Potential Role of IMiDs and Other Agents as Therapy for Myeloma Bone Disease

2010 ◽  
pp. 199-209
Author(s):  
Suzanne Lentzsch
Keyword(s):  
Bone Disease ◽  
Potential Role ◽  
Myeloma Bone Disease

scholarly journals Role of microRNAs in Diagnosis, Prognosis and Management of Multiple Myeloma

2020 ◽  
Vol 21 (20) ◽  
pp. 7539
Author(s):  
Amro M. Soliman ◽  
Teoh Seong Lin ◽  
Pasuk Mahakkanukrauh ◽  
Srijit Das
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Tumor Growth ◽  
Malignant Transformation ◽  
Bone Disease ◽  
Clinical Management ◽  
Potential Role ◽  
Plasma Cells ◽  
The Usa

Multiple myeloma (MM) is a cancerous bone disease characterized by malignant transformation of plasma cells in the bone marrow. MM is considered to be the second most common blood malignancy, with 20,000 new cases reported every year in the USA. Extensive research is currently enduring to validate diagnostic and therapeutic means to manage MM. microRNAs (miRNAs) were shown to be dysregulated in MM cases and to have a potential role in either progression or suppression of MM. Therefore, researchers investigated miRNAs levels in MM plasma cells and created tools to test their impact on tumor growth. In the present review, we discuss the most recently discovered miRNAs and their regulation in MM. Furthermore, we emphasized utilizing miRNAs as potential targets in the diagnosis, prognosis and treatment of MM, which can be useful for future clinical management.

Immunoexpression of Macrophage Inflammatory Protein-1 Alpha on Bone Marrow Trephine Biopsies Correlates with the Extent of Bone Disease in Newly Diagnosed Patients with Multiple Myeloma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5119-5119
Author(s):  
Maria Roussou ◽  
Anna Tasidou ◽  
Efstathios Kastritis ◽  
Magdalini Migkou ◽  
Maria Gavriatopoulou ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Disease ◽  
Newly Diagnosed ◽  
Santa Cruz ◽  
Myeloma Bone Disease ◽  
Inflammatory Protein ◽  
Lytic Lesions ◽  
Intermediate Expression ◽  
Macrophage Inflammatory Protein

Abstract Macrophage inflammatory protein-1 alpha (MIP-1alpha) is a low molecular weight chemokine that belongs to the RANTES family and is a potent osteoclast stimulator. Previous studies have shown that malignant plasma cells (PCs) from myeloma cell lines produce MIP-1alpha, while MIP-1alpha levels are elevated in the bone marrow plasma and the serum of patients with multiple myeloma (MM) and correlate with the extent of bone disease. The purpose of our study was to evaluate the role of MIP-1alpha immunoexpression on bone marrow trephine biopsies in myeloma bone disease and examine possible correlations between MIP-1alpha expression with survival and prognostic factors of MM. We evaluated formalin fixed paraffin-embedded bone marrow sections of 130 patients with newly diagnosed MM (66M/64F, median age: 68 years). Bone marrow sections were subjected to immunohistochemistry study using the anti-MIP- 1alpha monoclonal antibody (Santa Cruz Biotechnology Inc., Santa Cruz, CA, USA). The immunoreactivity of MIP-1alpha was examined on the basis of positive PCs with the following cut off values: <20% positive PCs (negative expression group, group I), 20–50% positive PCs (intermediate expression group, group II) and >50% positive PCs (high expression group, group III). Moreover MIP-1alpha was measured using ELISA methodology (R&D Systems, Minneapolis, MN, USA) in the serum of the patients. The extent of bone disease was assessed radiographically, and grading was performed as follows: group A included 43 patients (33%) who had no lytic lesions and/or osteoporosis only, group B included 24 patients (18%) who had lytic lesions in 1–3 areas, whereas group C included 63 patients (48%) with lytic lesions in >3 areas and/or a bone fracture. Thirty-seven (28%) patients had negative MIP-1alpha expression, 17 (13%) intermediate expression and 79 (59%) high expression of MIP-1alpha. MIP-1alpha expression of ≥20% PCs in the trephine biopsies significantly correlated with the extent of bone disease (Figure 1, ANOVA p<0.0001). Furthermore, 91 patients (70%) had values of serum MIP-1alpha >14 pg/ml, which was the median value observed in 20 controls of similar age and gender (p<0.001). MIP-1alpha serum levels also correlated with the extent of bone disease (ANOVA p<0.0001). In terms of overall survival, no significant association was observed in relation to MIP-1alpha expression. Increased immunoexpression of MIP-1alpha was associated with high plasma cell infiltration in the bone marrow (r=0.348, p<0.0001), low platelet count (r=0.282; p=0.0012), hypercalcemia (r=0.246; p=0.022), elevated serum creatinine (r=0.258, p=0.027), and advanced disease stage (ISS, p=0.034). Our findings underline, for the first time, the increased incidence of high immunoexpression of MIP-1alpha in the malignant PCs of myeloma patients and the correlation between the expression of MIP-1alpha by myeloma PCs in the trephine biopsies and the extent of lytic bone disease. These results confirm the significant role of MIP-1alpha in the pathogenesis of myeloma bone disease and suggest that MIP-1alpha may represent a rational therapeutic target for the management of bone destruction in myeloma. Figure Figure

Induction of CXCL1 in Osteoblasts by Myeloma Cells Promotes Migration of Osteoclast Precursors

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 441-441
Author(s):  
Martin F. Kaiser ◽  
Ulrike Heider ◽  
Maren Mieth ◽  
Jozef Zustin ◽  
Andrea Kuehnl ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Healthy Volunteers ◽  
Bone Disease ◽  
Bone Marrow Microenvironment ◽  
Bone Microenvironment ◽  
Bone Marrow Biopsies ◽  
Myeloma Cells ◽  
Myeloma Bone Disease ◽  
Immunomagnetic Sorting

Abstract Abstract 441 Introduction Multiple myeloma (MM) causes a dysbalance in the bone microenvironment between bone building osteoblasts and bone resorbing osteoclasts (OCs), with an increase in OC recruitment, differentiation and activation, leading to myeloma bone disease (MBD). Presence of MBD has a major impact on the quality of life of MM patients and novel treatment approaches for MBD are urgently needed. Several factors have been identified that play a role in this process, e.g. receptor activator of NF-kB ligand (RANKL). However, the pathomechanism of increased osteoclast recruitment and activation is not completely understood. Here, we investigated the role of the chemokine CXCL1 and its receptor CXCR2 in the bone microenvironment in MM. Material and Methods Serum samples from 52 patients with newly diagnosed MM and from 22 healthy volunteers were assayed using a CXCL1 ELISA. Primary human mesenchymal stem cells (hMSCs) were cultured from bone marrow aspirates and primary human differentiated osteoblasts (hOBs) were cultured from trabecular bone fragments, both from healthy volunteers. Osteoclast precursors (pre-OCs) were generated by immunomagnetic sorting of CD14-positive cells from the peripheral blood of healthy volunteers. Human myeloma cell lines (HMCLs) U-266, RPMI-8226 and LP-1 and primary bone marrow myeloma cells (pMMCs) selected using CD138 immunomagnetic sorting were used for the experiments. Co-cultures of HMCLs and pMMCs with hMSCs or hOBs were performed using 0.45 μm transwell inserts, allowing for the exchange of soluble mediators. Migration assays were performed using 8 μm transwell inserts and human recombinant CXCL1. Immunohistochemistry was performed on paraffin-embedded bone marrow biopsies from MM patients using an anti-CXCR2 monoclonal antibody. All experimental procedures involving patient material were approved by the local ethics committee and conducted after informed consent was obtained. Results CXCL1 serum levels were found to be significantly higher in MM patients than in healthy individuals (193.4 pg/mL vs. 137 pg/mL, respectively, p<0.05), indicating a role for CXCL1 in MM pathophysiology. We went on to investigate the role of CXCL1 in MBD and performed co-cultures of HMCLs and pMMCs with hMSCs or hOBs. Baseline CXCL1 expression was absent in HMCLs and low or absent in hMSCs or hOBs at baseline. RNA expression as well as protein excretion by hMSCs and hOBs were induced after co-culture with myeloma cells. For example, pMMCs from different individuals led to a mean 154-fold upregulation of CXCL1 mRNA levels in hMSCs and to a mean upregulation of CXCL1 protein in cell culture supernatants from <31.5 pg/mL at baseline to 2140 pg/mL after co-cultures. In order to investigate the potential function of elevated CXCL1 levels in the bone marrow microenvironment, the expression of CXCR2, the receptor for CXCL1, was analyzed. Pre-OCs as well as a majority of pMMCs expressed CXCR2 mRNA. CXCR2 protein expression in pMMCs was verified using immunohistochemistry on MM bone marrow biopsies. Human recombinant CXCL1 significantly increased pre-OC cell migration in a dose-dependent manner. For example, 50 ng/mL or 100 ng/mL of CXCL1 increased mean pre-OC migration along a CXCL1 gradient 2.5-fold and 5.6-fold over baseline, respectively. In addition, mean pMMC migration was increased 3.8-fold compared to baseline along a 100 ng/mL gradient of recombinant CXCL1. The osteoclastogenic capacity of the migrated pre-OCs was confirmed by TRAP expression after stimulation with RANKL and M-CSF. Conclusion We describe here a novel role for the chemokine CXCL1 in myeloma bone disease. We demonstrate that CXCL1 is induced in hMSCs and hOBs by co-culture with MM cells. CXCL1 leads to chemoattraction of both pre-OCs and pMMCs. These effects could lead to co-localization of OCs and MM cells in the bone marrow microenvironment and contribute to the tumor-promoting interaction between these cell types. Our data indicate the CXCL1-CXCR2 axis as a therapeutic target in myeloma bone disease. Disclosures: No relevant conflicts of interest to declare.

Loss of CYR61 in Myeloma Microenvironment Is Associated with Poor Survival

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1813-1813
Author(s):  
Sarah K. Johnson ◽  
Peter Stewart ◽  
Shmuel Yaccoby ◽  
Fenghuang Zhan ◽  
Bart Barlogie ◽  
...  
Keyword(s):  
Cell Growth ◽  
Bone Disease ◽  
Plasma Cells ◽  
Αvβ3 Integrin ◽  
Newly Diagnosed ◽  
Poor Survival ◽  
Myeloma Bone Disease ◽  
Healthy Donors ◽  
Bone Biopsies

Abstract Abstract 1813 Previously, we used gene expression profiling (GEP) on whole-bone biopsies (BX) and plasma cells (PCs) of newly diagnosed multiple myeloma (MM) patients and age-matched controls to identify 62 non-PC-related genes that were significantly differentially expressed in bone biopsies of MM. CYR61/CCN1 was the most significantly overexpressed gene in BX in subsets of MGUS and MM patients. We hypothesize that alteration of the microenvironment may be central to the conversion of MGUS to MM and that abnormal expression of CYR61 may precede this conversion. CYR61 has been shown to promote proliferation, migration, adhesion and angiogenesis and is expressed in many cell types. Within the bone, CYR61 is induced during osteoblast differentiation by endothelin-1, (Clines et al., 2007) and by Wnt3a (Si et al., 2006). CYR61 also inhibits the formation of multinucleate osteoclasts in vitro (Crockett et al., 2007). To investigate the role of CYR61 in MM pathogenesis CYR61 protein production in MM was analyzed in sera of 192 newly diagnosed myeloma patients by ELISA. In agreement with that observed by GEP, CYR61 is significantly elevated in a subset of MM patients (144/192) at diagnosis compared with healthy donors (p < 0.001). In Total Therapy 3 (TT3) patients low CYR61 (< 500 pg/ml) is associated with poor overall survival (p < 0.05) compared with levels greater than 500 pg/ml. CYR61 levels were also significantly elevated in MGUS, Waldenstrom's macroglobulinemia and smoldering/indolent myeloma compared with healthy donors (p < 0.001). Patient samples were grouped into the 8 GEP-defined MM molecular subtypes (Zhan et al., 2006) and CYR61 levels were significantly different from healthy donors in all subtypes with the exception of MY that typically is associated with a better prognosis. Analysis of CYR61 levels in TT3 patients 48h post-Velcade (Vel) revealed an inverse correlation between change in CYR61 levels post-Vel and 80-gene risk in TT3a patients (p < 0.01). Likewise, the change in CYR61 levels from diagnosis to remission is also inversely correlated with risk (p < 0.01). To better understand the mechanism by which loss of CYR61 might negatively affect risk we examined the GEP from MM Bx and CD138-selected plasma cells to compare gene signatures in patients with low CYR61 (Q1) and high CYR61 (Q4). Those genes that exhibited ≥ 2-fold difference were investigated further. Patients with low CYR61 differentially expressed 179 probesets in MMBX including elevated SFRP2 (4.1-fold), a Wnt inhibitor, and COL2A1 (3.5-fold) which are associated with myeloma bone disease and osteoarthritis, respectively. SFRP2 is also elevated (4.3-fold) in MMPCs (194 probesets elevated) along with TNFSF10 (2.1-fold) indicative of the HY subtype and FGFR3 (2.1-fold) which is elevated in the MS subtype. In patients with high CYR61, many muscle-specific genes were elevated in MM BX and may indicate a predominance of osteocytes. Additionally, BGLAP, whose loss is associated with poor survival in myeloma, is elevated (2-fold) in MM BX (171 probesets) with high CYR61 and EDN1, an activator of CYR61/CCN1, is elevated (2.8-fold) in MM PCs (111 probesets) with high CYR61. The test the effect of CYR61 on cell growth, H929 cells were exposed to rCYR61 which caused a dose- and time-dependent suppression of cell growth and survival. To examine the role of CYR61 in the MM ME, H929 cells transduced with empty vector, wild type CYR61 or CYR61 cDNA with a mutated αvβ3 binding site were injected into implanted bones in SCID-hu mice. CYR61-induced effects on bone have been shown to be mediated by the αvβ3 integrin, presumably through osteoblasts. X-rays of the implanted bone and serum measurement of hIg levels were taken weekly for 5 weeks. Quantitation of change in bone mineral density (BMD) over the course of the experiment showed that CYR61 inhibits osteolysis (p<0.04), whereas CYR61 that is incapable of binding αvβ3 attenuates this effect. These data indicate that the αvβ3 integrin mediates CYR61-induced inhibition of osteolysis in MM. Additionally, quantitation of serum hIg demonstrated that CYR61 significantly reduces MM tumor growth (p<0.04) and this is not effected by mutation of the avb3 binding site. Taken together these data suggest that loss of CYR61 in myeloma may be indicative of a dysfunctional ME and thus serve as a biomarker to monitor the MM ME. Finally, therapeutics that upregulate CCN1 will be tested as a novel treatment for myeloma bone disease. Disclosures: Shaughnessy: Myeloma Health, Celgene, Genzyme, Novartis: Consultancy, Employment, Equity Ownership, Honoraria, Patents & Royalties.

Impaired osteoblastogenesis in myeloma bone disease: role of upregulated apoptosis by cytokines and malignant plasma cells

2004 ◽  
Vol 126 (4) ◽  
pp. 475-486 ◽  
Author(s):  
Franco Silvestris ◽  
Paola Cafforio ◽  
Nicola Calvani ◽  
Franco Dammacco
Keyword(s):  
Bone Disease ◽  
Plasma Cells ◽  
Myeloma Bone Disease

OAB-020: The role of checkpoint inhibitor PD-1H/VISTA in Multiple Myeloma bone disease

2021 ◽  
Vol 21 ◽  
pp. S13
Author(s):  
Jing Fu ◽  
Shirong Li ◽  
Huihui Ma ◽  
Jun Yang ◽  
Gabriel Pagnotti ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Disease ◽  
Checkpoint Inhibitor ◽  
Myeloma Bone Disease

Role of the microenvironment in multiple myeloma bone disease

2006 ◽  
Vol 2 (3) ◽  
pp. 371-378 ◽  
Author(s):  
Alissa Huston ◽  
G David Roodman
Keyword(s):  
Multiple Myeloma ◽  
Bone Disease ◽  
Myeloma Bone Disease

scholarly journals Host-derived adiponectin is tumor-suppressive and a novel therapeutic target for multiple myeloma and the associated bone disease

Blood ◽  
2011 ◽  
Vol 118 (22) ◽  
pp. 5872-5882 ◽  
Author(s):  
Jessica A. Fowler ◽  
Seint T. Lwin ◽  
Matthew T. Drake ◽  
James R. Edwards ◽  
Robert A. Kyle ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Disease ◽  
Monoclonal Gammopathy ◽  
Myeloma Cell ◽  
Clinical Analysis ◽  
Therapeutic Benefit ◽  
Tumor Burden ◽  
Myeloma Bone Disease ◽  
Undetermined Significance

Abstract The contributions of the host microenvironment to the pathogenesis of multiple myeloma, including progression from the non-malignant disorder monoclonal gammopathy of undetermined significance, are poorly understood. In the present study, microarray analysis of a murine model requiring a unique host microenvironment for myeloma development identified decreased host-derived adiponectin compared with normal mice. In support, clinical analysis revealed decreased serum adiponectin concentrations in monoclonal gammopathy of undetermined significance patients who subsequently progressed to myeloma. We investigated the role of adiponectin in myeloma pathogenesis and as a treatment approach, using both mice deficient in adiponectin and pharmacologic enhancement of circulating adiponectin. Increased tumor burden and bone disease were observed in myeloma-bearing adiponectin-deficient mice, and adiponectin was found to induce myeloma cell apoptosis. The apolipoprotein peptide mimetic L-4F was used for pharmacologic enhancement of adiponectin. L-4F reduced tumor burden, increased survival of myeloma-bearing mice, and prevented myeloma bone disease. Collectively, our studies have identified a novel mechanism whereby decreased host-derived adiponectin promotes myeloma tumor growth and osteolysis. Furthermore, we have established the potential therapeutic benefit of increasing adiponectin for the treatment of myeloma and the associated bone disease.

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