P02: PROGNOSTIC STRATIFICATION OF STANDARD RISK MULTIPLE MYELOMA DEFINED BY REVISED ISS
Authors: G Barilà, L Bonaldi, A Martines, A Pascarella, S Vedovato, C Clissa, N Macrì, A Bonalumi, L Pavan, M Tinelli, S Nalio, A Teramo, G Calabretto, VR Gasparini, M Krampera, R Bassan, R Zambello
Journal: HemaSphere (2022)

Current Multiple Myeloma (MM) prognostic stratification relies on high risk (HR) cytogenetic aberrations identified by interphase fluorescent in situ hybridization (FISH). According to Revised International Staging System (R-ISS) t(4;14), t(14;16) and deletion of 17p13 are considered HR aberrations, while all other abnormalities are considered standard risk (ST) changes. However growing evidence suggests that gain 1q21 (+1q) associates with dismal outcome while data on t(11;14) are conflicting. In addition, hyperdiploid MM characterized by trisomies involving of odd chromosomes is associated to sensitivity to lenalidomide treatment and favourable outcome. The aim of this study was to evaluate the prognostic significance of specific MM genetic alterations including +1q, t(11;14) and 5-9-15 trisomy as surrogate of hyperdiploid MM in a cohort of standard risk MM patients according to R-ISS. Starting from a cohort of 476 patients affected by newly diagnosed MM and followed in three referral centers, we identified by FISH 226 cases of standard risk MM after excluding HR changes. Patients’ characteristics including clinical and biological features at diagnosis, type of treatment and OS were collected. The study cohort included 78 cases (34.5%) harboring t(11;14) confirmed by FISH while remnant 148 patients (65.5%) were t(11;14) negative. Within this subset, 40 cases displayed concomitant trisomy for chromosome 5-9-15 by FISH. Comparing t(11;14) to the other ST risk patients [non-t(11;14)], there were no differences in terms of ISS III stage, LDH levels, FLC ratio >100, hypercalcemia, renal injury, anemia and bone disease at the diagnosis, while t(11;14) patients were characterized by higher frequency of bone marrow plasmacells >60% (p=0.001). Considering the treatments, no differences were found in type and median number of previous treatments [median lines #2 in t(11;14) subgroup and #1 in the non t(11;14) subgroup, p=0.2266). Overall, chromosome 1 alterations, namely +1q and del1p were present in 35% and 7.5% of cases, respectively, with 8.9% of patients showing >3copies of 1q. Of notice +1q and del1p, were higher in the non-t(11;14) subgroup (39.9% vs 25.4%, p=0.0475 and 10% vs 2.7%, p=0.0594, respectively). With a median follow-up of 32 months, median overall survival (OS) of the entire cohort was 102 months. Patient harboring t(11;14) showed reduced although not significant survival compared to non-t(11;14) cases (80 vs 156 months, p=0.0698). Interestingly the presence of +1q was associated to a worst outcome in the entire study cohort (57 vs 105 months, p=0.0018) and in the t(11;14) and non-t(11;14) subgroups separately (31 vs 84 months, p=0.0015 and 62 vs not reached, p=0.0074, respectively). The role of +1q in the ST MM was further confirmed from the fact that, excluding +1q, there is no significant survival difference between t(11;14) and non-t(11;14) (84 months vs not reached, p=0.0909). However, patients with 5-9-15 trisomy, accounting for 27% of non-t(11;14) group, showed significantly better prognosis with respect to t(11;14) patients (p=0.0134). In conclusion, standard risk MM identified by R-ISS represents a heterogeneous subgroup of patients. In this subgroup, the presence of gain1q impacts on overall survival, suggesting that this alteration might be helpful in the stratification of non-HR MM. Within standard risk, 5-9-15 trisomy used as hyperdiploid surrogate identifies a subset of patients with particularly favorable outcome, also compared to t(11;14) cases.