Advances in Imaging and the Management of Myeloma Bone Disease

Osteolytic disease is a major complication of multiple myeloma that may lead to devastating skeletal-related events (SREs). Conventional radiography remains the gold standard for the evaluation of bone disease in patients with myeloma. However, whole-body magnetic resonance imaging (MRI) is recommended in patients with normal conventional radiography and should be performed as part of staging in all patients with a solitary plasmacytoma of bone. Urgent MRI is also the diagnostic procedure of choice to assess suspected cord compression, whereas computed tomography can guide tissue biopsy. Positron emission tomography with computed tomography can provide complementary information to MRI, but its use in multiple myeloma must be better defined by further studies. The incorporation of abnormal MRI findings into the definition of symptomatic myeloma also needs to be clarified. Bisphosphonates remain the cornerstone for the management of myeloma bone disease. Intravenous pamidronate and zoledronic acid are equally effective in reducing SREs, whereas zoledronic acid seems to offer survival benefits in symptomatic patients. Caution is needed to avoid adverse events, such as renal impairment and osteonecrosis of the jaw. Novel antiresorptive agents, such as denosumab, have given encouraging results, but further studies are needed before their approval for managing myeloma bone disease. Combination approaches with novel antimyeloma agents, such as bortezomib (which has anabolic effects on bone) with bisphosphonates or with drugs that enhance osteoblast function, such as antidickkopf-1 agents, antisclerostin drugs, or sotatercept, may favorably alter our way of managing myeloma bone disease in the near future.

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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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CCR1 Blockade by An Orally-Available CCR1 Antagonist Reduces Tumor Burden and Osteolysis In Vivo In a Mouse Model of Myeloma Bone Disease

Blood ◽

10.1182/blood.v116.21.3000.3000 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3000-3000 ◽

Cited By ~ 2

Author(s):

Babatunde Oyajobi ◽

Daniel Dairaghi ◽

Anjana Gupta ◽

Brandon McCluskey ◽

Yu Wang ◽

...

Keyword(s):

Multiple Myeloma ◽

Zoledronic Acid ◽

Bone Disease ◽

Positive Control ◽

Tumor Burden ◽

Whole Body ◽

Vehicle Group ◽

Myeloma Cells ◽

Myeloma Bone Disease ◽

Ccr1 Antagonist

Abstract Abstract 3000 Myeloma bone disease has been shown to revolve around a complex interplay of multiple myeloma tumor cells and osteoclasts, each supporting the growth and development of the other. This pathogenic interplay is mediated, in part, by CCL3/MIP-1α, expressed by the myeloma cells, and its cognate receptor CCR1, expressed by precursor and mature osteoclasts. In this study, we show that osteoclast precursor cells respond to CCL3 with increased formation of mature osteoclasts, and this is blocked in the presence of a specific CCR1 antagonist, CCX721, that specifically inhibits mouse leukocyte migration. CCX721, an analogue of CCX354, a CCR1 antagonist currently in Phase 2 studies for RA, has high affinity for mouse CCR1 and thus is suitable for evaluation in rodent studies. We show in the immunocompetent murine 5TGM1 model of myeloma bone disease that blockade of CCR1 with CCX721, either prophylactically or therapeutically using an oral dosing regimen that results in plasma concentrations of antagonist that provide 85–95% CCR1 coverage of blood leukocytes at all times, reduces tumor burden and the level of osteolysis. 5TGM1-GFP myeloma cells express minimal levels of CCR1 but secrete high levels of CCL3 constitutively. Syngeneic C57BL/KaLwRij mice bearing 5TGM1-GFP cells were treated with CCX721 (100 mg/kg dosed orally, twice daily), vehicle (100% sesame oil, 2.5 ml/kg) or a positive control, zoledronic acid (0.12 mg/kg, sc injection, dosed twice weekly). In the first study, treatment was initiated one day before 5TGM1-GFP cells were injected into the mice (d0) and the study continued for 28 days. At the conclusion of this treatment regimen, the serum monoclonal paraprotein (IgG2bκ) levels (surrogate marker of tumor burden) were reduced from 19.9 ± 5.9 mg/ml to 1.7 ± 0.2 mg/ml for the mice treated with CCX721 (p<0.0001, Mann Whitney), and the number of TRAP-stained osteoclasts in the femurs of CCX721-treated tumor-bearing mice was concomitantly reduced. The reduction in overall tumor burden was consistent with reduced tumor-associated green fluorescence on whole body live GFP scans. In addition, the attenuation of serum paraprotein levels was comparable to that achieved with the positive control, zoledronic acid (0.8 ± 0.1 mg/ml). In a second study, treatment with the CCR1 antagonist was only initiated 18 days after tumor cell inoculation, when establishment of tumors in the medullary cavities was confirmed by whole animal GFP scans. Administration of CCX721 in this setting for 10 days thereafter also resulted in a significant reduction in serum IgG2bκ levels in the CCX721-treated group compared to the vehicle group (1.9 ± 0.2 mg/ml versus 6.0 ± 0.6 mg/ml, p=0.001, Mann Whitney), an effect that compared favorably to that of zoledronic acid (1.7 ± 0.1 mg/ml) and which was also confirmed by whole body GFP scans. Together, these results provide a strong rationale for further development of CCX721 and/or other CCR1 antagonists for the treatment of multiple myeloma. Disclosures: Dairaghi: ChemoCentryx: Employment. Wang:ChemoCentryx: Employment. Seitz:ChemoCentryx: Employment. Powers:ChemoCentryx: Employment. Miao:ChemoCentryx: Employment. Zhang:ChemoCentryx: Employment. Schall:ChemoCentryx: Employment. Jaen:ChemoCentryx: Employment.

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Positron Emission Tomography (PET) Radiopharmaceuticals in Multiple Myeloma

Molecules ◽

10.3390/molecules25010134 ◽

2019 ◽

Vol 25 (1) ◽

pp. 134 ◽

Cited By ~ 1

Author(s):

Christos Sachpekidis ◽

Hartmut Goldschmidt ◽

Antonia Dimitrakopoulou-Strauss

Keyword(s):

Computed Tomography ◽

Positron Emission Tomography ◽

Multiple Myeloma ◽

Bone Marrow ◽

Bone Disease ◽

Emission Tomography ◽

Whole Body ◽

Positron Emission ◽

Pet Ct ◽

18F Fdg

Multiple myeloma (MM) is a plasma cell disorder, characterized by clonal proliferation of malignant plasma cells in the bone marrow. Bone disease is the most frequent feature and an end-organ defining indicator of MM. In this context, imaging plays a pivotal role in the management of the malignancy. For several decades whole-body X-ray survey (WBXR) has been applied for the diagnosis and staging of bone disease in MM. However, the serious drawbacks of WBXR have led to its gradual replacement from novel imaging modalities, such as computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography/computed tomography (PET/CT). PET/CT, with the tracer 18F-fluorodeoxyglucose (18F-FDG), is now considered a powerful diagnostic tool for the detection of medullary and extramedullary disease at the time of diagnosis, a reliable predictor of survival as well as the most robust modality for treatment response evaluation in MM. On the other hand, 18F-FDG carries its own limitations as a radiopharmaceutical, including a rather poor sensitivity for the detection of diffuse bone marrow infiltration, a relatively low specificity, and the lack of widely applied, established criteria for image interpretation. This has led to the development of several alternative PET tracers, some of which with promising results regarding MM detection. The aim of this review article is to outline the major applications of PET/CT with different radiopharmaceuticals in the clinical practice of MM.

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

Blood ◽

10.1182/blood.v110.11.3518.3518 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3518-3518

Author(s):

Martin Kaiser ◽

Maren Mieth ◽

Peter Liebisch ◽

Susanne Rötzer ◽

Christian Jakob ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Disease ◽

Serum Levels ◽

Conventional Radiography ◽

Bone Lesions ◽

X Rays ◽

Myeloma Bone Disease ◽

Lytic Lesions ◽

Significant Difference ◽

First Time

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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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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Comparison of whole-body 64-slice multidetector computed tomography and conventional radiography in staging of multiple myeloma

European Radiology ◽

10.1007/s00330-007-0738-3 ◽

2007 ◽

Vol 18 (1) ◽

pp. 51-58 ◽

Cited By ~ 76

Author(s):

Patric Kröpil ◽

Roland Fenk ◽

Lars B. Fritz ◽

Dirk Blondin ◽

Guido Kobbe ◽

...

Keyword(s):

Computed Tomography ◽

Multiple Myeloma ◽

Multidetector Computed Tomography ◽

Conventional Radiography ◽

Whole Body

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Comparison of whole-body low-dose computed tomography and conventional radiography in the staging of multiple myeloma

Clinical Lymphoma Myeloma & Leukemia ◽

10.1016/j.clml.2015.07.306 ◽

2015 ◽

Vol 15 ◽

pp. e120 ◽

Cited By ~ 1

Author(s):

H. Plonkova ◽

K. Miklosova ◽

T. Jelinek ◽

L. Zahradova ◽

P. Krupa ◽

...

Keyword(s):

Computed Tomography ◽

Multiple Myeloma ◽

Low Dose ◽

Conventional Radiography ◽

Whole Body ◽

Low Dose Computed Tomography

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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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