to first progression of this subgroup of pts was significantly shorter as compared to that of pts with branching evolution (24 vs 35 months, range 4-41 and 7-123 months, respectively, p=0,01).
Conclusion: The genomic architecture of a subgroup of relapsed MM pts, up-front responsive to new drugs-based combination therapies, resulted overall different from that of diagnosis, suggesting a branching evolution of the disease, sustained by the shrinking of the most prevalent clone (therapy-sensitive), as well as by the expansion of subclones (therapy-resistant) not already evident at diagnosis. This observation raises the question whether re-treatment of relapsed pts should be appropriate in the case of branching evolution.
Acknowledgements: AIRC (MC), Fondazione Berlucchi (CT), FUV (EB).
Citation Format: Carolina Terragna, Marina Martello, Barbara Santacroce, Vincenza Solli, Lucia Pantani, Elena Zamagni, Paola Tacchetti, Beatrice Zannetti, Katia Mancuso, Giulia Marzocchi, Nicoletta Testoni, Gaia Ameli, Rosalinda Termini, Angela Flores Dico, Enrica Borsi, Giovanni Martinelli, Michele Cavo. A branching evolution model at relapse characterizes multiple myeloma patients who responded to upfront combination therapy including new drugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3936. doi:10.1158/1538-7445.AM2017-3936