N-Terminal Pro-Brain Natriuretic Peptide (NT-proBNP) Is Associated with Both Left Ventricular Diastolic Dysfunction and Myeloma-Related Renal Insufficiency and Robustly Predicts Mortality in Patients with Symptomatic Multiple Myeloma
Authors: Abe Yoshiaki , Kobayashi Tetsuya , Narita Kentaro , Kobayashi Hiroki , Kitadate Akihiro , Takeuchi Masami , Matsue Kosei 
Published: October 2019

Abstract
Background: AlthoughN-terminal pro-brain natriuretic peptide (NT-proBNP) is an established biomarker as a prognostic predictor in patients with light-chain (AL) amyloidosis, its prognostic value and association with cardiac or renal functions remain unclear in patients with symptomatic multiple myeloma (MM). The aims of this study included to validate the prognostic significance of the baseline NT-proBNP levels comparing with the brain natriuretic peptide (BNP) levels and to identify clinical factors and mechanisms which are reflected by NT-proBNP and more directly affect mortality in newly diagnosed, symptomatic MM.
Methods: We retrospectively analyzed prognostic relevance of NT-proBNP in comparison with brain natriuretic peptide (BNP) and its association with cardiac functions on echocardiography or renal functions in 153 consecutive patients with newly diagnosed, symptomatic MM who were diagnosed and treated with chemotherapy between April 2008 to March 2018 at Kameda Medical Center, Kamogawa, Japan. We included only patients who had been treated with novel agents. Patients with pathologically proven organ involvement with light-chain (AL) amyloidosis were excluded from the analysis. The presence of LV diastolic dysfunction (LVDD) was determined individually according to the 2016 American Society of Echocardiography and European Association of Cardiovascular Imaging guidelines.
Results: Median age of the patients was 74.2 years [interquartile range (IQR): 66.7-80.8 years]. The median observation period was 26.4 months (IQR: 10.8-49.1 months). Receiver operating characteristic(ROC) curves for BNP and NT-proBNP predicting the highest risk of death within five years were shown in Figure 1A and 1B, respectively. According to the ROC analysis, the optimal cutoff of NT-proBNP was determined as 341.0 pg/ml. The comparison of area under curve (AUC) between BNP and NT-proBNP was shown in Figure 1C. The AUC was significantly greater for NT-proBNP than for BNP (0.818 vs. 0.731; P=0.024).Subsequently, we divided patients into two patient groups with lower (n=83) and higher (n=68) NT-proBNP according to the cutoff. Patients with higher NT-proBNP were significantly older, had poorer performance status, Instrumental Activity of Daily Living and Charlson Comorbidity Index scores, and included more patients with higher disease stages. Notably, patients with higher NT-proBNP included more patients with LVDD than patients with lower NT-proBNP (71.4% vs. 33.3%, respectively; P<0.001, Figure 2A), and all diastolic function-related parameters showed associations with NT-proBNP, although the difference in septal e' did not reach statistical significance (Figure 2B-E). However, there was no significant difference in left ventricular ejection fraction between patients with lower and higher NT-proBNP (Figure 2F). We also investigated the association between NT-proBNP and myeloma-related renal insufficiency shown in Figure 3. Patients with higher NT-proBNP included more patients with renal insufficiency (58.8% vs. 15.3%, respectively; P<0.001) or light-chain cast nephropathy (41.2% vs. 8.2%, respectively; P<0.001) with their involved free-light chain and corrected calcium levels significantly higher than patients with lower NT-proBNP (Figure 3A-D). Patients with higher NT-proBNP showed significantly shorter overall survival (OS) than those with lower NT-proBNP (median: 33.6 months and not reached, respectively; P<0.001, Figure 4). NT-proBNP levels discriminated patients with significantly different survivals even in both younger (<75 years) and older (≥75 years)patients or in both patients with and without decreased renal functions (estimated glomerular filtration rate ≥ and <50 ml/min/1.73m2).Furthermore, NT-proBNP retained its significant prognostic value for OS on multivariate analysis with the highest hazard ratio (HR) (HR; 7.66, 95% confidence interval; 3.52-16.68, P<0.001) (Table 1).
Conclusions: Our findings revealed that the NT-proBNP levels were associated with both LVDD as a host risk factor and myeloma-related renal insufficiency resulting from aggressive disease nature and consequently provided a robustly predictive information for OS in patients with symptomatic MM who did not harbor concomitant AL amyloidosis. Further studies should explore the synergistic prognostic potential of NT-proBNP.

Disclosures
No relevant conflicts of interest to declare.