The novel ims / IMWG high-risk multiple myeloma criteria may omit individuals with renal impairment and adverse disease prognosis

Abstract Background: Renal impairment (RI) is common in newly diagnosed multiple myeloma (NDMM). Since serum β2-microglobulin (sb2m) is a marker of tumor burden but also increases with renal dysfunction, its inclusion in the newly HRMM criteria only when serum creatinine (sCr) is not elevated (<1.2mg/dL), may confoundi the evaluation of risk in patients (pts) with RI. Methods In order to assess the impact of RI (sCr≥1.2mg/dL) on the prognostic value of the novel HRMM criteria, we analyzed consecutive NDMM pts treated and followed at a single center between 1/1/2020 and 31/12/2024. Results A total of 1209 pts were enrolled; 702 (58.1%) aged over 65 years and the median follow-up was 2.07 years. 305 (25.2%) pts were characterized as high-risk per the novel HRMM-criteria. Those pts showed a 71% higher risk of death (HR=1.71, 95%CI:1.51-2.18, p<0.001), compared to standard risk. At diagnosis, 419 (34.7%) pts had RI (sCr≥1.2mg/dL). Compared to those with normal renal function, these pts were older (median age 73 vs 66 years, p<0.001) and fewer patients had HRMM [72/419 (17.2%) vs 233/790 (29.5%), p<0.001]. Pts with RI exhibited an increased risk of death (HR=1.98, 95%CI:1.67-2.34, p<0.001). Adjusting for RI in multivariate analyses, the novel HRMM criteria maintained their prognostic significance (aHR=1.94, 95%CI:1.45–2.59, p<0.001). Among those with RI, 72 HRMM pts demonstrated a 71% higher risk of death (HR=1.71, 95%CI:1.25-2.33, p<0.001), compared to standard risk. Moreover, 272/419 (64.9%) pts had isolated high sb2m (≥5.5mg/dL). These individuals were not labeled as high-risk due to elevated sCr, but when pooled with the HRMM RI pts, an increased risk for death was observed compared to standard risk in the multivariate analysis (aHR=2.57, 95%CI:1.71–3.86, p<0.001). When considered as an independent subgroup, those pts had dismal prognosis compared to standard risk (aHR=2.61, 95%CI:1.27–5.37, p=0.009). Furthermore, 309 (25.6%) pts had RI defined as CKD-EPI eGFR<45ml/min at diagnosis. Those pts showed an increased risk of death (HR=2.21, 95% CI: 1.86-2.64, p<0.001). Among them, 53/309 (17.2%) were high-risk per the novel HRMM criteria. Adjusting for RI in multivariate analyses, the novel HRMM criteria maintained their prognostic significance (aHR=1.70, 95%CI:1.38–2.11, p<0.001). Moreover, 200/309 pts had isolated high sb2m (≥5.5mg/dL). They were not labeled as high-risk due to elevated sCr, but when pooled with the HRMM RI pts, an increased risk for death was observed compared to standard risk (HR=1.93, 95%CI: 1.01-3.69, p=0.047). Additionally, 57/110 pts with eGFR≥45 but sCr≥1.2mg/dL were characterized as high risk based on both HRMM criteria and high sb2m, and they had adverse prognosis compared to standard risk (aHR=2.44, 95% CI:1.28-4.63, p=0.007). However, Sb2m may increase in pts with RI of any etiology. In order to address this confounding effect, we carried two additional exploratory analyses that included 433 pts with measurable Bence-Jones proteinuria (>200mg/24h) and 227 pts with dFLC>500mg/L, in which RI (sCR>1.2mg/dL, n=226, 52.2% and n=135, 59.5%; respectively) is probably attributed to myeloma. Within these subgroups, pts with RI had almost twice the risk of death (HR=1.87, 95%CI:1.43–2.44, p<0.001 and 1.84, 95%CI:1.24–2.73, p=0.002; respectively), compared to those with normal renal function. Among those with RI, 36 (15.9%) and 22 (16.3%) pts were labeled as high-risk, demonstrating an increased risk of death (HR=2.00, 95%CI:1.32–3.01, p=0.001, and HR=1.79, 95%CI:1.03–3.12, p=0.040, respectively). Additionally, 166 (73.5%) and 96 (71.1%) had Sb2m≥5.5mg/dL, respectively. In both cases, when pooled with the other high-risk pts, they had a significantly higher risk of death in the multivariate analyses (aHR=3.97, 95%CI:1.31–12.05, p=0.015 and aHR=7.54, 95%CI: 1.77–32.15, p=0.006; respectively). When considered as an independent subgroup, pts with isolated high Sb2m had dismal outcomes in multivariate analyses (aHR=3.00, 95%CI:1.43–6.29, p=0.001 and HR=6.69, 95%CI:1.59–28.24, p=0.010; respectively). Conclusion Although pts with isolated high sb2m are excluded from high-risk classification when sCr is elevated, our findings indicate that these individuals have dismal outcomes. The novel HRMM criteria should be further validated in pts with renal dysfunction.