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- Terpos, Evangelos, et al.
(författare)
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Bortezomib-based therapy for relapsed/refractory multiple myeloma in real-world medical practice
- 2018
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Ingår i: European Journal of Haematology. - : WILEY. - 0902-4441 .- 1600-0609. ; 101:4, s. 556-565
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The efficacy and safety of bortezomib-based therapy for relapsed/refractory multiple myeloma (RRMM) in clinical trials may differ from the oncology practice experience. The electronic VELCADE (R) OBservational Study was designed to prospectively evaluate bortezomib for multiple myeloma (MM) in real-world medical practice. Method: Patients scheduled to receive intravenous bortezomib for MM were eligible. The primary objective was to evaluate clinical outcomes, including response, time to response, time to next therapy, treatment-free interval, progression-free survival (PFS), and overall survival (OS). Secondary objectives included safety and healthcare resource utilization. Results: In total, 873 patients with a median of two therapy lines prior to initiating bortezomib were included. The overall response rate (amp;gt;= partial response) was 69%, including 37% complete response/near-complete response. Median time to response was 1.8 months, median time to next therapy was 9.7 months, and median treatment-free interval was 7.9 months. After 22.6 months median follow-up, median PFS was 12.0 months and median OS was 36.1 months. The most common adverse events (AEs) were neuropathy not otherwise specified (19%), diarrhea NOS, and thrombocytopenia (each 17%); 230 (26%) patients discontinued bortezomib due to AEs. Of 689 (79%) patients without baseline peripheral neuropathy (PN), the rate of new-onset any-grade PN increased to 51% (12% grade 3/4) by cycle 8. Overall, 244 (28%) patients were hospitalized, 372 (43%) attended an outpatient visit, and 341 (39%) underwent a diagnostic/therapeutic procedure during bortezomib treatment. Conclusion: These prospective real-world data demonstrate the effectiveness and safety of bortezomib-based therapy for RRMM and confirm high response rates and long OS for this population.
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- Terpos, Evangelos, et al.
(författare)
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Elevated circulating sclerostin correlates with advanced disease features and abnormal bone remodeling in symptomatic myeloma: Reduction post-bortezomib monotherapy
- 2011
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Ingår i: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 131:6, s. 1466-1471
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Tidskriftsartikel (refereegranskat)abstract
- Sclerostin is a Wingless and Int-1 inhibitor, which is produced by osteocytes and inhibits osteoblast-driven bone formation. Sclerostin is implicated in the pathogenesis of bone loss in metabolic bone disorders but there is no information for its effect on multiple myeloma (MM)-related osteolytic disease. We evaluated circulating sclerostin in 157 newly diagnosed patients with symptomatic myeloma, in 25 with relapsed myeloma who received bortezomib monotherapy, in 21 patients with monoclonal gammopathy of undetermined significance (MGUS), and in 21 healthy controls. Patients with active myeloma had elevated circulating sclerostin compared to MGUS patients and controls (p < 0.01). MM patients who presented with fractures at diagnosis (n = 34) had very high levels of circulating sclerostin compared with all others (p < 0.01), whereas sclerostin correlated negatively with bone specific alkaline phosphatase (a bone formation marker; r = -0.541, p < 0.0001) and positively with C-telopeptide of collagen type-1 (a bone resorption marker; r = 0.524, p < 0.0001). Patients with International Staging System (ISS)-3 disease had higher circulating sclerostin compared to ISS-1 and ISS-2 MM (p = 0.001). Furthermore, patients with high sclerostin (upper quartile, n = 40) had a median survival of 27 months versus 98 months of all others (p = 0.031). Relapsed MM patients had higher levels of circulating sclerostin even compared to newly diagnosed patients (p < 0.01). Bortezomib monotherapy resulted in a reduction of sclerostin by almost 50% in both responders and non-responders. These results suggest that patients with active myeloma have elevated circulating sclerostin, which correlated with advanced disease features including severe bone disease. Our study indicates sclerostin as a possible target for the development of novel therapies to enhance osteoblast function in myeloma.
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| 4. |
- Terpos, Evangelos, et al.
(författare)
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High Serum Sclerostin Correlates with Advanced Stage, Increased Bone Resorption, Reduced Osteoblast Function, and Poor Survival in Newly-Diagnosed Patients with Multiple Myeloma.
- 2009
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 114:22, s. 425-425
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Tidskriftsartikel (refereegranskat)abstract
- Multiple myeloma (MM) is characterized by the presence of lytic bone disease due to increased osteoclast activity which is accompanied by reduced osteoblast function. To-date dickkopf-1 (Dkk-1) is considered as the main osteoblast inhibitor which is overproduced by myeloma cells and inhibits Wnt signaling leading to osteoblast exhaustion. Sclerostin is another canonical Wnt antagonist through its binding to low-density lipoprotein-receptor-related protein 5/6. Sclerostin is specifically expressed by osteocytes and inhibits bone morphogenic protein-induced osteoblast differentiation and ectopic bone formation. Osteonectin (SPARC) is a multi-faceted protein that belongs to a family of matricellular proteins. It is secreted by osteoblasts during bone formation, initiating mineralization and promoting mineral crystal formation. SPARC shows affinity for collagen in addition to bone mineral calcium. The aim of this study contacted by the Greek Myeloma Study Group in collaboration with Biomarker Design Forschungs GmbH (BDF), Vienna, Austria was to evaluate, for the first time in the literature, the serum levels of sclerostin in patients with MM and explore possible correlations with clinical and laboratory data, including SPARC levels, ISS stage and survival. One hundred and fifty-seven patients (87M/70F, median age 68 years) with MM at diagnosis before the administration of any type of therapy, including bisphosphonates, were evaluated. Serum sclerostin and SPARC were measured using an ELISA methodology developed by BDF for Biomedica Medizinprodukte GmbH & Co KG (Vienna, Austria). Both assays are sandwich type ELISA using biotinylated antibodies/HRP-streptavidine for the detection of sclerostin and SPARC in the serum. The detection limit of the sclerostin ELISA was 0.18 ng/ml and the coefficient of variation (CV) 6%. The standard range was set from 0.3-3 ng/ml. For the SPARC ELISA we found a detection limit of 1.95 ng/ml and CVs of 8% using a standard range from 5-130 ng/ml. Serum sclerostin and SPARC were determined in MM patients, 21 patients with MGUS and 21 healthy controls, of similar gender and age. Bone remodeling was also studied by the measurement of a series of serum indices within one week from diagnosis: i) osteoclast regulators [sRANKL and osteoprotegerin (OPG)], ii) Dkk-1, iii) bone resorption markers [C-terminal cross-linking telopeptide of collagen type-I (CTX) and 5b-isoenzyme of tartrate resistant acid phosphatase (TRACP-5b)], and iv) bone formation markers [bone-specific alkaline phosphatase (bALP) and osteocalcin (OC)]. Patients with MM had increased levels of serum sclerostin compared with MGUS patients (mean value±SD: 0.48±0.46 vs. 0.26±0.29 ng/ml; p=0.004) and healthy controls (0.31±0.20 ng/ml, p=0.01). In contrast, both patients with MM and MGUS had reduced levels of serum SPARC (26.3±16.2 and 27.2±18.0 ng/ml, respectively) compared to controls (52.8±50.2 ng/ml; p<0.001). Sclerostin values strongly correlated with beta2-microglobulin (r=0.354, p<0.0001), cystatin-C (r=0.389, p<0.0001), serum creatinine (r=0.380, p<0.0001), and bALP (r=-0.541, p<0.0001). No correlations were observed between sclerostin with sRANKL, OPG, Dkk-1 or SPARC. Patients with advanced bone disease assessed by conventional radiography (>3 lytic lesions and/or a pathological fracture) had a borderline increase of sclerostin compared to all others (median value: 0.51 vs. 0.41 ng/ml, p=0.09). Patients with ISS-3 disease had increased levels of sclerostin compared to patients with ISS-1 and ISS-2 MM (ANOVA p=0.001). Median survival of MM patients was 48 months and median follow-up period was 20 months. Patients who had a serum sclerostin of ≥0.62 ng/ml (upper quartile, n=40 patients) had a median survival of 27 months, while median survival of all other patients was 98 months (p=0.031). In conclusion, our study provided evidence that sclerostin is increased in the serum of patients with MM and correlates with advanced ISS stage, increased bone resorption, reduced osteoblast function and poor survival. SPARC is reduced in MM possibly confirming the reduced osteoblast function observed in these patients. Sclerostin seems to participate in the biology of MM and thus it may be a possible target for the development of novel therapies that can both increase osteoblast function and target myeloma cells.
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