scholarly journals Carfilzomib Improves Bone Metabolism in Patients with Advanced Relapsed/Refractory Multiple Myeloma: Results of the CarMMa Study

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1257
Author(s):  
Evangelos Terpos ◽  
Ioannis Ntanasis-Stathopoulos ◽  
Eirini Katodritou ◽  
Marie-Christine Kyrtsonis ◽  
Vassiliki Douka ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Formation ◽  
Bone Metabolism ◽  
Bone Disease ◽  
Response To Treatment ◽  
Tartrate Resistant Acid Phosphatase ◽  
Type I ◽  
Refractory Multiple Myeloma ◽  
Osteolytic Bone Disease ◽  
Targeted Agent

Carfilzomib with dexamethasone (Kd) is a well-established regimen for the treatment of relapsed/refractory multiple myeloma (RRMM). There is limited information for the effects of Kd on myeloma-related bone disease. This non-interventional study aimed to assess skeletal-related events (SREs) and bone metabolism in patients with RRMM receiving Kd, in the absence of any bone-targeted agent. Twenty-five patients were enrolled with a median of three prior lines of therapy; 72% of them had evidence of osteolytic bone disease at study entry. During Kd treatment, the rate of new SREs was 28%. Kd produced a clinically relevant (≥30%) decrease in C-telopeptide of collagen type-1 (p = 0.048) and of tartrate-resistant acid phosphatase-5b (p = 0.002) at 2 months. This reduction was at least partially due to the reduction in the osteoclast regulator RANKL/osteoprotegerin ratio, at 2 months (p = 0.026). Regarding bone formation, there was a clinically relevant increase in osteocalcin at 6 months (p = 0.03) and in procollagen type I N-propeptide at 8 months post-Kd initiation. Importantly, these bone metabolism changes were independent of myeloma response to treatment. In conclusion, Kd resulted in a low rate of SREs among RRMM patients, along with an early, sustained and clinically relevant decrease in bone resorption, which was accompanied by an increase in bone formation, independently of myeloma response and in the absence of any bone-targeted agent use.

Diffuse MRI Pattern of Marrow Infiltration Correlates with Suppressed Bone Formation and Increased Incidence of Vertebral Fractures in Multiple Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5018-5018
Author(s):  
Evangelos Terpos ◽  
Lia A. Moulopoulos ◽  
Athanasios Anagnostopoulos ◽  
Efstathios Kastritis ◽  
Maria Roussou ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Growth Factor ◽  
Bone Formation ◽  
Vertebral Fractures ◽  
Bone Marrow Involvement ◽  
Tartrate Resistant Acid Phosphatase ◽  
Type I ◽  
Bone Formation Markers ◽  
Tracp 5B ◽  
Focal Pattern

Abstract Bone lytic disease is a major feature of multiple myeloma (MM) and is characterized by an increased osteoclast activity which is accompanied by a suppressed osteoblast function. Furthermore, increased angiogenesis is implicated in the pathogenesis of both bone disease and myeloma cell growth and survival. Magnetic resonance imaging (MRI) pattern of bone marrow involvement correlate with prognosis in MM. The aim of this study was to evaluate the MRI pattern of marrow infiltration in correlation with markers of bone remodeling and angiogenesis in 44 newly diagnosed, untreated, MM patients (42 with symptomatic and 2 with asymptomatic MM). MRI of the spine was performed at the same time with measurement of a series of biochemical serum indices of bone metabolism and angiogenesis: osteoclast stimulators [soluble receptor activator of nuclear factor-κB ligand (sRANKL), osteoprotegerin (OPG), and osteopontin], bone resorption markers [C- and N-telopeptide of collagen type-I (CTX, and NTX, respectively), and tartrate-resistant acid phosphatase isoform 5b (TRACP-5b)], bone formation markers [bone alkaline phosphatase (bALP), and osteocalcin (OC)], and angiogenic cytokines [vascular endothelial growth factor (VEGF), VEGF-A, angiogenin (ANG), angiopoietin-2 (ANGP-2), and basic fibroblast growth factor (bFGF)]. Myeloma patients had increased values of sRANKL (p<0.0001), OPG (p=0.01), sRANKL/OPG ratio (p<0.0001), NTX (p<0.0001), CTX (p=0.04), TRACP-5b (p<0.0001), VEGF (p=0.03), VEGF-A (p<0.0001), ANG (p<0.001), ANGP-2 (p=0.001), and bFGF (p=0.007) compared with respective values of 33, gender and age matched, controls. MRI revealed that 19 patients had focal pattern of marrow involvement, 11 diffuse, 10 normal, and 4 had a variegated pattern. Patients with diffuse MRI pattern also had reduced values of bALP (p<0.0001) compared to controls, while patients with normal pattern had reduced levels of both formation markers (OC and bALP; p=0.04 and <0.0001, respectively) and normal levels of OPG. On the contrary, patients with focal and variegated patterns had normal values of bALP and OC. Bone formation as assessed by bALP was more suppressed in patients with diffuse or normal MRI patterns compared to patients of focal or variegated patterns (mean±SD: 15.9±7.3 U/L vs. 29.3±24.5 U/L; p=0.02), while there was no difference between these groups in terms of resorption markers or osteoclast stimulators’ levels. In addition, patients with diffuse and normal MRI pattern also had increased levels of VEGF-A compared to patients of focal or variegated patterns (mean±SD: 83±68.4 pg/mL vs. 38.4±55 pg/mL; p=0.04). All but two patients of diffuse pattern (81%) had at least one vertebral fracture on radiographic evaluation of the axial skeleton compared to ten patients with focal pattern (52%). These results suggest that patients with diffuse MRI pattern have suppressed bone formation, increased levels of the major angiogenic cytokine VEGF-A, and increased incidence of vertebral fractures compared to patients who showed a focal pattern of myeloma infiltration.

Bone Remodeling in Patients with Relapsed/Refractory Multiple Myeloma Who Receive Lenalidomide-Based Regimens.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4745-4745
Author(s):  
Evangelos Terpos ◽  
Dimitrios Christoulas ◽  
Efstathios Kastritis ◽  
Eirini Katodritou ◽  
Xenophon Papanikolaou ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Resorption ◽  
Bone Formation ◽  
Bone Metabolism ◽  
Bone Remodeling ◽  
Response To Therapy ◽  
Type I ◽  
Fracture Group ◽  
Lytic Lesions ◽  
Tracp 5B

Abstract Lenalidomide in combination with dexamethasone is very effective for the management of refractory/relapsed multiple myeloma (MM). However, there is very little information for the effect of lenalidomide on bone metabolism in MM. We evaluated bone remodeling in 36 patients (22M/14F; median age 64 years) with refractory/relapsed MM who received lenalidomide-based regimens: 27 received the combination of lenalidomide at the standard dose of 25mg/day x 21 days, every 28 days, with either high (n=18) or low (n=9) dose dexamethasone, while 9 patients received the combination of lenalidomide/low dose dexamethasone plus bortezomib (BDR) at a dose of 1 mg/m2, iv, on days 1, 4, 8, 11 every 28 days. The following serum indices of bone turnover were measured on day 1 of cycle 1, and then on day 28 of cycle 3: osteoblast inhibitor dickkopf-1 (Dkk-1); osteoclast regulators: soluble RANKL (sRANKL) and osteoprotegerin (OPG); bone resorption markers: C-telopeptide of collagen type-I (CTX) and tartrate-resistant acid phosphatase type-5b (TRACP-5b); and bone formation markers: bone-specific ALP (bALP) and osteocalcin (OC). We also studied 20 healthy controls of similar gender and age. The median number of previous therapies was 3 (range: 2–7). At baseline, 9 patients had no lytic lesions (group A), while 3 patients had 1–3 lytic lesions (group B) and 24 patients had more than 3 lytic lesions and/or a pathological fracture (group C) in plain radiography of the skeleton. After 3 cycles of therapy the objective response (CR+PR) rate was 77% (21/27) in lenalidomide/dexamethasone patients and 55% (5/9) in BDR patients. MM patients at baseline had increased levels of Dkk-1 (p=0.002), sRANKL (p=0.04), and both markers of bone resorption (p<0.01) compared to controls. In contrast, bone formation as assessed by serum bALP and OC was significantly reduced (p<0.01). Patients with advanced bone disease (group C) had increased levels of CTX (p<0.001), TRACP-5b (p<0.01), Dkk-1 (p=0.04) and reduced levels of OC (p=0.04) compared with all others. Moreover, serum levels of DKK-1 correlated with TRACP-5b (r=0.614, p<0.0001), CTX (r=0.29, p=0.03), sRANKL (r=0.423, p=0.001) and OPG (r=0.572, p<0.0001). The administration of lenalidomide-based regimens produced only a reduction of Dkk-1 (p=0.04) and TRACP-5b (p=0.03) after 3 cycles of therapy. Interestingly, patients who received BDR showed a dramatic reduction of sRANKL (p=0.02), sRANKL/OPG ratio (p=0.03) and Dkk-1 (p=0.02), which associated with an increase in both markers of bone formation (p=0.04). The % reduction of sRANKL and TRACP-5b and the % increase of bALP and OC was higher in BDR patients compared with others. There was no correlation between response to therapy and bone markers’ changes. In conclusion, the combination of lenalidomide plus dexamethasone seems not to have a clear effect on bone metabolism after 3 cycles of therapy, possibly due to administration of high dose dexamethasone in the majority of patients. BDR patients had a beneficial effect mainly on bone formation, reflecting the bone anabolic effect of bortezomib and/or the lower dose of dexamethasone given in these patients. Longer follow-up is needed to exact final conclusions for the effect of lenalidomide on bone metabolism in relapsed/refractory MM.

Myeloma Cells Induce Osteoblast Suppression through Sclerostin Secretion

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2961-2961 ◽  
Author(s):  
Silvia Colucci ◽  
Giacomina Brunetti ◽  
Angela Oranger ◽  
Giorgio Mori ◽  
Francesca Sardone ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Formation ◽  
Bone Disease ◽  
Culture System ◽  
Conflicts Of Interest ◽  
Negative Regulator ◽  
Type I ◽  
Myeloma Cells ◽  
Myeloma Bone Disease ◽  
Osteoblast Activity

Abstract Abstract 2961 Reduced osteoblast activity contributes to the development of multiple myeloma-bone disease. Wingless-type (Wnt) signalling pathway is critical in osteoblastogenesis, and it is negatively regulated by molecules such as frizzled-related proteins (sFRPs), Dickkopf proteins (DKKs) and sclerostin. Myeloma cells are known to induce inhibition of osteoblastogenesis through Wnt antagonists such as DKK-1 and sFRP-2 and -3 whereas the role of sclerostin, an osteocyte-expressed negative regulator of bone formation, has not been yet investigated. We provide novel evidence showing sclerostin expression by myeloma cells from patients with multiple myeloma-bone disease and human myeloma cell lines (HMCLs). By means of a co-culture system of bone marrow stromal cells (BMSCs) and HMCLs, we demonstrated that sclerostin expression by myeloma cells and HMCLs is responsible for reduced expression of major osteoblastic specific proteins namely bone-specific alkaline phosphatase, collagen-type I, bone sialoprotein II and osteocalcin as well as decreased mineralized nodule formation and attenuated expression of member of the AP-1 transcription factor family (i.e. Fra-1, Fra-2 and Jun-D). The addition of a neutralizing anti-sclerostin antibody to our co-culture system can restore the above parameters, through the intranuclear accumulation of β-catenin in BMSCs. On the other hand, we demonstrated that sclerostin is also involved in inducing increased receptor activator of nuclear factor-k B ligand (RANKL) and decreased osteoprotegerin (OPG) expression in osteoblasts, contributing to the enhanced osteoclast activity occurring in patients with multiple myeloma-bone disease. Our data suggest that myeloma cells contribute to the suppression of bone formation through sclerostin secretion. Disclosures: No relevant conflicts of interest to declare.

Multiple Myeloma Cell-Osteoblast Interaction Results in Impaired Bone Formation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4764-4764
Author(s):  
Sonia Vallet ◽  
Teru Hideshima ◽  
Samantha Pozzi ◽  
Nileshwari Vaghela ◽  
Gaurav Gharti-Chhetri ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Bone Formation ◽  
Cell Lines ◽  
Bone Matrix ◽  
Type I ◽  
Dependent Manner ◽  
Alizarin Red ◽  
Matrix Mineralization ◽  
Osteolytic Bone Disease

Abstract Osteolytic bone disease is a common complication of multiple myeloma (MM) resulting from uncoupled bone remodeling due to enhanced bone resorption and reduced bone formation. Bone formation is a complex process requiring functionally mature osteoblasts (OB). Mesenchymal stem cells differentiate into mature OB and following an active period of bone matrix synthesis lasting 1–2 weeks, they finally differentiate into inactive bone-lining cells or osteocytes. Although several studies have demonstrated that MM cells inhibit osteoblastogenesis via secretion of DKK1, a Wnt-pathway antagonist, the functional sequelae of interaction of mature OB with MM cells remains to be elucidated. Here, we studied the morphological and functional consequences induced by MM cells interacting with mature OB. Mature OB were generated from MM patients’ bone marrow mononuclear cells by cultivation in differentiation media consisting of αMEM with 20% fetal bovine serum, β-glycerol phosphate (2.16 mg/ml), ascorbic acid (0.05 mg/ml) and dexamethasone (10 nM). These mature OBs were alkaline phosphatase (ALP) positive and secreted and mineralized bone matrix, as demonstrated by Alizarin Red staining. MM cell lines INA6 and MM1.S were co-cultured with mature OB at a 5:1 ratio for 2, 4 and 7 days in OB differentiation media and bone marrow stromal cells (BMSC) were used as negative controls. After 4 days of co-culture, we observed phenotypic changes featured by acquisition of a spindle-like shape with reduced ALP staining in OB. In contrast, OB alone were intensely ALP-positive and cuboidal-shaped cells. Co-culture with INA-6 MM cells induced a reduction in ALP enzymatic activity in a time-dependent manner by 28% (± 10%) at day 2 and 72% (± 5%) at day 4 (p<0.05), respectively, whereas co-culture with MM1.S induced a 38% (± 5%) reduction after 4 days. Other MM cell lines induced similar effects. We then verified OB activity by assessing osteocalcin release and matrix mineralization. Importantly, osteocalcin secretion was completely abrogated in the presence of INA6, while MM1.S reduced it by 50% as early as day 2 (p<0.05). Moreover, Alizarin red staining demonstrated an impairment of matrix mineralization after 7 days of co-culture. Reduced OB function in the presence of MM cells was further confirmed by downregulation of Type-I collagen expression in OB. These effects were associated with only modest (10%) OB apoptosis as demonstrated by APO2.7 staining after 4 days of co-culture compared to OB alone. These phenotypic and functional sequelae on OB were not induced by co-culture supernatants, suggesting the requirement for direct MM cell/OB contact. These results therefore suggest that MM cell/mature OB interactions result in inhibition of bone formation by inactivation of mature OB. Ongoing studies are characterizing the mechanism by which MM cells induce OB inactivation and whether these changes affect the OC compartment. These studies of MM cell-OB interactions will form the basis for evaluation of novel agents with anabolic effects on the bone in the future.

Inhibiting Dickkopf-1 (Dkk1) Removes Suppression of Bone Formation and Prevents the Development of Osteolytic Bone Disease in Multiple Myeloma

2009 ◽  
Vol 24 (3) ◽  
pp. 425-436 ◽  
Author(s):  
Deborah J Heath ◽  
Andrew D Chantry ◽  
Clive H Buckle ◽  
Les Coulton ◽  
John D Shaughnessy ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Formation ◽  
Bone Disease ◽  
Osteolytic Bone Disease ◽  
Dickkopf 1

scholarly journals A Molecular Signature of Circulating MicroRNA Can Predict Osteolytic Bone Disease in Multiple Myeloma

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3877
Author(s):  
Aristea-Maria Papanota ◽  
Panagiotis Tsiakanikas ◽  
Christos K. Kontos ◽  
Panagiotis Malandrakis ◽  
Christine-Ivy Liacos ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Logistic Regression ◽  
Bone Disease ◽  
Characteristic Curve ◽  
Molecular Signature ◽  
Circulating Microrna ◽  
Prognostic Role ◽  
Clinical Value ◽  
Osteolytic Bone Disease ◽  
Circulating Levels

Background: Multiple myeloma bone disease (MMBD) constitutes a common and severe complication of multiple myeloma (MM), impacting the quality of life and survival. We evaluated the clinical value of a panel of 19 miRNAs associated with osteoporosis in MMBD. Methods: miRNAs were isolated from the plasma of 62 newly diagnosed MM patients with or without MMBD. First-strand cDNA was synthesized, and relative quantification was performed using qPCR. Lastly, we carried out extensive biostatistical analysis. Results: Circulating levels of let-7b-5p, miR-143-3p, miR-17-5p, miR-214-3p, and miR-335-5p were significantly higher in the blood plasma of MM patients with MMBD compared to those without. Receiver operating characteristic curve and logistic regression analyses showed that these miRNAs could accurately predict MMBD. Furthermore, a standalone multi-miRNA–based logistic regression model exhibited the best predictive potential regarding MMBD. Two of those miRNAs also have a prognostic role in MM since survival analysis indicated that lower circulating levels of both let-7b-5p and miR-335-5p were associated with significantly worse progression-free survival, independently of the established prognostic factors. Conclusions: Our study proposes a miRNA signature to facilitate MMBD diagnosis, especially in ambiguous cases. Moreover, we provide evidence of the prognostic role of let-7b-5p and miR-335-5p as non-invasive prognostic biomarkers in MM.

scholarly journals Reduced Serum Levels of Bone Formation Marker P1NP in Psoriasis

2021 ◽  
Vol 8 ◽  
Author(s):  
Julia Mentzel ◽  
Tabea Kynast ◽  
Johannes Kohlmann ◽  
Holger Kirsten ◽  
Matthias Blüher ◽  
...  
Keyword(s):  
Bone Formation ◽  
Bone Metabolism ◽  
Type I Collagen ◽  
Skin Inflammation ◽  
Serum Levels ◽  
Serum Markers ◽  
Chronic Inflammatory Disease ◽  
Type I ◽  
Patient Counseling ◽  
Type I Procollagen

Psoriasis is a chronic inflammatory disease of the skin and joints. More recent data emphasize an association with dysregulated glucose and fatty acid metabolism, obesity, elevated blood pressure and cardiac disease, summarized as metabolic syndrome. TNF-α and IL-17, central players in the pathogenesis of psoriasis, are known to impair bone formation. Therefore, the relation between psoriasis and bone metabolism parameters was investigated. Two serum markers of either bone formation—N-terminal propeptide of type I procollagen (P1NP) or bone resorption—C-terminal telopeptide of type I collagen (CTX-I)—were analyzed in a cohort of patients with psoriasis vulgaris. In patients with psoriasis, P1NP serum levels were reduced compared to gender-, age-, and body mass index-matched healthy controls. CTX-I levels were indistinguishable between patients with psoriasis and controls. Consistently, induction of psoriasis-like skin inflammation in mice decreases bone volume and activity of osteoblasts. Moreover, efficient anti-psoriatic treatment improved psoriasis severity, but did not reverse decreased P1NP level suggesting that independent of efficient skin treatment psoriasis did affect bone metabolism and might favor the development of osteoporosis. Taken together, evidence is provided that bone metabolism might be affected by psoriatic inflammation, which may have consequences for future patient counseling and disease monitoring.

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