A possible way to prevent the progression of bone lesions in multiple myeloma via Src‐homology‐region‐2‐domain‐containing‐phosphatase‐1 activation

Our case demonstrates severe bone disease in primary AL-amyloidosis without concomitant multiple myeloma. A 30-year-old man had spontaneous vertebral fracture Th8. A computed tomography scan suggested multiple foci of lesions in all the bones. In bone marrow and resected rib werent detected any tumor cells. After 15 years from the beginning of the disease, nephrotic syndrome developed. Based on the kidney biopsy, AL-amyloidosis was confirmed. Amyloid was also detected in the bowel and bone marrow. On the indirect signs (thickening of the interventricular septum 16 mm and increased NT-proBNP 2200 pg/ml), a cardial involvement was confirmed. In the bone marrow (from three sites) was found 2.85% clonal plasma cells with immunophenotype СD138+, СD38dim, СD19-, СD117+, СD81-, СD27-, СD56-. FISH method revealed polysomy 5,9,15 in 3% of the nuclei. Serum free light chain Kappa 575 mg/l (/44.9) was detected. Multiple foci of destruction with increased metabolic activity (SUVmax 3.6) were visualized on PET-CT, and an surgical intervention biopsy was performed from two foci. The number of plasma cells from the destruction foci was 2.5%, and massive amyloid deposition was detected. On CT scan foci of lesions differed from bone lesions at multiple myeloma. Bone fragments of point and linear type (button sequestration) were visualized in most of the destruction foci. The content of the lesion was low density. There was no extraossal spread from large zones of destruction. There was also spontaneous scarring of the some lesions (without therapy). Thus, the diagnosis of multiple myeloma was excluded on the basis based on x-ray signs, of the duration of osteodestructive syndrome (15 years), the absence of plasma infiltration in the bone marrow, including from foci of bone destruction by open biopsy. This observation proves the possibility of damage to the skeleton due to amyloid deposition and justifies the need to include AL-amyloidosis in the spectrum of differential diagnosis of diseases that occur with osteodestructive syndrome.

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Diagnostic Value of Whole-Body MRI Short Protocols in Bone Lesion Detection in Multiple Myeloma Patients

Diagnostics ◽

10.3390/diagnostics11061053 ◽

2021 ◽

Vol 11 (6) ◽

pp. 1053

Author(s):

Davide Ippolito ◽

Teresa Giandola ◽

Cesare Maino ◽

Davide Gandola ◽

Maria Ragusi ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow Involvement ◽

Bone Lesion ◽

Diagnostic Value ◽

Lesion Detection ◽

Lower Limbs ◽

Whole Body ◽

Bone Lesions ◽

Whole Body Mri ◽

Mri Protocol

The aim of the study is to evaluate the effectiveness of short whole-body magnetic resonance imaging (WBMRI) protocols for the overall assessment of bone marrow involvement in patients with multiple myeloma (MM), in comparison with standard whole-body MRI protocol. Patients with biopsy-proven MM, who underwent a WBMRI with full-body coverage (from vertex to feet) were retrospectively enrolled. WBMRI images were independently evaluated by two expert radiologists, in terms of infiltration patterns (normal, focal, diffuse, and combined), according to location (the whole skeleton was divided into six anatomic districts: skull, spine, sternum and ribs, upper limbs, pelvis and proximal two-thirds of the femur, remaining parts of lower limbs) and lytic lesions number (<5, 5–20, and >20). The majority of patients showed focal and combined infiltration patterns with bone lesions predominantly distributed in the spine and pelvis. As skull and lower limbs are less frequently involved by focal bone lesions, excluding them from the standard MRI protocol allows to obtain a shorter protocol, maintaining a good diagnostic value.

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Hypoxia-induced CREB cooperates MMSET to modify chromatin and promote DKK1 expression in multiple myeloma

Oncogene ◽

10.1038/s41388-020-01590-8 ◽

2021 ◽

Author(s):

Yinyin Xu ◽

Jing Guo ◽

Jing Liu ◽

Ying Xie ◽

Xin Li ◽

...

Keyword(s):

Multiple Myeloma ◽

Combined Treatment ◽

Hypoxia Inducible Factor ◽

Bone Destruction ◽

Bone Lesions ◽

Myeloma Cells ◽

Downstream Target ◽

Dkk1 Expression

AbstractMyeloma cells produce excessive levels of dickkopf-1 (DKK1), which mediates the inhibition of Wnt signaling in osteoblasts, leading to multiple myeloma (MM) bone disease. Nevertheless, the precise mechanisms underlying DKK1 overexpression in myeloma remain incompletely understood. Herein, we provide evidence that hypoxia promotes DKK1 expression in myeloma cells. Under hypoxic conditions, p38 kinase phosphorylated cAMP-responsive element-binding protein (CREB) and drove its nuclear import to activate DKK1 transcription. In addition, high levels of DKK1 were associated with the presence of focal bone lesions in patients with t(4;14) MM, overexpressing the histone methyltransferase MMSET, which was identified as a downstream target gene of hypoxia-inducible factor (HIF)-1α. Furthermore, we found that CREB could recruit MMSET, leading to the stabilization of HIF-1α protein and the increased dimethylation of histone H3 at lysine 36 on the DKK1 promoter. Knockdown of CREB in myeloma cells alleviated the suppression of osteoblastogenesis by myeloma-secreted DKK1 in vitro. Combined treatment with a CREB inhibitor and the hypoxia-activated prodrug TH-302 (evofosfamide) significantly reduced MM-induced bone destruction in vivo. Taken together, our findings reveal that hypoxia and a cytogenetic abnormality regulate DKK1 expression in myeloma cells, and provide an additional rationale for the development of therapeutic strategies that interrupt DKK1 to cure MM.

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Bone lesions simulating multiple myeloma: Unusual presentation of esophageal cancer

European Journal of Internal Medicine ◽

10.1016/j.ejim.2008.07.010 ◽

2009 ◽

Vol 20 (1) ◽

pp. e14 ◽

Cited By ~ 1

Author(s):

Hortensia Álvarez Díaz ◽

Mar Used Aznar ◽

Francisco Javier Afonso Afonso

Keyword(s):

Multiple Myeloma ◽

Esophageal Cancer ◽

Unusual Presentation ◽

Bone Lesions

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Comparison of the diagnostic performance and impact on management of 18F-FDG PET/CT and whole-body MRI in multiple myeloma

European Journal of Nuclear Medicine and Molecular Imaging ◽

10.1007/s00259-020-05182-2 ◽

2021 ◽

Author(s):

Olwen Westerland ◽

◽

Ashik Amlani ◽

Christian Kelly-Morland ◽

Michal Fraczek ◽

...

Keyword(s):

Multiple Myeloma ◽

Clinical Data ◽

Bone Disease ◽

Fdg Pet ◽

Diagnostic Performance ◽

Whole Body ◽

Bone Lesions ◽

Pet Ct ◽

18F Fdg ◽

Fdg Pet Ct

Abstract Purpose Comparative data on the impact of imaging on management is lacking for multiple myeloma. This study compared the diagnostic performance and impact on management of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) and whole-body magnetic resonance imaging (WBMRI) in treatment-naive myeloma. Methods Forty-six patients undergoing 18F-FDG PET/CT and WBMRI were reviewed by a nuclear medicine physician and radiologist, respectively, for the presence of myeloma bone disease. Blinded clinical and imaging data were reviewed by two haematologists in consensus and management recorded following clinical data ± 18F-FDG PET/CT or WBMRI. Bone disease was defined using International Myeloma Working Group (IMWG) criteria and a clinical reference standard. Per-patient sensitivity for lesion detection was established. McNemar test compared management based on clinical assessment ± 18F-FDG PET/CT or WBMRI. Results Sensitivity for bone lesions was 69.6% (32/46) for 18F-FDG PET/CT (54.3% (25/46) for PET component alone) and 91.3% (42/46) for WBMRI. 27/46 (58.7%) of cases were concordant. In 19/46 patients (41.3%) WBMRI detected more focal bone lesions than 18F-FDG PET/CT. Based on clinical data alone, 32/46 (69.6%) patients would have been treated. Addition of 18F-FDG PET/CT to clinical data increased this to 40/46 (87.0%) patients (p = 0.02); and WBMRI to clinical data to 43/46 (93.5%) patients (p = 0.002). The difference in treatment decisions was not statistically significant between 18F-FDG PET/CT and WBMRI (p = 0.08). Conclusion Compared to 18F-FDG PET/CT, WBMRI had a higher per patient sensitivity for bone disease. However, treatment decisions were not statistically different and either modality would be appropriate in initial staging, depending on local availability and expertise.

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An Unprecedented Case of p190 BCR-ABL Chronic Myeloid Leukemia Diagnosed during Treatment for Multiple Myeloma: A Case Report and Review of the Literature

Case Reports in Hematology ◽

10.1155/2018/7863943 ◽

2018 ◽

Vol 2018 ◽

pp. 1-5

Author(s):

Kosuke Miki ◽

Naoshi Obara ◽

Kenichi Makishima ◽

Tatsuhiro Sakamoto ◽

Manabu Kusakabe ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Plasma Cells ◽

Bone Marrow Examination ◽

Bone Lesions ◽

Dexamethasone Treatment ◽

Lytic Bone Lesions

We report the case of a 76-year-old man who was diagnosed as having chronic myeloid leukemia (CML) with p190 BCR-ABL while receiving treatment for symptomatic multiple myeloma (MM). The diagnosis of MM was based on the presence of serum M-protein, abnormal plasma cells in the bone marrow, and lytic bone lesions. The patient achieved a partial response to lenalidomide and dexamethasone treatment. However, 2 years after the diagnosis of MM, the patient developed leukocytosis with granulocytosis, anemia, and thrombocytopenia. Bone marrow examination revealed Philadelphia chromosomes and chimeric p190 BCR-ABL mRNA. Fluorescence in situ hybridization also revealed BCR-ABL-positive neutrophils in the peripheral blood, which suggested the emergence of CML with p190 BCR-ABL. The codevelopment of MM and CML is very rare, and this is the first report describing p190 BCR-ABL-type CML coexisting with MM. Moreover, we have reviewed the literature regarding the coexistence of these diseases.

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Stability of Spinal Bone Lesions in Patients With Multiple Myeloma After Radiotherapy—A Retrospective Analysis of 130 Cases

Clinical Lymphoma Myeloma & Leukemia ◽

10.1016/j.clml.2017.09.005 ◽

2017 ◽

Vol 17 (12) ◽

pp. e99-e107 ◽

Cited By ~ 1

Author(s):

Kristin Lang ◽

Laila König ◽

Thomas Bruckner ◽

Robert Förster ◽

Tanja Sprave ◽

...

Keyword(s):

Multiple Myeloma ◽

Retrospective Analysis ◽

Bone Lesions

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Molecular cloning of a novel protein-tyrosine phosphatase SH-PTP3 with sequence similarity to the src -homology region 2

FEBS Letters ◽

10.1016/0014-5793(92)81500-l ◽

1992 ◽

Vol 314 (3) ◽

pp. 335-339 ◽

Cited By ~ 56

Author(s):

Masaaki Adachi ◽

Masuo Sekiya ◽

Toshiki Miyachi ◽

Keiki Matsuno ◽

Yuji Hinoda ◽

...

Keyword(s):

Molecular Cloning ◽

Protein Tyrosine Phosphatase ◽

Sequence Similarity ◽

Tyrosine Phosphatase ◽

Protein Tyrosine ◽

Homology Region ◽

Src Homology ◽

Novel Protein

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The Evolution in The Treatment of Multiple Myeloma Towards Targeted Magnetic Molecularly Imprinted Nanomedicines

Edelweiss: Cancer Open Access ◽

10.33805/2689-6737.101 ◽

2015 ◽

pp. 1-2

Author(s):

Edgar Pérez-Herrero

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Bacterial Infections ◽

Plasma Cells ◽

The Body ◽

Western World ◽

Bone Lesions ◽

Non Hodgkin Lymphoma ◽

Clonal Proliferation ◽

Tract Infections

Multiple myeloma is the second more frequently haematological cancer in the western world, after non-Hodgkin lymphoma, being about the 1-2 % of all the cancers cases and the 10-13% of hematologic diseases. The disease is caused by an uncontrolled clonal proliferation of plasma cells in the bone marrow that accumulate in different parts of the body, usually in the bone marrow, around some bones, and rarely in other tissues, forming tumor deposits, called plasmocytomas. This uncontrolled clonal proliferation of plasma cells produces the secretion of an abnormal monoclonal immunoglobulin (paraprotein or M-protein) and prevents the formation of the other antibodies produced by the normal plasma cells that are destroyed. The anormal secretion of paraproteins unbalance the osteoblastosis and osteoclastosis processes, leading to bone lesions that cause lytic bone deposits and the release of calcium from bones (hypercalcemia) that may produce renal failure. Regions affected by bone lesions are the skull, spine, ribs, sternum, pelvis and bones that form part of the shoulders and hips. The substitution of the healthy bone marrow by infiltrating malignant cells and the inhibition of the normal production of red blood cells produce anaemia, thrombocytopenia and leukopenia. Multiple myeloma patients are immunosuppressed because of leukopenia and the abnormal immunoglobulin production caused by the uncontrolled clonal proliferation of plasma cells, being susceptible to bacterial infections, like pneumonias and urinary tract infections. The interaction of immunoglobulin with hemostatic mechanisms may lead to haemorrhagic diathesis or thrombosis. Also, disorders of the central and peripheral nervous system are part of the disease, being the more common neurological manifestations the spinal cord compressions and the peripheral neuropathies.

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Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma

Blood ◽

10.1182/blood-2008-11-191577 ◽

2009 ◽

Vol 114 (2) ◽

pp. 371-379 ◽

Cited By ~ 264

Author(s):

Mariateresa Fulciniti ◽

Pierfrancesco Tassone ◽

Teru Hideshima ◽

Sonia Vallet ◽

Puru Nanjappa ◽

...

Keyword(s):

Multiple Myeloma ◽

Cell Growth ◽

Murine Model ◽

Severe Combined Immunodeficiency ◽

Neutralizing Antibody ◽

Nuclear Factor Κb ◽

Bone Lesions ◽

Wnt Inhibitor

Abstract Decreased activity of osteoblasts (OBs) contributes to osteolytic lesions in multiple myeloma (MM). The production of the soluble Wnt inhibitor Dickkopf-1 (DKK1) by MM cells inhibits OB activity, and its serum level correlates with focal bone lesions in MM. Therefore, we have evaluated bone anabolic effects of a DKK1 neutralizing antibody (BHQ880) in MM. In vitro BHQ880 increased OB differentiation, neutralized the negative effect of MM cells on osteoblastogenesis, and reduced IL-6 secretion. In a severe combined immunodeficiency (SCID)–hu murine model of human MM, BHQ880 treatment led to a significant increase in OB number, serum human osteocalcin level, and trabecular bone. Although BHQ880 had no direct effect on MM cell growth, it significantly inhibited growth of MM cells in the presence of bone marrow stromal cells (BMSCs) in vitro. This effect was associated with inhibition of BMSC/MM cell adhesion and production of IL-6. In addition, BHQ880 up-regulated β-catenin level while down-regulating nuclear factor-κB (NF-κB) activity in BMSC. Interestingly, we also observed in vivo inhibition of MM cell growth by BHQ880 treatment in the SCID-hu murine model. These results confirm DKK1 as an important therapeutic target in myeloma and provide the rationale for clinical evaluation of BHQ880 to improve bone disease and to inhibit MM growth.

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