Anti-sclerostin treatment prevents multiple myeloma bone disease and reduces tumour burden

Abstract Objectives: Lytic bone disease is a hallmark of multiple myeloma (MM) and is caused by osteoclast activation and osteoblast inhibition. Secretion of Dickkopf (DKK)-1 by myeloma cells was reported to cause inhibition of osteoblast precursors. DKK-1 is an inhibitor of the Wnt/β-catenin signaling, which is a critical signaling pathway for the differentiation of mesenchymal stem cells into osteoblasts. So far there is no study showing a significant difference in serum DKK-1 levels in MM patients with or without lytic bone lesions. Methods: DKK-1 serum levels were quantified in 184 previously untreated MM patients and 33 MGUS patients by ELISA, using a monoclonal anti-DKK-1 antibody. For the evaluation of bone disease, skeletal X-rays were performed. Results: Serum DKK-1 was elevated in MM as compared to MGUS (mean 11,963 pg/mL versus 1993 pg/mL, P < 0.05). Serum DKK-1 levels significantly correlated with myeloma stage according to Durie and Salmon (mean 2223 pg/mL versus 15,209 pg/mL in stage I and II/III, respectively; P = 0.005). Importantly, myeloma patients without lytic lesions in conventional radiography had significantly lower DKK-1 levels than patients with lytic bone disease (mean 3114 pg/mL versus 17,915 pg/mL; P = 0.003). Of interest, serum DKK-1 correlated with the number of bone lesions (0 vs. 1–3 vs. >3 lesions: mean 3114 pg/mL vs. 3559 pg/mL vs. 24,068 pg/mL; P = 0.002). Conclusion: This is the largest study of DKK-1 serum levels in multiple myeloma patients and data show for the first time a correlation between DKK-1 serum concentration and the amount of lytic bone disease, suggesting that DKK1 is an important factor for the extent of bone disease and supporting the hypothesis of DKK-1 as a therapeutic target in myeloma bone disease.

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Bone Turnover Biomarkers Are Useful In Monitoring Myeloma Bone Disease and As Early Predictor Biomarkers For Relapse Disease In Multiple Myeloma

Blood ◽

10.1182/blood.v122.21.1869.1869 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1869-1869

Author(s):

Kay Reen Ting ◽

Abdul Hameed ◽

Jennifer Brady ◽

Paul Dowling ◽

Colin Clarke ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Turnover ◽

Bone Disease ◽

Newly Diagnosed ◽

Serum Free ◽

Myeloma Bone Disease ◽

And Control ◽

Early Predictor

Abstract Background Multiple myeloma is a plasma cell disorder characterised by bone marrow infiltration with clonal plasma cells that secrete monoclonal immunoglobulin which is detected in serum or urine samples. Bone disease is a well-known devastating complication. It has a significant impact to the quality of life and morbidity in multiple myeloma. The uncoupling effect of osteoblast and osteoclast activity is the major element in development of myeloma bone disease (MBD). Imaging techniques are used as the current standard method for detection of bony lesions. They have limitations as they cannot provide a real-time assessment of bone turnover. Early detection of relapse disease is crucial to allow preventative therapeutic intervention as it could significantly impact on quality of life. Aims Bone biomarkers such as C-terminal telopeptide of type 1 collagen (CTX-1) and procollagen type 1 N-propeptide (P1NP) can be used as an early predictor marker for MBD relapses and a monitor for MBD at different stages of the disease. Methods CTX-1 and P1NP were measured by chemiluminescent immunoassay on fasting plasma samples from 111 patients including newly diagnosed multiple myeloma (n=28), remission (n=34), relapses (n=22) and control (n=27). These were measured at regular intervals over a 30 month study period. Relapse disease was identified by conventional biomarkers like paraprotein and serum free light chains, and confirmed by imaging and bone marrow biopsy. In a subset of patients with disease relapse, the Mann-Whitney test was used to compare bone markers pre-relapse and at relapse. Results CTX-1 levels were significantly higher in newly diagnosed multiple myeloma compared to remission and control groups (p < 0.0001). In relapse group, CTX-1 rose significantly at the time of pre-relapse to relapse state (p=0.0001). A rise of ≥ 2.0 fold rise in the level of CTX-1 from remission to relapse disease was noted. The median time between the pre-relapse sample and relapse disease was 3 months (range 1-14 months). Most of them had new bone lesions at relapse. This proves that it has potential as an early predictor of relapse or progressive bone disease. A case showed CTX-1 level was the only biochemical parameter to rise significantly prior to relapse as compared to the other conventional biomarkers (ie. paraprotein and serum free light chain). As for P1NP, the rise in P1NP from pre-relapse to relapse was not significant (p=0.0810). Conclusion Osteoclast biomarker serum CTX-1 correlates accurately with the disease burden in newly diagnosed multiple myeloma patients as compared to the rest of the groups. It is a more sensitive early predictor of relapse/progressive disease than established biomarkers. It is a more robust marker than P1NP. The rise in P1NP goes against the theory that there is an uncoupling of bone turnover in MBD and requires further study. CTX-1 is more cost effective and accessible than imaging and should be used routinely when monitoring bone disease activity in multiple myeloma patients, facilitating early intervention when relapse occurs. Disclosures: No relevant conflicts of interest to declare.

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Mechanisms of multiple myeloma bone disease

BoneKEy Reports ◽

10.1038/bonekey.2012.135 ◽

2012 ◽

Vol 1 (8) ◽

Cited By ~ 34

Author(s):

Deborah L Galson ◽

Rebecca Silbermann ◽

G David Roodman

Keyword(s):

Multiple Myeloma ◽

Bone Disease ◽

Myeloma Bone Disease

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Whole-Body Low-Dose Computed Tomography and Advanced Imaging Techniques for Multiple Myeloma Bone Disease

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-14-1692 ◽

2014 ◽

Vol 20 (23) ◽

pp. 5888-5897 ◽

Cited By ~ 39

Author(s):

Matthew J. Pianko ◽

Evangelos Terpos ◽

G. David Roodman ◽

Chaitanya R. Divgi ◽

Sonja Zweegman ◽

...

Keyword(s):

Computed Tomography ◽

Multiple Myeloma ◽

Bone Disease ◽

Low Dose ◽

Imaging Techniques ◽

Whole Body ◽

Advanced Imaging ◽

Myeloma Bone Disease ◽

Low Dose Computed Tomography

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An Improved Animal Model of Multiple Myeloma Bone Disease

Cancers ◽

10.3390/cancers13174277 ◽

2021 ◽

Vol 13 (17) ◽

pp. 4277

Author(s):

Syed Hassan Mehdi ◽

Carol A Morris ◽

Jung Ae Lee ◽

Donghoon Yoon

Keyword(s):

Multiple Myeloma ◽

Bone Disease ◽

Plasma Cells ◽

Bone Lesions ◽

Myeloma Bone Disease ◽

Nsg Mice ◽

Morphometric Analyses ◽

Imaging Results ◽

Nsg Mouse

Multiple myeloma (MM) is a plasma cell malignancy that causes an accumulation of terminally differentiated monoclonal plasma cells in the bone marrow, accompanied by multiple myeloma bone disease (MMBD). MM animal models have been developed and enable to interrogate the mechanism of MM tumorigenesis. However, these models demonstrate little or no evidence of MMBD. We try to establish the MMBD model with severe bone lesions and easily accessible MM progression. 1 × 106 luciferase-expressing 5TGM1 cells were injected into 8–12 week-old NOD SCID gamma mouse (NSG) and C57BL/KaLwRij mouse via the tail vein. Myeloma progression was assessed weekly via in vivo bioluminescence (BL) imaging using IVIS-200. The spine and femur/tibia were extracted and scanned by the micro-computer tomography for bone histo-morphometric analyses at the postmortem. The median survivals were 56 days in NSG while 44.5 days in C57BL/KaLwRij agreed with the BL imaging results. Histomorphic and DEXA analyses demonstrated that NSG mice have severe bone resorption that occurred at the lumbar spine but no significance at the femur compared to C57BL/KaLwRij mice. Based on these, we conclude that the systemic 5TGM1 injected NSG mouse slowly progresses myeloma and develops more severe MMBD than the C57BL/KaLwRij model.

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Circulating microRNAs Correlate with Multiple Myeloma and Skeletal Osteolytic Lesions

Cancers ◽

10.3390/cancers13215258 ◽

2021 ◽

Vol 13 (21) ◽

pp. 5258

Author(s):

Sara Reis Moura ◽

Hugo Abreu ◽

Carla Cunha ◽

Cláudia Ribeiro-Machado ◽

Carla Oliveira ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Disease ◽

Area Under The Curve ◽

Genetic Alterations ◽

Disease Stage ◽

Bone Lesions ◽

Healthy Controls ◽

Osteolytic Lesions ◽

Circulating Micrornas ◽

Myeloma Bone Disease

Multiple myeloma (MM) is the second most frequent hematological disease and can cause skeletal osteolytic lesions. This study aims to evaluate the expression of circulating microRNAs (miRNAs) in MM patients and to correlate those levels with clinicopathological features, including bone lesions. A panel of miRNAs associated with MM onset and progression, or with bone remodeling, was analyzed in the plasma of 82 subjects (47 MM patients; 35 healthy controls). Results show that miR-16-5p, miR-20a-5p, and miR-21-5p are differently expressed between MM patients and healthy controls. Receiver operating characteristic analyses indicate that their combined expression has potential as a molecular marker (Area Under the Curve, AUC of 0.8249). Furthermore, significant correlations were found between the analyzed miRNAs and disease stage, treatment, β2 microglobulin, serum albumin and creatinine levels, but not with calcium levels or genetic alterations. In this cohort, 65.96% of MM patients had bone lesions, the majority of which were in the vertebrae. Additionally, miR-29c-3p was decreased in patients with osteolytic lesions compared with patients without bone disease. Interestingly, circulating levels of miR-29b-3p correlated with cervical and thoracic vertebral lesions, while miR-195-5p correlated with thoracic lesions. Our findings suggest circulating miRNAs can be promising biomarkers for MM diagnosis and that their levels correlate with myeloma bone disease and osteolytic lesions.

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Myeloma bone disease: from biology findings to treatment approaches

Blood ◽

10.1182/blood-2018-11-852459 ◽

2019 ◽

Vol 133 (14) ◽

pp. 1534-1539 ◽

Cited By ~ 19

Author(s):

Evangelos Terpos ◽

Ioannis Ntanasis-Stathopoulos ◽

Meletios A. Dimopoulos

Keyword(s):

Quality Of Life ◽

Multiple Myeloma ◽

Bone Loss ◽

Bone Turnover ◽

Bone Disease ◽

Osteoclast Activity ◽

Myeloma Bone Disease ◽

Key Players ◽

Skeletal Related Events

Abstract Bone disease is a cardinal complication of multiple myeloma that affects quality of life and survival. Osteocytes have emerged as key players in the development of myeloma-related bone disease. Along with other factors, they participate in increased osteoclast activity, decreased osteoblast function, and immunosuppressed marrow microenvironment, which deregulate bone turnover and result in bone loss and skeletal-related events. Denosumab is a novel alternative to bisphosphonates against myeloma bone disease. Special considerations in this constantly evolving field are thoroughly discussed.

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