Next generation sequencing (NGS) studies have highlighted the role of aberrant activity of APOBEC DNA deaminases in generating the mu- tational repertoire of multiple myeloma (MM). However, the contribu- tion of this mutational process across the landscape of plasma cell dyscrasias, or its prognostic role, has never been investigated in detail. To answer these unexplored aspects of MM biology, we used published NGS data from our own work as well as others, including the large CoMMpass trial for a total of 1153 whole-exomes of MM. Furthermore, we investigated 5 MGUS, 6 primary plasma cell leukemias (pPCL) and 18 MM cell lines (MMCL). Overall, we identified signatures of two mu- tational processes, one related to spontaneous deamination of methy- lated cytosines (30% of variants, range 0-100%) and one attributed to aberrant APOBEC activity (70% of variants, range 0-100%). APOBEC contribution was extremely heterogeneous among MM patients, but was correlated with a higher mutational burden (r=0.71, p=<0.0001) and with MAF gene translocations t(14;16) and t(14;20). The activity of APOBEC increased from MGUS to MM to pPCL, both in terms of ab- solute number of mutations and as percentage contribution. In MMCL we instead observed a bi-modal distribution whereby 8 cell lines showed the highest numbers of mutations caused by APOBEC (5/8 car- ried MAF translocations), while 10 where virtually devoid of APOBEC mutations (0/10 carried MAF translocations). The contribution of APOBEC to the total mutational repertoire in MM had a clear prognos- tic impact. MM patients with APOBEC mutations in the lowest quartile had a survival advantage over patients with APOBEC mutations in the highest quartile both in terms of progression-free survival (3-y PFS 46% vs 67% months, p=<0.0001) and overall survival (3-y OS 52% vs 83%, p=0.0084). This association was retained in a multivariate model that included age, gender, cytogenetic class, ISS, and quartiles of mutational load both in PFS [p=0.02, HR 2.06 (95IC 1.11-3.81] and OS [p=0.02, HR 2.88 (95IC 1.17-7.09)]. Interestingly we found that APOBEC mutations in the 4th quartile retained its independent prognostic respect to high mutational load and presence of MAF translocations. Overall, our data suggest that APOBEC-mediated mutagenesis is strongly involved in MM pathogenesis and its activity persists during different phases of evolution, playing a critical role in MM genomic complexity, and im- pacting prognosis of the patients
