The Ratio of Angiopoietin-1 to Angiopoietin-2 Is Reduced and Predicts Independently for Survival in Newly Diagnosed Patients with Multiple Myeloma.

Abstract Angiogenesis represents an essential step of disease progression in several hematological malignancies, including multiple myeloma (MM). Angiopoietin-1 (Ang-1) and its natural antagonist angiopoietin-2 (Ang-2), both ligands for the receptor tyrosine kinase Tie-2, are essential cytokines for angiogenesis process. Maturation and stabilization of the vascular wall are critically regulated by Ang-1 binding to Tie-2 receptor, while Ang2- antagonizes Tie-2 binding and induces vessel destabilization, which leads to the angiogenic sprouting. Vascular endothelial growth factor (VEGF), angiogenin and basic fibroblast growth factor (bFGF) are also potent stimulators of both physiological and pathological angiogenesis. The aim of this study was to evaluate the serum levels of the above angiogenesis cytokines and explore possible correlations with clinical data, including survival, in 143 newly diagnosed, untreated, MM patients (75M/68F; median age: 68 years, range: 40–94 years). According to ISS, 49 patients had stage 1, 46 stage 2 and 48 stage 3 disease. Serum levels of Ang-1, Ang-2, VEGF, VEGF-A (the major angiogenesis component of VEGF), angiogenin, and bFGF were evaluated using ELISA methodology (R&D Systems, Minneapolis, MN, USA, for all, except VEGF-A: Diaclone, Bensancon, France). MM patients had increased serum levels of Ang-2 (p<0.0001), angiogenin (p<0.0001), VEGF (p=0.033) and VEGF-A (p=0.010) compared with 25 controls of similar age and gender. Ang-1 levels were not different between patients and controls; thus the ratio of Ang-1/Ang-2 was reduced in MM (p<0.0001). Ang-1/Ang-2 ratio correlated with ISS (p=0.022) and beta2-microglobulin (p=0.03), while angiogenin showed strong correlations with ISS (p<0.0001), bone disease status (p=0.01) and hemoglobin (p=0.01). Interestingly, VEGF levels correlated with both Ang-1 (p<0.0001) and Ang-2 (p<0.0001) as well as with bFGF (p<0.0001) and LDH (p=0.01) serum levels. The median survival of all patients was 47 months and the median follow-up was 20 months. The univariate analysis revealed that ISS stage (p=0.001), serum LDH (p=0.001), serum beta2-microglobulin (p=0.0002), bone disease status (p=0.0007), serum creatinine (p=0.045), and the ratio of Ang-1/Ang-2 predicted for survival. Patients with serum Ang-1/Ang-2 of below or equal to the median value (4.8) had a median survival of 25 months, while patients with Ang-1/Ang-2 values of above the median value of 4.8 had a median survival of 53 months (p=0.0065). The multivariate analysis revealed that only serum LDH (p=0.003), Ang-1/Ang-2 ratio (p=0.005) and bone disease status (p=0.015) could independently predict for survival. These results reveal for the first time in MM patients the correlation of reduced Ang-1/Ang-2 ratio with advanced disease and highlight the role of Ang-1/Ang-2 pathway in the biology of plasma cell growth as reflected by its influence on survival. These observations reveal Ang-1/Ang-2/Tie-2 system as a possible target for the development of novel anti-myeloma agents.

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Serum C-Terminal Telopeptide Maintains Its Correlation with Bone Disease in Myeloma Patients Even Under Treatment with Bisphosphonates

Blood ◽

10.1182/blood.v120.21.4003.4003 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4003-4003

Author(s):

Lara Pochintesta ◽

Silvia Mangiacavalli ◽

Federica Cocito ◽

Cristiana Pascutto ◽

Alessandra Pompa ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Disease ◽

Type I Collagen ◽

Conflicts Of Interest ◽

Univariate Analysis ◽

Positive Association ◽

Disease Status ◽

Serum Levels ◽

Patient Specific ◽

Type I

Abstract Abstract 4003 Skeletal related events (SREs) are a significant cause of morbidity and mortality in multiple myeloma (MM). Markers of bone turn-over, in particular serum C-terminal telopeptide of type I collagen (CTX), can be used for monitoring early signs of bone damage either in osteoporosis or in neoplasm such as Multiple Myeloma. Since serum CTX levels are significantly decreased during bisphosphonate treatments (Dennis, N Engl J Med 2008), it is not clear whether serum CTX monitoring still retain a role in predicting SREs once bisphosphonate treatments was started. Aim of this study was to test whether serum CTX monitoring significantly correlates with active bone disease in a population of MM patients irrespective of concomitant bisphosphonate treatment. An unselected cohort of 87 patients with multiple myeloma diagnosed at our Hematology Division with the following characteristics entered this study: the availability of a baseline determination of serum CTX prior to start bisphosphonate therapy, multiple sequential serum CTX determinations (≥2 performed with an interval of at least 4 weeks), a radiologic evaluation available at the time of any SREs. The study was approved by our local ethical committee and conducted according to Helsinki Declaration guidelines. Patients baseline characteristics were the following: M/F 59%/41%, median age 60 (range 37–86), Durie and Salmon stage I/II/III (11%/14%/75%). During the study period (median follow-up 2.8 year, range 0.4–21 years), 73 patients (83%) experienced at least one SRE. Development of SRE was evaluated by standard skeletal x-ray, CT or MRI scan. Serum CTX was measured by an enzyme chemiluminescence method. A total of 260 serum CTX determinations were available for statistical analysis (median number of determinations for each patient 3, range 2–9). Univariate analysis found a statistically significant association between serum CTX and bone disease status with higher values in patients with active lytic lesions when compared to patients without radiological evidence of bone disease (median value 0.411 vs 0.356, p<0.001). By contrast, we observed significantly lower serum CTX values in patients under bisphosphonates treatment (median value 0.160 vs 0.355, p=<0.001). Association between serum CTX values, bone disease status and active bisphosphonates treatment was analyzed with a time-series linear model, accounting for measurement being repeated sequentially on each patient (random-effects GLS regression). Bone disease status and bisphosphonates treatment resulted significantly and independently associated to serum CTX (regression coefficient 0.222, 95%CI: 0.107–0.338, p<0.001 and 0.208 95%,CI: 0.320–0.096, p<0.001 respectively for bone disease status and bisphosphonates, cfr Tab 1). In addition, variations of CTX serum levels correlated significantly with the presence of active bone disease even under treatment with bisphosphonates (p<0.001). In conclusion, this study confirmed a positive association between serum CTX and presence of active bone disease. In addition serum CTX levels show a significant decrease under treatment with bisphosphonates. Taking into account these observations, patient-specific variations rather than the absolute serum CTX value should be used for detecting the onset of new SREs during a concomitant bysphosphonates treatment. Tab 1: Levels of serum CTX according to bone disease status and bisphosphonates treatment. Bisphosphonates treatment Progression in bone disease Active None Yes 0.219 (0.03–1.79) 0.533 (0.02–4.14) No 0.139 (0.03–0.69) 0.345 (0.071–1.57) Disclosures: No relevant conflicts of interest to declare.

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The Combination of Bortezomib, Doxorubicin, and Dexamethasone (PAD) Is an Effective Regimen for High Risk, Newly Diagnosed, Patients with Multiple Myeloma, Reduces Bone Resorption and Normalizes Angiopoietin-1 to Angiopoietin-2 Ratio.

Blood ◽

10.1182/blood.v110.11.3596.3596 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3596-3596 ◽

Cited By ~ 1

Author(s):

Evangelos Terpos ◽

Sosana Delimpasi ◽

Konstantinos Anargyrou ◽

Ioannis Baltathakis ◽

Efstathios Kastritis ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Bone Resorption ◽

Serum Levels ◽

Significant Activity ◽

Newly Diagnosed ◽

Bone Resorption Markers ◽

Tracp 5B ◽

Angiopoietin 2 ◽

Angiopoietin 1

Abstract Bortezomib has significant activity in multiple myeloma (MM). Its efficacy is increased with the addition of dexamethasone and doxorubicin in vitro, thus providing the rationale for combination regimens with these agents. The aim of this study was to evaluate the efficacy and safety of PAD regimen (bortezomib, doxorubicin, dexamethasone) in high-risk, newly diagnosed, MM patients and evaluate its effect on bone remodeling and angiogenesis. The inclusion criteria included newly diagnosed MM, ISS 2/3 disease or del13q detected by FISH. Patients received four 21-day cycles of PAD: bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11; dexamethasone 40 mg on days 1–4 and 8–11; bolus doxorubicin 9 mg/m2 on days 1–4. All patients received monthly zoledronic acid and prophylactic dose of co-trimoxazole and acyclovir. Following peripheral blood stem cell (PBSC) collection, eligible patients received high-dose melphalan with PBSC transplantation. Effect of PAD on angiogenesis was evaluated by measuring serum levels of VEGF, VEGF-A, angiogenin, angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), and basic fibroblast growth factor at baseline and on day 21 of cycle 4. Bone remodeling was studied by the measurement of serum indices: osteoclast stimulators [soluble RANKL, and osteoprotegerin (OPG)], bone resorption markers [C-telopeptide of collagen type-I (CTX), and tartrate resistant acid phosphatase-5b (TRACP-5b)], and bone formation markers [bone alkaline phosphatase (bALP), and osteocalcin] at baseline and on day 21 of cycle 4. All above molecules were also measured in 22 healthy controls of similar age and gender. To-date, 23 patients (14M/9F, median age 60 years) completed 4 cycles of therapy: 12 (52%) had ISS stage 2 and 11 (47%) stage 3 disease. Del13q was detected in 12 patients. The majority of patients (n=12) had more than 3 lytic lesions and/or a pathological fracture in the plain radiography of the skeleton. The objective response rate was 95% (22/23 patients): CR 26%, vgPR 13% and PR 56%. Median time to response was 35 days. Grade 3/4 adverse events included infections (7 patients-30%; one died due to septicemia), lymphopenia (6-26%), thrombocytopenia (6–26%), neutropenia (4–17%), peripheral neuropathy (3–13%), fatigue (2–8%), and hyponatremia (2–8%). At baseline, MM patients had increased serum levels of CTX, TRACP-5b, OPG, angiogenin, and Ang-2 compared with controls (p<0.01), while the ratio of Ang-1/Ang-2 was reduced. The administration of PAD resulted in a dramatic reduction of bone resorption markers (p<0.01) and a borderline increase in bALP (p=0.09). PAD also produced a significant increase of Ang-1/Ang-2 ratio (p=0.006), which was normalized. No patient developed a skeletal related event during 4 cycles of therapy. Eight patients (34%) had a PBSC collection; the median number of CD34+ cells was 6.45x106/kg (range: 2.3-13x106cells/kg). In conclusion, PAD has significant activity in high-risk, newly diagnosed patients with MM, overriding del13q. This regimen reduces bone resorption and normalizes Ang-1/Ang-2 balance which is crucial for the process of angiogenesis in MM.

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Angiogenesis-Related Cytokines, RANKL, and Osteoprotegerin in Multiple Myeloma Patients in relation to Clinical Features and Response to Treatment

Mediators of Inflammation ◽

10.1155/2011/867576 ◽

2011 ◽

Vol 2011 ◽

pp. 1-7 ◽

Cited By ~ 10

Author(s):

K. Sfiridaki ◽

C. A. Pappa ◽

G. Tsirakis ◽

P. Kanellou ◽

M. Kaparou ◽

...

Keyword(s):

Multiple Myeloma ◽

Growth Factor ◽

Serum Levels ◽

Response To Treatment ◽

Disease Stage ◽

Vascular Endothelial ◽

Newly Diagnosed ◽

Plateau Phase ◽

Endothelial Growth Factor ◽

Hepatocyte Growth

An essential cytokine system for the osteoclast biology in multiple myeloma (MM) consists of the receptor of activator of NF-κB ligand (RANKL), its receptor (RANK), and the soluble decoy receptor, osteoprotegerin (OPG). Myeloma cells cause imbalance in OPG/RANKL interactions. We measured serum levels of OPG, soluble (s) RANKL, sRANKL/OPG ratio, markers of disease activity [LDH, CRP, interleukin-6 (IL-6),β2-microglobulin (B2M)], and angiogenic factors [hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF)], in 54 newly diagnosed MM patients and in 25 of them in plateau phase. All the above values were higher in MM patients compared to controls and decreased in plateau phase. sRANKL and RANKL/OPG were higher with advancing disease stage and skeletal grade. Significant correlations were found among RANKL and RANKL/OPG with HGF, LDH, VEGF, IL-6, and B2M. In conclusion, RANKL and OPG play significant roles in MM pathophysiology, as regulators of bone turnover and mediators of angiogenesis.

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Clinical Significance of Serum Levels of Vascular Endothelial Growth Factor, Angiopoietin-1, and Angiopoietin-2 in Patients with Rheumatoid Arthritis

The Journal of Rheumatology ◽

10.3899/jrheum.090941 ◽

2010 ◽

Vol 37 (6) ◽

pp. 1121-1128 ◽

Cited By ~ 44

Author(s):

DAITARO KUROSAKA ◽

KENICHIRO HIRAI ◽

MAKIKO NISHIOKA ◽

YUKIO MIYAMOTO ◽

KEN YOSHIDA ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Serum Levels ◽

Vascular Endothelial ◽

Angiopoietin 2 ◽

Serum Crp ◽

Endothelial Growth Factor ◽

Vegf Level ◽

Angiopoietin 1

Objective.To evaluate the clinical significance of serum levels of vascular endothelial growth factor (VEGF), angiopoietin-1 (Ang-1), and angiopoietin-2 (Ang-2) in patients with rheumatoid arthritis (RA).Methods.The subjects were 70 patients with RA. Serum VEGF, Ang-1, and Ang-2 levels were determined by ELISA. As indices of disease activity, serum levels of C-reactive protein (CRP) and matrix metalloprotease (MMP)-3 were examined, and the 28-joint count Disease Activity Score (DAS28)-CRP was calculated. Power Doppler ultrasonography was performed in the bilateral wrists, elbows, shoulders, knees and ankles. The synovial blood flow signals were scored using a 3-grade scale (0–2), and the total of the scores in the 10 joints was regarded as the total signal score (TSS).Results.Serum VEGF level showed significant correlations with serum CRP and MMP-3 levels, DAS28-CRP, and TSS. Serum Ang-1 level showed significant correlations with serum MMP-3 level and DAS28-CRP. Serum Ang-2 level showed significant correlations with serum CRP level and TSS.Conclusion.The serum VEGF level is important as an index of the activity of RA based on angiogenesis and a prognostic factor regarding joint destruction. Serum Ang-1 level may be useful as an index of sustained arthritis based on the maintenance of newly formed vessels. Serum Ang-2 level may reflect a state of marked angiogenesis.

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Circulating angiopoietin-1 to angiopoietin-2 ratio is an independent prognostic factor for survival in newly diagnosed patients with multiple myeloma who received therapy with novel antimyeloma agents

International Journal of Cancer ◽

10.1002/ijc.26062 ◽

2011 ◽

Vol 130 (3) ◽

pp. 735-742 ◽

Cited By ~ 21

Author(s):

Evangelos Terpos ◽

Konstantinos Anargyrou ◽

Eirini Katodritou ◽

Efstathios Kastritis ◽

Athanasios Papatheodorou ◽

...

Keyword(s):

Multiple Myeloma ◽

Prognostic Factor ◽

Independent Prognostic Factor ◽

Newly Diagnosed ◽

Angiopoietin 2 ◽

Angiopoietin 1

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Serum Levels of Leptin in Multiple Myeloma Patients and Its Relation to Angiogenic and Inflammatory Cytokines

The International Journal of Biological Markers ◽

10.1177/172460080401900107 ◽

2004 ◽

Vol 19 (1) ◽

pp. 52-57 ◽

Cited By ~ 17

Author(s):

M.G. Alexandrakis ◽

F.H. Passam ◽

A. Sfiridaki ◽

C.A. Pappa ◽

J.A. Moschandrea ◽

...

Keyword(s):

Multiple Myeloma ◽

Growth Factor ◽

Interleukin 1 ◽

Serum Levels ◽

Disease Stage ◽

Newly Diagnosed ◽

Before And After ◽

Reflect Disease Severity ◽

Disease Stabilization ◽

Beta 2 Microglobulin

Background Leptin, apart from the regulation of food intake, has been implicated in hematopoiesis, the immune response and angiogenesis. Leptin has been found to be decreased in various hematological malignancies. In the present study leptin was measured in multiple myeloma (MM) patients before and after treatment and correlated with other angiogenic molecules and markers of disease activity. Methods Serum leptin, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (b-FGF), interleukin-1 beta (IL-1β), beta 2 microglobulin (β2M) and C-reactive protein (CRP) were measured in 62 newly diagnosed MM patients, 22 of whom obtaining disease stabilization after treatment. The same parameters were measured in 20 healthy controls. Disease stage was defined according to the Durie-Salmon criteria. Results Leptin, VEGF, b-FGF, IL-1β, and β2M were significantly higher in newly diagnosed MM patients than in controls (p<0.05). VEGF, b-FGF, IL-1β, β2M, CRP but not leptin increased with advancing stage of disease (p<0.01). All parameters decreased significantly following treatment (p<0.001). Although IL-1β correlated positively with VEGF, β2M, b-FGF and CRP, leptin did not correlate with any of the measured parameters. Conclusion Leptin serum levels do not reflect disease severity in MM. However, there seems to be a decrease in leptin following treatment, which may be associated with an alteration in the metabolic state or the chemokine milieu.

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Circulating Levels of the Wnt Inhibitors Dickkopf-1 and Sclerostin In Different Phases of Multiple Myeloma: Alterations Post-Therapy with Lenalidomide and Dexamethasone with or without Bortezomib

Blood ◽

10.1182/blood.v116.21.2963.2963 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2963-2963 ◽

Cited By ~ 6

Author(s):

Evangelos Terpos ◽

Dimitrios Christoulas ◽

Maria Gkotzamanidou ◽

Cornelia Bratengeier ◽

Maria Gavriatopoulou ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Disease ◽

Serum Levels ◽

Bone Resorption Marker ◽

Newly Diagnosed ◽

Plateau Phase ◽

Median Increase ◽

Asymptomatic Patients ◽

Circulating Levels ◽

Dickkopf 1

Abstract Abstract 2963 Dickkopf-1 (Dkk-1) and sclerostin are inhibitors of the Wingless-type and integrase 1 (Wnt) signaling and they are implicated in the pathogenesis of multiple myeloma (MM) bone disease through inhibition of osteoblast function. There is very limited information for the circulating levels of Dkk-1 and sclerostin in different phases of MM and their alterations post therapies with novel agents. Therefore, we studied 284 MM patients (153M/131F, median age 66 years): 167 consecutive patients were newly-diagnosed (20 had asymptomatic MM and 147 symptomatic MM), 29 patients were at the plateau phase of MM and 88 patients had relapsed/refractory MM and received therapy with the combination of lenalidomide plus dexamethasone with or without bortezomib (VRD or RD; Dimopoulos et al, Leukemia 2010). For newly diagnosed patients, serum was stored at the time of diagnosis, while for patients at the plateau phase serum was collected at the time of confirmation of the plateau (at least 6 months with stable M-protein without criteria confirming progression) and for relapsed/refractory patients on day 1 of cycles 1, 4 and 7 of VRD or RD administration. Circulating levels of Dkk-1 and sclerostin were measured using ELISA methodology (R&D Systems, Minneapolis, MN, USA and Biomedica Medizinprodukte, Vienna, Austria, respectively) in all patients and in 20 gender- and age- matched healthy controls. Circulating Dkk-1 and sclerostin concentrations of newly diagnosed symptomatic patients (median: 1383 pg/mL, range:274-32, 862 pg/mL and 415 pg/mL, 0–3,340 pg/mL respectively) were increased compared to controls (1069 pg/mL, 540-2, 709 pg/mL; p<0.001 and 250 pg/mL, 0–720 pg/mL; p=0.03, respectively) and to asymptomatic patients at diagnosis (1044 pg/mL, 480-2, 335 pg/mL; p<0.001 and 140 pg/mL, 0–1,100 pg/mL; p=0.001, respectively). Patients at plateau phase had increased circulating levels of sclerostin (704 pg/mL, 68–2000 pg/mL; p <0.001) compared to controls (p=0.002) as well as to MM patients at diagnosis (p=0.02). In contrast, they had lower serum levels of Dkk-1 (1013 pg/mL, 414–1729 pg/mL) compared to MM patients at diagnosis (p<0.001) and no difference compared to controls. Patients with ISS-3 myeloma at diagnosis had higher values of Dkk-1 and sclerostin than ISS-1 and ISS-2 patients [median Dkk-1 values for ISS-1, ISS-2 and ISS-3 were: 1059 pg/mL, 1290 pg/mL and 2649 pg/mL, respectively; p(ANOVA)=0.031; median sclerostin values for ISS-1, ISS-2 and ISS-3 were: 394 pg/mL, 392 pg/mL and 714 pg/mL, respectively; p(ANOVA)=0.001]. Patients with lytic disease at diagnosis (n=116) had increased levels of Dkk-1 compared with patients with no lytic disease (n=51): 1475 pg/mL, 327-32, 862 pg/mL vs. 840 pg/mL, 274–1112 pg/mL; p=0.002. There was no difference in sclerostin levels between these patients; however, patients with advanced bone disease (>3 lytic lesions and/or a fracture) had a borderline increase in their circulating sclerostin compared to all others (p=0.072). Dkk-1 circulating levels correlated weakly with sclerostin (r=0.201, p=0.05). Relapsed patients had increased Dkk-1 (1218 pg/mL, 161-19, 325 pg/mL) and sclerostin (886 pg/mL, 90-6, 272 pg/mL) levels compared to controls and to asymptomatic patients at diagnosis (p<0.001 for all comparisons). In patients who received RD, Dkk-1 was increased and sclerostin was decreased after 6 cycles of therapy. Responders to RD had a median increase of 9% in Dkk-1 serum levels after 6 cycles of therapy, while non-responders had a median increase of 91% compared to baseline values (p<0.01). Patients who did not respond to RD showed an increase in bone resorption marker CTX (p=0.021) after 6 cycles of therapy. VRD administration resulted in a significant reduction of sRANKL (p=0.024) and increase of bone formation marker, osteocalcin (p=0.01) after 6 cycles, but showed only minimal reduction of Dkk-1 (p=0.08) and no alterations on sclerostin. In conclusion our study suggests that Dkk-1 is elevated in active myeloma, while sclerostin is elevated even in the plateau phase of the disease. Both correlated with adverse disease features. The increase of Dkk-1 by RD seems to be balanced by a reduction effect of bortezomib on Dkk-1 in VRD. Furthermore, the reduction of sclerostin in RD patients may represent a modulatory effect of lenalidomide on marrow microenvironment. These results further support the rationale for the use of drugs targeting Dkk-1 and sclerostin in MM. Disclosures: No relevant conflicts of interest to declare.

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The Administration of Bortezomib, Dexamethasone and Thalidomide (VTD) after ASCT in Myeloma Patients Who Do Not Receive Bisphosphonates Normalizes sRANKL, Dickkopf-1 and Improves Abnormal Osteoclast Function and Impaired Angiogenesis.

Blood ◽

10.1182/blood.v112.11.1728.1728 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1728-1728

Author(s):

Evangelos Terpos ◽

Efstathios Kastritis ◽

Dimitrios Christoulas ◽

Magdalini Migkou ◽

Maria Gavriatopoulou ◽

...

Keyword(s):

Growth Factor ◽

Bone Metabolism ◽

Serum Levels ◽

Type I ◽

Tracp 5B ◽

Osteoclast Function ◽

Angiopoietin 2 ◽

Dickkopf 1 ◽

Impaired Angiogenesis ◽

Angiopoietin 1

Abstract Bortezomib (V) monotherapy has been associated with increased osteoblastic activity, reduced osteoclast function and decreased angiogenesis in relapsed/refractory myeloma. The effects of V on bones may be direct or may reflect the reduction of myeloma burden. The co-administration of zoledronic acid, in all reported studies to-date, may also suggest a synergistic stimulation on osteoclast/osteoblast interactions by the two agents but has not allowed the independent evaluation of V on bone metabolism. Previous studies have shown that the combination of V with other agents, such as thalidomide (T) and melphalan, although reduced osteoclast activity, did not enhance osteoblast function. We evaluated the effect of VDT consolidation therapy on bone metabolism and angiogenesis in myeloma patients who underwent high dose melphalan (200 mg/m2) followed by autologous stem cell transplantation (ASCT). In this prospective study, only patients in first remission or with primary refractory disease to one frontline treatment were included. Patients did not receive any bisphosphonate during or post-ASCT as throughout the period of VDT consolidation. VDT was given on day 100 after ASCT: V was administered at a dose of 1.0 mg/m2 on days 1,4,8,11, while T was given at a dose of 100 mg/day, po, on days 1–21 and D at a dose of 40mg/day on days 1–4 of a 21-day cycle. Patients received 4 VDT cycles (first course) and 4 more VDT cycles (second course) 100 days post-day 21 of the 4th cycle. Bone remodeling was studied by the measurement of a series of serum indices on day 1 of cycles 1 & 5 and on day 21 of cycle 8: i) osteoclast regulators [soluble receptor activator of nuclear factor-κB ligand (sRANKL) and osteoprotegerin], ii) osteoblast inhibitor dickkopf-1 (Dkk-1), iii) bone resorption markers [C-telopeptide of collagen type-I (CTX) and tartrate resistant acid phosphatase isoform 5b (TRACP-5b)], and iv) bone formation markers [bone-specific alkaline phosphatase (bALP) and osteocalcin (OC)]. Effect of VDT on angiogenesis was evaluated by measuring the serum levels of angiogenic cytokines, such as vascular endothelial growth factor (VEGF), angiogenin, angiopoietin-1, angiopoietin-2, and basic fibroblast growth factor (bFGF) on the same dates. The above biochemical markers and cytokines were also measured in 18, gender and age-matched, controls. To-date, 18 patients (7M/11F, median age 60 years) have been entered into this study. On day 100 after ASCT, just before VDT, 5 patients were in CR (2 in sCR), 11 in vgPR and 2 in PR, according to IMWG response criteria. At baseline, although the vast majority of patients were in ≥vgPR, they had increased serum levels of sRANKL (p=0.015), Dkk-1 (p=0.025), CTX (p=0.001), TRACP-5b (p=0.032), VEGF (p<0.0001), bFGF (p<0.0001), angiogenin (p=0.01) and reduced levels of angiopoietin-1/angiopoietin-2 ratio (p<0.0001) compared to controls. Serum levels of sRANKL strongly correlated with CTX (r=0.701, p=0.002) and OPG (r=0.733, p=0.0001), while levels of CTX correlated with TRACP-5b (r=0.619, p=0.0008). The administration of 4 VDT cycles resulted in a significant reduction of sRANKL (p=0.02), TRACP-5b (p=0.016), angiogenin (p=0.03), Dkk-1 (p=0.047), but also of bALP (p=0.003) and OC (p=0.016). A borderline reduction of CTX (p=0.071), and VEGF (p=0.056) was also observed. The levels of sRANKL, Dkk-1, TRACP and angiogenin did not differ from control values, while the reduction of bALP and OC did not produce significant differences compared to controls, after 4 VDT cycles. However, levels of VEGF, angiopoietin-1/angiopoietin-2 ratio and bFGF values continued to be elevated compared to controls’ values, while CTX levels were slightly increased compared to controls (p=0.049). The results of this on going study suggests that VDT consolidation post-ASCT normalizes sRANKL and Dkk-1 serum levels and improves impaired angiogenesis. However, as in other combination regimens (i.e. VMDT in relapsed/refractory patients), bortezomib could not produce an anabolic effect on bones when combined with TD even in these patients with low myeloma burden.

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Cystatin-C Is a Sensitive Marker of Renal Impairment with an Independent Predictive Value for Survival in Multiple Myeloma; Reduction Post Bortezomib Monotherapy.

Blood ◽

10.1182/blood.v110.11.1484.1484 ◽

2007 ◽

Vol 110 (11) ◽

pp. 1484-1484 ◽

Cited By ~ 4

Author(s):

Evangelos Terpos ◽

Eirini Katodritou ◽

Evangelos Tsiftsakis ◽

Efstathios Kastritis ◽

Anastasia Pouli ◽

...

Keyword(s):

Multiple Myeloma ◽

Renal Impairment ◽

Serum Creatinine ◽

Median Survival ◽

Cystatin C ◽

Normal Limit ◽

Univariate Analysis ◽

Cysteine Proteinase Inhibitor ◽

Newly Diagnosed ◽

Sensitive Marker

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<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<0.0001) and stage 2 patients (0.95 mg/L; p<0.0001). Cys-C showed strong correlations with beta2-microglobulin (r=0.648, p<0.0001), creatinine (r=0.705, p<0.0001), Ccr (r=−0.549, p<0.0001) and urea (r=0.471, p<0.0001), and weaker correlations with albumin (r=−0.241, p=0.002), hemoglobin (r=−0.333, p<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 (>0.95 mg/L) the median survival was 27 months (95% CI 16.9–37.0; p<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 (>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<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<0.0001) and newly-diagnosed patients (p<0.01). Bortezomib therapy produced a strong reduction of Cys-C levels (median: 1.07 mg/L, p<0.01). Responders had a greater reduction than non-responders (p<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.

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