Bone Lesions In Multiple Myeloma Research Articles

Current Status and Future of Artificial Intelligence in MM Imaging: A Systematic Review.

Artificial intelligence (AI) has attracted increasing attention as a tool for the detection and management of several medical conditions. Multiple myeloma (MM), a malignancy characterized by uncontrolled proliferation of plasma cells, is one of the most common hematologic malignancies, which relies on imaging for diagnosis and management. We aimed to review the current literature and trends in AI research of MM imaging. This study was performed according to the PRISMA guidelines. Three main concepts were used in the search algorithm, including "artificial intelligence" in "radiologic examinations" of patients with "multiple myeloma". The algorithm was used to search the PubMed, Embase, and Web of Science databases. Articles were screened based on the inclusion and exclusion criteria. In the end, we used the checklist for Artificial Intelligence in Medical Imaging (CLAIM) criteria to evaluate the manuscripts. We provided the percentage of studies that were compliant with each criterion as a measure of the quality of AI research on MM. The initial search yielded 977 results. After reviewing them, 14 final studies were selected. The studies used a wide array of imaging modalities. Radiomics analysis and segmentation tasks were the most popular studies (10/14 studies). The common purposes of radiomics studies included the differentiation of MM bone lesions from other lesions and the prediction of relapse. The goal of the segmentation studies was to develop algorithms for the automatic segmentation of important structures in MM. Dice score was the most common assessment tool in segmentation studies, which ranged from 0.80 to 0.97. These studies show that imaging is a valuable data source for medical AI models and plays an even greater role in the management of MM.

Glutamine Addiction of Multiple Myeloma Cells Reprograms Mesenchymal Stromal Cell Enzymes and Transporters Towards a Pro-Tumor Phenotype

Metabolic alterations in cancer are not only functional to ensure malignant cell growth but also shape a pro-tumor behavior of normal cell populations in the tumor microenvironment. Multiple myeloma (MM) is the only human cancer that is both glutamine-addicted and glutamine-auxotroph, a feature that renders MM growth completely dependent upon extracellular glutamine availability. Indeed, plasma cells from most MM patients do not express Glutamine Synthetase (GS), the only enzyme able to synthetize glutamine from glutamate and ammonium, while express high levels of Glutaminase (GLS), which catalyze the first step of glutaminolysis by deamidating glutamine into glutamate and ammonium. As a consequence, the bone marrow (BM) plasma of MM patients has low-glutamine/high glutamate levels compared to patients with smoldering MM (SMM) and Monoclonal Gammopathy of Uncertain Significance (MGUS), as firstly demonstrated by our group. This particular metabolic microenvironment induces GS expression in mesenchymal stromal cells (MSCs) impairing osteoblast (OB) differentiation of MSCs, thus favoring MM bone lesions typical of active MM. The impact of these metabolic alterations on other BM cell populations is much less defined and it has been investigated in this study. For instance, although MM BM displays an oversized adipocyte population, which sustain MM growth by providing free fatty acids, the effects of MM metabolism on MSCs and their adipocyte differentiation remain to be characterized. First we show that 13C 5-Gln isotopomer distribution revealed that almost 50% of total glutamate in human myeloma cell lines (HMLCs) directly derives from glutamine deamidation by GLS. Furthermore, in standard culture conditions, HMLCs secreted glutamate likely through the SLC7A11 transporter, whose activity was higher in HMLCs than in MSCs. On the other hand, HMCLs were not able to take up glutamate from the extracellular space, while human primary MSCs isolated from healthy donors displayed high activity of the sodium-dependent glutamate transporters of the EAAT family. Moreover, glutamate uptake was higher in undifferentiated MSCs than in MSC incubated for 14 days in osteogenic medium (10 -8 M dexamethasone and 50 µg/ml ascorbic acid). Consistently, a public transcriptional profile of MSCs and OBs obtained from bone biopsies of healthy donors (n=7) or MM patients (n=16) revealed that the expression of the inward Glu transporter EAAT3 is higher in MSCs compared to OBs. In glutamine-free conditions, MSCs produced and secreted glutamine, a process boosted by extracellular glutamate in a dose-dependent manner. Glutamine secretion was hindered by either l-methionine sulfoximine (MSO), an irreversible inhibitor of GS, or D-aspartate (D-Asp), a high-affinity inhibitor of EAAT3 that hinders glutamate uptake. In a co-culture system, HMCLs induced the expression of SNAT5 glutamine efflux transporter in MSCs. Consistently, upon glutamine withdrawal, primary undifferentiated MSCs from healthy donors sustained HMCLs growth, while this nutritional support was markedly impaired by either inhibition or silencing of GS and EAAT3, with a substantial decrease in MM cell viability. Lastly, primary human MSCs were incubated under adipogenic conditions (0.5 mM 3-Isobutyl-1-methylxanthine, 5 µM indomethacin, 50 µM dexamethasone and 10 mg/ml human insulin) in the presence or in the absence of glutamine to mimic, respectively, normal or MM BM microenvironment. Glutamine deprivation increased lipogenesis, assessed with Oil Red O staining, as well as the expression of the adipocyte markers PPARG, LEP, and ADIPOQ. These data point to a MM-driven metabolic pro-tumor BM niche in which MSCs feed glutamine-addicted MM cells, and MSC differentiation is skewed from osteogenesis to adipogenesis. Several steps of these deranged pathways are amenable to pharmacological inhibition, pointing to possible novel therapeutic approaches to counteract MM growth and its effects on the BM niche.

Phase II Multi-Institutional Study of a Low-Dose (4 Gy) Palliative Response-Adapted Radiotherapy Regimen for Symptomatic Bone Metastases from Multiple Myeloma: Planned Interim Analysis of First 40 Patients

Painful bone lesions are common in patients with multiple myeloma (MM). Radiotherapy (RT) is effective in providing pain relief from MM bone lesions in over 80% of patients. There is no consensus as to the most effective dose or fractionation for palliation. Shorter courses of therapy are not only more convenient for patients, but they also have less impact on timing of systemic therapies. There is precedent for using 4 Gy in the palliation of lymphomas, which have similar radiosensitivity to myeloma. The primary objective of this trial is to determine whether treatment with a total dose of 4 Gy to a painful myeloma bone lesion achieves patient-reported pain reduction comparable to historical controls at 4 weeks. Patients with a known diagnosis of MM and a painful bone lesion that was not at the base of skull, in need of stabilization, or causing cord compression were treated with 4 Gy (2 Gy x 2 or 4 Gy x 1). Patients' pain was measured using the brief pain index (BPI) prior to treatment and at 2, 4, 8 weeks and 6 months following treatment. Pain response was determined by the international consensus on palliative radiotherapy and considered change in BPI and oral morphine equivalent dose (OMED). A planned interim analysis for futility was completed after 40 patients. Reirradiation with clinician choice regimens could be considered at ≥4 weeks following initial treatment for indeterminate pain response or pain progression. Forty patients were treated at 6 institutions between 2019 and 2022. Median age was 65 years with 40% women and 88% with an ECOG of 0-1. A complete response (CR) was defined as a BPI score of 0 with no concomitant increase in OMED. A partial response (PR) was defined as BPI reduction in 2 or more without analgesic increase, or an OMED reduction of 25% or more without an increase in pain. An indeterminate response (IR) was any response that is not captured by a CR, PR or pain progression. A CR was achieved in 48%, a PR in 38% of patients, an IR in 13% with 1 patient who refused participation. Pain response was achieved in 86% of patients. Seven patients (18%) requested reirradiation at ≥4 weeks. Median BPI at baseline and 4 weeks after RT for patients with CR, PR, and IR were 3.75 and 0, 4.00 and 1, and 5.25 and 4.75, respectively. Median change of BPI between baseline and 4 weeks after RT for all responders (CR and PR) was -3.25. The median PTV volume (cc) for patients with CR, PR and IR were 81, 140 and 226, respectively. Based on these results, the futility threshold was not met, and the recommendation by the DSMC is to continue the trial. In the first 40 patients who received 4 Gy palliation for painful bone lesions from multiple myeloma, there were 86% that had a pain response (48% CR, 38% PR). This low dose, response-adapted treatment, led to reirradiation in less than 20% of patients.

Whole-body low-dose computed tomography in primary patients with multiple myeloma

Imaging of bone lesions has an important role in diagnosis of multiple myeloma (MM) and evaluating the response to treatment. Computed tomography scan (CT) allows to detect osteolysis, plasmacytoma and the risk of fractures with high sensitivity. In the National Research Center For Hematologysince 2014 all patients with MM are diagnosed with the whole-body low-dose CT.The aim of the study was to demonstrate the sensitivity of the whole-body low-dose CT and to characterize localization, number and size of bone lesions in primary MM patients.Materials and methods. 50 patients with newly diagnosed MM were enrolled in the study. The diagnosis was established in accordance with international diagnostic criteria. All patients received the whole-body low-dose CT. According to the Durie-Salmon and ISS staging systems 62% and 66% of patients had stage III, respectively.Results. 96% of MM patients had bone lesions. In 30% of patients, bone involvement was the only criterion for CRAB. Pelvic bone lesions was most often diagnosed (92%). The destruction of the long bones of the arms and legs were most rarely detected (42% of patients) and mostly small. The presence of intraosseous plasmocytoma was noted in 40% of cases.Conclusion. The whole-body low dose CT was found to be the most sensitive modality for detection osteolytic bone lesions. Low-dose CT is available in MM case with bone disease only, for establish symptomatic stage. This patients require immedate antimyeloma treatment.

Diagnostic value of WB-DWI versus 18F-FDG PET/CT for the detection of multiple myeloma.

Whole-body diffusion-weighted imaging (WB-DWI) is commonly used for the detection of multiple myeloma (MM). Comparative data on the efficiency of WB-DWI compared with F-18 fluoro-2-deoxy-d-glucose positron emission tomography-computed tomography (18F-FDG PET/CT) to detect MM is limited. This was a retrospective, single-center study of 22 patients with MM enrolled from January 2018 to December 2019. All patients underwent WB-DWI and 18F-FDG PET/CT. Pathological and clinical manifestations, as well as radiologic follow-up, were used for diagnosis. The overall accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of both methods were compared. The apparent diffusion coefficient (ADC) values of MM lesions and false-positive lesions were estimated. A total of 214 MM bone lesions were evaluated. There was no significant difference in the accuracy of WB-DWI and PET/CT (86.92 versus 88.32%). Though WB-DWI had a higher sensitivity (99.26% versus84.56%) and PET-CT had a higher specificity (96.10% versus 64.56%), these differences were not statistically significant. There was a statistically significant difference in PPV (83.33% versus 96.64%) and NPV (98.08% versus 77.89%) of WB-DWI and PET/CT, respectively. The ADC value for MM lesions was significantly lower than that for false-positive lesions (P < 0.001). Receiver operating curve analysis showed that the AUC was 0.846, and when the cut-off value was 0.745 × 10-3 mm2/s, the sensitivity and specificity were 86.3 and 83.4%, respectively, which distinguished MM lesions from non-MM lesions. WB-DWI and PET-CT scans have similar overall accuracy for detecting MM lesions. The higher PPV of PET-CT and NPV of WB-DWI make them complementary imaging modalities. The ADC value for MM lesions is significantly lower than that for false-positive lesions. An ADC cutoff value of 0.745 × 10-3 mm2/s results in sensitivity and specificity of 86.3 and 83.4%, respectively.

A deep learning algorithm for detecting lytic bone lesions of multiple myeloma on CT.

Whole-body low-dose CT is the recommended initial imaging modality to evaluate bone destruction as a result of multiple myeloma. Accurate interpretation of these scans to detect small lytic bone lesions is time intensive. A functional deep learning) algorithm to detect lytic lesions on CTs could improve the value of these CTs for myeloma imaging. Our objectives were to develop a DL algorithm and determine its performance at detecting lytic lesions of multiple myeloma. Axial slices (2-mm section thickness) from whole-body low-dose CT scans of subjects with biochemically confirmed plasma cell dyscrasias were included in the study. Data were split into train and test sets at the patient level targeting a 90%/10% split. Two musculoskeletal radiologists annotated lytic lesions on the images with bounding boxes. Subsequently, we developed a two-step deep learning model comprising bone segmentation followed by lesion detection. Unet and "You Look Only Once" (YOLO) models were used as bone segmentation and lesion detection algorithms, respectively. Diagnostic performance was determined using the area under the receiver operating characteristic curve (AUROC). Forty whole-body low-dose CTs from 40 subjects yielded 2193 image slices. A total of 5640 lytic lesions were annotated. The two-step model achieved a sensitivity of 91.6% and a specificity of 84.6%. Lesion detection AUROC was 90.4%. We developed a deep learning model that detects lytic bone lesions of multiple myeloma on whole-body low-dose CTs with high performance. External validation is required prior to widespread adoption in clinical practice.

Percutaneous CT-Guided Biopsy of the Craniovertebral Junction: Safety, Diagnostic Yield, and Technical Notes.

The craniovertebral junction defined as the occiput, the atlas, and the axis is a complex bony region that contains vital neural and vascular structures. We report the experience of a single academic institution regarding CT-guided biopsy of this skeletal region. We reviewed all of the CT-guided biopsies performed in our department, completed in the craniovertebral junction. We collected data in regard to biopsy procedures, patients’ vital statistics, and histopathological diagnosis. In total, 16 patients (8M and 8F; mean age 52; range 16–86 years old) were included in this series. In eight patients, the lesions were located in the atlas vertebra (8/16—50%), in six patients in the axis (37.5%), and in two patients in the occiput (12.5%). No complications were observed during or after the procedures. All of the procedures were technically successful. The biopsy was diagnostic in 13/16 patients (81.3%): four metastatic lesions (25%—three breast and one prostate cancers), four multiple myeloma bone lesions (25%), three aneurismal bone cysts (18.8%), one aggressive hemangioma (6.3%), and one pseudogout (6.3%). Moreover, in two-thirds (66.6%) of non-diagnostic histological reports, malignancies were excluded. CT-guided percutaneous biopsy is a safe tool and allows obtaining a histological diagnosis, in most cases, even in the most delicate site of the human skeleton—the craniovertebral junction.

Phase II Multi-Institutional Study of Low-Dose (2 Gy x 2) Palliative Radiotherapy for Symptomatic Bone Metastases From Multiple Myeloma

<h3>Purpose/Objective(s)</h3> Painful osteolytic bone lesions are common in patients with multiple myeloma (MM). Radiotherapy (RT) is effective in providing pain relief from MM bone lesions in over 80% of patients. There is no consensus as to the most effective dose or fractionation for palliation. Shorter courses of RT are not only more convenient for patients and their families, but they also have less impact on timing of systemic therapies. There is precedent for using 2 Gy x 2 for palliation of lymphomas, which have similar radiosensitivity to myeloma. The primary objective is to determine whether treatment with 2 Gy x 2 to painful myeloma bone lesions achieves patient-reported pain reduction comparable to historical controls at 4 weeks. Secondary objectives will assess QOL endpoints, use of analgesia and time to pain relief, and duration of pain relief. <h3>Materials/Methods</h3> Patients who consent to participation will complete quality of life and pain questionnaires (Brief Pain Index, EORTC QLQ-BM22, and EORTC QLQ-C30) prior to treatment and at 2,4,8 weeks and 6 months following treatment. Pain response, as defined by the international consensus on palliative RT for bone metastases, will be measured based on BPI and daily oral morphine equivalent. Reirradiation at standard dose can be considered at ≥4 weeks following initial treatment for indeterminate pain response or pain progression. Cytogenetics and International Myeloma Working Group risk stratification and response criteria are recorded, when available, but are not required for patient participation. <h3>Results</h3> This trial, supported by ILROG, has opened at 7 institutions with one more in process of opening. Prior to COVID, accrual was 1.5 patients per month. Since COVID, enrollment has been at 0.7 patients per month. A total of 18 patients have been accrued. The median age of patients accrued is 65.5 years with 7/18 female patients. Fourteen patients are Caucasian. Twelve patients have an ECOG performance score of 1-2. Thirteen patients had pain response captured at 4 weeks following RT. Of the 5 patients that did not complete questionnaires at 4 weeks post-RT, 2 expired, 1 was lost to follow-up, 1 had a missed evaluation and 1 had pain progression). The most common site of treatment was the shoulder (4/18). <h3>Conclusion</h3> This ongoing prospective trial in palliation of multiple myeloma bone lesions is feasible and able to accrue at multiple institutions and will provide valuable information as to the role of low-dose RT in this population.

Prognostic Significance of Medullary Abnormalities of the Appendicular Skeleton Detected By Low-Dose Whole-Body Multidetector Computed Tomography in Patients with Multiple Myeloma

BackgroundWhole-body low-dose multidetector computed tomography (MDCT) is used to assess bone lesions of multiple myeloma (MM), because it can provide more information on lytic bone lesions than plain conventional X-ray examination. MDCT can also depict bone marrow involvement of the appendicular skeleton (AS) in patients with MM. However, there is little evidence whether MDCT-based imaging can predict prognosis in patients with MM. Previously, we reported the prognostic implications of medullary abnormalities of AS in patients with MM (Blood Cancer J 2015;5:e2329). Here, we updated our previous observations and confirmed the prognostic relevance of medullary abnormalities of AS detected by MDCT in patients with MM.Patients and MethodsThe initial study population consisted of 193 consecutive patients with newly diagnosed MM (NDMM) between January 2008 and June 2017 at Kameda Medical Center, Japan, undergoing MDCT in parallel with initial MM work-up. Six patients with cardiac amyloidosis were excluded because of its impact on survival. To differentiate marrow infiltration from physiological residual hematopoietic red marrow, a threshold of 30 HU was set. The normal pattern was defined as an absence of focal or diffuse high-density area in the medullary lesion with ≥ -30 HU recognized by MDCT. The diffuse pattern was defined as the presence of the abnormal CT value accounting for ≥ 70% of the bony canal. The focal pattern was defined as the presence of circumscribed high-density area which did not meet the definition of the normal or diffuse pattern (Figure A). Statistical analyses were performed with EZR, which is a graphical user interface for R ver. 3.2.2Ethical considerationsThis study was approved by the institutional review board of Kameda Medical Center and conducted in accordance with the principles of the Declaration of Helsinki.ResultsThe median age of the patients was 73 years and median observation period was 34.3 months. Among 187 patients, the numbers of patients with normal, focal, and diffuse pattern were 49 (26%), 101 (54%), and 37 (20%), respectively. All of the patients were treated with bortezomib or immunomodulatory drug (IMiD)-based combined chemotherapy in the frontline setting. There were no significant differences in age, sex, M-protein subtype, or clinical response between the three groups. There were significant differences in the proportion of patients with International Staging System (ISS) stage III (33%, 55%, 81%, respectively; P < 0.001) and Revised International Staging System (R-ISS) stage III (14%, 27%, 49%, respectively; P = 0.009) between the normal, focal, and diffuse medullary patterns of AS. The differences in progression free survival (PFS) between the three groups were not statistically significant (log-rank test P=0.18), but overall survival (OS) showed significant differences between groups (log-rank test P < 0.001; Figure B). The 5-year survival rates were 79%, 44%, and 33% for normal, focal, and diffuse patterns, respectively. Median OS values were 92 months, 56 months, and 41 months, respectively. The mortality risk was associated with age, ISS III, Druie & Salmon stage III, creatinine ≥ 2 mg/dL, and receipt of autologous stem cell transplantation (ASCT) on univariate analysis. On multivariate Cox regression analysis, the presence of abnormal medullary lesions detected by MDCT remained as the independent prognostic predictor for OS (normal vs. focal; hazard ratio 2.573; 95% confidence interval, 1.274 - 5.196; P= 0.008: normal vs. diffuse; hazard ratio 4.092; 95% confidence interval, 1.895 - 8.835; P < 0.001: Table).ConclusionOur results indicated that the presence of abnormal bone marrow lesions in the AS detected by MDCT is an independent prognostic factor in patients with NDMM, and patients with a diffuse pattern have shorter survival period than those with the focal pattern. Therefore, assessment of bone marrow involvement of AS detected by MDCT should be considered not only for diagnostic purposes for bony lytic lesions but also to predict the prognosis of NDMM in addition to other imaging modalities. [Display omitted] DisclosuresKitadate:Otsuka: Research Funding; Fujimoto: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Toyama kagaku: Research Funding; Chugai: Research Funding; Asahi Kasei: Research Funding; Kyowa Kirin: Research Funding; Eisai: Research Funding.

Effective Pain Control With Very Low Dose Palliative Radiation Therapy for Patients With Multiple Myeloma With Uncomplicated Osseous Lesions

Background: Osteolytic lesions are present in 75% of patients with multiple myeloma (MM) and frequently require palliation with radiation therapy (RT). Prior case series of patients with MM with bone pain undergoing palliative RT suggests doses ≥12 Gy (equivalent dose in 2Gy fractions, EQD2) provide excellent bone pain relief. However, recent advances in care and novel biologic agents have significantly improved overall survival and quality of life for patients with MM. We hypothesized that lower-dose RT (LDRT, EQD2 <12 Gy) offers an effective alternative to higher-dose RT (HDRT, EQD2 ≥12 Gy) for palliation of painful, uncomplicated MM bone lesions. Methods: We retrospectively identified patients with MM treated with RT for uncomplicated, painful bone lesions and stratified by EQD2 ≥/< 12 Gy. Clinical pain response (CPR) rates, acute and late toxicity, pain response duration, and retreatment rates between LDRT and HDRT groups were analyzed. Results: Thirty-five patients with 70 treated lesions were included: 24 patients (48 lesions) treated with HDRT and 11 patients (22 lesions) with LDRT. Median follow-up was 14 and 16.89 months for HDRT and LDRT, respectively. The median dose of HDRT treatment was 20 Gy versus 4 Gy in the LDRT group. The CPR rate was 98% for HDRT and 95% for LDRT. There was no significant difference in any-grade acute toxicity between the HDRT and LDRT cohorts (24.5% vs 9.1%, Χ2P = .20). Pain recurred in 10% of lesions (12% HDRT vs 9.5% LDRT). Median duration of pain response did not significantly differ between cohorts (P = .91). Five lesions were retreated, 2 (9.5%) in the LDRT cohort, and 3 (6.3%) in the HDRT cohort. Conclusion: In this study, LDRT effectively palliated painful, uncomplicated MM bony lesions with acceptable CPR and duration of palliation. These data support prospective comparisons of LDRT versus HDRT for palliation of painful, uncomplicated MM bony lesions.

Bone remineralization of lytic lesions in multiple myeloma - The Arkansas experience.

Multiple myeloma (MM) patients frequently present with extensive osteolytic bone lesions. However, the impact of myeloma treatment on focal lytic lesion remineralization has not been extensively studied. In this study, the effect of anti-myeloma treatment on the extent of bone remineralization was examined and potential mediators identified. Newly diagnosed MM patients enrolled in the Total Therapy 4 and 5 (TT4; n = 231, TT5; n = 64) protocols were longitudinally evaluated for changes in radiological parameters for a median of 6.1 years. Bone remineralization was defined as a sclerotic CT change within the lytic lesion and quantified as a percentage of remineralization, using the initial lesion size as a reference. Such changes were correlated to clinical and biochemical parameters, and the gene expression profile of bone marrow biopsy. Overall, remineralization occurred in 72% of patients (213/295). Of those patients that experienced remineralization, 36% (107/295) achieved at least 25% of bone remineralization. Patients with high-risk disease defined by gene expression profile signature (GEP70 ≥ 0.66) experienced significant remineralization compared to low-risk MM. Female patients were also more likely to experience bone remineralization and in a shorter median time (2.0 vs. 3.3 y). Factors such as serum alkaline phosphatase along with high levels of RUNX2 and SOX4 gene expression correlated with increasing extent of bone remineralization. This analysis demonstrated significant remineralization of lytic lesions in MM patients treated on TT clinical trials. While the underlying mechanism remains elusive these findings support the hypothesis that patient baseline bone-related factors play a fundamental role in the skeletal repair of bone lesions in MM that provide new opportunities for improving patient outcomes.

Computed tomography characteristics of multiple myeloma and other osteolytic metastatic bone lesions.

Differentiation of multiple myeloma (MM) from osteolytic metastatic (OM) bone lesions may be critical in patients with lytic bone lesions but can be challenging for radiologists. To determine whether computed tomography (CT) can be used to distinguish between MM and other OM bone lesions. In this retrospective study, 320 lesions of 207 patients diagnosed with MM or OM, based on biopsy or clinical examination, were evaluated. Eight qualitative features were evaluated by two radiologists blinded to the diagnoses. The chi-square and Fisher exact tests, and logistic regression analysis, were used to evaluate the relationships between the CT findings and diagnoses. High-density areas were more common in OM than MM lesions (85.2% and 19%, P < 0.001), as were perilesional sclerosis (38.9% vs. 13.2%, P < 0.001), heterogeneity (on non-contrast CT images, 60% vs. 19.1%, P < 0.001; on contrast enhanced CT images, 80.6% vs. 28.2%, P < 0.001), and ill-defined margins (34.6% vs. 9.1%, P < 0.001). Similarly, OM lesions showed high-density areas more than MM in evaluation of skeletal system subgroups (vertebrae, 93.8% vs. 29.8%, P < 0.0001; thoracic cage bones, 69.6% vs. 19.2%, P < 0.001; pelvic bones and sacrum, 84.8% vs. 7.7%, P < 0.001; peripheral skeletal bones, 81.5% vs. 8.3%, P < 0.001). Logistic regression analysis revealed that the presence of a high-density area in the lesion increased the probability of a metastasis 25.88-fold (R2 = 0.516, P < 0.001). MM and OM lesions can be differentiated by CT; OM lesions exhibit high- density areas.

The Role of PET-MRI in Multiple Myeloma Patients

Introduction Low-dose CT scans and magnetic resonance imaging (MRI) using T2- and T1-weighted contrasted enhanced images are the standard methods of bone staging for newly diagnosed and relapsed multiple myeloma (MM) patients. Fluoro-desoxy-glucose positron emission tomography (18F-FDG PET) is also a validated procedure for the imaging of MM bone lesions and the evaluation of extramedullary plasmacytoma. Furthermore, PET CT is useful to determine the prognosis and to assess the minimal residual disease. A new hybrid technology combining PET and MRI provides metabolic and anatomic information simultaneously. We evaluated the results obtained using this new examination. Materials and Methods Thirty-nine MM patients were prospectively included in this single center observational study. Fifty-one PET-MRI scans were performed in 4 patient populations: 1/ newly diagnosed smoldering MM (NDSMM, n =10); 2/ newly diagnosed symptomatic MM (NDMM, n=18); 3/ MM patients with long term follow-up (FU, n=17); 4/ MM patients with biochemical relapse (Rel, n=6). The imaging protocol consisted of T1-weighted, DIXON and diffusion-weighted (b=50 and b=800) axial sequences from the head to the knees simultaneously acquired by PET, followed by coronal and sagittal T1-weighted and T2-weighted sequences centered on the full spine and basin. MRI was considered to be positive in the case of diffuse bone marrow infiltration (DI), diffuse patchy bone marrow infiltration (DPI), focal bone marrow lesions (FL) or extra-medullary disease (EMD). PET was considered to be positive when FDG-avid focal bone lesions, a diffuse medullary area and/or FDG-avid EMD were observed. Medullary compression was also evaluated using MRI. Results The characteristics of the patients are summarized in Table 1. They were classified according to the ISS scale (I, n=18; II, n=7; III, n=3; missing, n=11) and none had high-risk cytogenetics or extra-medullary disease. The hybrid PET-MRI technique provided good image quality in all cases with no artefacts. No medullary compression was detected by MRI. Among the overall 51 PET-MRI examinations, 38 (74%) were positive for MRI and 27 (53%) for PET. Table 2 summarizes the bone marrow results obtained using MRI and PET in the four groups of patients. EMD was not detected by either MRI or PET. In NDSMM patients, MRI was positive and PET was negative in 30%, while none were positive only for PET. In NDMM, MRI was positive and PET was negative in 22% of cases, while 5% were positive only for PET (Figure 1 shows a negative PET and a positive MRI scan in the same patient). In FU patients, 35% of MRI scans remained positive with PET negative, while 6% were PET-positive and MRI-negative. In the case of relapsed patients, MRI and PET scans were in 100% agreement. Conclusions Using PET-MRI, in addition to a search for medullary compression, MRI can provide additional bone marrow information with respect to PET in about 22 to 30% of cases, particularly in NDSMM and NDMM. In a single examination, PET-MRI can detect bone, as well as potential extra-medullary lesions and medullary compression, without irradiation. The baseline PET examination is useful to evaluate the prognosis. Legend to Figure 1: PET and MRI scans in an asymptomatic myeloma patient. PET is negative but MRI reveals a bone lesion in the left iliac crest (arrow). Disclosures Leblond: Janssen: Honoraria; Lilly: Honoraria; Astra Zeneca: Honoraria; Roche: Honoraria; Amgen: Honoraria; Gilead: Honoraria; Beigene: Honoraria; Beigene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria.

Denosumab Versus Zoledronic Acid in the Prevention of Skeletal-related Events in Vulnerable Cancer Patients: A Meta-analysis of Randomized, Controlled Trials

PurposeBone metastases from solid tumors and multiple myeloma (MM) represent an important source of morbidity. The present meta-analysis was performed with the purpose of comparing the efficacy and tolerability of denosumab versus zoledronic acid (ZA) in the prevention of skeletal-related events (SREs) in patients with bone metastases secondary to solid tumors or bone lesions in multiple myeloma. MethodsWe searched PubMed, PubMed Central, EMBASE, the Cochrane Library, and ClinicalTrials.gov for relevant studies published until April 23, 2020. We included randomized, controlled trials that investigated the efficacy and tolerability of denosumab 120 mg SC versus ZA 4 mg IV, given every 4 weeks, in patients with bone lesions in multiple myeloma or bone metastases secondary to advanced solid tumors. Two reviewers independently identified studies, assessed the risk for bias, and extracted the data. Times to event outcomes were analyzed using hazard ratios (HRs) and 95% CIs. We analyzed tolerability outcomes using risk ratios (RRs) and 95% CIs, with a fixed-effects model. FindingsFour randomized, controlled trials (7379 patients) were identified as suitable for analysis. The pooled data indicated that denosumab was more favorable than ZA in delaying the time to first on-study SRE (HR = 0.86; 95% CI, 0.80–0.93; P = 0.0001) as well as the time to first and subsequent on-study SREs (HR = 0.83; 95% CI, 0.76–0.90; P < 0.0001); however, the results on overall survival and disease progression were similar between the 2 drugs. Additionally, denosumab was associated with lower risks for bone pain (risk ratio [RR] = 0.88; 95% CI, 0.80–0.97; P = 0.01), osteonecrosis of the jaw (RR = 0.75; 95% CI, 0.61–0.93; P = 0.007), and acute-phase reactions (RR = 0.47; 95% CI, 0.40–0.56; P < 0.00001). ImplicationsCompared with ZA, denosumab demonstrated efficacy in significantly delaying on-study SREs. Furthermore, it showed a better tolerability profile, despite being associated with potential yet manageable adverse events. This study was registered with PROSPERO (identifier: CRD42019126390).

Functional Comparison between Healthy and Multiple Myeloma Adipose Stromal Cells.

Multiple myeloma (MM) is an incurable B cell neoplasia characterized by the accumulation of tumor plasma cells within the bone marrow (BM). As a consequence, bone osteolytic lesions develop in 80% of patients and remain even after complete disease remission. We and others had demonstrated that BM-derived mesenchymal stromal cells (MSCs) are abnormal in MM and thus cannot be used for autologous treatment to repair bone damage. Adipose stromal cells (ASCs) represent an interesting alternative to MSCs for cellular therapy. Thus, in this study, we wondered whether they could be a good candidate in repairing MM bone lesions. For the first time, we present a transcriptomic, phenotypic, and functional comparison of ASCs from MM patients and healthy donors (HDs) relying on their autologous MSC counterparts. In contrast to MM MSCs, MM ASCs did not exhibit major abnormalities. However, the changes observed in MM ASCs and the supportive property of ASCs on MM cells question their putative and safety uses at an autologous or allogenic level.

Osteoclast-Induced Immunosuppression Occurs through Dysregulation of Immune Checkpoint Axes in Multiple Myeloma

Osteolytic bone disease has a significant impact on both quality of life and overall survival of patients with multiple myeloma (MM). Given that bone and immune cells share the same microenvironment and interact with each other via cytokines, signaling molecules and regulatory proteins in the bone marrow (Tsukasaki M et al., Nat Rev Immunol 2019), we sought to elucidate the effect of osteoclasts (OCs) on the immune microenvironment. Specifically, T cells significantly suppress differentiation of OCs through signaling crosstalk between RANKL and IFN-γ (Takayanagi H et al., Nature 2000). However, little is known regarding the effect of OCs on the immune system. Here we investigated the effect of OCs on immune cells, especially on T cells. Dysregulation of several checkpoint molecules has been shown in MM (Kwon M et al., J Immunol 2017). We, therefore, assessed the expression of various immune checkpoint receptors, such as PD-1, TIGIT, OX40 and CD137 on T cells in co-culture with or without autologous OCs by multi-color flow cytometry. OC co-culture significantly increased co-inhibitory checkpoint (PD-1 and TIGIT) through direct contact, while decreasing co-stimulatory checkpoint (OX40 and CD137) in CD3+ T cells. Expression of the checkpoint ligand, PD-L1 was significantly increased on MM cells in the presence of both T cells and OCs compared to the presence of T cells alone. Conversely, OCs in the absence of T cells did not induce significant increase of PD-L1 on MM cells. According to previous literature, PD-L1 expression on MM cells is induced in part by IFN-γ (Liu J et al., Blood 2007). Interestingly, our data demonstrated that OCs activated IFN-γ producing T cells in co-culture conditions. Furthermore, we observed that T cell and OC-mediated upregulation of PD-L1 on MM cells was partially reversed by using IFN-γ neutralizing antibody. This implies that OCs indirectly induce PD-L1 upregulation on MM cells by enhancing IFN-γ secretion from T cells. In addition, we found that naïve CD4+ T cells have a higher propensity to differentiate into Th17 lineage in the presence of Th17 differentiation cytokines when co-cultured with OCs. Moreover, we observed an increased expansion of Th17 cells in co-culture with OCs. Those Th17 cells also showed a similar pattern of dysregulation of immune checkpoint axes. Our study demonstrates that OCs positively regulate co-inhibitory checkpoint molecules and negatively regulate co-stimulatory molecules on T cells. These findings indicate that OCs play an important role in inhibiting T cell-mediated antitumor immunity. Targeting OCs may help restore impaired immune surveillance in MM in addition to their critical role in preventing lytic bone lesions in MM. These data may support the role of antiresorptives in immune surveillance with indirect anti-tumor effects. Disclosures No relevant conflicts of interest to declare.

TUMOR-DERIVED EXTRACELLULAR VESICLES INHIBIT OSTEOGENESIS AND EXACERBATE MYELOMA BONE DISEASE

Background As a hallmark driver of multiple myeloma (MM), MM bone disease (MBD) is unique in thatit is characterized by severely impaired osteoblast activity resulting from blocked osteogenesis in bonemarrow-derived mesenchymal stem cells (BM-MSCs). The mechanisms underlying this preferentialblockade are incompletely understood. Methods miRNA expression of MM cell-derived extracellular vesicles (MM-EVs) was detected by RNAsequencing. MM-EVs impaired osteogenesis and exacerbated MBD were in vitro and in vivo validated byhistochemical staining, qPCR and micro-CT. We additionally examined the correlation between CD138+circulating EVs (cirEVs) count and bone lesion in de novo MM patients. Results Here, by sequencing and bioinformatics analysis, we found that MM-EVs were enriched invarious molecules negatively regulating osteogenesis. We experimentally verified that MM-EVs inhibitedBM-MSC osteogenesis, induced elevated expression of miR-103a-3p inhibiting osteogenesis in BM-MSCs,and increased cell viability and interleukin-6 secretion in MM cells. In a mouse model, MM-EVs that wereinjected into the marrow space of the left tibia led to impaired osteogenesis and exacerbated MBD andMM progression. Furthermore, the levels of CD138+ cirEVs in the peripheral blood were positivelycorrelated with the number of MM bone lesions in MM patients. Conclusions These findings suggest that MM-EVs play a pivotal role in the development of severelyimpaired osteoblast activity, which represents a novel biomarker for the precise diagnosis of MBD and acompelling rationale for exploring MM-EVs as a therapeutic target.

Лучевая диагностика экстрамедуллярных поражений у пациента со множественной миеломой

Extraosseous manifestations are found in less than 5% of patients with multiple myeloma. Involvement of the gastrointestinal system in the course of multiple myeloma (MM) is extremely rare. Imaging is required for correct staging, in the followup after treatment and is predictor of prognosis. Several imaging technologies are used for the diagnosis and management of patients with MM. Conventional radiography, computed tomography (CT), magnetic resonance imaging (MRI) and nuclear medicine imaging - positron emission tomography (PET) combined with CT (PET/CT) and PET combined with MRI (PET/MRI) are all used in clarifying the extent of bone and soft tissue lesions in MM. The brief literature review on extramedullary lesions in MM and their imaging with recommendations is given. We describe the imaging in diagnostics and management of an rare case of secondary extramedullary plasmacytoma (EMP) in relapse involving the pancreas and duodenum with the bleeding in a patient with MM, IgA lambda, stage II, after 6-years treatment with chemotherapy, autologous peripheral blood stem cell transplantation and radiotherapy. EMP was detected by PET/CT before the appearance of obvious clinical signs, and then EMP was monitoring by PET/CT, X-ray and ultrasound.

Utilization Patterns of Single Fraction Radiation Therapy for Multiple Myeloma

BackgroundPatients with multiple myeloma (MM) are living longer than ever before thanks to new therapies. As a consequence, radiation therapy (RT) is increasingly important in the management of bone lesions from MM. Current American Society for Radiation Oncology guidelines recommend greater usage of 8 Gy in 1 fraction for treatment of these lesions. The objective of this study is to analyze utilization of 8 Gy in 1 fraction for treatment of MM bone lesions in the United States utilizing the National Cancer Data Base (NCDB). Materials and MethodsThe NCDB was used to identify patients with MM treated with palliative RT for painful bony lesions in the period between 2004 and 2014. Utilization rate of RT in this patient population as well as single-fraction (SFRT) versus multiple-fraction RT (MFRT) was compared according to demographic, socioeconomic, and logistic details. ResultsA total of 95,190 patients met our inclusion criteria. Of these, 10,261 (10.8%) patients received RT, and a total of 243 (2.4%) of these patients received SFRT over the 10-year period. There was an 11.73% annual increase (P = .0001) in SFRT utilization from 2004 to 2014. Older age, black race, longer distance from the treatment facility, lower degree of education, treatment at an academic or integrated healthcare network, worse comorbidities, and more recent diagnoses were all associated with increased usage of SFRT. ConclusionSFRT for the management of MM painful bony metastases remains underutilized. Trends show that radiation oncologists do not appear to be changing their approach to treating this disease.

Tumor-derived extracellular vesicles inhibit osteogenesis and exacerbate myeloma bone disease.

Background: As a hallmark driver of multiple myeloma (MM), MM bone disease (MBD) is unique in that it is characterized by severely impaired osteoblast activity resulting from blocked osteogenesis in bone marrow-derived mesenchymal stem cells (BM-MSCs). The mechanisms underlying this preferential blockade are incompletely understood.Methods: miRNA expression of MM cell-derived extracellular vesicles (MM-EVs) was detected by RNA sequencing. MM-EVs impaired osteogenesis and exacerbated MBD were in vitro and in vivo validated by histochemical staining, qPCR and micro-CT. We additionally examined the correlation between CD138+ circulating EVs (cirEVs) count and bone lesion in de novo MM patients.Results: Here, by sequencing and bioinformatics analysis, we found that MM-EVs were enriched in various molecules negatively regulating osteogenesis. We experimentally verified that MM-EVs inhibited BM-MSC osteogenesis, induced elevated expression of miR-103a-3p inhibiting osteogenesis in BM-MSCs, and increased cell viability and interleukin-6 secretion in MM cells. In a mouse model, MM-EVs that were injected into the marrow space of the left tibia led to impaired osteogenesis and exacerbated MBD and MM progression. Furthermore, the levels of CD138+ cirEVs in the peripheral blood were positively correlated with the number of MM bone lesions in MM patients.Conclusions: These findings suggest that MM-EVs play a pivotal role in the development of severely impaired osteoblast activity, which represents a novel biomarker for the precise diagnosis of MBD and a compelling rationale for exploring MM-EVs as a therapeutic target.