Myeloma Patients Research Articles

Identifying immune checkpoints on dysregulated T-cells as prognostic biomarkers for multiple myeloma patients with COVID-19.

Broad T cell phenotypic alterations and potential dysfunctions were prominent in COVID-19. There are few and inconclusive data about the role of immune checkpoints for T cell exhaustion/activation during SARS-CoV-2 infection in multiple myeloma (MM) patients. We tested T cell subsets and immune checkpoints in 177 MM patients with COVID-19, as well as in 32 healthy infected controls and 42 uninfected MM patients. The percentage of CD4+ and CD8+ subpopulation and immune checkpoints (PD-1, TIGIT, TIM-3, LAG-3, CTLA-4, OX40, and 4-1BB) were evaluated by flow cytometry. We have found that pronounced lymphopenia and inverted CD4/CD8 ratio in severe COVID-19 patients were especially developed within the first month after infection. And T cell subset dysregulation was persistent in severe patients recovering from SARS-CoV-2 infection. Immune checkpoints on CD4+ T cells were variable and uncorrelated with the level of adaptive immunity, while the proportion of CD4+ T cells was positively correlated with humoral immune response. PD-1 and TIGIT on CD8+ T cells were significantly elevated in severe patients and sustained for more than 2 months, which was associated with impaired cellular immune function. Moreover, exhausted molecules PD-1 and TIGIT on T cells were reduced in immunotherapy patients. The prolonged T cell dysregulation after severe SARS-CoV-2 infection highlights the close surveillance from reinfection in MM patients even during convalescence. PD-1 and TIGIT on CD8+ T cells could be important prognostic factors to stratify prognosis in MM patients with COVID-19. Moreover, immunotherapy may downregulate the expression of exhausted checkpoints PD-1 and TIGIT, leading to T cell overactivation and severe COVID-19.

Modeling serum M-protein response for early detection of biochemical relapse in myeloma patients treated with bortezomib, lenalidomide and dexamethasone.

Multiple myeloma (MM) treatment guidelines recommend waiting for formal progression criteria (FPC) to be met before proceeding to the next line of therapy. As predicting progression may allow early switching to next-line therapy while the disease burden is relatively low, we evaluated the predictive accuracy of a mathematical model to anticipate relapse 180 days before the FPC is met. A subset of 470/1143 patients from the IA16 dataset who were initially treated with VRd (Velcade (bortezomib), Revlimid (lenalidomide), and dexamethasone) in the CoMMpass study (NCT01454297) were randomly split 2:1 into training and testing sets. A model of M-protein dynamics was developed using the training set and used to predict relapse probability in patients in the testing set given their response histories up to 12 or more months of treatment. The predictive accuracy of this model and M-protein "velocity" were assessed via receiver operating characteristics (ROC) analysis. The final model was a two-population tumor growth inhibition model with additive drug effect and transit delay compartments for cell killing. The ROC area under the curve value of relapse prediction 180 days ahead of observed relapse by FPC was 0.828 using at least 360 days of response data, which was superior to the M-protein velocity ROC score of 0.706 under the same conditions. The model can predict future relapse from early M-protein responses and can be used in a future clinical trial to test whether early switching to second-line therapy results in better outcomes in MM.

COVID-19 in patients receiving treatment at an outpatient chemotherapy unit.

During the COVID-19 pandemic period, many patients who required outpatient chemotherapy developed COVID-19, requiring chemotherapy interruption. However, there are no clear guidelines regarding the safe timing for restarting chemotherapy. We conducted a retrospective study to assess when such patients can safely recommence chemotherapy. Of the 40 patients included in this study, 34 restarted anticancer drug therapy after COVID-19 infection. Six patients, four with multiple myeloma, and one each with follicular lymphoma and glioma, remained SARS-CoV-2 antigen positive >20days after COVID-19 onset. Multiple myeloma patients recorded significantly higher frequencies of SARS-CoV-2 antigen positivity >20days after COVID-19 onset compared with solid tumor patients, with no significant differences in the frequency of SARS-CoV-2 positivity during 5-20days from COVID-19 onset between them. According to our data, most solid tumor patients achieved SARS-CoV-2 antigen negativity after 20days from COVID-19 onset. On the other hand, multiple myeloma patients might need serial antigen tests before restarting anticancer therapy in the outpatient chemotherapy setting.

Interferon Regulatory Factor 4: An Alternative Marker for Plasma Cells in Daratumumab-Treated Patients With Multiple Myeloma.

Anti-CD38 therapeutic modalities (e.g., daratumumab) can impede classical CD38 and CD138 gating use for plasma cell (PC) detection in multiple myeloma (MM) patients with minimal residual disease (MRD). We assessed the applicability of CD229, CD269, and interferon regulatory factor (IRF-4) for PC detection in MM MRD patients. Bone marrow samples were collected from patients with MM. Through multiparameter flow cytometry, we evaluated the suitability of CD229, CD269, and IRF-4 for distinguishing PCs from other hematopoietic cells and compared their expression pattern on normal PCs (nPCs) and aberrant PCs (aPCs). We also assessed IRF-4 expression stability after sample storage under different conditions. A 10-color MRD antibody panel was used to determine whether IRF-4 is an alternative primary PC-gating marker for MM MRD assessment. IRF-4 was expressed specifically on all PCs; its mean fluorescence intensity (MFI) was highest on PCs among all hematopoietic cells. This MFI did not decrease even after sample storage at 4°C or 25°C for 72 h. In all 42 MRD assessment samples, except for samples (n = 10) with no PCs, the use of IRF-4 enabled accurate nPC (n = 12), aPC (n = 13), and nPC + aPC (n = 7) identification. Even samples from daratumumab-treated patients had high IRF-4 MFI, with no difference between pre-treatment and post-treatment (n = 7; p = 0.610). IRF-4 demonstrates high MFI on PCs, and it is not expressed on other leukocytes. In MM patients with MRD, daratumumab treatment does not affect IRF-4 expression. IRF-4 is a promising marker for PC identification in MRD assessment of MM patients undergoing anti-CD38 therapy.

Chromosome 1q21 Aberrations Are Poor Prognostic Factors for Newly Diagnosed Multiple Myeloma Patients.

Chromosome 1q21 aberrations are one of the most common cytogenetic abnormalities in patients with multiple myeloma (MM). However, the prognostic value remains controversial. This study aimed to determine the prognostic value of numerical abnormalities of chromosome 1q21 for newly diagnosed patients with MM patients in Chinese population. We retrospectively analyzed 629 patients with newly diagnosed MM who received the detection of chromosome 1q21 by fluorescence insitu hybridization in China. Among 629 patients, 309 (49.1%) had 1q21 abnormalities, of which 187 (29.7%) had three copies and 122 (19.4%) had four or more copies. Patients with two copies of 1q21 had a significantly longer median overall survival (OS) than those with three copies or ≥4 copies and also had longer progression-free survival (PFS). However, patients with three or ≥4 copies had similar OS and PFS. Univariate Cox proportional hazards regression analyses determined that 1q21 aberrations are associated with shorter OS and PFS. 1q21 aberrations are also independent poor prognostic factors for OS and PFS in multivariable analyses. Del(17p), t(4;14), and t(14;16) are common high-risk cytogenetic abnormalities (HRCAs) in patients with MM. Patients with 1q21+ alone or 1q21+ combined with HRCAs had shorter OS and PFS than patients without cytogenetic abnormalities. Patients with 1q21+ and t(11;14) also had shorter PFS but had similar OS than patients without cytogenetic abnormalities. Our study showed that chromosome 1q21 aberrations are poor prognostic factors for newly diagnosed patients with MM.

Development of a Novel Peptide-Based PET Tracer [68Ga]Ga-DOTA-BP1 for BCMA Detection in Multiple Myeloma.

B-cell maturation antigen (BCMA) has emerged as a promising tumor marker for the diagnosis and treatment of multiple myeloma. The noninvasive and rapid detection of BCMA expression in vivo provides significant value in screening and evaluating multiple myeloma patients receiving BCMA-targeted therapy. We identified the BCMA-targeting peptide BP1 from a one-bead-one-compound (OBOC) peptide library using a high-throughput microarray strategy. The BCMA-targeting specificity and affinity of BP1 were assessed by surface plasmon resonance imaging (SPRi), flow cytometry, and confocal imaging. BCMA-positive (H929) and BCMA-negative (K562) subcutaneous tumor models were established and labeled with 68Ga for BP1, followed by PET imaging and biodistribution studies. PET imaging demonstrated that 68Ga-labeled BP1 has significant specific uptake in multiple myeloma, enabling rapid identification of BCMA expression and precise delineation of the disease. Thus, BP1 represents an ideal candidate for multiple myeloma imaging.

Launch of the myeloma and AL amyloidosis European clinical trial navigator by Myeloma Patients Europe: interview with Dr Solène Clavreul

Launch of the myeloma and AL amyloidosis European clinical trial navigator by Myeloma Patients Europe: interview with Dr Solène Clavreul

CXCR4-Targeted PET Imaging in Hematologic Malignancies: A Systematic Review and Meta-analysis.

The aims of this study were to perform a comprehensive review and meta-analyses and to report pooled diagnostic results on CXCR4-targeted PET, particularly considering detection, visualization, and prognostication. This study followed PRISMA-DTA. A systematic search was conducted on major medical literature databases up to March 1, 2024. The search strategy was designed to include CXCR4 PET studies in hematologic malignancies. A random-effects model combined sensitivity values derived from 2-by-2 contingency tables. Pooled means for SUVmax were computed. Analyses were performed by R software. The initial search resulted in a total of 1428 studies. Ultimately, 18 were eligible for systematic review and meta-analytic calculations. Twelve studies (320 patients) included B-cell lymphoma. The pooled detection rate of CXCR4 PET was 99.4% (95% confidence interval [CI]: 88.3%-100%). Marginal zone lymphoma was investigated in 5 studies (209 patients), with a pooled sensitivity of 97.6% (95% CI: 79.7%-99.8%). In studies on central nervous system lymphoma, CXCR4 PET demonstrated 100% accuracy at both patient and lesion levels. Also, it demonstrated a significantly higher tumor-to-background ratio than 18F-FDG PET. For multiple myeloma, 5 studies (116 patients) showed a patient-level pooled sensitivity of 77.8% (95% CI: 64.4%-87.2%), whereas 18F-FDG PET had 65.0% (95% CI: 55.2%-73.7%). The pooled SUVmax for CXCR4 PET was 13.6 (95% CI: 9.3-17.8) versus 9.0 (95% CI: 6.3-11.7) for 18F-FDG PET. Additionally, CXCR4 PET-derived parameters were significant predictors of survival in multiple myeloma. CXCR4 PET can be a helpful imaging tool for evaluating hematologic malignancies, particularly in B-cell lymphoma and multiple myeloma patients. In specific clinical scenarios, it appears to be superior compared with the current standard-of-care imaging.

Changes in immune subsets during chemotherapy as prognosis biomarkers for multiple myeloma patients by longitudinal monitoring.

Multiple myeloma (MM) is a malignancy of plasma cells accompanied by immune dysfunction. This study aimed to provide a comprehensive and dynamic characterization of the peripheral immune environment in MM patients and find its diagnostic and prognostic values for therapy. The peripheral immune profiles of MM inpatients and healthy controls were assessed by flow cytometry. A longitudinal study of immune subsets was observed during cycles of chemotherapy. The diagnostic and prognostic models were established based on immune subsets by the absolute shrinkage and selection operator (LASSO) and multivariate regression. MM patients possessed an impeded immune landscape, including reduced activation of B cells, increased effective T cells and regulatory T cells (Tregs), augmented CD16 expression on monocytes and dendritic cell percentages, decreased CD56dimCD16+ natural killer cells (NKs), and amplified CD56bright and HLA-DR+ natural killer T cells (NKTs). Chemotherapy has different dynamic effects on specific cells, of which 2 cycles is the key turning point. NKT, dendritic cells, naïve Tc and Th cells, HLA-DR+ Tc cells, CD56dim NKTs, CD16++ monocytes, and CD25+ B cells could have the diagnostic value, and a prognostic model including neutrophils, naïve Tc cells, CD56brightCD16dim NKs, and CD16+ dendritic cells was established with acceptable accuracy. Our data showed dynamic and abnormal peripheral immune profiles in MM patients, which had prognostic values and could provide the basis for clinical therapy.

Modest survival benefits of autologous stem cell transplantation in multiple myeloma with renal impairment: a critical appraisal of the pre-antibody era

The benefit of high-dose melphalan followed by autologous hematopoietic stem cell transplantation (HDM-ASCT) for multiple myeloma (MM) patients with renal insufficiency (RI) is debated. A systematic review and meta-analysis were conducted to assess the safety and efficacy of HDM-ASCT in MM patients with RIs, and the findings were compared with real-world data. The study included 26 articles, 13 of which were pooled for meta-analysis. We compared three different types of MM patients with RI against MM patients with normal renal function (NRF). These patients were: MM patients with RI at the time of transplantation; MM patients with RI at the time of diagnosis; MM patients with RI at diagnosis but with NRF at transplantation. The meta-analysis indicated that MM patients with RIs conditioned with melphalan ≤ 140 mg/m2 followed by ASCT had transplant-related mortality rates comparable to those without RIs. The complete response rates post-ASCT were similar between MM patients with RIs and those with NRF. Although progression-free survival (PFS) was statistically similar between the groups, MM patients with RIs had significantly poorer overall survival (OS) than those with NRF. The real-world data supported these findings. With a reduced dose of melphalan, ASCT is safe and effective for MM patients with RI. MM patients with RI have similar complete response rates and PFS after ASCT compared to MM patients with NRF. The lower OS in MM patients with RI indicates the need for further research to improve OS in these patients.

Increased RNA and protein degradation is required for counteracting transcriptional burden and proteotoxic stress in human aneuploid cells.

Aneuploidy results in a stoichiometric imbalance of protein complexes that jeopardizes cellular fitness. Aneuploid cells thus need to compensate for the imbalanced DNA levels by regulating their RNA and protein levels, but the underlying molecular mechanisms remain unknown. Here, we dissected multiple diploid vs. aneuploid cell models. We found that aneuploid cells cope with transcriptional burden by increasing several RNA degradation pathways, and are consequently more sensitive to the perturbation of RNA degradation. At the protein level, aneuploid cells mitigate proteotoxic stress by reducing protein translation and increasing protein degradation, rendering them more sensitive to proteasome inhibition. These findings were recapitulated across hundreds of human cancer cell lines and primary tumors, and aneuploidy levels were significantly associated with the response of multiple myeloma patients to proteasome inhibitors. Aneuploid cells are therefore preferentially dependent on several key nodes along the gene expression process, creating clinically-actionable vulnerabilities in aneuploid cells.

Induction prior to autologous haematopoietic cell transplantation in multiple myeloma.

Induction chemotherapy followed by autologous haematopoietic cell transplantation and post-transplant therapy (including maintenance therapy with or without prior consolidation) is still considered as the standard of care for newly diagnosed young and fit multiple myeloma patients. Over the last years, superiority of quadruplet regimens for induction was established, with the addition of an anti-CD38 monoclonal antibody to triplet regimen including a proteasome inhibitor, an IMiD (thalidomide or lenalidomide) or cyclophosphamide, and dexamethasone. Given quadruplet induction regimens are associated with deep response, including a high-rate of sustained measurable residual disease negativity in a significant proportion of patients, they are now recommended for induction chemotherapy when available.

Description of Feelings, Perception, and Experience Before and After Switching from IV Daratumumab to the SC Form: A Mixed-Method, Cross-Sectional Survey in Multiple Myeloma Patients in Europe.

To provide real-world data on patient perceptions and experiences with subcutaneous (SC) versus intravenous (IV) daratumumab. This was a cross-sectional, mixed-method (qualitative/quantitative) survey conducted in France, Germany, Spain and the United Kingdom involving multiple myeloma (MM) patients who switched from IV to SC daratumumab in the last 12 months (qualitative phase) or 24 months (quantitative phase [26 months in the UK]) prior to enrollment in the study. Nine patients (mean age 65 years) participated in the qualitative phase and 113 patients (mean age 65.1 years) in the quantitative phase. Qualitative study results provided insights for the quantitative study and highlighted the benefits of switching from daratumumab IV to daratumumab SC as an improvement and a satisfactory change in patients' treatment journey. Quantitative survey showed that patients were significantly less anxious, stressed and nervous before SC injections than IV infusions (mean score: 1.3, 1.1, 1.4 versus 2.1, 2.0, 2.0 respectively, p<0.001), and significantly more reassured, ready/well-prepared, usual self and relieved (mean score: 3.8, 4.3, 3.7, 3.6 versus 3.0, 3.6, 3.1, 3.0 respectively, p<0.001). Immediately after SC first injection, 96.5% patients were feeling well or very well versus 77.9% immediately after IV first infusion (p<0.001). 97.3% patients were satisfied with their SC treatment versus 89.4% for the IV injection (p<0.001). Patients spent significantly less time in hospital for an SC injection of daratumumab than for an IV infusion, 1.5 hours and 5.0 hours respectively (p<0.001). In the UK, the differences between the two administration forms were less visible, likely because of confounding factors including a longer time passed since the switch from the IV to the SC form and administration of the survey. In line with results from other studies, the SC form of daratumumab had less impact on patients' emotional burden than the IV form.

Adjuvant therapy with zinc supplementation; anti-inflammatory and anti-oxidative role in multiple myeloma patients receiving autologous hematopoietic stem cell transplantation: a randomized controlled clinical trial.

Multiple myeloma (MM) patients are often accompanied by heightened levels of oxidative stress, even following bone marrow transplantation. Trace mineral supplements have been found to regulate and inhibit the activity of oxidative radicals and inflammatory factors, which are involved in the pathogenesis of MM. The study sought to evaluate the effectiveness of the supplementation by analyzing changes in oxidative, anti-oxidative, and inflammation markers. Patients were randomly assigned to a zinc or placebo group, with the former receiving 30mg of zinc or placebo tablets daily for 1month. Blood samples were collected from the patients on the day of transplantation, 15days, and 30days post-transplantation. Real-time PCR was employed to measure the expression of oxidative/antioxidative genes. Furthermore, the protein level of oxidative markers in serum samples was assessed. Finally, serum TNF-α concentrations were measured using the ELISA technique. The expression levels of SOD1, SOD2, and NRF2 genes were significantly higher on days 15 and 30 compared to the control group (P < 0.05), with a greater increase on day 30 (P < 0.05). Conversely, the expression levels of Keap1 and NOX2 genes were lower on day 30 than those of the control group (P < 0.05), with a further decrease from day 15 to day 30 (P < 0.05). The experimental group exhibited a notable reduction in TNF-α cytokine levels on day 30 compared to the control and placebo groups (P < 0.05). All findings were coordinated according to the nutritional questionnaire. Our findings suggest a potential benefit of zinc supplementation in managing the adverse effects of chemotherapy in MM patients, warranting further investigation.

Efficacy of CARVYKTI in CARTITUDE-4 versus other conventional treatment regimens for lenalidomide-refractory multiple myeloma using inverse probability of treatment weighting.

Aim: The phase III randomized controlled trial (RCT) CARTITUDE-4 (NCT04181827) demonstrated superiority of CARVYKTI (ciltacabtagene autoleucel; cilta-cel) over daratumumab, pomalidomide and dexamethasone (DPd) and pomalidomide, bortezomib and dexamethasone (PVd) for relapsed/refractory multiple myeloma (RRMM) patients who have received one to three prior line(s) of therapy (LOT[s]) including an immunomodulatory agent and a proteasome inhibitor, and are refractory to lenalidomide. These analyses estimate the relative efficacy between cilta-cel and other common treatment regimens, for which no direct comparative evidence is available. Materials & methods: Patient data were available from the CARTITUDE-4, CASTOR, CANDOR and APOLLO RCTs. Imbalances between cohorts on key patient characteristics were adjusted for using inverse probability of treatment weighting (IPTW). Relative efficacies were estimated with response rate ratios (RRs) and 95% confidence intervals (CIs) for overall response rate (ORR), very good partial response or better rate (≥VGPR) and complete response or better rate (≥CR), and with hazard ratios (HRs) and 95% CIs for progression-free survival (PFS). Sensitivity analyses using different analytical methods and additional covariates were explored. Results: Key characteristics were well balanced across cohorts after IPTW. Cilta-cel showed statistically significant benefit in PFS (HRs: 0.11-0.51), ≥VGPR (RRs: 1.51-5.13) and ≥CR (RRs: 2.90-35.24) versus all comparators, and statistically significant improvements in ORR over most comparator regimens (RRs: 1.22-1.90). Results were consistent across sensitivity analyses. Conclusion: Cilta-cel demonstrated benefit over other common treatment regimens, highlighting its potential to become a new standard of care option for lenalidomide-refractory RRMM patients with one to three prior LOT(s). These comparisons help to demonstrate the improved efficacy of cilta-cel in countries where the standard of care may differ from DPd/PVd.

Exploring the Link Between High-Risk Cytogenetics and Skeletal Lytic Lesions in African American (AA) Multiple Myeloma (MM) Patients: Insights From a Decade-Long Study

Exploring the Link Between High-Risk Cytogenetics and Skeletal Lytic Lesions in African American (AA) Multiple Myeloma (MM) Patients: Insights From a Decade-Long Study

Dose-Adjusted Melphalan Yields Comparable MRD-Negativity to Full-Dose Melphalan in Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplant

Dose-Adjusted Melphalan Yields Comparable MRD-Negativity to Full-Dose Melphalan in Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplant

Real-Life Management of Patients Aged 80 Years Old and Over With Multiple Myeloma: Results of the EMMY Cohort

Multiple myeloma patients aged 80 years and older are a population more prone to comorbidities and frailty. We aim to describe the real-life management and outcomes of this population. EMMY is a descriptive large-scale study. Between 2017 and 2021 we included 4383 patients of which 894 (20.3%) were aged ≥ 80 years. Four cohorts of patients aged ≥ 80 years were analysed: line 1 (L1), line 2 (L2), line 3 (L3) or line 4+ (L4+).The proportion of patients ≥ 80 years old was 20.8% in L1, 21.3% in L2, 20.9% in L3 and 17.8% in L4+. L1 patients received more treatment including a proteasome inhibitor (PI) (42.9%), L2 patients received mainly an immunomodulator (IMID) (65.9%) or an anti-CD38 (31.5%). For L3, IMID was used in 71.4% than an anti-CD38 (33.5%). L4+ patients received a PI (40.6%), IMID (33.2%) or an anti-CD38 (29.1%). Regarding efficacy, the median progression-free survival was 18.4 months in L1, 15.1 months in L2, 10.4 months in L3 and 6.5 months in L4+. The median overall survival was 49 months in L1, 31.3 months in L2, 21.4 months in L3 and 13.6 months in L4+.EMMY cohort confirmed that patients ≥ 80 years of age represent an important proportion of MM patients, in the de novo or relapse setting. This study is an important step in improving our comprehension and management of treatment in elderly patients.

Real World Outcome of High-Risk Multiple Myeloma: An Indian Tertiary Care Centre Experience

High risk myeloma is a heterogeneous disease cohort with significant variation in risk stratification across literatures. Real world outcomes differ from controlled clinical trials and affected by socioeconomical determinants of health. This study from an Indian tertiary care set up highlights’ treatment patterns and outcome of real-world high risk myeloma patients. Out of 384,76(19.7%) high risk myeloma patients were analyzed (median age 58 years). Most common HRCA was 1 q gain 36(47.4%) followed by del17p 32(42.1%). 61/76(80.2%) received Bortezomib based triplets and 15(19.74%) daratumumab based quadruplets induction, 31(40.79%) received ASCT. Median duration of follow up was 19.5 months. The 2 year OS and PFS was 73.8%, 52.6% respectively. Estimated 3 year OS was 74.7% in ASCT cohort versus 52.9% (P = .0067) without. Estimated 3-year PFS in the ASCT cohort was 72.1% versus 30.3% (P = .0026) without. Estimated 3-year OS for single hit and multi hit ultra HRMM was 67.7% and 61.9% (P = .642) whereas PFS was 58.2% and 35.2% (P = .486) respectively. In multivariate analysis ASCT correlated with better OS (HR 0.3, P = .041) and PFS (HR 0.35,P = .012). Absence of baseline renal impairment correlated with better OS (HR 4.12, P = .004) only. Early aggressive therapy with prompt ASCT translates to a better survival in high risk myeloma. Emphasis on real world clinical outcome is the need of the hour for addressing practical issues and improving global myeloma outcome.

Impact of MRD Status on Survival Rates in Newly Diagnosed Transplant-Eligible Multiple Myeloma Patients: A Systematic Review and Meta-Analysis

Impact of MRD Status on Survival Rates in Newly Diagnosed Transplant-Eligible Multiple Myeloma Patients: A Systematic Review and Meta-Analysis