Evaluation Of Multiple Myeloma Research Articles

Comorbidity indices for prognostic evaluation in multiple myeloma: a comprehensive evaluation of the Revised Myeloma Comorbidity Index and other comorbidity indices with pro- and retrospective applications.

Not available.

Constitutive Turbodomains enhance expansion and antitumor activity of allogeneic BCMA CAR T cells in preclinical models.

The magnitude of CAR T cell expansion has been associated with clinical efficacy. Although cytokines can augment CAR T cell proliferation, systemically administered cytokines can result in toxicities. To gain the benefits of cytokine signaling while mitigating toxicities, we designed constitutively active synthetic cytokine receptor chimeras (constitutive Turbodomains) that signal in a CAR T cell-specific manner. The modular design of Turbodomains enables diverse cytokine signaling outputs from a single homodimeric receptor chimera and allows multiplexing of different cytokine signals. Turbodomains containing an IL-2/15Rβ-derived signaling domain closely mimicked IL-15 signaling and enhanced CAR T cell potency. Allogeneic TurboCAR T cells targeting BCMA showed no evidence of aberrant proliferation yet displayed enhanced expansion and antitumor activity, prolonging survival and preventing extramedullary relapses in mouse models. These results illustrate the potential of constitutive Turbodomains to achieve selective potentiation of CAR T cells and demonstrate the safety and efficacy of allogeneic BCMA TurboCAR T cells, supporting clinical evaluation in multiple myeloma.

Potential future direction of measurable residual disease evaluation in multiple myeloma

AbstractMultiple myeloma remains an incurable disease plagued by high relapse rates. Deeper and more sustainable responses, however, have been consistently shown to improve outcomes and could eventually pave the way to achieving a cure. Our understanding of disease response has surpassed complete response (CR), because the current definitions are suboptimal, and the treatment goal should aim even beyond stringent CR, toward molecular and flow CR, that is, measurable residual disease (MRD) negativity. It has been more than 20 years since the discrepancy in the outcome between patients in CR with and without MRD has been demonstrated, and the field has come a long way from multiparameter flow cytometry to next-generation flow and next-generation sequencing, able to detect up to a limit of detection of a single myeloma cell from 1 million healthy counterparts. This review aims to summarize the current available data regarding MRD but also its potential future use as a coprimary outcome both in clinical and trial settings as a survival surrogate as well as its use to evaluate treatment efficacy and for adaptive response-based and early-rescue therapy. Furthermore, we discuss whether these concepts are applicable in different settings (eg, newly diagnosed and relapsed/refractory myeloma, patients who are eligible and ineligible for tansplant, and standard- and high-risk disease).

The Global Prevalence of Vitamin D Deficiency and Insufficiency in Patients with Multiple Myeloma: A Systematic Review and Meta-Analysis.

Multiple myeloma (MM) is a hematological malignancy characterized by the exponential growth of malignant plasma cells. Individuals diagnosed with MM exhibit a deficiency in vitamin D and may suffer fatigue, a loss of muscular strength, persistent musculoskeletal aches, and pain. The objective of this systematic review and meta-analysis is to determine the prevalence of vitamin D insufficiency and deficiency in individuals diagnosed with MM. We searched five electronic databases using relevant keywords. The quality of the included studies was evaluated using the critical appraisal tool developed by the Joanna Briggs Institute. We employed a random-effects model and presented the findings in the form of percentages accompanied by 95% confidence intervals (CI). This protocol has been officially registered in PROSPERO under the registration number CRD42021248710. The meta-analysis comprised a total of eighteen studies and found that, among patients with MM, the occurrence of serum vitamin D deficiency and insufficiency was 39.4% (95% CI: 25.8 to 52.9, n = 3746) and 34.1% (95% CI: 20.9 to 47.2, n = 3559), respectively. The findings indicate that a greater proportion of newly diagnosed patients exhibited vitamin D deficiency and insufficiency, with rates of 43.0% and 41.6%, respectively, compared to those receiving treatment (rates of 41.6% and 32.3%, respectively). The findings of the sensitivity analyses were consistent, and most of the studies (72.2%) were deemed to be of high quality. The results of Egger's test indicated the absence of publication bias. Patients diagnosed with MM have been found to exhibit significantly elevated levels of both vitamin D deficiency and insufficiency. Therefore, it is recommended to consider vitamin D testing as an additional parameter in the current criteria for the clinical evaluation of MM.

Drug combinations identified by high-throughput screening promote cell cycle transition and upregulate Smad pathways in myeloma

Drug resistance and disease progression are common in multiple myeloma (MM) patients, underscoring the need for new therapeutic combinations. A high-throughput drug screen in 47 MM cell lines and in silico Huber robust regression analysis of drug responses revealed 43 potentially synergistic combinations. We hypothesized that effective combinations would reduce MYC expression and enhance p16 activity. Six combinations cooperatively reduced MYC protein, frequently over-expressed in MM and also cooperatively increased p16 expression, frequently downregulated in MM. Synergistic reductions in viability were observed with top combinations in proteasome inhibitor-resistant and sensitive MM cell lines, while sparing fibroblasts. Three combinations significantly prolonged survival in a transplantable Ras-driven allograft model of advanced MM closely recapitulating high-risk/refractory myeloma in humans and reduced viability of ex vivo treated patient cells. Common genetic pathways similarly downregulated by these combinations promoted cell cycle transition, whereas pathways most upregulated were involved in TGFβ/SMAD signaling. These preclinical data identify potentially useful drug combinations for evaluation in drug-resistant MM and reveal potential mechanisms of combined drug sensitivity.

Liquid biopsy and blood-based minimal residual disease evaluation in multiple myeloma.

Novel drug availability has increased the depth of response and revolutionised the outcomes of multiple myeloma patients. Minimal residual disease evaluation is a surrogate for progression-free survival and overall survival and has become widely used not-only in clinical trials but also in daily patient management. Bone marrow aspiration is the gold standard for response evaluation, but due to the patchy nature of myeloma, false negatives are possible. Liquid biopsy and blood-based minimal residual disease evaluation consider circulating plasma cells, mass spectrometry or circulating tumour DNA. This approach is less invasive, can provide a more comprehensive picture of the disease and could become the future of response evaluation in multiple myeloma patients.

What matters most to patients with multiple myeloma? A Pan-European patient preference study.

Given the rapid increase in novel treatments for patients with multiple myeloma (MM), this patient preference study aimed to establish which treatment attributes matter most to MM patients and evaluate discrete choice experiment (DCE) and swing weighting (SW) as two elicitation methods for quantifying patients' preferences. A survey incorporating DCE and SW was disseminated among European MM patients. The survey included attributes and levels informed by a previous qualitative study with 24 MM patients. Latent class and mixed logit models were used to estimate the DCE attribute weights and descriptive analyses were performed to derive SW weights. MM patients and patient organisations provided extensive feedback during survey development. 393 MM patients across 21 countries completed the survey (M years since diagnosis=6; M previous therapies=3). Significant differences (p<.01) between participants' attribute weights were revealed depending on participants' prior therapy experience, and their experience with side-effects and symptoms. Multivariate analyses showed that participants across the three MM patient classes identified via the latent class model differed regarding their past number of therapies (F=4.772, p=.009). Patients with the most treatments (class 1) and those with the least treatments (class 3) attached more value to life expectancy versus quality of life-related attributes such as pain, mobility and thinking problems. Conversely, patients with intermediary treatment experience (class 2) attached more value to quality of life-related attributes versus life expectancy. Participants highlighted the difficulty of trading-off between life expectancy and quality of life and between physical and mental health. Participants expressed a need for greater psychological support to cope with their symptoms, treatment side-effects, and uncertainties. With respect to patients' preferences for the DCE or SW questions, 42% had no preference, 32% preferred DCE, and 25% preferred SW. Quality of life-related attributes affecting MM patients' physical, mental and psychological health such as pain, mobility and thinking problems were considered very important to MM patients, next to life expectancy. This underscores a need to include such attributes in decision-making by healthcare stakeholders involved in MM drug development, evidence generation, evaluation, and clinical practice. This study highlights DCE as the preferred methodology for understanding relative attribute weights from a patient's perspective.

The Apparent Diffusion Coefficient of Diffusion-Weighted Whole-Body Magnetic Resonance Imaging Affects the Survival of Multiple Myeloma Independently.

BackgroundDiffusion-weighted whole-body MRI (DW-MRI) is increasingly used to evaluate bone diseases of multiple myeloma (MM), but there is lack of quantitative indicator for DW-MRI to reflect the prognosis of MM. Apparent diffusion coefficient (ADC) values in DW-MRI has potential correlations between some indexes of MM, but the influence of ADC on MM survival needs to be further verified.MethodsA total of 381 newly diagnosed MM patients were enrolled in the study to analyze the effect of ADC values in DW-MRI on progression-free survival (PFS) and overall survival (OS). The Kaplan–Meier method was used to perform univariate survival analysis, and the Cox proportional hazards model was used for multivariate analysis. In addition to the ADC value, genetic and serological indexes were also included.ResultsThe survivals were observed in univariate ADC stratification with median PFS of 52.0, 45.0, 34.0, and 26.0 months (the unit of ADC value was 10−3 mm2/s; the ADC ranges were ADC < 0.4886, 0.4886 ≤ ADC < 0.6545, 0.6545 ≤ ADC < 0.7750, and ADC ≥ 0.7750; 95% CI, 43.759–62.241, 46.336–53.664, 39.753–46.247, and 27.812–32.188). The OS were 81.0, 61.0, 47.0, and 36.0 months (p < 0.001; 95% CI, 71.356–82.644, 67.630–70.370, 57.031–60.969, and 36.107–43.893). In Cox proportional hazards model, the ADC value was considered to be an independent risk factor affecting PFS and OS of MM (both p < 0.001).ConclusionsThis study supports that ADC in DW-MRI may independently stratify MM patients and better predict their prognosis. The combined use of DW-MRI and other parameters allows more accurate evaluation of MM survival.Trial Registrationhttp://www.chictr.org.cn/showproj.aspx?proj=49012, ChiCTR2000029587.

Machine Learning and Deep Learning Applications in Multiple Myeloma Diagnosis, Prognosis, and Treatment Selection.

Simple SummaryMultiple myeloma is a malignant neoplasm of plasma cells with complex pathogenesis. With major progresses in multiple myeloma research, it is essential that we reconsider our methods for diagnosing and monitoring multiple myeloma disease. This fact needs the integration of serology, histology, radiology, and genetic data; therefore, multiple myeloma study has generated massive quantities of granular high-dimensional data exceeding human understanding. With improved computational techniques, artificial intelligence tools for data processing and analysis are becoming more and more relevant. Artificial intelligence represents a wide set of algorithms for which machine learning and deep learning are presently among the most impactful. This review focuses on artificial intelligence applications in multiple myeloma research, first illustrating machine learning and deep learning procedures and workflow, followed by how these algorithms are used for multiple myeloma diagnosis, prognosis, bone lesions identification, and evaluation of response to the treatment.Artificial intelligence has recently modified the panorama of oncology investigation thanks to the use of machine learning algorithms and deep learning strategies. Machine learning is a branch of artificial intelligence that involves algorithms that analyse information, learn from that information, and then employ their discoveries to make abreast choice, while deep learning is a field of machine learning basically represented by algorithms inspired by the organization and function of the brain, named artificial neural networks. In this review, we examine the possibility of the artificial intelligence applications in multiple myeloma evaluation, and we report the most significant experimentations with respect to the machine and deep learning procedures in the relevant field. Multiple myeloma is one of the most common haematological malignancies in the world, and among them, it is one of the most difficult ones to cure due to the high occurrence of relapse and chemoresistance. Machine learning- and deep learning-based studies are expected to be among the future strategies to challenge this negative-prognosis tumour via the detection of new markers for their prompt discovery and therapy selection and by a better evaluation of its relapse and survival.

MiRNA-seq and clinical evaluation in multiple myeloma: miR-181a overexpression predicts short-term disease progression and poor post-treatment outcome.

Despite significant advances in multiple myeloma (MM) therapy, disease relapse and treatment resistance remain major obstacles in clinical management. Herein, we have studied the clinical utility of miRNAs in improving patients' risk-stratification and prognosis. miRNA-seq was performed in CD138+ plasma cells of MM, smoldering multiple myeloma (sMM) and monoclonal gammopathy of undetermined significance (MGUS) patients. The screening MM cohort consisted of 138 patients. miRNA levels of CD138+ plasma cells were quantified by RT-qPCR following 3'-end RNA polyadenylation. Disease progression and patients' death were used as clinical end-point events. Internal validation was conducted by bootstrap analysis. Clinical net benefit on disease prognosis was assessed by decision curve analysis. Kruykov et al. 2016 served as validation cohort (n = 151). miRNA-seq highlighted miR-181a to be upregulated in MM vs. sMM/MGUS, and R-ISS III vs. I patients. Screening and validation cohorts confirmed the significantly higher risk for short-term progression and worse survival of the patients overexpressing miR-181a. Multivariate models integrating miR-181a with disease established markers led to superior risk-stratification and clinical benefit for MM prognosis. CD138+ overexpression of miR-181a was strongly correlated with inferior disease outcome and contributed to superior prediction of MM patients early progression, supporting personalised prognosis and treatment decisions.

Harmonization of Flow Cytometric Minimal Residual Disease Assessment in Multiple Myeloma in Centers of Polish Myeloma Consortium.

Minimal residual disease (MRD) status is now considered as one of the most relevant prognostic factors in multiple myeloma (MM) while MRD negativity became an important endpoint in clinical trials. Here, we report the results of the first study evaluating the reproducibility of high-sensitivity flow cytometry MM MRD assessment in four laboratories in Poland. EuroFlow protocols for instrument setting standardization and sample preparation in MM MRD assessment were implemented in each laboratory. In the inter-laboratory reproducibility study, 12 bone marrow samples from MM patients were distributed and processed in participant laboratories. In the inter-operator concordance study, 13 raw data files from MM MRD measurements were analyzed by five independent operators. The inter-laboratory study showed high 95% overall concordance of results among laboratories. In the inter-operator study, 89% of MRD results reported were concordant, and the highest immunophenotype interpretation differences with regard to expression of CD27, CD45, CD81 were noticed. We confirmed the applicability and feasibility of the EuroFlow protocol as a highly sensitive method of MRD evaluation in MM. Results of our inter-center comparison study demonstrate that the standardization of MM MRD assessment protocols is highly desirable to improve quality and comparability of results within and between different clinical trials.

P-011: 18F-FDG PET/MRI for imaging minimal residual disease evaluation in Multiple Myeloma

<h3>Background</h3> Functional imaging in Multiple Myeloma (MM) plays a crucial role in defining bone disease response. According to IMWG guidelines,18FDG PET/CT represents the only technique recognized to define imaging minimal residual disease (MRD) negativity. More recently, Whole body Diffusion Weighted Imaging (WB DWI)-MRI represents a non ionizing radiation imaging modality with a potential impact on evaluating myeloma bone disease response. Consequently, patients achieving both PET/CT and WB DWI-MRI negativity after treatment showed improved progression free survival (PFS) as compared to patients with single PET or MRI negativity. In the last years, a novel functional technique combining both 18FDG PET with WB DWI-MRI (PET/MRI) has been developed. In this study, we evaluated PET/MRI for bone disease response assessment in MM. <h3>Methods</h3> We retrospectively studied 27 patients (12 female and 15 male) affected by newly diagnosed active MM. All patients received a combined 18F-FDG PET/MRI registering T1w signal, T2w STIR (short tau inversion recovery) signal, DWI (diffusion weighted imaging) signal, mean ADC (apparent diffusion coefficient) value and SUV (standardized uptake volume) max value at diagnosis and at the end of the therapeutic program [after autologous stem cell transplantation (ASCT) or consolidation treatment]. PET and MRI negativity was assessed using Deauville score (DS) and MY-RADS Response Assessment Category (RAC). Median age of the entire cohort was 57 years (44-69). Considering high risk disease features, 7/27 cases were ISS III (25.9%), 2/27 were R-ISS III (7.4%) while 7/26 (26.9%) patients harbored high risk FISH abnormalities [including t(4;14), t(14;16) and del17p]. Bone lytic lesions were detected in almost all patients (24/27, 88.9%), followed by anemia (17/27, 63%), hypercalcemia (3/27, 11.1%) and renal injury (2/27, 7.4%). All patients received bortezomib-thalidomide-dexamethasone induction regimen followed by ASCT. <h3>Results</h3> At the end of the therapeutic program, the overall response rate was 92.6%, with 37% (10/27) achieving a complete response. Regarding baseline PET/MRI evaluation, focal lesions (FLs) were detected in 23 patients, with mean SUVmax of 4.4+/-2.78 and mean ADC of 963+/-264.6 mm2/s. End of treatment PET/MRI showed a PET negativity (DS<3) in 14/27 (51.9%) patients and an MRI negativity (MY-RADS<2) in 18/27 (66.7%) cases. With a median follow up of 33 months, patients with concomitant PET and MRI negativity showed improved PFS with respect to patients with PET or MRI positivity (not reached vs 58 months, p=0.0396). By multivariate analysis, concomitant PET and MRI negativity was associated with better PFS independently from ISS and FISH (p=0.0472). <h3>Conclusions</h3> To our knowledge, this is the first study evaluating PET/MRI for bone disease response in MM. Our data provide evidence that PET/MRI represents a promising tool for imaging MRD negativity evaluation, with patients being both PET and MRI negative showing improved PFS.

Role of whole-body diffusion-weighted imaging in evaluation of multiple myeloma.

The evaluation of bone disease in multiple myeloma (MM) is an important topic in imaging. This study retrospectively investigated whole-body diffusion-weighted imaging (WB-DWI) in the evaluation of bone marrow infiltration and treatment response in MM.A total of 126 patients with MM who underwent WB-DWI between January 2016 and December 2020 were enrolled. All the patients received 4-course induction chemotherapy. WB-DWI was performed before and after chemotherapy to measure the apparent diffusion coefficient (ADC) values. According to gender and Revised International Staging System (RISS) staging groups, the relationship between ADC value and bone marrow plasma cell infiltration ratio before treatment were explored using Spearman and Pearson correlation coefficients. Comparison of ADC values before and after treatment according to different chemotherapy regimens and treatment response was performed by 2-independent samples non-parametric tests and t test.There was a negative correlation between the ADC value and the degree of bone marrow infiltration and this was statistically significant (r = –0.843, P < .001). In different gender and RISS groups, ADC value before treatment was negatively correlated with the proportion of plasma cell infiltration (male, r = –0.849; female, r = –0.836; Stage I, r = –0.659; Stage II, r = –0.870; Stage III, r = –0.745; all P < .001). The ADC values of all subjects increased to varying degrees after 4-course induction chemotherapy, including different chemotherapy regimens and treatment responses (all P < .05 except for progressive disease group).The ADC value was negatively correlated with the degree of bone marrow infiltration in different gender and RISS stages. The ADC value increased after treatment, but it was not consistent with progressive disease group. The increase of ADC value may indicate the disease burden and outcome of MM induced chemotherapy.

Patient Preferences for Multiple Myeloma Treatments: A Multinational Qualitative Study.

Background: Investigational and marketed drugs for the treatment of multiple myeloma (MM) are associated with a range of characteristics and uncertainties regarding long term side-effects and efficacy. This raises questions about what matters most to patients living with this disease. This study aimed to understand which characteristics MM patients find most important, and hence should be included as attributes and levels in a subsequent quantitative preference survey among MM patients.Methods: This qualitative study involved: (i) a scoping literature review, (ii) discussions with MM patients (n = 24) in Belgium, Finland, Romania, and Spain using Nominal Group Technique, (iii) a qualitative thematic analysis including multi-stakeholder discussions.Results: MM patients voiced significant expectations and hopes that treatments would extend their lives and reduce their cancer signs and symptoms. Participants however raised concerns about life-threatening side-effects that could cause permanent organ damage. Bone fractures and debilitating neuropathic effects (such as chronic tingling sensations) were highlighted as major issues reducing patients' independence and mobility. Patients discussed the negative impact of the following symptoms and side-effects on their daily activities: thinking problems, increased susceptibility to infections, reduced energy, pain, emotional problems, and vision problems. MM patients were concerned with uncertainties regarding the durability of positive treatment outcomes, and the cause, severity, and duration of their symptoms and side-effects. Patients feared short-term positive treatment responses complicated by permanent, severe side-effects and symptoms.Conclusions: This study gained an in-depth understanding of the treatment and disease-related characteristics and types of attribute levels (severity, duration) that are most important to MM patients. Results from this study argue in favor of MM drug development and individual treatment decision-making that focuses not only on extending patients' lives but also on addressing those symptoms and side-effects that significantly impact MM patients' quality of life. This study underscores a need for transparent communication toward MM patients about MM treatment outcomes and uncertainties regarding their long-term efficacy and safety. Finally, this study may help drug developers and decision-makers understand which treatment outcomes and uncertainties are most important to MM patients and therefore should be incorporated in MM drug development, evaluation, and clinical practice.

New Alternatives for the Evaluation of Minimal Residual Disease (MRD) Detection By Next Generation Sequencing in Multiple Myeloma

New Alternatives for the Evaluation of Minimal Residual Disease (MRD) Detection By Next Generation Sequencing in Multiple Myeloma

Next Generation Flow (NGF) Cytometry for Minimal Residual Disease (MRD) Evaluation in Multiple Myeloma (MM) Patients with Sustained Complete Response (CR) after Frontline Therapy: Results of a Prospective Single-Center Analysis

MRD evaluation is included in the novel IMWG response criteria with a minimum sensitivity level for MRD- that of 10-5. However, several data suggest a sensitivity level of at least 10- for MRD- may be more appropriate. Such high sensitivity would be particularly relevant to identify, among MM patients who remain at sustained response for several years, those who may still be at risk of relapse due to persistent MRD and for whom closer monitoring could be beneficial. Thus, the primary endpoint of this prospective study was to evaluate the incidence of MRD- in patients who remained in CR for ≥2-years after first line therapy, using NGF. Secondary endpoints included the detection level of MRD, the reproducibility of the method, and the correlation of MRD status with the hematopoietic bone marrow (BM) profile defined by NGF as well as with prognostic factors at diagnosis. Fifty-two patients who were treated at the Department of Clinical Therapeutics (Athens, Greece) and were in sustained CR for ≥2-years (median period of CR: 58 months, range: 24-197 months) were evaluated for the presence of MRD using NGF, according to the EuroFlow guidelines. BM samples were labeled using two independent 8-color panels, both containing CD19-PEC7, CD27-BV510, CD38-FITC, CD45-PERCP, CD56-PE, CD138-BV421 and additionally CD81-APCC750 and CD117-APC for the surface tube or CyIgκ-APC and CyIgλ-APCC750 for the intracytoplasmic tube. A minimum of ten million events were recorded per patient-sample with a BD FACSCantoII and data analysis was conducted with Infinicyt software, allowing merging of the two panels and detection of MRD with a median sensitivity level of 2.2x10-6 (range, 2.1x10-6 - 2.8x10-6). Two independent experts evaluated the results for reproducibility assessment. Using the same markers, we identified the major BM cell subsets (erythroid and myeloid progenitors, erythroblasts, T, NK and NKT cells, naive B cells, memory B cells and B-cell precursors, neutrophils, monocytes, basophils, eosinophils and mast cells) and analyzed the hematopoietic profile of each patient. Our analysis revealed 30 (58%) MRD- and 22 (42%) MRD+ patients, mostly at the level of 10-5 (n=7/22, 32%) and 10-6 (n=5/22, 23%). The reproducibility of the method was 98%, as there was only one disagreement between the two independent researchers (one patient who was MRD+ at the level of 10-6) and MRD levels were significantly correlated (r=0.892, p The MRD status was not associated with any of the prognostic clinical parameters at diagnosis (age, ISS, cytogenetic profile or LDH), although the majority of MRD+ had ISS-1 disease (58%). Three (10%) MRD- patients and 3 (14%) MRD+ had high-risk cytogenetics. Nineteen (61%) MRD- patients and 13 (62%) MRD+ had received ASCT. There were no differences regarding frontline therapy among MRD- and MRD+ patients (PI- vs IMiDs- vs PI+IMiD-based therapies). We demonstrated that the NGF method by EuroFlow can be standardized, and provide a detection MRD level of 2.1x10-6 with high reproducibility rate. We also showed that 40% of MM patients in prolonged CR have persistent MRD+. Interestingly, such patients displayed more erythroblasts and monocytes together with increased T, NK and NK-T cell numbers. By contrast, no significant clinical differences were observed between MRD+ and MRD- patients with ≥2-years in CR. Thus, NGF-based MRD assessment is warranted to discriminate independently of treatment or disease risk, patients reaching sustained CR that could have higher risk of relapse due to persistent MRD and may benefit from closer monitoring. Disclosures Terpos: Janssen: Honoraria, Research Funding; Amgen: Honoraria, Other: SC member, Research Funding; Abbvie: Honoraria; BMS: Honoraria; Genesis/Celgene: Honoraria, Other: DMC member, Research Funding; GSK: Honoraria; Takeda: Honoraria, Other: SC member. Kastritis: Genesis pharma: Honoraria; Janssen: Honoraria; Prothena: Honoraria; Takeda: Honoraria; Amgen: Honoraria, Research Funding. Paiva: EngMab: Research Funding; Amgen: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Novartis: Honoraria; Sanofi: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Merck: Honoraria. Dimopoulos: Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology: Consultancy, Honoraria, Other: Advisory Committee: Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology; Novartis: Consultancy, Honoraria; Genesis Pharma: Research Funding.

Malignant plasmacytes in bone marrow detected by flow cytometry as a predictor for the risk stratification system of multiple myeloma.

Multiple myeloma (MM) is a clonal disorder characterized by the proliferation of plasma cells and their accumulation within the bone marrow (BM). The flow cytometric analysis is an essential method for the hematological diseases because of high sensitivity. This study evaluates the indication role of malignant plasmacytes (PCs) in BM detected by flow cytometry for the risk stratification of MM. Whole BM samples from 92 newly diagnosed MM patients were included in the study. We collected 106 cells each sample by flow cytometry. Then we analyzed the correlation between the malignant PCs in BM and the characteristics of patients. In this study, patients were stratified according to different baseline characteristics and the median ratio of the malignant PCs were compared. The significant statistical differences (p < 0.05) were: Hb < 100 g/L versus ≥100 g/L; β2-microglobulin <3.5 mg/dL versus 3.5-5.5 mg/dL versus >5.5 mg/dL; LDH > 250 U/L versus LDH 250 U/L; ISS I versus ISS II versus ISS III; R-ISS I versus II versus III. The detailed data are showed in Table 2. The significant correlations were observed between the malignant PCs in BM and (Figure 1): plasma cell of biopsy, hemoglobin, β2-microglobulin, lactate dehydrogenase (LDH), creatinine. "Double hit" or "triple hit" are defined as containing any two or three of the high risk cytogenetic abnormalities (t(4;14), t(14;16), t(14;20); del17q; TP53 mutation; 1q21 gain) by mSMAR. "Double or triple hit" had independently unfavorable significance for overall survival. As expected, the malignant PCs of "double or triple hit" group is significantly higher than the group B (one high risk genetic factor) and the group A (normal cytogenetic) (p < 0.0001 and p < 0.019). Multiparametric flow cytometry is a highly sensitive method to identify and quantify malignant PCs. And the ratio of malignant PCs detected by MFC showed strongly correlation with the severity of the pathology of MM. Malignant PCs in BM detected by flow cytometry could be regarded as a predictor for the risk stratification system of MM. Thus, it should be considered applying in the routine evaluation of MM at diagnosis and after therapy.

Analysis of Serum Metabonomics in Patients with Multiple Myeloma Based on Liquid Chromatography-Mass Spectrometry

To observe the changes of serum metabolites in patients with multiple myeloma (MM) by metabonomics, and explore the potential biomarkers for diagnosis, prognosis, and progression of MM. Serum samples were collected from 26 patients with MM and 50 healthy controls. The data detected by liquid chromatography-mass spectrometry (LC-MS) was input into SIMCA-14.0 software for multivariate statistical analysis. Principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), and orthogonal partial least squares discriminant analysis (OPLS-DA) were used to analyze the changes of metabolites. The metabolic change of uric acid and trans-vaccenic acid in serum samples of MM patients was 9.39 times and 2.77 times of these in healthy people, respectively, which were significantly higher than those of healthy people, and the difference was statistically significant(P<0.01). Uric acid and trans-vaccenic acid are expected to be important metabolic indicators for the diagnosis, prognosis, and efficacy evaluation of MM, thus providing some clues for the pathogenesis of MM.

Is whole body low dose CT still necessary in the era of 18F-FDG PET/CT for the assessment of bone disease in multiple myeloma patients?

Whole body low dose computed tomography (WBLDCT) is the first-choice imaging modality to identify bone involvement in multiple myeloma (MM). Because the unenhanced LDCT co-registered to positron emission tomography (PET) (LDCT/PET) has similar technical characteristics to WBLDCT, we aimed to assess its reliability in the detection of bone disease, for employing fluorine-18-fluorodeoxyglucose (18F-FDG) PET/CT as unique multimodality imaging method in MM patients. Thirty three consecutive MM patients were prospectively enrolled and evaluated with WBLDCT to assess bone involvement. In addition, patients underwent 18F-FDG PET/CT using a disease-tailored optimized LDCT protocol. To compare both methods, skeletal anatomical regions were identified and a per-region and per-patient analysis were performed using Cohen's k test. Low dose computed tomography/PET sensitivity, specificity and accuracy were also calculated. The two imaging modalities resulted highly concordant considering both patient-based (k=0.841) and region-based analysis; some discrepancies were observed in dorsal spine (k=0.809) and thorax (k=0.756). Low dose computed tomography/PET sensitivity, specificity and accuracy were 89.4%, 98.3% and 93.5%, respectively. Low dose computed tomography co-registered PET has comparable performance to WBLDCT. If confirmed on a lager sample, these encouraging results suggest the possibility to use this multimodal hybrid imaging as the only method for MM evaluation, rather than both exams, providing both morphologic and metabolic information in one session with impact on patient compliance, health care spending and especially radiation exposure.

A Tangle of Genomic Aberrations Drives Multiple Myeloma and Correlates with Clinical Aggressiveness of the Disease: A Comprehensive Review from a Biological Perspective to Clinical Trial Results.

Multiple myeloma (MM) is a genetically heterogeneous disease, in which the process of tumorigenesis begins and progresses through the appearance and accumulation of a tangle of genomic aberrations. Several are the mechanisms of DNA damage in MM, varying from single nucleotide substitutions to complex genomic events. The timing of appearance of aberrations is well studied due to the natural history of the disease, that usually progress from pre-malignant to malignant phase. Different kinds of aberrations carry different prognostic significance and have been associated with drug resistance in some studies. Certain genetic events are well known to be associated with prognosis and are incorporated in risk evaluation in MM at diagnosis in the revised International Scoring System (R-ISS). The significance of some other aberrations needs to be further explained. Since now, few phase 3 randomized trials included analysis on patient’s outcomes according to genetic risk, and further studies are needed to obtain useful data to stratify the choice of initial and subsequent treatment in MM.