Genetic justification of COVID-19 patient outcomes using DERGA, a novel data ensemble refinement greedy algorithm.

Complement inhibition has shown promise in various disorders, including COVID-19. A prediction tool including complement genetic variants is vital. This study aims to identify crucial complement-related variants and determine an optimal pattern for accurate disease outcome prediction. Genetic data from 204 COVID-19 patients hospitalized between April 2020 and April 2021 at three referral centres were analysed using an artificial intelligence-based algorithm to predict disease outcome (ICU vs. non-ICU admission). A recently introduced alpha-index identified the 30 most predictive genetic variants. DERGA algorithm, which employs multiple classification algorithms, determined the optimal pattern of these key variants, resulting in 97% accuracy for predicting disease outcome. Individual variations ranged from 40 to 161 variants per patient, with 977 total variants detected. This study demonstrates the utility of alpha-index in ranking a substantial number of genetic variants. This approach enables the implementation of well-established classification algorithms that effectively determine the relevance of genetic variants in predicting outcomes with high accuracy.

Thrombotic and bleeding complications in patients with AL amyloidosis.

Haemostatic abnormalities and deregulated coagulation are common complications in AL amyloidosis. The relevant risks of thromboembolic and haemorrhagic events have not been thoroughly evaluated. To describe clinically significant thrombotic/haemorrhagic events in 450 consecutive patients with AL amyloidosis. Venous thromboembolic events (VTEs) were reported in 6% and arterial embolic events (AEEs) in 5% of patients, respectively, during a 55-month median follow-up. Lower albumin, lower eGFR, higher BM infiltration, soft tissue involvement, IMiD-based therapy and prior thrombosis were associated with VTE risk. Prior thrombosis was the only independent prognostic variable (HR 9.3, p = 0.001). Coronary arterial disease, prior AEE, 24-h proteinuria and higher platelet counts were associated with AEE risk. Significant bleeding events were reported in 9%, and associated mortality was 19%. Liver involvement, higher serum creatinine and higher baseline VWF:Ag levels were linked to bleeding risk. Using competing risk analysis, the cumulative probability of thrombosis/bleeding was higher during the first year following diagnosis, but a stable lower risk for both events remained for the duration of follow-up. In AL amyloidosis patients, the risk of thrombotic/arterial embolic events is significant, but the bleeding risk is also high. A multiparametric assessment is required to initiate anti-thrombotic or anti-platelet therapy appropriately.

Small RNA-seq and clinical evaluation of tRNA-derived fragments in multiple myeloma: Loss of mitochondrial i-tRFHisGTG results in patients' poor treatment outcome.

Despite the substantial progress in multiple myeloma (MM) therapy nowadays, treatment resistance and disease relapse remain major clinical hindrances. Herein, we have investigated tRNA-derived fragment (tRF) profiles in MM and precursor stages (smoldering MM/sMM; monoclonal gammopathy of undetermined significance/MGUS), aiming to unveil potential MM-related tRFs in ameliorating MM prognosis and risk stratification. Small RNA-seq was performed to profile tRFs in bone marrow CD138+ plasma cells, revealing the significant deregulation of the mitochondrial internal tRFHisGTG (mt-i-tRFHisGTG) in MM versus sMM/MGUS. The screening cohort of the study consisted of 147 MM patients, and mt-i-tRFHisGTG levels were quantified by RT-qPCR. Disease progression was assessed as clinical end-point for survival analysis, while internal validation was performed by bootstrap and decision curve analyses. Screening cohort analysis highlighted the potent association of reduced mt-i-tRFHisGTG levels with patients' bone disease (p = 0.010), osteolysis (p = 0.023) and with significantly higher risk for short-term disease progression following first-line chemotherapy, independently of patients' clinical data (HR = 1.954; p = 0.036). Additionally, mt-i-tRFHisGTG-fitted multivariate models led to superior risk stratification of MM patients' treatment outcome and prognosis compared to disease-established markers. Notably, our study highlighted mt-i-tRFHisGTG loss as a powerful independent indicator of post-treatment progression of MM patients, leading to superior risk stratification of patients' treatment outcome.

Early microvascular coronary endothelial dysfunction precedes pembrolizumab-induced cardiotoxicity. Preventive role of high dose of atorvastatin.

Immune checkpoint inhibitors (ICIs) exhibit remarkable antitumor activity and immune-related cardiotoxicity of unknown pathomechanism. The aim of the study was to investigate the ICI class-dependent cardiotoxicity in vitro and pembrolizumab's (Pem's) cardiotoxicity in vivo, seeking for translational prevention means. Cytotoxicity was investigated in primary cardiomyocytes and splenocytes, incubated with ipilimumab, Pem and avelumab. Pem's cross-reactivity was assessed by circular dichroism (CD) on biotechnologically produced human and murine PD-1 and in silico. C57BL6/J male mice received IgG4 or Pem for 2 and 5 weeks. Echocardiography, histology, and molecular analyses were performed. Coronary blood flow velocity mapping and cardiac magnetic resonance imaging were conducted at 2 weeks. Human EA.hy926 endothelial cells were incubated with Pem-conditioned media from human mononuclear cells, in presence and absence of statins and viability and molecular signaling were assessed. Atorvastatin (20 mg/kg, daily) was administered in vivo, as prophylaxis. Only Pem exerted immune-related cytotoxicity in vitro. Pem's cross-reactivity with the murine PD-1 was confirmed by CD and docking. In vivo, Pem initiated coronary endothelial and diastolic dysfunction at 2 weeks and systolic dysfunction at 5 weeks. At 2 weeks, Pem induced ICAM-1 and iNOS expression and intracardiac leukocyte infiltration. At 5 weeks, Pem exacerbated endothelial activation and triggered cardiac inflammation. Pem led to immune-related cytotoxicity in EA.hy926 cells, which was prevented by atorvastatin. Atorvastatin mitigated functional deficits, by inhibiting endothelial dysfunction in vivo. We established for the first time an in vivo model of Pem-induced cardiotoxicity. Coronary endothelial dysfunction precedes Pem-induced cardiotoxicity, whereas atorvastatin emerges as a novel prophylactic therapy.

Belantamab mafodotin, lenalidomide and dexamethasone in transplant-ineligible patients with newly diagnosed multiple myeloma: part 1 results of a phase I/II study.

Preclinical and clinical data demonstrate synergy between belantamab mafodotin (belamaf) and immunomodulatory drugs with limited overlapping toxicities. We investigated the safety and efficacy of belamaf with lenalidomide 25 mg on days 1-21 every 28 days and dexamethasone 40 mg weekly (belamaf-Rd) in transplant-ineligible patients with newly diagnosed multiple myeloma. Thirty-six patients (median age, 72.5 years) were randomized to receive belamaf at three different doses (2.5, 1.9, or 1.4 mg/kg) every 8 weeks. The dosing schedule was extended to every 12 weeks to mitigate ocular toxicity. Most common grade ≥3 adverse events were fatigue (n=21, 58.3%), rash (n=6, 16.7%), diarrhea (n=8, 22.2%) and COVID-19 (n=5, 13.9%). Grade 3-4 ocular adverse events, comprising visual acuity decline from baseline and/or keratopathy, were reported in 39/216 (18.1%), 33/244 (13.5%), and 26/207 (12.6%) ophthalmological assessments in the 2.5, 1.9, and 1.4 mg/kg cohorts, respectively. Importantly, grade 3-4 keratopathy was identified in 9/216 (4.2%), 1/244 (0.4%) and 1/207(0.5%) assessments. Most patients (32/36, 88.9%) were treated with the extended, every-12-week schedule, during which 40, 33 and 16 doses were withheld due to ocular adverse events in the 2.5, 1.9, and 1.4 mg/kg cohorts, respectively. Overall, the rates of very good partial response and better and complete response and better were 83.3% and 52.8%, respectively, without significant differences among cohorts. Over a median follow-up of 20.3 months no disease progression was reported; six patients discontinued treatment due to infection-related death (4 cases of COVID-19, 2 cases of pneumonia) and one patient withdrew consent. Based on the toxicity/efficacy balance, the recommended phase II dose was 1.9 mg/kg every 8 weeks, extended to every 12 weeks because of toxicity. In conclusion, Belamaf-Rd, with the extended schedule for belamaf, showed important clinical activity and a significant improvement of ocular adverse events with minimal impact on vision-related functioning in an elderly, non-transplant eligible population.

ROP-ET: a prospective phase III trial investigating the efficacy and safety of ropeginterferon alfa-2b in essential thrombocythemia patients with limited treatment options.

Interferon-based therapies, such as ropeginterferon alfa-2b have emerged as promising disease-modifying agents for myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET). Current ET treatments aim to normalize hematological parameters and reduce the thrombotic risk, but they do not modify the natural history of the disease and hence, have no impact on disease progression. Ropeginterferon alfa-2b (trade name BESREMi®), a novel, monopegylated interferon alfa-2b with an extended administration interval, has demonstrated a robust and sustained efficacy in polycythemia vera (PV) patients. Given the similarities in disease pathophysiology and treatment goals, ropeginterferon alfa-2b holds promise as a treatment option for ET. The ROP-ET trial is a prospective, multicenter, single-arm phase III study that includes patients with ET who are intolerant or resistant to, and/or are ineligible for current therapies, such as hydroxyurea (HU), anagrelide (ANA), busulfan (BUS) and pipobroman, leaving these patients with limited treatment options. The primary endpoint is a composite response of hematologic parameters and disease-related symptoms, according to modified European LeukemiaNet (ELN) criteria. Secondary endpoints include improvements in symptoms and quality of life, molecular response and the safety profile of ropeginterferon alfa-2b. Over a 3-year period the trial assesses longer term outcomes, particularly the effects on allele burden and clinical outcomes, such as disease-related symptoms, vascular events and disease progression. No prospective clinical trial data exist for ropeginterferon alfa-2b in the planned ET study population and this study will provide new findings that may contribute to advancing the treatment landscape for ET patients with limited alternatives. TRIAL REGISTRATION: EU Clinical Trials Register; EudraCT, 2023-505160-12-00; Registered on October 30, 2023.

COVID-19 in patients with anemia and haematological malignancies: risk factors, clinical guidelines, and emerging therapeutic approaches.

Extensive research in countries with high sociodemographic indices (SDIs) to date has shown that coronavirus disease 2019 (COVID-19) may be directly associated with more severe outcomes among patients living with haematological disorders and malignancies (HDMs). Because individuals with moderate to severe immunodeficiency are likely to undergo persistent infections, shed virus particles for prolonged periods, and lack an inflammatory or abortive phase, this represents an overall risk of morbidity and mortality from COVID-19. In cases suffering from HDMs, further investigation is needed to achieve a better understanding of triviruses and a group of related variants in patients with anemia and HDMs, as well as their treatment through vaccines, drugs, and other methods. Against this background, the present study aimed to delineate the relationship between HDMs and the novel COVID-19, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Besides, effective treatment options for HDM cases were further explored to address this epidemic and its variants. Therefore, learning about how COVID-19 manifests in these patients, along with exploiting the most appropriate treatments, may lead to the development of treatment and care strategies by clinicians and researchers to help patients recover faster. Video Abstract.

Efficacy and safety of daratumumab with ixazomib and dexamethasone in lenalidomide-exposed patients after one prior line of therapy: Final results of the phase 2 study DARIA.

The use of lenalidomide in frontline therapy for patients with newly diagnosed multiple myeloma (MM) has increased the number of those who become refractory to lenalidomide at second line. In this context, we assessed the efficacy of daratumumab in combination with ixazomib and dexamethasone (Dara-Ixa-dex) in the prospective phase 2 study DARIA. Eligible patients had relapsed/refractory MM (RRMM) after one prior line with a lenalidomide-based regimen. The primary endpoint was overall response rate (ORR). Secondary endpoints included survival outcomes, safety and changes in biomarkers of bone metabolism. Overall, 50 patients were enrolled (median age 69 years, 56% males). 32 (64%) patients were refractory to lenalidomide, and 17 (34%) had undergone autologous transplant. The ORR was 64% (n = 32); whereas 17 (34%) had a very good partial response or better. The median time to first response was 1.0 month. After a median follow-up of 23.4 months, the median PFS and OS were 8.1 and 39.2 months, respectively. Furthermore, significant changes in markers of bone metabolism became evident as early as at 6 months on treatment. Regarding safety, 21 (42%) patients had ≥1 grade 3/4 adverse event (AE); the most common was thrombocytopenia (n = 9, 18%). 14 (28%) patients had ≥1 serious AE (SAE), the most common being acute kidney injury and pneumonia (n = 2, each). Four patients died due to infections. In conclusion, second-line treatment with Dara-Ixa-dex in patients with RRMM pre-treated with a lenalidomide-based regimen resulted in rapid responses along with a favorable effect on bone metabolism.

Low circulating tumor cell levels correlate with favorable outcomes and distinct biological features in multiple myeloma.

There is growing interest in multiple myeloma (MM) circulating tumor cells (CTCs), but their rareness in peripheral blood (PB) and inconsistency in cutoffs question their clinical utility. Herein, we applied next-generation flow cytometry in 550 bone marrow (BM) and matched PB samples to define an optimal CTC cutoff for both transplant-eligible and transplant-ineligible newly diagnosed MM (NDMM) patients. Deep phenotyping was performed to investigate unique microenvironmental features associated with CTC dissemination. CTCs were detected in 90% of patients (median 0.01%; range: 0.0002%-12.6%) and increased levels associated with adverse features. Correlations were observed between high CTC percentages and a diffused MRI pattern, a distinct BM composition characterized by altered B-cell differentiation together with an expansion of effector cells and tumor-associated macrophages, as well as a greater phenotypic dissimilarity between BM and PB clonal cells. Progression-free survival (PFS) and overall survival (OS) gradually worsened with each logarithmic increment of CTCs. Conversely, NDMM patients without CTCs showed unprecedented outcomes, with 5-year PFS and OS rates of 83% and 97%, respectively. A cutoff of 0.02% CTCs was independent of the ISS, LDH, and cytogenetics in a multivariate analysis of risk factors for PFS. The 0.02% CTC cutoff synergized with the MGUS-like phenotype and the R-ISS for improving the risk stratification systems. MRD negativity was less frequent if CTCs were ≥0.02% at diagnosis, but whenever achieved, the poor prognosis of these patients was abrogated. This study shows the clinical utility of CTC assessment in MM and provides evidence toward a consensus cutoff for risk stratification.

Central nervous system multiple myeloma: A real-world multi-institutional study of the Greek Myeloma Study Group.

Central nervous system (CNS) involvement is a rare and aggressive complication of multiple myeloma (MM). We identified 54/4352 MM patients (1.2%), who developed CNS-MM between 2000 and 2022. A matched-control group of MM patients without CNS-MM was used for comparisons. Median age was 63 years. Median time to CNS-MM was 28 months; 6/54 experienced CNS-MM at MM diagnosis. Abnormal lactate dehydrogenase (LDH), high-risk cytogenetics, and extramedullary involvement (EMI), that is, soft tissue plasmacytomas and/or plasma cell leukemia (PCL), were more frequent in CNS-MM versus controls (p < .05); 13/54 had PCL at CNS-MM. The majority had leptomeningeal infiltration (LMI) (66%); 26% had CNS-MM without systemic myeloma; EMI was the strongest predictor for CNS-MM (OR: 6.3). Median overall survival (OS) of CNS-MM patients versus controls was 43 months (95% CI: 32-54) versus 60 months (95% CI: 38-82) (p < .001); treatment of CNS-MM included mainly bortezomib/thalidomide/chemotherapy whereas 20% received novel drugs/immunotherapy combinations; 28 patients underwent cerebrospinal fluid infusions; EMI was the strongest negative predictor for post CNS-MM OS (p = .005; HR: 2.9). Treatment after 2016 predicted significantly for OS (p = .002; HR: 0.27). Median post CNS-MM OS was 4 months (95% CI: 2.6-5.4); in patients treated after 2016 median OS was 12 months. In conclusion, we have demonstrated in this large real-world series that survival of CNS-MM remains poor; however, there is a positive impact of treatment after 2016, related to the efficacy of modern anti-myeloma therapy; EMI significantly increases the probability to develop CNS-MM and the risk of post CNS-MM death, indicating a potential need for CNS prophylaxis for those patients.

INSURE: a pooled analysis of ixazomib-lenalidomide-dexamethasone for relapsed/refractory myeloma in routine practice.

Aim: We pooled data from three observational studies (INSIGHT MM, UVEA-IXA and REMIX) to investigate the real-world effectiveness of ixazomib-lenalidomide-dexamethasone (IRd) in relapsed/refractory myeloma. Materials & methods: INSIGHT MM was a prospective study conducted in countries across Europe, Asia and North/Latin America while UVEA-IXA and REMIX were multicenter, retrospective/prospective studies conducted in Europe. Patients who had received IRd as ≥2nd line of therapy were analyzed. Primary outcomes were time-to-next treatment (TTNT) and progression-free survival (PFS). Results: Overall, 564 patients were included (median follow-up: 18.5 months). Median TTNT and PFS were 18.4 and 19.9 months; both outcomes were numerically longer for earlier versus later lines. Median treatment duration was 14.0 months. Overall response rate was 64.6%. No new safety concerns were noted. Conclusion: The effectiveness of IRd in routine practice appears similar to the efficacy observed in TOURMALINE-MM1. IRd benefit in earlier versus later lines was consistent with previous reports.

The Interplay between the DNA Damage Response (DDR) Network and the Mitogen-Activated Protein Kinase (MAPK) Signaling Pathway in Multiple Myeloma.

The DNA damage response (DDR) network and the mitogen-activated protein kinase (MAPK) signaling pathway are crucial mechanisms for the survival of all living beings. An accumulating body of evidence suggests that there is crosstalk between these two systems, thus favoring the appropriate functioning of multi-cellular organisms. On the other hand, aberrations within these mechanisms are thought to play a vital role in the onset and progression of several diseases, including cancer, as well as in the emergence of drug resistance. Here, we provide an overview of the current knowledge regarding alterations in the DDR machinery and the MAPK signaling pathway as well as abnormalities in the DDR/MAPK functional crosstalk in multiple myeloma, the second most common hematologic malignancy. We also present the latest advances in the development of anti-myeloma drugs targeting crucial DDR- and MAPK-associated molecular components. These data could potentially be exploited to discover new therapeutic targets and effective biomarkers as well as for the design of novel clinical trials. Interestingly, they might provide a new approach to increase the efficacy of anti-myeloma therapy by combining drugs targeting the DDR network and the MAPK signaling pathway.

Circulating Ferritin in Patients with Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-analysis.

Objectives: To synthesize data on circulating ferritin between patients with histologically confirmed nonalcoholic fatty liver disease (NAFLD) and non-NAFLD controls. Methods: A systematic literature search was conducted in PubMed, Scopus, and the Cochrane Library. Thirty-one studies comprising data on 5631 individuals (2929 biopsy-proven NAFLD patients and 2702 controls) were included in the meta-analysis. Results: Higher circulating ferritin levels were observed in NAFLD patients than in controls [standardized mean difference (SMD) 1.14; 95% confidence interval (95% CI) 0.73-1.55], in patients with simple nonalcoholic fatty liver (NAFL) than in controls (SMD 0.57; 95% CI 0.34-0.80), in patients with nonalcoholic steatohepatitis (NASH) than in controls (SMD 0.95; 95% CI 0.69-1.22), and in NASH than in NAFL patients (SMD 0.62; 95% CI 0.25-0.99). There was moderate-to-high heterogeneity among studies in the above pairs of comparisons (I2 = 68-97%); no risk of publication bias was observed by Egger's test (P = 0.81, P = 0.72, P = 0.59, P = 0.42, respectively). The heterogeneity was reduced in the subgroup of biopsy-proven controls in all pairs of comparisons (I2 = 0-65%). The heterogeneity was also reduced after excluding studies with the Newcastle-Ottawa Scale (NOS) score <7 (n = 10) for the comparison of NAFLD patients vs. controls (I2 = 54%, P = 0.02). The meta-regression analysis revealed that the male ratio was positively associated with ferritin SMD in the comparison between NAFLD patients and controls and accounted for 32.7% (P = 0.002) of the heterogeneity in this pair of comparison. Conclusions: Circulating ferritin was higher in NAFLD (or NAFL or NASH) patients compared with controls. Higher levels of circulating ferritin were also associated with the severity of the disease, which, however, should be cautiously interpreted.PROSPERO registration ID: CRD42022354025.

Retinopathy in a Patient With IgM MGUS: Causal Association or an Epiphenomenon?

BACKGROUND/AIM: The presence of a monoclonal gammopathy of undetermined significance (MGUS) even in small amounts may trigger tissue damage through immunological or other mechanisms, irrespective of the potential for malignant transformation. The aim of the study was to present a case of monoclonal gammopathy of clinical significance with ocular manifestations and discuss relevant literature. CASE REPORT: In our case, a patient presented with vision disturbances that was eventually attributed to the underlying IgM MGUS after extensive workup to exclude other potential etiologies. The patient showed a clinical response with the fixed-duration DRC (dexamethasone, rituximab, cyclophosphamide) regimen that persisted for at least 1.5 years. Herein, we present, in detail, the patient management and discuss the underlying pathophysiology of this rare entity with few available published data in this field. CONCLUSION: A high level of clinical suspicion is necessary in order to detect the association between MGUS and a clinical sign or symptom that cannot be attributed elsewhere.

High-Oxygen-Affinity Hemoglobins-Case Series and Review of the Literature.

Modifications of the hemoglobin (Hb) structure in regions involving the regulation of oxygen transport may lead to an increased oxygen affinity for the hemoglobin molecule and impaired oxygen delivery to the tissues. Herein, we present six patients with high-oxygen-affinity Hb variants, either in heterozygous form or in compound heterozygosity (such as heterozygosity for Hb Hiroshima, Köln, Crete, and compound heterozygosity Hb Crete with ß or 뫧 thalassemia), in order to demonstrate the need for prompt and accurate diagnosis and enrich the limited literature due to the rarity of such cases. Hb Crete, Hb Hiroshima, and Hb Köln have distinct pathophysiologies and may result in different clinical phenotypes. In conclusion, high-oxygen-affinity hemoglobins are rare and inherited within a dominant autosomal manner, have various clinical presentations, and should always be suspected in patients with erythrocytosis. Their management (as phlebotomy or low-dose aspirin) should be based on an individualized assessment of the risk of complications, the medical history, concomitant symptoms, and quality of life.

Long-term Survival in a Patient With Transformation of Waldenström's Macroglobulinemia into DLBCL.

Background/Aim: Waldenström's macroglobulinemia (WM) is a rare slow-growing B-cell lymphoma that is characterized by lymphoplasmacytic bone marrow infiltration and the production of monoclonal immunoglobulin M (IgM) paraprotein. In 5-10% of patients, WM undergoes transformation into diffuse large B-cell lymphoma (DLBCL), which is more aggressive, with poor prognosis and a low survival rate. Case Report: Α 69-year-old woman was diagnosed with WM in 2009. She received six cycles of chemoimmunotherapy and a remarkable remission was achieved. However, in 2013 the disease transformed into DLBCL. The patient received chemotherapy and after the completion of the first cycle of therapy, the disease was significantly minimized. At the end of the therapy, there was no evidence of disease, and the patient remains disease-free. The cytogenetic profile of the patient did not reveal expression of BCL2 apoptosis regulator, BCL6 transcription repressor, Epstein-Barr virus small RNA, syndecan 1 nor cyclin D1. According to a staging system based on the platelet count, lactate dehydrogenase and previous treatment for WM, the described patient was classified as being at intermediate risk with an expected 2-year survival probability of 47% after WM transformation into DLBCL. However, the patient unexpectedly exceeded these prognostic indications. Conclusion: The findings for this patient are of great interest compared with the existing literature which suggests that the survival and prognosis for patients with transformed DLBCL are not favorable.

Multiple myeloma.

Multiple myeloma (MM) is a haematological lymphoid malignancy involving tumoural plasma cells and is usually characterized by the presence of a monoclonal immunoglobulin protein. MM is the second most common haematological malignancy, with an increasing global incidence. It remains incurable because most patients relapse or become refractory to treatments. MM is a genetically complex disease with high heterogeneity that develops as a multistep process, involving acquisition of genetic alterations in the tumour cells and changes in the bone marrow microenvironment. Symptomatic MM is diagnosed using the International Myeloma Working Group criteria as a bone marrow infiltration of ≥10% clonal plasma cells, and the presence of at least one myeloma-defining event, either standard CRAB features (hypercalcaemia, renal failure, anaemia and/or lytic bone lesions) or biomarkers of imminent organ damage. Younger and fit patients are considered eligible for transplant. They receive an induction, followed by consolidation with high-dose melphalan and autologous haematopoietic cell transplantation, and maintenance therapy. In older adults (ineligible for transplant), the combination of daratumumab, lenalidomide and dexamethasone is the preferred option. If relapse occurs and requires further therapy, the choice of therapy will be based on previous treatment and response and now includes immunotherapies, such as bi-specific monoclonal antibodies and chimeric antigen receptor T cell therapy.

Exploring the molecular biomarker utility of circCCT3 in multiple myeloma: A favorable prognostic indicator, particularly for R-ISS II patients.

Circular RNAs (circRNAs) are associated with the pathobiology of multiple myeloma (MM). Recent findings regarding circCCT3 support its involvement in the development and progression of MM, through microRNA sponging. Thus, we aimed to examine the expression of circCCT3 in smoldering and symptomatic MM and to assess its clinical importance. Three cell lines from plasma cell neoplasms were cultured and bone marrow aspirate (BMA) samples were collected from 145 patients with MM or smoldering MM. Next, CD138+ enrichment was performed in BMA samples, followed by total RNA extraction and reverse transcription. Preamplification of circCCT3 and GAPDH cDNA was performed. Finally, a sensitive assay for the relative quantification of circCCT3 using nested real-time quantitative polymerase chain reaction was developed, optimized, and implemented in the patients' samples and cell lines. MM patients exhibited significantly higher intracellular circCCT3 expression in their CD138+ plasma cells, compared to those from SMM patients. In addition, MM patients overexpressing circCCT3 had longer progression-free and overall survival intervals. The favorable prognostic significance of high circCCT3 expression in MM was independent of disease stage (either International Staging System [ISS] or revised ISS [R-ISS]) and age of MM patients. Interestingly, circCCT3 expression could serve as a surrogate molecular biomarker of prognosis in MM patients, especially those of R-ISS stage II. In conclusion, our study sheds new light on the significance of circCCT3 as a promising molecular marker for predicting MM patients' prognosis.