Cystatin-C Is a Sensitive Marker of Renal Impairment with an Independent Predictive Value for Survival in Multiple Myeloma; Reduction Post Bortezomib Monotherapy.
Authors: Terpos Evangelos , Katodritou Eirini , Tsiftsakis Evangelos , Kastritis Efstathios , Pouli Anastasia , Christoulas Dimitrios , Michali Evridiki , Verrou Evgenia , Banti Anastasia , Tsionos Konstantinos , Dimopoulos Meletios A. , Zervas Konstantinos 
Published: April 2020

Abstract
Renal impairment is a common complication of multiple myeloma (MM). Standard assessment of kidney function in MM includes serum creatinine and creatinine clearance (Ccr) that possibly underestimate the prevalence of renal impairment in this disease. Cystatin-C (Cys-C) is a cysteine-proteinase inhibitor, which participates in the intracellular protein catabolism. It is freely filtered in the glomeruli and totally reabsorbed in the proximal tubular cells; therefore, it is a perfect endogenous marker of glomerular filtration rate. The aim of this study was to evaluate the serum levels of Cys-C in MM and explore possible correlations with clinical data, including survival. We studied 157 newly-diagnosed MM patients (87M/70F, median age 68 years), 28 patients with relapsed disease (17M/11F, median age 68 years) pre- and post-bortezomib therapy, and 15 healthy controls (9M/6F, median age 67 years). Serum Cys-C was determined by particle enhanced immunonephelometry (Dade Behring, Liederbach, Germany). In newly-diagnosed MM patients, serum Cys-C was increased compared with controls [median (range) 1.01 mg/L (0.24–5.61 mg/L) vs. 0.7 mg/L (0.59–0.95 mg/L); p&lt;0.0001]. Ninety patients (57.3%) had higher Cys-C levels than the upper normal limit of 0.95 mg/L, while only 35 (22.2%) had elevated serum creatinine. Patients with ISS stage 3 had increased median Cys-C (1.91 mg/L) compared with stage 1 (0.84 mg/L; p&lt;0.0001) and stage 2 patients (0.95 mg/L; p&lt;0.0001). Cys-C showed strong correlations with beta2-microglobulin (r=0.648, p&lt;0.0001), creatinine (r=0.705, p&lt;0.0001), Ccr (r=−0.549, p&lt;0.0001) and urea (r=0.471, p&lt;0.0001), and weaker correlations with albumin (r=−0.241, p=0.002), hemoglobin (r=−0.333, p&lt;0.0001), LDH (r=0.177, p=0.027) and ferritin (r=0.277, p=0.001). The median survival of all patients was 48 months and the median follow-up period was 26 months. The univariate analysis showed that Cys-C, beta2-microglobulin, LDH, hemoglobin, Ccr, and ISS stage predicted for survival. The median survival for patients with normal Cys-C levels (≤0.95 mg/L) has not been reached yet, while in patients with high Cys-C (&gt;0.95 mg/L) the median survival was 27 months (95% CI 16.9–37.0; p&lt;0.0001). The multivariate analysis revealed that only Cys-C and LDH had independent prognostic value. Patients with both high levels of Cys-C and LDH (&gt;upper normal limit) (n=46) had a median survival of 24 months (95% CI 18.2–29.7), while the median survival of all other patients has not been reached yet (p&lt;0.0001). Cys-C could also separate patients with ISS 2 in terms of survival: patients with elevated Cys-C (n=25) had a median survival of 37 months, while the median survival of patients with normal Cys-C levels (n=26) has not been reached yet (p=0.021). Patients with relapsed myeloma had increased median Cys-C (1.36 mg/L) compared with controls (p&lt;0.0001) and newly-diagnosed patients (p&lt;0.01). Bortezomib therapy produced a strong reduction of Cys-C levels (median: 1.07 mg/L, p&lt;0.01). Responders had a greater reduction than non-responders (p&lt;0.01). The results of this study suggest that Cys-C is a sensitive marker of renal impairment and predicts independently for survival in MM. Furthermore, Cys-C seems to be able to separate ISS 2 patients in terms of survival. Bortezomib monotherapy reduces Cys-C levels, mainly in responders.