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Objective: To evaluate the role of diffusion-weighted imaging (DWI) in the initial diagnosis, staging, and assessment of treatment response in patients with multiple myeloma (MM)., Materials and Methods: A systematic literature review was conducted in PubMed, the Cochrane Library, EMBASE, Scopus, and Web of Science databases. The primary endpoints were defined as the diagnostic performance of DWI for disease detection, staging of MM, and assessing response to treatment in these patients., Results: Of 5881 initially reviewed publications, 33 were included in the final qualitative and quantitative meta-analysis. The diagnostic performance of DWI in the detection of patients with MM revealed pooled sensitivity and specificity of 86% (95% CI: 84-89) and 63% (95% CI: 56-70), respectively, with a diagnostic odds ratio (OR) of 14.98 (95% CI: 4.24-52.91). The pooled risk difference of 0.19 (95% CI: - 0.04-0.42) was reported in favor of upstaging with DWI compared to conventional MRI (P value = 0.1). Treatment response evaluation and ADC mean value changes across different studies showed sensitivity and specificity of approximately 78% (95% CI: 72-83) and 73% (95% CI: 61-83), respectively, with a diagnostic OR of 7.21 in distinguishing responders from non-responders., Conclusions: DWI is not only a promising tool for the diagnosis of MM, but it is also useful in the initial staging and re-staging of the disease and treatment response assessment. This can aid clinicians with earlier initiation or change in treatment strategy, which could have prognostic significance for patients., (© 2022. The Author(s), under exclusive licence to International Skeletal Society (ISS).)

Bone imaging has been intimately associated with the diagnosis and staging of multiple myeloma (MM) for more than 5 decades, as the presence of bone lesions indicates advanced disease and dictates treatment initiation. The methods used have been evolving, and the historical radiographic skeletal survey has been replaced by whole body CT, whole body MRI (WB-MRI) and [ 18 F]FDG-PET/CT for the detection of bone marrow lesions and less frequent extramedullary plasmacytomas.Beyond diagnosis, imaging methods are expected to provide the clinician with evaluation of the response to treatment. Imaging techniques are consistently challenged as treatments become more and more efficient, inducing profound response, with more subtle residual disease. WB-MRI and FDG-PET/CT are the methods of choice to address these challenges, being able to assess disease progression or response and to detect "minimal" residual disease, providing key prognostic information and guiding necessary change of treatment.This paper provides an up-to-date overview of the WB-MRI and PET/CT techniques, their observations in responsive and progressive disease and their role and limitations in capturing minimal residual disease. It reviews trials assessing these techniques for response evaluation, points out the limited comparisons between both methods and highlights their complementarity with most recent molecular methods (next-generation flow cytometry, next-generation sequencing) to detect minimal residual disease. It underlines the important role of PET/MRI technology as a research tool to compare the effectiveness and complementarity of both methods to address the key clinical questions., (© 2021. The Author(s).)

Tumor-mediated immunosuppression via regulatory T-cells is a key player among the various immune-escape mechanisms in multiple myeloma. We analyzed the generation, distribution, function and immunophenotype of CD8 + CD28 - regulatory T-cells in patients with multiple myeloma. Functionality of CD8 + CD28 - T-cells was assessed by immunological assays using ex vivo generated antigen-specific T-cells from patients with plasma cell dyscrasias and healthy donors. Detailed analysis of distribution, immunophenotype and cytotoxic potential of CD8 + CD28 - T-cells was performed by flow cytometry and ELISA. We found that the amount of CD8 + CD28 - T-cells was directly correlated with the suppression of antigen-specific T-cell responses in patients with plasma cell dyscrasia. Analyzing the CD8 + CD28 - T-cells in detail, increased numbers of these cells were observed in the bone marrow (i.e., tumor microenvironment) of patients with plasma cell dyscrasia. Furthermore, we identified the expression of lymphocyte function-associated antigen 1 (LFA-1) as a marker of immunosuppression and defined the CD8 + CD28 - CD57 + LFA-1 high population as the relevant immunosuppressive compartment. These regulatory T-cells act as immunosuppressors via soluble factors and incubation with IL-10 augmented their immunosuppressive capacity. The immunosuppressive regulatory network of IL-10 and the CD8 + CD28 - CD57 + LFA-1 high regulatory T-cells show unique characteristics and contribute to the tumor immune escape mechanism in patients with multiple myeloma.

Background and Objectives: In this study, we evaluated methods of quantification of tumor mass in whole-body MRI (wb-MRI) in multiple myeloma and correlated these with disease-related parameters in serum and bone marrow., Materials and Methods: We retrospectively evaluated wb-MRIs of 52 patients with focal infiltration pattern and a total of 700 focal lesions (subsequently called lesions). We determined the longest diameter (LD), the segmented volume (SV), and the morphology (spherical or non-spherical). We correlated total number/volume of the lesions with clinical parameters and prognosis and furthermore LD with SV. After that we analyzed the agreement of SV and estimated volume (EV) using the volume formula of a sphere based on LD., Results: Results showed no significant correlations of total number/volume with prognosis or clinical parameters. The latter were situated predominantly in the normal range. Furthermore, 10% of lesions were spherical. SV and LD correlated significantly in single lesions and on patient level. SV was in lesions <6 cm 3 systematically larger and in lesions ≥6 cm 3 smaller than EV. In 95%, we found in small lesions a deviation of EV versus SV from +0.9 cm 3 to -4.6 cm 3 and in large lesions from +160 cm 3 to -111 cm 3 (EV-SV)., Conclusions: Quantification of tumor mass in the focal infiltration pattern is performed more accurately by volumetry than LD due to the predominant existence of non-spherical lesions. The patient cohort with clinical parameters predominantly in the normal range is distributed to ISS stage I and partly pretreated, a fact that makes interpretation of absent correlations more difficult. Consider also a variation in activitiy of lesions and a diffuse infiltration not detectable by MRI.

Modern imaging techniques have demonstrated that monoclonal plasma cell diseases infiltrate the bone marrow in a diffuse, focal, mixed pattern. While focal lesions can be easily counted and measured, the diffuse lesions of the infiltration are hard to assess. We therefore investigated 31 patients with monoclonal plasma cell diseases of all stages with intravoxel incoherent motion imaging of the same region of the pelvis from where afterwards a biopsy was obtained. We found a significant correlation between plasma cell percentage in bone marrow histology and the imaging parameters "apparent diffusion coefficient" and the diffusion coefficient D. Furthermore, those parameters correlated with other factors of disease activity, e.g., monoclonal protein, hemoglobin, and immunoparesis. In summary, we found that the non-invasively acquired imaging parameters correlated with the degree of plasma cell infiltration in the bone marrow.

Clinical/methodical Issue: Imaging in monoclonal plasma cell disease serves to detect end organ damage, i.e., osteoporosis or bone destruction. Diffuse or circumscribed bone marrow infiltration without damage to mineralized bone is so far not regarded as end organ damage., Standard Radiological Methods: Skeletal plain x-ray film survey to detect bone destruction, osteoporosis or fractures., Methodical Innovations: Whole body low-dose computed tomography (CT) and whole body magnetic resonance imaging (MRI) allow a more sensitive assessment of both mineralized bone and bone marrow, with greater patient comfort and in the case of MRI without ionizing radiation., Performance: According to the literature, cross-sectional imaging is clearly superior to skeletal surveys and MRI is more sensitive than CT. Every locally destructive lesion will be detectable with MRI but for assessing the damage to mineralized bone CT is indispensible. The sensitivities of positron emission tomography (PET)/CT and MRI are comparable., Achievements: If available whole body MRI and whole body low dose CT should replace conventional skeletal surveys. This has already been implemented in several centers in Germany., Practical Recommendations: For the initial diagnosis of monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma or symptomatic multiple myeloma, a whole-body MRI and a whole body low-dose CT should be performed. For MGUS and asymptomatic myeloma, whole body MRI only should be performed for follow-up until detection of first bone destruction. Patients with symptomatic multiple myeloma and known bone destruction will usually have whole body low-dose CT, supplemented by MRI studies where clinically required.

Solitary plasmacytoma of the bone (SBP) or extramedullary plasmacytoma (EP) are rare neoplasms amenable to local radiotherapy. In this retrospective analysis, we report the University Heidelberg experience in the treatment of solitary plasmacytoma. From 1995 to 2008, 18 patients were treated with local radiotherapy. Ten patients suffered from SBP, eight patients showed a single extramedullary lesion. Local radiotherapy with a median dose of 45 Gy yielded excellent local control with only one patient suffering from local relapse. SBP and EP had significantly different 5-year multiple myeloma-free survival rates of 36.8% and 86.7%, respectively. However, no significant difference in overall survival could be detected. Radiotherapy can achieve excellent local control of solitary plasmacytoma. Progression to multiple myeloma, especially in the case of SBP, remains to be addressed by further studies.

Monoclonal gammopathy of unknown significance (MGUS) as one of the most common premalignant disorders and smoldering multiple myeloma (sMM) are both caused by a proliferation of monoclonal plasma cells leading to a detectable serum monoclonal protein and/or excess of plasma cells in the bone marrow. Prerequisite for the diagnosis is that plasma cell disease does not cause clinical symptoms. Cytogenetic aberrations are detectable in the majority of patient in the clonally expanded plasma cells. MGUS consistently proceeds symptomatic MM. The lifetime risk of progression into symptomatic multiple myeloma lies between 15% and 59% for patients with MGUS or sMM. Prognostic parameters for development of symptomatic multiple myeloma from MGUS or sMM are concentration of monoclonal protein, bone marrow plasmocytosis, a non- IgG subtype and an abnormal free-light chain ratio. Detection of more than 1 focal lesion in whole body MRI, 95% or more of bone marrow plasma cells displaying an aberrant phenotype in flow cytometry and an evolving clinical course in two consecutive follow-up visits are additional prognostic parameters for sMM. Currently there is no accepted secondary prevention strategy available for sMM and MGUS progression. Future studies are required to combine increasing knowledge on risk factors and molecular pathogenesis with targeted agents to prevent progression.

The immunomodulatory drugs thalidomide and lenalidomide have enhanced activity in patients with multiple myeloma (MM). Their efficacy is increased with the addition of dexamethasone, but significant rates of venous thromboembolism (VTE) are a severe side effect. Based on this evidence, it is recommended that VTE prophylaxis be prescribed in these patients. However, the optimal prophylaxis remains controversial. We analyzed 45 patients with relapsed MM who were treated with lenalidomide and dexamethasone at our center. The 45 patients received a total number of 192 cycles, respectively a median of three cycles; the median dosage of dexamethasone was 240 mg per cycle. All patients received prophylactic anticoagulation with low molecular weight heparin (LMWH). Moreover, 86.6% of patients had at least one additional VTE risk factor beside the myeloma-related risk. One out of 45 patients developed a deep vein thrombosis and pulmonary embolism. None of the other 44 patients had clinical signs of thrombosis or embolism and none of all patients experienced complications or side effects due to anticoagulation. Our results indicate that prophylactic anticoagulation with LMWH is safe and effective. Therefore, we propose LMWH should be used in patients being treated with lenalidomide and dexamethasone at least for the first 3 months of treatment until randomized trials have proven the equality of other pharmacological prophylaxis.

Aim of the Study: Investigation of the quantitative microcirculation parameters amplitude A and exchange rate constant k21 determined by contrast-enhanced dynamic magnetic resonance imaging (d-MRI) in multiple myeloma (MM)., Methods: d-MRT of lumbar spine and right spina iliaca superior posterior of 16 controls (ctr) and 35 patients with active MM. Generation of colour-coded images of microcirculation parameters superimposed onto static MRI images., Results: Amplitude A and k21 parameters were significantly increased in patients with MM and down modulated by therapy in 7 of 8 MM cases in a follow-up investigation [p < 0.01; median Actr = 0.2 (0.09-0.4); median AMM = 0.93 (0.2-1.52); median k21ctr = 0.09 min-1 (0.03-0.9); median k21MM = 4.57 min-1 (0.21-23.8)]. Thirteen patients revealed a "diffuse" and 22 a "focal" pattern of distribution of microcirculation parameters. Bone marrow biopsies in 8 cases revealed an correlation between bone marrow plasma cell infiltration and increased microcirculation parameters., Conclusion: Identification of microcirculation changes by d-MRI is a novel imaging technique for the detection and monitoring of MM bone lesions.