Serum Concentrations of DKK-1 Correlate with the Extent of Bone Disease in Multiple Myeloma.

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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What Is Important Factor of Bone Disease in Multiple Myeloma?.

Blood ◽

10.1182/blood.v104.11.4855.4855 ◽

2004 ◽

Vol 104 (11) ◽

pp. 4855-4855

Author(s):

Shoso Munemasa ◽

Akira Sakai ◽

Yoshiko Okikawa ◽

Yoshiaki Kuroda ◽

Yuta Katayama ◽

...

Keyword(s):

Multiple Myeloma ◽

Cyclin D1 ◽

Bone Disease ◽

Tissue Growth ◽

Good Survival ◽

Bone Lesions ◽

Rt Pcr ◽

Myeloma Cells ◽

Significant Difference ◽

Chromosome 13Q

Abstract New International Prognostic Index (IPI) staging system of multiple myeloma (MM) is a combination of the level of serum β2-microglobulin and serum albumin. Particularly, good survival (median survival >5 years) is associated with absence of chromosome 13q deletion. Recently, correlations between molecular subtypes and prognosis have been identified as a good prognosis with t(11;14) and a poor prognosis with t(4;14) and t(14;16) besides chromosome 13 abnormalities. We have reported that some MM cases with cyclin D1 overexpression detected by competitive RT-PCR were not caused by t(11;14)(q13;q32) or extra copies of 11q13 (In J Oncol, in press). A recent report revealed that subtypes of MM cases with the translocation of cyclin D showed a close correlation with bone disease and high level of DKK1. We also have been studing about the correlation between bone disease and bone morphogenetic protein (BMP) 2, or connective tissue growth factor (CTGF) that is supposed to inhibit the VEGF binding to its receptor or modulate cell signaling by BMP. First, we analyzed IPI staging in 91 MM cases, and then analyzed the relation between IPI staging and existence of cyclin D1 overexpression, or t(11;14)(q13;q32) and extra copies of 11q13. Competitive RT-PCR was performed in 77 cases, and cyclin D1 overexpression was detected in 40/77 (52%). Deletion of chromosome 13q was detected in 32/87 (37%), and t(11;14)(q13;q32) or extra copies of 11q13 was detected in 11/50 (22%) and 7/50 (14%), respectively. There were no significant differences of those factors among IPI staging. And we analyzed the scale of bone lesion by bone x-ray in 81 cases. We could not detect the relation between bone disease and cyclin D1 overexpression or translocation of 11q13. Furthermore, we analyzed the expression of BMP2 and CTGF by quantitative real time-PCR in purified myeloma cells or in bone marrow mononuclear cells (BMMNC) reduced myeloma cells less than 5%. We have gotten results that MM cases have a tendency to show higher CTGF expression in BMMNC compared with that of normal BM, but there was no significant difference of BMP2 expression in BMMNC between them. And there was no correlation between cyclin D1 overexpression and BMP2 or CTGF expression. So far a cause of bone lesions in MM is supposed to be the activity of osteoclast, however, our preliminary examination by TRAP staining revealed that osteoclast differentiation from BMMNC in MM cases by adding M-CSF (25 ng/ml) and RANKL (50 ng/ml) decreased compared with that in normal BM, and osteoblast diffentiation also decreased in MM by cytochemical staining for alkaline phosphatase (AP). We guess that both osteoclast and osteobalst differentiation are suppressed in MM and CTGF is a candidate for the suppressor of osteoblast differentiation. We will be able to show the result of AP activity of osteoblast and the effect of recombinant CTGF on osteoblast in meeting.

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Serum Levels of OPG and MIP-1α in Untreated Multiple Myeloma Patients. Correlations with Staging, Survival and Bone Disease.

Blood ◽

10.1182/blood.v106.11.5074.5074 ◽

2005 ◽

Vol 106 (11) ◽

pp. 5074-5074

Author(s):

Argyro Papadogiannis ◽

Marie-Cristine Kyrtsonis ◽

Theodoros P. Vassilakopoulos ◽

Tatiana Tzenou ◽

Antonios G. Antoniadis ◽

...

Keyword(s):

Bone Disease ◽

Staging System ◽

Serum Levels ◽

High Serum ◽

Stage I ◽

Stage Ii ◽

Stage Iii ◽

Bone Lesions ◽

Disease Biology ◽

Significant Difference

Abstract Cytokines, such as MIP-1a (macrophage inhibiting factor) and OPG (osteoprotegerin) are assumed to play a role in MM disease biology and bone disease, by mechanisms that are still under investigation. MIP-1a is constitutively secreted by myeloma cells, plays a possible role in the development of MM bone lesions, enhance MM cell adhesion to stromal cells and its serum levels have been recently related to survival in MM. OPG is a soluble decoy receptor which acts as a soluble receptor antagonist that prevents osteoclasts activation and the development of bone disease. Reported findings on serum OPG levels in MM patients are controversial as well as its possible role in the biology of the disease. In order to investigate the possible relationship of MIP-1a and OPG levels in MM patients with prognosis and bone disease, we determined by ELISA serum MIP-1a and OPG levels in 20 MGUS, 82 MM patients and 27 healthy individuals (HI). Both cytokines were determined by ELISA (R&D, Quantikine, USA) in frozen sera collected at dignosis, before treatment. The median age of MM patients was 69 years (44–84) and 50% were males. MM patients’ stage was as follows: 23 stage I, 28 stage II, 31 stage III according to Durie-Salmon staging system and 27 stage I, 17 stage II, 35 stage III according to the International Scoring System (ISS). In HI median MIP-1a was 28 pg/ml (15–54) and median OPG 1600 pg/ml (450–4600). In subjects with MGUS, median MIP-1a was 34 pg/ml (17–58) and median OPG 2300 pg/ml (820–6200). In MM patients, median pretreatment serum MIP-1a was 32 pg/ml (16–100) and OPG 3000 pg/ml (820–25000). No statistical significant difference was observed between HI, MGUS and MM patients with regard to MIP-1a levels but for OPG levels differences between HI and MM patients and between MGUS and MM patients were both significant (0.01 and 0.05 respectively). No relationship was found between MIP-1a or OPG levels and bone disease. However, there was a trend for longer survival in patients with MIP-1a or OPG levels lower than median (5-year overall survival 60 ± 12 vs 38 ± 14, p=0.08 and 66 ± 13 vs 29 ± 13, p=0.07 respectively). In addition MIP-1a levels were correlated with ISS stage: MIP-1a levels were 28.3±11.3 in ISS stage 1, 29.8±11.1 in ISS stage 2, 39±19.2 in ISS stage 3 (p=0.02). In conclusion, in our experience serum OPG levels are higher in MM patients than in MGUS or HI, MIP-1a levels are correlated with the ISS stage and both high serum MIP-1a and OPG levels at diagnosis are related with a shorter survival.

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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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Bones in Multiple Myeloma: Imaging and Therapy

American Society of Clinical Oncology Educational Book ◽

10.1200/edbk_205583 ◽

2018 ◽

pp. 638-646 ◽

Cited By ~ 12

Author(s):

Elena Zamagni ◽

Michele Cavo ◽

Bita Fakhri ◽

Ravi Vij ◽

David Roodman

Keyword(s):

Multiple Myeloma ◽

Bone Disease ◽

Standard Of Care ◽

Conventional Radiography ◽

Imaging Modalities ◽

Whole Body ◽

Clinical Feature ◽

Bone Lesions ◽

Low Sensitivity ◽

Fdg Pet Ct

Bone disease is the most frequent disease-defining clinical feature of multiple myeloma (MM), with 90% of patients developing bone lesions over the course of their disease. For this reason, imaging plays a major role in the management of disease in patients with MM. Although conventional radiography has traditionally been the standard of care, its low sensitivity in detecting osteolytic lesions has called for more advanced imaging modalities. In this review, we discuss the advantages, indications, and applications of whole-body low-dose CT (WBLDCT), 18F-fluorodeoxyglucose (FDG)-PET/CT, MRI, and other novel imaging modalities in the management of disease in patients with plasma cell dyscrasias. We also review the state of the art in treatment of MM bone disease (MMBD) and the role of bisphosphonates and denosumab, a monoclonal antibody that binds and blocks the activity of receptor activator of nuclear factor-kappa B ligand (RANKL), which was recently approved by the U.S. Food and Drug Administration for MMBD.

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Treatment of Bortezomib Increases Osteoblast Function in Patients with Multiple Myeloma.

Blood ◽

10.1182/blood.v106.11.3457.3457 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3457-3457 ◽

Cited By ~ 1

Author(s):

Ulrike Heider ◽

Martin Kaiser ◽

Christian Müller ◽

Carsten-Oliver Schulz ◽

Christian Jakob ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Disease ◽

Clinical Evidence ◽

Proteasome Inhibitors ◽

Proteasome Inhibition ◽

Serum Levels ◽

Myeloma Bone Disease ◽

Osteoblast Function ◽

Osteoblast Activity ◽

Osteoblast Markers

Abstract Myeloma bone disease is caused by an enhanced osteoclast activation and impaired osteoblast function. Until now, there is no specific treatment to restore osteoblast activity, and anti-myeloma therapies that lead to a disease remission are usually not associated with an increase of osteoblast markers. Recently, preclinical data suggested that proteasome inhibitors may enhance osteoblast function. Bortezomib (Velcade) represents the first substance from this group which is clinically used in relapsed multiple myeloma. To evaluate whether there is clinical evidence for an osteoblast stimulation under bortezomib treatment, we analyzed serum levels of two specific osteoblast markers, i.e. bone-specific alkaline phosphatase (BAP) and osteocalcin, in 25 multiple myeloma patients treated with bortezomib alone or in combination with dexamethasone. 56 percent of patients achieved a complete or partial remission. In the whole group of patients, mean serum levels of osteocalcin significantly increased from 6.3 μg/l before treatment to 10.8 μg/l after three months of therapy (P=0.024). In parallel, mean levels of BAP increased from 19.7 U/l to 30.2 U/l (P<0.0005). The increase in BAP was irrespective of the combination with dexamethasone and was noted both in responders and in non-responders. This is of special interest, since it implicates that the increase in osteoblast function may be a direct effect of bortezomib on osteoblasts and not an indirect consequence of the reduced myeloma burden. Proteasome inhibition may modulate the Wnt/b-catenin pathway, a major signalling pathway in osteoblasts. Myeloma patients with osteolytic lesions have been shown to overexpress DKK-1, an inhibitor of the Wnt/b-catenin pathway. Recent experiments on mesenchymal cells showed that proteasome inhibitors decreased the DKK-1 production. Moreover, proteasome inhibition elevates cytoplasmatic b-catenin levels by inhibition of its degradation. In addition, animal models gave evidence that proteasome inhibitors stimulate the bone morphogenetic protein (BMP)-2 mediated osteoblast differentiation. Taken together, these preclinical observations suggest that proteasome inhibition may enhance osteoblast activity. Our study gives clinical evidence for a significant improvement of osteoblast function under bortezomib. This is of special interest, since it demonstrates additional effects of proteasome inhibitors and may provide a novel treatment approach in myeloma bone disease.

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African-American Multiple Myeloma Patients Exhibit Less Bone Disease Compared to Other Racial/Ethnic Groups

Blood ◽

10.1182/blood.v116.21.4994.4994 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4994-4994

Author(s):

Eric W. Dean ◽

Elad Ziv

Keyword(s):

Multiple Myeloma ◽

African American ◽

African Americans ◽

Ethnic Groups ◽

Bone Disease ◽

Conflicts Of Interest ◽

Compression Fractures ◽

Lytic Lesions ◽

Significant Difference ◽

Racial Ethnic

Abstract Abstract 4994 Background: Bone destruction remains one of the major complications in Multiple Myeloma (MM) leading to morbidity and mortality. African-Americans have a higher incidence of MM but exhibit longer survivals compared to Caucasians. We analyzed bone involvement in a cohort of patients with MM to determine if non African American (non AA) vs. African American (AA) race predicts the presence and severity of bone disease at presentation. Methods: Clinical data was gathered on 197 (176 non AA and 21 AA) MM patients at the University of California, San Francisco. Each patient had a skeletal survey at diagnosis and identified as having 0 lytic lesions, 1–2 lytic lesions or 3 or more lytic lesions. The presence of compression fractures was also documented for each patient as was age and sex. Results: The presence of compression fractures strongly correlated with the number of lytic lesions in both the non AA and AA groups, with no compression fractures observed in the patients with zero lytic lesions (p<0.001). Among the AA group, there were fewer (6 of 15) patients with compression fractures compared with patients from the non AA group (92 of 161) (p=0.02). There was also a trend towards fewer lytic lesions among the AA group (p=0.053). No significant difference was observed between the extent of bone disease and age or sex between the two groups. Conclusions: Within this cohort of patients, there is a significantly lower rate of compression fractures among African-Americans. These data supports the idea that African-American patients present with less bone disease which confers a survival advantage compared to other racial/ethnic groups. Disclosures: No relevant conflicts of interest to declare.

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Animal Models of Multiple Myeloma Bone Disease

Frontiers in Genetics ◽

10.3389/fgene.2021.640954 ◽

2021 ◽

Vol 12 ◽

Author(s):

Syed Hassan Mehdi ◽

Sana Nafees ◽

Syed Jafar Mehdi ◽

Carol A. Morris ◽

Ladan Mashouri ◽

...

Keyword(s):

Multiple Myeloma ◽

Animal Models ◽

Bone Disease ◽

Plasma Cells ◽

Compression Fracture ◽

Bone Lesions ◽

Significant Treatment ◽

Myeloma Bone Disease ◽

Incurable Disease ◽

Cumulative Evidence

Multiple myeloma (MM) is a clonal B-cell disorder characterized by the proliferation of malignant plasma cells (PCs) in the bone marrow, the presence of monoclonal serum immunoglobulin, and osteolytic lesions. It is the second most common hematological malignancy and considered an incurable disease despite significant treatment improvements. MM bone disease (MMBD) is defined as the presence of one or more osteolytic bone lesions or diffused osteoporosis with compression fracture attributable to the underlying clonal PC disorder. MMBD causes severe morbidity and increases mortality. Cumulative evidence shows that the interaction of MM cells and bone microenvironment plays a significant role in MM progression, suggesting that these interactions may be good targets for therapy. MM animal models have been developed and studied in various aspects of MM tumorigenesis. In particular, MMBD has been studied in various models, and each model has unique features. As the general features of MM animal models have been reviewed elsewhere, the current review will focus on the features of MMBD animal models.

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Serum High Expression of Micorna-214 Is a Novel Predictor for Myeloma Bone Disease and Poor Prognosis

Blood ◽

10.1182/blood.v126.23.4186.4186 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4186-4186

Author(s):

Mu Hao ◽

Meirong Zang ◽

Yan Xu ◽

Yu Qin ◽

Lei Zhao ◽

...

Keyword(s):

Bone Disease ◽

Operating Characteristic ◽

Area Under The Curve ◽

Serum Levels ◽

Bone Lesions ◽

Myeloma Bone Disease ◽

Serum Mirna ◽

Normal Bone ◽

Healthy Donors ◽

Lytic Bone Lesions

Abstract Background: Multiple myeloma (MM) originates from clonal expansion of malignant plasma cells in bone marrow, leading to multiple destructive lytic bone lesions that occur in more than 80% of MM patients. MicroRNAs (miRNAs), such as miR-214, miR-34a and Mir-135 are reported to be involved in maintaining normal bone formation and development of metastatic bone lesions in cancers. Recent studies have demonstrated that miRNAs are stably expressed in human plasma and serum samples. And serum miRNAs have been used as biomarkers in diagnosis and prognosis of multiple cancers, including MM. However, the functional roles of miRNA in myeloma bone disease have not been elucidated yet. Materials and methods: In the present study, the serum miRNA expression was assessed from 152 samples including 108 MM samples and 44 healthy donors (HD) of serum. Microarray-based assay and real-time PCR was used to determine differentially expressed miRNAs. The correlation of miRNA expression and bone disease detected by whole body X-ray scanning was evaluated by the receiver operating characteristic (ROC) curve and the area under the curve (AUC). Survival analysis was performed using the Kaplan-Meier method with a log-rank test and the generalized Wilcoxon procedure. Results: We performed serum miRNA profiles from 7 newly diagnosed MMs and 5 normal donors using a microarray-based assay. Our results identified that twenty-seven miRNAs which were reported to be involved in maintaining normal bone formation and development of bone lesions were significantly dysregulated, 4 miRNAs were significantly up-regulated and 23 miRNAs were significantly down-regulated in patient serum. We further performed real-time PCR to verify the expression of miR-214, miR-135, miR-132 and miR-92a in a large cohort of 108 MM patients and 44 healthy donors. We found that miR-214 (0.43±0.17 vs. 2.3±0.14, p<0.0001) and miR-135 (-0.13±0.08 vs. 1.84±0.13, p=0.0022) levels were significantly increased, while serum levels of miR-92a (-0.19±0.20 vs. -1.03±0.11, p=0.0023) were significantly decreased in MM patients. However, we did not found that miR-132 was obviously altered between normal and patient serum. Furthermore, serum levels of miR-214 and miR-135 were notably increased in the patients with lytic bone lesions compared to those without bone disease (both p<0.0001), and a positive correlation was observed between the expression levels of miR-214 (r=0.455, p<0.0001) and miR-135 (r=0.404, p<0.001) with grades of lytic bone lesions. Receiver operating characteristic (ROC) analysis revealed that serum levels of miR-214 and miR-135 can be used to distinguish bone disease in myeloma patients with area under the curve (AUC) > 0.7. Moreover, patients had a significantly shortened OS with high levels of circulating miR-214 (50.0 months vs. NR (not reached); p=0.039) or miR-135 (34.0 months vs.NR; p=0.041) versus those patients with down-regulated levels of miR-214 and miR-135. Patients with higher serum levels of miR-214 were responsible to bisphosphonates with extended OS (NR comparing to 26.0 months, p=0.029), suggesting that bisphosphonates is suitable to treat patients with high expression of circulating miR-214. Conclusion: Our findings reveal that the circulating miR-214 level is a biomarker for prediction of bone disease and prognosis in multiple myeloma. The detail mechanism how miR-214 involves in disease progression will be further explored. The result of this study also set the foundation for searching more circulating miRNA as biomarkers for metastatic bone lesions. Disclosures No relevant conflicts of interest to declare.

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The glycosphingolipid inhibitor eliglustat inhibits autophagy in osteoclasts to increase bone mass and reduce myeloma bone disease

10.1101/2021.02.05.429906 ◽

2021 ◽

Author(s):

Houfu Leng ◽

Hanlin Zhang ◽

Linsen Li ◽

Shuhao Zhang ◽

Yanping Wang ◽

...

Keyword(s):

Multiple Myeloma ◽

Zoledronic Acid ◽

Bone Disease ◽

Drug Dose ◽

Bone Lesions ◽

Myeloma Bone Disease ◽

Plasma Membrane Fluidity ◽

Autophagic Degradation ◽

High Doses

AbstractMultiple myeloma (MM) is a fatal hematological malignancy, where the majority of patients are diagnosed with, or develop, destructive and debilitating osteolytic bone lesions. Current treatments for MM bone disease such as the bisphosphonate zoledronic acid can result in deleterious side effects at high doses. In this study, eliglustat, an FDA approved glycosphingolipid inhibitor, was shown to reduce MM bone disease in preclinical models of MM. Mechanistically, eliglustat alters the lipid composition and plasma membrane fluidity and acts as an autophagy flux inhibitor in bone-resorbing osteoclasts (OC). Autophagic degradation of the signaling molecule TRAF3 is key step in OC differentiation; this was prevented by eliglustat in OC precursors. In addition, eliglustat works depend on TRAF3 in vivo. Furthermore, the combination of eliglustat and zoledronic acid was found to have an additive effect to reduce MM bone disease, suggesting the potential for combination therapies that would allow for drug dose reductions. Taken together, this project identifies a novel mechanism in which glycosphingolipid inhibition reduces osteoclastogenesis via autophagy and highlights the translational potential of eliglustat for the treatment of bone loss disorders such as MM.One Sentence SummaryTranslational use of eliglustat as an autophagy inhibitor to limit bone lesions in multiple myeloma.

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