Validation of the new ims/IMWG consensus genomic staging (CGS) of high-risk multiple myeloma (HRMM) in a contemporary cohort of 1209 patients

Abstract Despite significant improvements in multiple myeloma (MM) therapy, the outcome of patients (pts) remain heterogeneous. Prognostic factors, based on data from pts treated with older therapies, may no longer accurately capture prognosis, when novel drugs and their combinations are used. The International Myeloma Society and the International Myeloma Working Group formulated a Consensus Genomic Staging (CGS) of high-risk MM (HRMM) defined as the presence of at least one of: del(17p) (20% clonal fraction) and/or TP53 mutation; IgH translocation t(4;14), t(14;16) or t(14;20) along with 1q+ and/or del1p32 (IgH/Chr1abn); monoallelic del1p32 along with 1q+ or biallelic del1p32 (Chr1abn) or β2 microglobulin (b2m) ≥5.5 mg/L with serum creatinine (sCr) 1.2 mg/dL. The IMS/IMWG panel developed this consensus from data derived from several clinical trials' cohorts; however, the new HRMM criteria have not been validated yet. We evaluated the new HRMM criteria in a large cohort of 1209 consecutive NDMM pts with complete data (except TP53 mutations), treated in a single center (Department of Clinical Therapeutics, Athens, Greece) with contemporary regimens, including triplets and quadruplets, between 2010 and 2024. The median age was 68 (32-98) years; 44% were females. At diagnosis distribution per ISS stage 1,2, and 3 was 31%, 30% and 39%; for R-ISS-I, II 30 ml/min/1.73 m2, but 419 (35%) pts had sCr 1.2 mg/dl. Primary treatment included PI 29% received HDM-ASCT, 74% received maintenance or were on continuous therapy. Per the new IMS definition, 25.2% of pts had HRMM. Among pts with sCr 1.2 mg/dl, 233 (29.5%) had HRMM, due to del17p in 69 (9%), IgH/Chr1abn in 61 (8%), Chr1abn only in 17 (4%), b2m≥5.5 mg/L in 136 (17%). The number of HR features in those with sCr 1.2 mg/dl was 1 in 188 (24%), 2 in 40 (5%), 3 in 5 (0.6%) pts. Among 419 pts with sCr 1.2 mg/dl, HRMM was present in 72 (17%), due to del17p in 47 (11%), IgH/Chr1abn in 26 (6%) and Chr1abn only in 7 (1.5%). The number of HR features in those with sCr 1.2 mg/dl was one in 64 (15%) and two in 8 (2%). If b2m had been included as HR feature in this subgroup, then 346 (83%) would have been rated as HRMM. Among HRMM features the hazard ratios (HzR) for del17p was 1.94 (p0.001); for IgH/Chr1abn was 2.14 (p0.001); for del1p/+1q21 was 2.64 (p=0.014) and for b2m5.5 mg/dl (only in pts with sCr 1.2 mg/dl) was 2.31 (p0.001). The median follow-up of the whole cohort was 5 years; median OS is 75 months (95%CI: 67-84). The median OS for HRMM (vs SR) was 44 vs 93 months (HzR: 1.81). The median OS of pts with sCr 1.2 mg/dl was 99 months vs 40.3 months for those with sCr 1.2 mg/dl (HzR: 1.98, p0.001), suggesting a significant impact of renal dysfunction in prognosis. The median OS according to the number of HRMM features (not including b2m in pts with sCr 1.2 mg/dl) was 52 months for one vs 25 months for one (p=0.001). Age is a major prognostic factor: median OS of 11.5 years for pts 65 and 49 months for those 65 years. The distribution of HRMM in the two age groups was similar (25.2% and 25%) and its prognostic impact was significant in both age groups but more pronounced in those 65 years (HzR: 2.97, p0.001) than in those 65 years (HzR: 1.41, p=0.003). We also evaluated HRMM in pts treated before and after 2020; in both periods there was a significant impact of HRMM (after 2020, HzR: 1.91, p=0.003 and before 2020, HzR: 1.76, p0.001). Notably, there has been a significant improvement in the outcome between the two periods both in pts with HRMM (HzR: 0.62; p=0.020) and with SRMM (HzR: 0.53, p0.001). The prognostic impact of HRMM was significant in non-anti-CD38 treated pts (HzR:1.81, p0.001) but did not reach statistical significance in anti-CD38 treated pts (HzR:2.19, p=0.076). In a sensitivity analysis, the OS of anti-CD38 treated pts was substantially better than that of the other pts (HzR:0.34, p0.001) and were more often 65 years (54% vs 38 %, p0.001). In conclusion, the new IMS criteria identify HRMM pts, independently of renal function and age group. However, the criteria may need refinement for pts with mild or moderate renal dysfunction and require further validation in pts treated with upfront anti-CD38 MoAbs combinations.