Evangelos Terpos

Role of Magnetic Resonance Imaging in the Management of Patients with Multiple Myeloma: a Consensus Statement

PURPOSE The aim of International Myeloma Working Group was to develop practical recommendations for the use of magnetic resonance imaging (MRI) in multiple myeloma (MM). METHODS An interdisciplinary panel of clinical experts on MM and myeloma bone disease developed recommendations for the value of MRI based on data published through March 2014. RECOMMENDATIONS MRI has high sensitivity for the early detection of marrow infiltration by myeloma cells compared with other radiographic methods. Thus, MRI detects bone involvement in patients with myeloma much earlier than the myeloma-related bone destruction, with no radiation exposure. It is the gold standard for the imaging of axial skeleton, for the evaluation of painful lesions, and for distinguishing benign versus malignant osteoporotic vertebral fractures. MRI has the ability to detect spinal cord or nerve compression and presence of soft tissue masses, and it is recommended for the workup of solitary bone plasmacytoma. Regarding smoldering or asymptomatic myeloma, all patients should undergo whole-body MRI (WB-MRI; or spine and pelvic MRI if WB-MRI is not available), and if they have > one focal lesion of a diameter > 5 mm, they should be considered to have symptomatic disease that requires therapy. In cases of equivocal small lesions, a second MRI should be performed after 3 to 6 months, and if there is progression on MRI, the patient should be treated as having symptomatic myeloma. MRI at diagnosis of symptomatic patients and after treatment (mainly after autologous stem-cell transplantation) provides prognostic information; however, to date, this does not change treatment selection.

RANKL inhibition: Clinical implications for the management of patients with multiple myeloma and solid tumors with bone metastases

Background: Receptor activator of NF-κB ligand (RANKL) binds to RANK on the surface of osteoclast precursors and enhances their differentiation, survival and fusion, activates mature osteoclasts and inhibits their apoptosis. Osteoprotegerin (OPG) is the decoy receptor of RANKL. Disruption of the RANK/RANKL/OPG axis is implicated in bone metastases. Objective/methods: A review of the role of RANKL signaling in bone development and the rationale for targeting RANKL in treatment of bone metastases and myeloma bone disease. Results/conclusions: In preclinical models of solid tumors and myeloma, RANKL inhibition reduced osteoclast numbers and subsequent bone resorption, prevented development of osteolytic lesions and decreased tumor burden. Preliminary clinical studies with denosumab, an anti-RANKL fully human monoclonal antibody, in patients with solid tumors with bone metastases and myeloma showed that targeting RANKL reduces osteoclastogenesis, bone resorption markers and skeletal-related events, supporting further study of this molecule and others with anti-RANKL activity.

The Role of Imaging in the Treatment of Patients With Multiple Myeloma in 2016.

The novel criteria for the diagnosis of symptomatic multiple myeloma have revealed the value of modern imaging for the management of patients with myeloma. Whole-body low-dose CT (LDCT) has increased sensitivity over conventional radiography for the detection of osteolytic lesions, and several myeloma organizations and institutions have suggested that whole-body LDCT should replace conventional radiography for the work-up of patients with myeloma. MRI is the best imaging method for the depiction of marrow infiltration by myeloma cells. Whole-body MRI (or at least MRI of the spine and pelvis if whole-body MRI is not available) should be performed for all patients with smoldering multiple myeloma with no lytic lesions to look for occult disease, which may justify treatment. In addition, MRI accurately illustrates the presence of plasmacytomas, spinal cord, and/or nerve compression for surgical intervention or radiation therapy; it is also recommended for the work-up of solitary bone plasmacytoma, and it may distinguish malignant from benign fractures (which is very important in cases of patients in biochemical remission with no other signs of progression). Diffusion weighted imaging (DWI) seems to improve MRI diagnosis in patients with myeloma. PET/CT is a functional imaging technique, more sensitive than conventional radiography for the detection of lytic lesions, which probably allows better definition of complete response and minimal residual disease compared with all other imaging methods. PET/CT has shown the best results in the follow-up of patients with myeloma and has an independent prognostic value both at diagnosis and following treatment. PET/CT can also be used for the work-up of solitary bone plasmacytoma and nonsecretory myeloma.

Multiple Myeloma Bone Disease

Abstract Bone disease is very common in patients with multiple myeloma and is one of the main causes of morbidity. Its clinical manifestations are lytic bone lesions and/or osteoporosis and might be associated with pain, fractures, spinal cord compression, and hypercalcemia. The pathogenesis of myeloma bone disease is due to imbalance between bone resorption and bone regeneration due to inhibition of osteoblasts-induced bone formation and increased activity of osteoclasts. Furthermore, the interactions in the bone marrow microenvironment may contribute to both disease evolution and bone disease. Although the incorporation of novel agents has improved significantly the survival of the patients, myeloma still remains an incurable disease. Therefore, the understanding of the exact underlying pathophysiological mechanisms is essential in order to achieve tailored therapeutic strategies and improve patients quality of life.

Osteoimmunology and Cancer - Clinical Implications

The skeletal and immune systems are interconnected in normal (physiologic) and pathologic conditions. Both systems are intimately coupled, as osteoclastogenesis and hematopoiesis occur in the bone marrow. Osteoclasts, macrophages, and dendritic cells also share common precursors. Furthermore, the skeletal and immune systems share various cytokines, receptors, adaptor proteins, signaling molecules, and transcription factors, thereby allowing crosstalk to occur between the various cells and their respective signal transduction pathways involved in osteoclastogenesis and hematopoiesis. Hematopoietic stem cells are maintained in the bone marrow. Adjacent osteoblast precursors produce signals that control hematopoietic stem cell replication and differentiation. Hematopoietic stem cells may either maintain their pluripotency or differentiate into multipotential progenitor cells, which have the capacity to form common lymphoid progenitor or common myeloid precursor cells. Common lymphoid progenitor cells undergo additional differentiation to form T lymphocytes, B lymphocytes, or natural killer cells, whereas common myeloid precursor cells form all other myeloid lineages and preosteoclasts. Activated osteoclasts are formed from the fusion of preosteoclasts and multinucleated osteoclasts, the regulation of which is complex and affected by multiple factors. Multipotential stem cells differentiate into chondrocytes, adipocytes, and mesenchyme precursors; the latter undergo differentiation to form preosteoblasts and, eventually, mature matrix-producing osteoblasts. Osteoblasts may remain on the bone surface as lining cells or undergo terminal differentiation to form osteocytes, which become encased in the mineralized bone matrix [1]. The shared lineages and paracrine signaling between osteoclasts and hematopoietic cells highlight the potential for bone-targeted agents to influence the immune system.