Bone Disease in Multiple Myeloma: Pathophysiology and Management

Myeloma bone disease (MBD) is a devastating complication of multiple myeloma (MM). More than 80% of MM patients suffer from destructive bony lesions, leading to pain, fractures, mobility issues, and neurological deficits. MBD is not only a main cause of disability and morbidity in MM patients but also increases the cost of management. Bone destruction and lack of bone formation are main factors in the development of MBD. Some novel factors are found to be involved in the pathogenesis of MBD, eg, receptor activator of nuclear factor kappa-B ligand (RANKL), osteoprotegerin (OPG) system (RANKL/OPG), Wingless (Wnt), dickkopf-1 (Wnt/DKK1) pathway. The addition of novel agents in the treatment of MM, use of bisphosphonates and other supportive modalities such as radiotherapy, vertebroplasty/kyphoplasty, and surgical interventions, all have significant roles in the treatment of MBD. This review provides an overview on the pathophysiology and management of MBD.

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Deciphering spatial genomic heterogeneity at a single cell resolution in multiple myeloma

10.21203/rs.3.rs-146899/v1 ◽

2021 ◽

Author(s):

Maximilian Merz ◽

Almuth Merz ◽

Jie Wang ◽

Lei Wei ◽

Qiang Hu ◽

...

Keyword(s):

Multiple Myeloma ◽

Single Cell ◽

Bone Disease ◽

Plasma Cells ◽

Bone Destruction ◽

Integrated Analysis ◽

Myeloma Bone Disease ◽

Additional Layer ◽

Whole Exome ◽

Transcriptional Changes

Abstract Osteolytic lesions (OL) characterize symptomatic multiple myeloma. The mechanisms of how malignant plasma cells (PC) cause OL in one region while others show no signs of bone destruction despite subtotal infiltration remain unknown. We report the first single-cell RNA sequencing (scRNA-seq) study of PC obtained prospectively from random bone marrow aspirates (BM) and paired imaging-guided biopsies of OL. We analyzed 148,630 PC from 24 different locations in 10 patients and observed vast inter- and intra-patient heterogeneity based on scRNA-seq analyses. Beyond the limited evidence for spatial heterogeneity from whole-exome sequencing, we found an additional layer of complexity by integrated analysis of anchored scRNA-seq datasets from the BM and OL. PC from OL were characterized by differentially expressed genes compared to PC from BM, including upregulation of genes associated with myeloma bone disease like DKK1, HGF and TIMP-1 as well as recurrent downregulation of JUN/FOS, DUSP1 and HBB. Assessment of PC from longitudinally collected samples revealed transcriptional changes after induction therapy. Our study, based on the largest number of PC analyzed by scRNA-seq, contributes to the understanding of destructive myeloma bone disease.

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Development of an in vivo model of human multiple myeloma bone disease

Blood ◽

10.1182/blood.v87.4.1495.bloodjournal8741495 ◽

1996 ◽

Vol 87 (4) ◽

pp. 1495-1501 ◽

Cited By ~ 76

Author(s):

M Alsina ◽

B Boyce ◽

RD Devlin ◽

JL Anderson ◽

F Craig ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Bone Resorption ◽

Bone Disease ◽

Bone Destruction ◽

Long Bone ◽

X Rays ◽

Myeloma Bone Disease ◽

Human Multiple Myeloma

Osteolytic bone destruction and its complications, bone pain, pathologic fractures, and hypercalcemia, are a major source of morbidity and mortality in patients with multiple myeloma. The bone destruction in multiple myeloma is due to increased osteoclast (OCL) activity and decreased bone formation in areas of bone adjacent to myeloma cells. The mechanisms underlying osteolysis in multiple myeloma in vivo are unclear. We used a human plasma cell leukemia cell line, ARH-77, that has disseminated growth in mice with severe combined immunodeficiency (SCID) and expresses IgG kappa, as a model for human multiple myeloma, SCID mice were irradiated with 400 rads and mice were injected either with 10(6) ARH-77 cells intravenously (ARH-77 mice) or vehicle 24 hours after irradiation. Development of bone disease was assessed by blood ionized calcium levels, x-rays, and histology. All ARH-77, but none of control mice that survived irradiation, developed hind limb paralysis 28 to 35 days after injection and developed hypercalcemia (1.35 to 1.46 mmol/L) a mean of 5 days after becoming paraplegic. Lytic bone lesions were detected using x-rays in all the hypercalcemic mice examined. No lytic lesions or hypercalcemia developed in the controls. Controls or ARH-77 mice, after developing hypercalcemia, were then killed and bone marrow plasma from the long bones were obtained, concentrated, and assayed for bone-resorbing activity. Bone marrow plasma from ARH-77 mice induced significant bone resorption in the fetal rat long bone resorption assay when compared with controls (percentage of total 45Ca released = 35% +/- 4% v 11% +/- 1%). Histologic examination of tissues from the ARH-77 mice showed infiltration of myeloma cells in the liver and spleen and marked infiltration in vertebrae and long bones, with loss of bony trabeculae and increased OCL numbers. Interestingly, cultures of ARH-77 mouse bone marrow for early OCL precursors (colony-forming unit-granulocyte- macrophage [CFU-GM]) showed a threefold increase in CFU-GM from ARH-77 marrow versus controls (185 +/- 32 v 40 +/- 3 per 2 x 10(5) cell plated). Bone-resorbing human and murine cytokines such as interleukin- 6 (IL-6), IL-1 alpha or beta, TGF-alpha, lymphotoxin, and TNF alpha were not significantly increased in ARH-77 mouse sera or marrow plasma, compared with control mice, although ARH-77 cells produce IL-6 and lymphotoxin in vitro. Conditioned media from ARH-77 cells induced significant bone resorption in the fetal rat long bone resorption assay when compared with untreated media (percentage of total 45Ca released = 22% +/- 2% v 11% +/- 1%). This effect was not blocked by anti-IL-6 or antilymphotoxin (percentage of total 45Ca released = 19% +/- 1% and 22% +/- 1%, respectively). Thus, we have developed a model of human multiple myeloma bone disease that should be very useful to dissect the pathogenesis of the bone destruction in multiple myeloma.

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A novel role of IL-17–producing lymphocytes in mediating lytic bone disease in multiple myeloma

Blood ◽

10.1182/blood-2010-05-283895 ◽

2010 ◽

Vol 116 (18) ◽

pp. 3554-3563 ◽

Cited By ~ 132

Author(s):

Kimberly Noonan ◽

Luigi Marchionni ◽

Judy Anderson ◽

Drew Pardoll ◽

G. David Roodman ◽

...

Keyword(s):

Multiple Myeloma ◽

T Cells ◽

Bone Disease ◽

Critical Role ◽

Bone Destruction ◽

Bone Lesions ◽

Interleukin 17 ◽

Myeloma Bone Disease ◽

Infiltrating Lymphocytes

Abstract Osteoclast (OC)–mediated lytic bone disease remains a cause of major morbidity in multiple myeloma. Here we demonstrate the critical role of interleukin-17–producing marrow infiltrating lymphocytes (MILs) in OC activation and development of bone lesions in myeloma patients. Unlike MILs from normal bone marrow, myeloma MILs possess few regulatory T cells (Tregs) and demonstrate an interleukin-17 phenotype that enhances OC activation. In univariate analyses of factors mediating bone destruction, levels of cytokines that selectively induce and maintain the Th17 phenotype tightly correlated with the extent of bone disease in myeloma. In contrast, MILs activated under conditions that skew toward a Th1 phenotype significantly reduced formation of mature OC. These findings demonstrate that interleukin-17 T cells are critical to the genesis of myeloma bone disease and that immunologic manipulations shifting MILs from a Th17 to a Th1 phenotype may profoundly diminish lytic bone lesions in multiple myeloma.

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Brain-Derived Neurotrophic Factor Enhances Osteoclastogenesis in Multiple Myeloma via Upregulation of RANKL/OPG Ratio Both in Vitro and in a Murine Model of Myeloma Bone Disease

Blood ◽

10.1182/blood.v120.21.568.568 ◽

2012 ◽

Vol 120 (21) ◽

pp. 568-568

Author(s):

Li-Sha Ai ◽

Chun-Yan Sun ◽

Tao Guo ◽

Ya-Dan Wang ◽

Lu Zhang ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Bone Disease ◽

Neurotrophic Factor ◽

Bone Destruction ◽

Osteoclast Formation ◽

Myeloma Bone Disease ◽

Trap Staining

Abstract Abstract 568 Osteolytic bone disease is a prominent feature of multiple myeloma (MM), resulting from aberrant osteoclastic bone resorption uncoupled with osteoblastic bone formation. Myeloma-induced osteoclastogenesis is largely depending on the increase of receptor activator of NF-κB ligand (RANKL) and decrease of osteoprotegerin (OPG) within the bone marrow milieu. Recently, brain-derived neurotrophic factor (BDNF) was identified as an MM-derived factor correlated with increased RANKL level and contributed to myeloma bone destruction. On the other hand, tyrosine receptor kinase B (TrkB), the receptor of BDNF, was found to be abundantly expressed by osteoblasts (OBs). Since OBs are the main source of RANKL and OPG in bone, here we sought to evaluate the involvement of BDNF/TrkB in the crosstalk between myeloma cells and OBs, as well as the effects of BDNF on RANKL/OPG ratio and myeloma bone disease. Co-cultures of OBs with pre-osteoclasts were performed in a non-contacted transwell system and treated with various concentration of BDNF. Osteoclast formation was detected with a tartrate-resistant acid phosphatase (TRAP) staining kit. Then, RANKL and OPG levels were measured when OBs cultures were exposed to BDNF or co-cultured with three human myeloma cell lines (RPMI8226, ARH-77 and U266). K252a (an inhibitor of TrkB) was present or absent in these systems to assess the effects of BDNF on RANKL/OPG expression in OBs. The involvement of downstream signaling molecules activated by BDNF in OBs was also investigated in this study, with the use of U0126 and a specific small interfering RNA (siRNA) for TrkB. For in vivo study, ARH-77 cells were stably transfected with an antisense short-hairpin RNA construct to BDNF (AS-ARH) or empty vector (EV-ARH). These cells were then intravenously injected to severe combined immunodeficiency (SCID) mice, to test their capacity to induce MM bone disease. Radiographs of mice tibiae and vertebrae were taken weekly by X ray. Changes in total body bone mineral density (BMD) of mice skeleton were recorded. At the end of the experiment, bone sections were stained with hematoxylin and eosin staining or TRAP staining. Secretion levels of RANKL and OPG in mice bone marrow were measured by ELISA. We showed that BDNF increased RANKL and decreased OPG production in OBs in a time- and dose-dependent manner, thus contributing to osteoclast formation in vitro. In addition, these effects were completely abolished by K252a and TrkB-siRNA (P < 0.05). BDNF regulates RANKL/OPG expression in OBs through the TrkB/ERK signaling pathway. Our in vivo results indicated that mice injected with AS-ARH cells, which expressed low levels of endogenous BDNF, were preserved and exhibited no radiologically identifiable osteolytic lesions. In addition, mice in AS-ARH group also had a lower incidence of vertebral compression deformities and paralysis in comparison with mice in EV-ARH group (P < 0.05). Further more, bones harboring AS-ARH cells showed marked reduction of RANKL/OPG ratio and osteoclast density when compared to the controls harboring EV-ARH cells (P < 0.05). Our results demonstrate that BDNF is an important contributor to osteoclastogenesis in MM. Antisense inhibition of BDNF in MM cells remarkably inhibited osteolytic bone destruction in SCID-ARH mice model. BDNF-induced bone destruction is partially mediated by MM-OB interactions via upregulation of RANKL/OPG ratio in the bone marrow milieu. These findings suggest targeting BDNF may become a new therapeutic strategy to improve patient outcome in MM. Disclosures: No relevant conflicts of interest to declare.

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Involvement of LIGHT in multiple myeloma bone disease

Bone Abstracts ◽

10.1530/boneabs.3.pp152 ◽

2014 ◽

Author(s):

Angela Oranger ◽

Giacomina Brunetti ◽

Giorgio Mori ◽

Claudia Carbone ◽

Isabella Gigante ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Disease ◽

Myeloma Bone Disease

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

Bone Abstracts ◽

10.1530/boneabs.5.cabs.oc3.4 ◽

2016 ◽

Author(s):

Michelle McDonald ◽

Michaela Reagan ◽

Rachael Terry ◽

Jessica Pettitt ◽

Lawrence Le ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Disease ◽

Tumour Burden ◽

Myeloma Bone Disease

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Bone disease as the first manifestation of systemic AL-amyloidosis

Terapevticheskii arkhiv ◽

10.26442/00403660.2020.07.000775 ◽

2020 ◽

Vol 92 (7) ◽

pp. 85-89

Author(s):

L. P. Mendeleeva ◽

I. G. Rekhtina ◽

A. M. Kovrigina ◽

I. E. Kostina ◽

V. A. Khyshova ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Bone Disease ◽

Plasma Cells ◽

Interventricular Septum ◽

Bone Destruction ◽

Amyloid Deposition ◽

Bone Lesions ◽

Al Amyloidosis ◽

Linear Type

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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GDF15 Promotes Osteoclast Differentiation and High Serum GDF15 Levels are Associated with Multiple Myeloma Bone Disease

Clinical Lymphoma Myeloma & Leukemia ◽

10.1016/j.clml.2015.07.493 ◽

2015 ◽

Vol 15 ◽

pp. e231

Author(s):

M. Westrin ◽

S.H. Moen ◽

T. Holien ◽

O.E. Olsen ◽

A.K. Mylin ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Disease ◽

Osteoclast Differentiation ◽

High Serum ◽

Myeloma Bone Disease

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Human myeloma cells stimulate the receptor activator of nuclear factor-κB ligand (RANKL) in T lymphocytes: a potential role in multiple myeloma bone disease

Blood ◽

10.1182/blood-2002-04-1121 ◽

2002 ◽

Vol 100 (13) ◽

pp. 4615-4621 ◽

Cited By ~ 179

Author(s):

Nicola Giuliani ◽

Simona Colla ◽

Roberto Sala ◽

Matteo Moroni ◽

Mirca Lazzaretti ◽

...

Keyword(s):

Multiple Myeloma ◽

T Cells ◽

T Lymphocytes ◽

Bone Disease ◽

Nuclear Factor Κb ◽

Myeloma Cell ◽

Nuclear Factor ◽

Free System ◽

Receptor Activator ◽

Ifn Γ

The biologic mechanisms involved in the pathogenesis of multiple myeloma (MM) bone disease are not completely understood. Recent evidence suggests that T cells may regulate bone resorption through the cross-talk between the critical osteoclastogenetic factor, receptor activator of nuclear factor-κB ligand (RANKL), and interferon γ (IFN-γ) that strongly suppresses osteoclastogenesis. Using a coculture transwell system we found that human myeloma cell lines (HMCLs) increased the expression and secretion of RANKL in activated T lymphocytes and similarly purified MM cells stimulated RANKL production in autologous T lymphocytes. In addition, either anti–interleukin 6 (anti–IL-6) or anti–IL-7 antibody inhibited HMCL-induced RANKL overexpression. Consistently, we demonstrated that HMCLs and fresh MM cells express IL-7 mRNA and secrete IL-7 in the presence of IL-6 and that bone marrow (BM) IL-7 levels were significantly higher in patients with MM. Moreover, we found that the release of IFN-γ by T lymphocytes was reduced in presence of both HMCLs and purified MM cells. Furthermore, in a stromal cell–free system, osteoclastogenesis was stimulated by conditioned medium of T cells cocultured with HMCLs and inhibited by recombinant human osteoprotegerin (OPG; 100 ng/mL to 1 μg/mL). Finally, RANKL mRNA was up-regulated in BM T lymphocytes of MM patients with severe osteolytic lesions, suggesting that T cells could be involved at least in part in MM-induced osteolysis through the RANKL overexpression.

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