Correction to “Incidence, Clinical Features, and Prognostic Value of New‐Onset Renal Impairment in Multiple Myeloma”

This study aims to perform a bibliometric visual analysis and bioinformatics analysis to explore the research hotspots and trends of renal impairment in multiple myeloma, including the associated genes and signal pathways over the past two decades. The Web of Science Core Collection database was utilized as the data source to retrieve literature on renal impairment in multiple myeloma from 2000 to 2023. The selected literature was analyzed using bibliometric and bioinformatics software, including Bibliometrix, VOSviewer 1.6.16, Citespace 5.7R5 and Cytoscape 3.7.1 software. This study encompassed 2152 articles that were published from 2000 to 2023, demonstrating an overall upward trend in annual publications and citations. Among the set of 27 core journals examined, the "CUREUS JOURNAL OF MEDICAL SCIENCE" exhibited the highest frequency of publications, while "BLOOD" emerged as the most frequently cited source. The global research on renal impairment in multiple myeloma research included contributions from 84 countries/regions, with the United States leading in terms of publication output and Mayo Clinic playing a central role in fostering inter-agency collaboration. Keywords such as "daratumumab", "carfilzomib", "diagnostic criteria" and "kidney biopsy" included recent research hotspots. We hypothesized that the TP53, AKT1, MYC, and CTNNB1 genes were involved in epithelial cell proliferation and the positive regulation of the MAPK cascade through signaling receptor activator activity, receptor-ligand interactions, and cytokine receptor binding. Simultaneously, they were implicated in renal impairment in multiple myeloma via the PI3K/Akt and MAPK signaling pathways. This research employed bibliometric visual analysis and bioinformatics analysis to identify the current focus and future directions of studying renal impairment in multiple myeloma, as well as to explore the associated genes and signaling pathways. The management of renal impairment in patients with multiple myeloma has a significant impact on medical costs. Clinical physicians need to consider how to allocate medical resources reasonably, ensure that patients can receive necessary diagnosis and treatment, and explore cost-effective treatment options. The management of these patients requires interdisciplinary medical services, which should integrate basic and clinical research, especially the development of new treatment plans, to improve patients' quality of life and guide future treatment choices.

Renal impairment (RI) is one of the hallmarks of multiple myeloma (MM) and carries a poor prognosis. Microvesicles (MVs) are membrane vesicles and play an important role in disease progression. Here, we investigated the role of MVs derived from MM cells (MM-MVs) in RI of MM. We found that MM-MVs significantly inhibited viability and induced apoptosis, but not epithelial-mesenchymal transition in human kidney-2 (HK-2), a human renal tubular epithelial cell line. The protein levels of cleaved caspase-3, 8, and 9, and E-cadherin, were increased, but vementin levels were decreased in the HK-2 cells treated with MM-MVs. Through a comparative sequencing and analysis of RNA content between the MVs from RPMI8226 MM cells (RPMI8226-MVs) and K562 leukemia cells, RPMI8226-MVs were enriched with more renal-pathogenic miRNAs, in which the selective miRNAs may participate in the up-regulation of the levels of cleaved caspase-3. Furthermore, the levels of CD138+ circulating MVs (cirMVs) in the peripheral blood were positively correlated with the severity of RI in newly-diagnosed MM. Our study supports MM-MVs representing a previously undescribed factor and playing a potential role in the development of RI of MM patients, and sheds light on the potential application of CD138+ cirMV counts in precise diagnosis of RI in MM and exploring MM-MVs as a therapeutic target.

Daratumumab, bortezomib, thalidomide and dexamethasone improves renal outcomes in multiple myeloma transplant eligible patients presenting with renal failure: A real life experience from northeastern Italy

Prevalence and Predictors of Renal Impairment Among Patients with Multiple Myeloma (MM): An Analysis of Oncology Clinic Electronic Health Records Linked to Commercial Claims in the United States

Screening of Serum Peptidome-Based Biomarker for Multiple Myeloma Renal Impairment

Use of Lenalidomide May Surmount the Adverse Prognosis Induced by Renal Impairment In Patients (pts) with Relapsed/Refractory Multiple Myeloma (MM)

ABSTRACTBackgroundPrevious studies mainly focused on renal impairment (RI) at multiple myeloma (MM) diagnosis, with few investigating new‐onset RI post‐MM diagnosis. This study aims to indicate the incidence, clinical characteristics and predictive value of new‐onset RI in MM patients.MethodsWe conducted a multicenter, retrospective cohort study including 1953 newly diagnosed MM patients from West China Hospital from July 1, 2008, to February 30, 2024 and the international MMRF‐CoMMpass database. Among them, 1770 patients received novel therapeutic agents including immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) as first‐line therapy. RI was defined as serum creatinine higher than 2 mg/dL or impaired creatinine clearance (< 40 mL/min/1.73m2). The association between new‐onset RI and mortality risk was investigated by Kaplan–Meier analysis and Cox proportional hazard models.ResultsOf the cohort, 16.6% developed new‐onset RI, with the majority (67.1%) occurring within 2 years post‐MM diagnosis. The median overall survival (OS) was significantly shorter in new‐onset RI than in those without RI (68 vs. 122 months, p < 0.001). New‐onset RI was an independent risk factor for mortality (HR 1.55, 95% CI 1.28–1.88, p < 0.001), and earlier onset of RI was associated with a higher mortality risk. Moreover, patients with recovery of renal function had prolonged OS compared to those without recovery (95 vs. 64.8 months, p = 0.01). Older age, higher stage of the international stage system (ISS) and RI at diagnosis seemed to be risk factors for new‐onset RI, while first‐line therapy with PIs and IMiDs combinations was associated with a lower risk of RI development (HR 0.69, 95% CI 0.51–0.94, p = 0.017).ConclusionsIn conclusion, the incidence of new‐onset RI is high in MM, and is a significant risk factor for mortality, posing a substantial threat to MM patients. Early identification of high‐risk patients for new‐onset RI and prompt preventive strategies is critical for improving MM prognosis.Trial RegistrationThis study was registered by the Chinese Clinical Trial Registry (ChiCTR2400081476, https://www.chictr.org.cn)

Higher Vascular Endothelial Growth Factor (VEGF) and Endothelial Progenitor Cells (EPCs) in Multiple Myeloma (MM) Patients (pts) as a Reflection of Their Governing Role in Pathological Angiogenesis: Comparison of VEGF and EPC Levels Between Healthy Donors (HD), MGUS and MM Pts and Correlation Analysis with MM Activity

Background: Nephrological changes in Multiple Myeloma occur mostly because of abnormal proteins (light chains) production by myeloma cells which causes deterioration of kidney functions. The aim of the study was to determine the renal impairment in multiple myeloma patients. Method: A total of 159 newly diagnosed multiple myeloma aged 24 to 85 patients were selected in this retrospective cross-sectional study conducted from January 2017 to December 2020 according to the selection criteria. Result: The study sample consists of 103 (64.8%) male patients and 56 (35.2%) female patients. The median age of the patients was 63±13 years. Among them, 6.9% patients were less than 40 years old, and 32.7% patients were more than 70 years old. Renal impairment was found in 86 (54%) patients. The highest incidence of renal impairment was found in 55–69-year age group and p-value was not statistically significant. Monoclonal gammopathy was detected in 138 (93.9%) patients. The study also stated that IgG Kappa was found in 41.8% patients, Kappa Light Chain was 4.1% and Lambda Light Chain was found in 4.1% patients. Conclusion: Multiple myeloma with renal involvement is a medical emergency. It needs immediate management, and the treatment plan is different in some regards. So, detection of nephrological abnormalities and treated accordingly is very crucial.

Prospective phase 2 trial of daratumumab with dexamethasone in patients with relapsed/refractory multiple myeloma and severe renal impairment or on dialysis: The DARE study.

Background: Renal impairment (RI) is a common complication of multiple myeloma (MM). Around 50% of patients with MM have RI at presentation, and up to 5% require dialysis treatment. Severe acute kidney injury (AKI) as a cause of RI is a particular challenge as historically the survival of patients who sustain this complication and require dialysis is very poor. However, in this current period, survival is improving and the focus is on optimum use of novel chemotherapies and the evaluation of extra-corporeal therapies for removal of serum immunoglobulin light chains. Summary: RI in patients with MM is commonly associated with excess monoclonal free light chain (FLC) production; myeloma cast nephropathy is the predominant renal pathology in patients presenting with severe RI secondary to AKI. The majority of patients have mild to moderate RI and recover renal function. However, patients with more severe RI, in particular those with a requirement for dialysis, are less likely to recover renal function. Rapid diagnosis and prompt institution of anti-myeloma therapy is an important determinant of renal function recovery, through targeting early and sustained reduction of involved monoclonal FLC. Novel agents are associated with excellent disease response, and bortezomib is now widely used as a first-line agent in the management of MM in patients with severe RI. Extended haemodialysis using high cut-off dialysers is more effective for extracorporeal removal of FLC than plasma exchange, and clinical trials are in process. High-dose chemotherapy with autologous stem cell transplantation does have a role in patients with severe RI but requires careful patient selection. Key Messages: RI is very common in patients with MM, and renal function recovery is associated with improved clinical outcomes. We summarise the epidemiology of MM in the UK, present the impact of RI and renal function recovery on patient outcome, and describe the current management of MM in western countries. Facts from East and West: (1) A serum creatinine level >2 mg/dl has been reported in 16, 21, 24, and 33% of patients with MM in cohort studies from Japan, Europe, China, and Korea, respectively. A creatinine clearance rate <30 ml/min was observed in 30 and 15% of patients in Chinese and Western MM cohorts, respectively. The commonest cause of severe RI in patients with MM is myeloma cast nephropathy. (2) The efficacy of novel treatments (bortezomib, carfilzomib, thalidomide, and lenalidomide) has predominantly been assessed in Western patients. Bortezomib and dexamethasone are the current standard of care for MM and severe RI in the West. Severe RI is not a contraindication to autologous stem cell transplantation (ASCT). Most of the data are from the West; there are case reports from China describing good outcomes with ASCT. The removal of FLC by high-cut-off hemodialysis is under evaluation in randomized controlled trials (RCTs) in the West. Studies in this area are not yet conducted in China. In China, new treatments, such as bortezomib, are more widely used than before, and favorable results are being reported; however, RCT studies are still needed in this area to confirm the efficacy and safety of this and other novel treatments.

Neutrophil Gelatinase--Associated Lipocalin and Cystatin C Are Sensitive Markers of Renal Injury in Patients With Multiple Myeloma.

We investigated the impact of renal impairment (RI) on the outcome in multiple myeloma (MM) patients following induction and autologous stem cell transplantation (ASCT). Among 349 patients who received a first ASCT for MM, 86 (24.6%) had RI at diagnosis, defined as estimation of glomerular filtration rate (eGFR) <40 mL/min/1.73 m2 according to the modification of diet in renal disease (MDRD) formula. Post induction reversal of renal function occurred in 68 (79%) patients including complete renal response in 37.2%. Two hundred and fifty-one patients had received novel agents for induction; posttransplant complete response (CR) rates were 71.4% for patients with renal impairment (RI) versus 67.2% in those without RI, p = 0.23. The quality of stem cell collection and days to engraftment were similar except that patients with RI required higher transfusion numbers of packed red cells (p < 0.002) and platelets (p < 0.007). The median overall survival (OS) was 96 months (95% confidence interval [CI] 72.80–119.20) for patients with eGFR ≥40 mL/min, n = 195) versus 62 months (95% CI 28.7–95.3) for 56 patients with RI (eGFR <40 mL/min), p = 0.15. The 5-year OS was 64.6% versus 54.4%, respectively. The median progression-free survival (PFS) was 52 months (95% CI 36.3–67.7) for patients with eGFR ≥40 mL/min versus “not reached” for those with eGFR <40 mL/min p = 0.87; and the 5-year PFS was 48.1% versus 51%, respectively. We conclude that induction with novel agents results in reversal of renal dysfunction in the majority of patients. Consolidation with Hemopoietic Stem Cell Transplantation (HSCT) overcomes the adverse impact of RI on survival.

Renal impairment (RI) is a common complication of multiple myeloma (MM) that significantly affects treatment efficacy and mortality. However, no useful biomarkers for early detection of renal damage in MM exist. Reports indicate that activin A, a multifunctional cytokine of the TGF-β superfamily, is involved in the development and progression of various kidney diseases. In the present study, we measured urinary activin A levels in patients with newly diagnosed MM (NDMM) (n=41), smoldering MM (SMM) (n=10), and monoclonal gammopathy of undetermined significance (MGUS) (n=28), including monoclonal gammopathy of renal significance (MGRS), and assessed the correlation between urinary activin A and several clinical parameters. Urinary activin A, undetectable in healthy volunteers, was significantly increased in NDMM patients but not in patients with SMM and MGUS (97.3, 25.0, and 6.61 mg/gCr, respectively, P<0.05). In all patients with NDMM, urinary activin A levels were significantly reduced after initial treatment regardless of the therapy regimen. There was a significant correlation of urinary activin A with spot urinary protein level (P<0.001) and serum M-protein (P=0.029) but not with estimated glomerular filtration rate (eGFR), serum creatinine (Cr), N-acetyl-glucosaminidase (NAG), and serum activin A level. Histological analysis using renal biopsy samples revealed that activin A, which was absent from normal kidneys, was detected in the renal tubular cells of patients with MGRS. These data suggest that urinary activin A reflects tubular injury in MM and might aid the early detection of RI in plasma cell neoplasms.

Limited Long-Term Benefit of Upfront Autologous Stem Cell Transplant on Survival in Severe Renal Impairment in Multiple Myeloma in Novel Drug Era, a Retrospective Multi-Center Study in China