BackgroundRenal impairment is a common complication of multiple myeloma. Cystatin-C is considered an accurate marker of glomerular filtration rate in several renal disorders. Microarray analysis has revealed that cystatin-C is one of the most highly up-regulated genes in multiple myeloma. The aim of this study was to evaluate the serum levels of cystatin-C in myeloma patients, explore possible correlations with clinical data, including survival, and assess the effect of bortezomib on cystatin-C in relapsed multiple myeloma. Design and MethodsWe measured serum cystatin-C in 157 newly diagnosed, previously untreated myeloma patients, in 28 patients with relapsed disease pre-and post-bortezomib therapy and in 52 healthy controls, using a latex particle-enhanced nephelometric immunoassay. ResultsIn newly diagnosed patients, cystatin-C was elevated and showed strong correlations with advanced ISS stage, extensive bone disease, high β2-microglobulin, high serum creatinine, and low creatinine clearance. Multivariate analysis revealed that only cystatin-C and lactate dehydrogenase had an independent prognostic impact on patients' survival. The combination of cystatin-C and lactate dehydrogenase revealed three prognostic groups of patients: a high-risk group (both elevated cystatin-C and lactate dehydrogenase) with a median survival of 24 months, an intermediate-risk group (elevated cystatin-C or elevated lactate dehydrogenase) with a median survival of 48 months and a low-risk group (both low cystatin-C and lactate dehydrogenase) in which median survival has not yet been reached (p<0.001). Cystatin-C could also identify a subset of ISS-II patients with worse outcome. Relapsed patients had higher cystatin-C levels even compared to newly diagnosed patients. Treatment with bortezomib produced a significant reduction of cystatin-C, mainly in responders. ConclusionsSerum cystatin-C is not only a sensitive marker of renal impairment but also reflects tumor burden and is of prognostic value in myeloma. Its reduction after treatment with bortezomib reflects bortezomib's anti-myeloma activity and possibly bortezomib's direct effect on renal function.Key words: multiple myeloma, renal impairment, cystatin-C, bortezomib, survival. Haematologica 2009; 94:372-379. doi:10.3324/haematol.2008 This is an open-access paper.Cystatin-C is an independent prognostic factor for survival in multiple myeloma and is reduced by bortezomib administration

β-thalassemia major (TM) is often accompanied by osteopenia or osteoporosis. 1,2 Bisphosphonates have been used in the management of TM-induced bone loss. [3][4][5][6][7] We report here the results of the long-term follow-up of our TM patients with osteoporosis who participated in a randomized, placebo-controlled trial with zoledronic acid (ZOL), the results of which at 12 months had been previously reported. 5 According to that study, 66 patients with TM-induced osteoporosis (21M/45F; median age 35.5 years) were studied. Patients were blindly randomized to receive 4 mg ZOL, iv, in 15 min. infusion, every six months (group A, n=23) or every three months (group B, n=21), or to receive placebo every three months (group C, n=22), for a period of one year.Patients of groups A and B then discontinued ZOL treatment, while patients of group C were given 4 mg ZOL, every three months, for 12 months, and subsequently stopped ZOL therapy. 5 Informed consent was obtained from all patients prior to inclusion in the study. The study was conducted with the approval of the Greek National Drug Organization Committee (Ref. No Aα-K∆-79/01/03) in keeping with the guidelines of Helsinki. Bone Mineral Density of the lumbar spine (L1-L4), femoral neck (FN) and wrist was evaluated in all patients prior to starting therapy and then after 12 and 36 months, using DEXA. 5 Serum markers of bone remodeling [C-telopeptide of collagen type-I (CTX) and bonespecific alkaline phosphatase (bALP)] were measured in patients and in a control group of 40, age and gendermatched, healthy blood donors, as previously described. 5 Patients were asked to quantify their degree of bone pain on Huskisson's visual analog scale (VAS) and the McGill-Melzack scoring system before entering the trial, and then every six months for 36 months. Statistical analysis was described in our initial report. 5 Patients of groups A and C showed no differences in BMD of all evaluated sites at the 12 th month, while patients of group B achieved a significant increase only in their L1-L4 BMD 5 (Figure 1A-1C). ZOL also reduced bone pain in groups A+B, while there was no pain relief in the placebo group after 12 months of therapy (Table 1). Similar results have been described in two subsequent trials where ZOL was given in TM patients with osteoporosis for 12 months 6,7 confirming the beneficial effect of ZOL in this setting. However, the treatment duration has not been clarified in any trial.Our patients were followed for 24 months after discontinuation of ZOL for groups A and B, and for 12 months for group C. Interestingly, at the 36 th month, patients of both groups A and B showed a significant increase in BMD of all studied sites compared with baseline values (p<0.01) (Figure 1A-1B). Patients of group C, who had received ZOL for 12 months after the placebo period, also increased their BMD of all studied sites at the 36 th month (p<0.01; Figure 1C), while they also reduced bone pain scores (Table 1). Furthermore, there was no more difference in BMD T-values of L1-L4 and forearm b...

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.

Zoledronic acid is a third generation aminobisphosphonate with proven efficacy in patients with thalassemia major (TM) and osteoporosis. We report here the results of the long-term follow-up (36 months) of our TM patients with osteoporosis who participated in a randomized, placebo-controlled, trial with zoledronic acid. Sixty-six patients with TM-induced osteoporosis (21M/45F; median age 35.5 years) were studied. The majority of patients had pathological fractures and/or bone pain due to osteoporosis. Patients were blindly randomized to receive zoledronic acid at a dose of 4 mg, iv, in 15 min infusion, every 6 months (group A, n=23) or every 3 months (group B, n=21), or to receive placebo every 3 months (group C, n=22) for a period of one year. There was no difference in terms of gonadal dysfunction between the three studied groups. All patients were under oral calcium (500 mg) administration during study period, while hypogonadic patients were allowed to continue their hormonal replacement therapy. After the first 12 months of therapy, patients of groups A and B discontinued zoledronic acid treatment, while patients of group C were allowed to receive zoledronic acid at a dose of 4 mg, every 3 months, for 12 months and then to stop zoledronic acid therapy. Effects were monitored by measuring BMD of the lumbar spine, femoral neck and forearm using DEXA, at baseline, and then after 12 and 36 months post zoledronic acid administration. Patients were also asked to quantify their degree of bone pain on Huskisson’s visual analogue scale and the McGill-Melzack scoring system at baseline, and then every 6 months for 36 months. Patients of groups A and C showed no differences in terms of BMD of all three evaluated sites after 12 months of therapy, while patients of group B achieved a significant increase in their lumbar spine BMD (p=0.028), and a borderline increase in their femoral neck BMD. Zoledronic acid reduced bone pain in groups A+B, while there was no bone pain relief in placebo group after 12 months of therapy. Interestingly, after 36 months, patients of both groups A and B showed a dramatic increase in BMD of all studied sites compared with baseline values (p=0.001, p=0.001, and <0.001 for BMD of lumbar spine, femoral neck, and forearm, respectively). Patients of group C who received zoledronic acid for 12 months after the placebo period showed also a dramatic increase in BMD of all studied sites at 36 month (p=0.008, p=0.018, and <0.001 for BMD of lumbar spine, femoral neck, and forearm, respectively), while they also reduced significantly bone pain scores (p<0.001). At 36 month, there was no difference in terms of BMD of lumbar spine and forearm between patients of groups A and B, while BMD of the femoral neck continued to be higher in group B (either as a T-score absolute value or as a T-score percentage change; p=0.01). No skeletal related events were observed during the study period. This study suggests that zoledronic acid is an effective treatment in increasing BMD in TM-induced osteoporosis. Its effect seems to be continued even 24 months after the discontinuation of the drug. Studies with larger number of patients are required to clarify the best dose and treatment duration of zoledronic acid for the management of TM-induced osteoporosis.

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