Acetate metabolism in Multiple Myeloma identifies11C-Acetate PET as a novel strategy to image bone disease and response to treatment in preclinical models

Carfilzomib with dexamethasone (Kd) is a well-established regimen for the treatment of relapsed/refractory multiple myeloma (RRMM). There is limited information for the effects of Kd on myeloma-related bone disease. This non-interventional study aimed to assess skeletal-related events (SREs) and bone metabolism in patients with RRMM receiving Kd, in the absence of any bone-targeted agent. Twenty-five patients were enrolled with a median of three prior lines of therapy; 72% of them had evidence of osteolytic bone disease at study entry. During Kd treatment, the rate of new SREs was 28%. Kd produced a clinically relevant (≥30%) decrease in C-telopeptide of collagen type-1 (p = 0.048) and of tartrate-resistant acid phosphatase-5b (p = 0.002) at 2 months. This reduction was at least partially due to the reduction in the osteoclast regulator RANKL/osteoprotegerin ratio, at 2 months (p = 0.026). Regarding bone formation, there was a clinically relevant increase in osteocalcin at 6 months (p = 0.03) and in procollagen type I N-propeptide at 8 months post-Kd initiation. Importantly, these bone metabolism changes were independent of myeloma response to treatment. In conclusion, Kd resulted in a low rate of SREs among RRMM patients, along with an early, sustained and clinically relevant decrease in bone resorption, which was accompanied by an increase in bone formation, independently of myeloma response and in the absence of any bone-targeted agent use.

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Prospective evaluation of spatial heterogeneity at single cell resolution in multiple myeloma.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.8524 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 8524-8524

Author(s):

Maximilian Merz ◽

Almuth Maria Anni Merz ◽

Jie Wang ◽

Lei Wei ◽

Qiang Hu ◽

...

Keyword(s):

Gene Expression ◽

Multiple Myeloma ◽

Bone Marrow ◽

Single Cell ◽

Bone Disease ◽

Bone Destruction ◽

The Body ◽

Response To Treatment ◽

Risk Scores ◽

Specific Gene

8524 Background: Osteolytic lesions (OL) characterize symptomatic multiple myeloma (MM). It is still unclear why plasma cells (PC) cause OL in certain regions of the body while other areas show no signs of bone destruction despite significant bone marrow infiltration. We conducted the first study of single cell RNA sequencing (scRNA-seq) and whole-exome sequencing (WES) of PC obtained from random bone marrow samples (RS) and paired OL. Methods: As part of a prospective clinical trial, patients consented to an imaging-guided biopsy of new OL identified by PET/CT in addition to the RS from the iliac crest. Both samples were acquired in the same session. On the same day PC were isolated using a CD138 positive selection kit and single cell gene expression libraries were generated for scRNA-seq. Frozen PC were subjected to DNA extraction and WES. Results: We sequenced 93569 purified, viable PC from paired samples from 15 different locations in the first 7 consecutive patients (median PC from location: 7203; range 1121-10279). Quality assessment of scRNA-seq data revealed no differences between PC in OL and RS. Based on scRNA-seq, 9-24 different subpopulations of PC in individual patients were identified. Over 90% of clusters found in the RS were also present in corresponding OL suggesting a common ancestor. This was true for patients with overlapping as well as divergent mutational profiles in RS and OL as shown by WES. In each patient we found PC clusters that were predominantly present in OL. Respective clusters were characterized by expression of Wnt-signaling inhibitors like DKK-1, Frzb and sFRP-2 and other genes linked to MM bone disease (HGF, CXCL-12, CCL3). Lysosome-associated membrane protein-like molecule 5 (LAMP5) and J-chain were overexpressed in OL clusters. Analysis of genes (IKZF1 and IKZF3) associated with response to treatment and outcome revealed vast heterogeneity and differences in risk scores (UAMS70 and IFM15) on a single cell level from different locations in individual patients. Conclusions: Our study provides the first evidence that PC from OL have distinct transcriptomic profiles that link site-specific gene expression to development of bone disease and adverse outcome.

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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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Contribution of multiple myeloma-derived exosomes to bone disease

Bone Abstracts ◽

10.1530/boneabs.5.p117 ◽

2016 ◽

Author(s):

Lavinia Raimondi ◽

Luca Angela De ◽

Valeria Carina ◽

Valentina Agnese ◽

Simona Fontana ◽

...

Keyword(s):

Multiple 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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Impact of Natural Dietary Agents on Multiple Myeloma Prevention and Treatment: Molecular Insights and Potential for Clinical Translation

Current Medicinal Chemistry ◽

10.2174/0929867325666180629153141 ◽

2020 ◽

Vol 27 (2) ◽

pp. 187-215 ◽

Cited By ~ 8

Author(s):

Lavinia Raimondi ◽

Angela De Luca ◽

Gianluca Giavaresi ◽

Agnese Barone ◽

Pierosandro Tagliaferri ◽

...

Keyword(s):

Signal Transduction ◽

Multiple Myeloma ◽

Natural Products ◽

Bone Disease ◽

Molecular Mechanisms ◽

Plasma Cells ◽

Hematologic Malignancy ◽

Signal Transduction Pathways ◽

Pharmacologically Active ◽

Dietary Agents

: Chemoprevention is based on the use of non-toxic, pharmacologically active agents to prevent tumor progression. In this regard, natural dietary agents have been described by the most recent literature as promising tools for controlling onset and progression of malignancies. Extensive research has been so far performed to shed light on the effects of natural products on tumor growth and survival, disclosing the most relevant signal transduction pathways targeted by such compounds. Overall, anti-inflammatory, anti-oxidant and cytotoxic effects of dietary agents on tumor cells are supported either by results from epidemiological or animal studies and even by clinical trials. : Multiple myeloma is a hematologic malignancy characterized by abnormal proliferation of bone marrow plasma cells and subsequent hypercalcemia, renal dysfunction, anemia, or bone disease, which remains incurable despite novel emerging therapeutic strategies. Notably, increasing evidence supports the capability of dietary natural compounds to antagonize multiple myeloma growth in preclinical models of the disease, underscoring their potential as candidate anti-cancer agents. : In this review, we aim at summarizing findings on the anti-tumor activity of dietary natural products, focusing on their molecular mechanisms, which include inhibition of oncogenic signal transduction pathways and/or epigenetic modulating effects, along with their potential clinical applications against multiple myeloma and its related bone disease.

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Serum levels of macrophage inflammatory protein-1 alpha (MIP-1α) correlate with the extent of bone disease and survival in patients with multiple myeloma

British Journal of Haematology ◽

10.1046/j.1365-2141.2003.04561.x ◽

2003 ◽

Vol 123 (1) ◽

pp. 106-109 ◽

Cited By ~ 114

Author(s):

Evangelos Terpos ◽

Marianna Politou ◽

Richard Szydlo ◽

John M. Goldman ◽

Jane F. Apperley ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Disease ◽

Serum Levels ◽

Inflammatory Protein ◽

Macrophage Inflammatory Protein

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A Molecular Signature of Circulating MicroRNA Can Predict Osteolytic Bone Disease in Multiple Myeloma

Cancers ◽

10.3390/cancers13153877 ◽

2021 ◽

Vol 13 (15) ◽

pp. 3877

Author(s):

Aristea-Maria Papanota ◽

Panagiotis Tsiakanikas ◽

Christos K. Kontos ◽

Panagiotis Malandrakis ◽

Christine-Ivy Liacos ◽

...

Keyword(s):

Multiple Myeloma ◽

Logistic Regression ◽

Bone Disease ◽

Characteristic Curve ◽

Molecular Signature ◽

Circulating Microrna ◽

Prognostic Role ◽

Clinical Value ◽

Osteolytic Bone Disease ◽

Circulating Levels

Background: Multiple myeloma bone disease (MMBD) constitutes a common and severe complication of multiple myeloma (MM), impacting the quality of life and survival. We evaluated the clinical value of a panel of 19 miRNAs associated with osteoporosis in MMBD. Methods: miRNAs were isolated from the plasma of 62 newly diagnosed MM patients with or without MMBD. First-strand cDNA was synthesized, and relative quantification was performed using qPCR. Lastly, we carried out extensive biostatistical analysis. Results: Circulating levels of let-7b-5p, miR-143-3p, miR-17-5p, miR-214-3p, and miR-335-5p were significantly higher in the blood plasma of MM patients with MMBD compared to those without. Receiver operating characteristic curve and logistic regression analyses showed that these miRNAs could accurately predict MMBD. Furthermore, a standalone multi-miRNA–based logistic regression model exhibited the best predictive potential regarding MMBD. Two of those miRNAs also have a prognostic role in MM since survival analysis indicated that lower circulating levels of both let-7b-5p and miR-335-5p were associated with significantly worse progression-free survival, independently of the established prognostic factors. Conclusions: Our study proposes a miRNA signature to facilitate MMBD diagnosis, especially in ambiguous cases. Moreover, we provide evidence of the prognostic role of let-7b-5p and miR-335-5p as non-invasive prognostic biomarkers in MM.

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Telomere Architecture Correlates with Aggressiveness in Multiple Myeloma

Cancers ◽

10.3390/cancers13081969 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1969

Author(s):

Aline Rangel-Pozzo ◽

Pak Yu ◽

Sadhana LaL ◽

Yasmin Asbaghi ◽

Luiza Sisdelli ◽

...

Keyword(s):

Multiple Myeloma ◽

Disease Progression ◽

Genomic Instability ◽

Clinical Decision Making ◽

Three Dimensional ◽

Clinical Decision ◽

Response To Treatment ◽

Average Intensity ◽

Patient Response ◽

Smoldering Multiple Myeloma

The prognosis of multiple myeloma (MM), an incurable B-cell malignancy, has significantly improved through the introduction of novel therapeutic modalities. Myeloma prognosis is essentially determined by cytogenetics, both at diagnosis and at disease progression. However, for a large cohort of patients, cytogenetic analysis is not always available. In addition, myeloma patients with favorable cytogenetics can display an aggressive clinical course. Therefore, it is necessary to develop additional prognostic and predictive markers for this disease to allow for patient risk stratification and personalized clinical decision-making. Genomic instability is a prominent characteristic in MM, and we have previously shown that the three-dimensional (3D) nuclear organization of telomeres is a marker of both genomic instability and genetic heterogeneity in myeloma. In this study, we compared in a longitudinal prospective study blindly the 3D telomeric profiles from bone marrow samples of 214 initially treatment-naïve patients with either monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), or MM, with a minimum follow-up of 5 years. Here, we report distinctive 3D telomeric profiles correlating with disease aggressiveness and patient response to treatment in MM patients, and also distinctive 3D telomeric profiles for disease progression in smoldering multiple myeloma patients. In particular, lower average intensity (telomere length, below 13,500 arbitrary units) and increased number of telomere aggregates are associated with shorter survival and could be used as a prognostic factor to identify high-risk SMM and MM patients.

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