Search Results (144)

CD38 is a multifunctional enzyme that plays a pivotal role in NAD⁺ metabolism and calcium signaling, and its abnormal activity is closely associated with multiple myeloma, age-related metabolic decline, neurodegenerative diseases, and other disorders. Although monoclonal antibodies such as daratumumab have been approved for clinical application, their inherent limitations necessitate the development of novel small-molecule CD38 inhibitors. In this study, we employed DNA-encoded library (DEL) technology for the high-throughput screening of CD38 inhibitors, using a DEL library containing more than 100,000 unique compounds to screen against recombinant human CD38. A total of 1043 enriched compounds were initially identified, and after rigorous validation and screening to exclude non-specific binding and previously reported active compounds, eight hit compounds with diverse chemical scaffolds were obtained, among which Fenbendazole—a clinically approved antiparasitic drug—was included. Surface plasmon resonance (SPR) assays confirmed the direct binding of these hit compounds to CD38, with dissociation constants (KD) ranging from 7.74 × 10⁻⁵ M to 2.15 × 10⁻⁴ M. Fluorescence-based enzymatic activity assays demonstrated that these compounds exert dose-dependent inhibitory effects on both the hydrolase (with ε-NAD as substrate) and cyclase (with NGD as substrate) activities of CD38. Further structure–activity relationship (SAR) analysis of Fenbendazole analogues revealed the critical structural features that regulate CD38 inhibitory potency, and Flubendazole was found to exhibit excellent inhibitory activity, with an IC₅₀ of 14.78 ± 4.21 μM against CD38 hydrolase and 26.31 ± 3.40 μM against cyclase. Molecular docking and 100 ns molecular dynamics (MD) simulations further elucidated the molecular mechanism of CD38 inhibition by lead compounds, confirming that van der Waals interactions are the main driving force for the binding of small-molecule ligands to CD38, with conserved aromatic residues in the active site mediating ligand recognition. This study validates DEL technology as an efficient and reliable platform for the discovery of CD38 inhibitors, and the identified lead compounds—especially Fenbendazole and its analog Flubendazole—provide valuable molecular scaffolds for the further structural optimization of CD38 inhibitors. These findings lay a solid foundation for the development of novel therapeutic agents for the treatment of CD38-associated diseases. Full article

Background and Clinical Significance: Plasmablastic lymphoma (PBL) is a rare and highly aggressive B-cell neoplasm most often associated with immunodeficiency. Transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) into PBL is exceptionally uncommon, particularly in immunocompetent individuals. This paper describes a rare synchronous SLL-to-PBL transformation and summarizes current knowledge on synchronous and metachronous cases reported in the literature. Case Presentation A midle-aged immunocompetent patent presented with generalized lymphadenopathy and lumbar pain. Concurrent biopsies of an axillary lymph node and a retroperitoneal mass were obtained. Diagnostic evaluation included immunohistochemistry; fluorescent in situ hybridization (FISH); PCR-based assessment of IGH, IGK, and IGL loci; and next-generation sequencing (NGS) of IGHV to assess clonal relatedness. The patient was treated with six cycles of Dara-CHOP, followed by autologous stem cell transplantation and maintenance therapy with daratumumab and ibrutinib. The axillary node showed SLL (CD20+, CD5+, CD23+), while the retroperitoneal mass demonstrated classic features of PBL (CD138+, MUM1+, MYC+, Ki-67 ~100%, CD20−). FISH detected MYC rearrangement in the PBL component. PCR and NGS confirmed identical IGHV1-69 rearrangements, establishing clonal relatedness and Richter transformation. A review of published cases shows that both synchronous and metachronous CLL/SLL-to-PBL transformations are exceedingly rare. The patient achieved partial metabolic remission after treatment and remains in sustained metabolic response 24 months after diagnosis. Conclusions: This case highlights a rare example of synchronous CLL/SLL-to-PBL transformation in an immunocompetent patient. Integration of detailed molecular diagnostics enabled early recognition and guided a personalized treatment approach incorporating CD38-targeted therapy and BTK inhibition, resulting in an excellent long-term clinical outcome. Full article

Background: Multiple myeloma (MM) is a clonal plasma cell neoplasm representing the second most common hematological malignancy. The combination of daratumumab, lenalidomide and dexamethasone (D-Rd) was first approved by the EMA (European Medicines Agency) for the treatment of relapsed/refractory multiple myeloma (RRMM) patients, and was subsequently approved for first-line therapy, based on the results of POLLUX and MAIA trials, respectively. Methods: In this survey, we retrospectively collected data from 96 consecutive transplant-ineligible newly diagnosed multiple myeloma (TIE-NDMM) patients treated with the D-Rd combination. Results: The median age was 73 years; the median progression free survival (mPFS) and median overall survival (mOS) were not reached (NR); the overall response rate (ORR), defined as patients who obtained at least a partial response (PR), was 90%; 59% of patients achieved a very good partial response (VGPR) or better. A strong negative correlation was observed between treatment response and elevated beta-2-microglobulin levels. Conclusions: This study confirms the efficacy of the D-Rd combination as first-line therapy for TIE-NDMM patients, suggesting that achieving at least a PR—and particularly a VGPR—may represent a strong predictor of long-term remission and survival, even in the era of new combinations based on the use of quadruplets. Full article

Background/Objectives: Previous studies suggested superior outcomes for AL amyloidosis patients eligible for consolidation with high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) compared to patients who did not receive these therapies. However, data are limited due to disease rarity, differing patient selection, and evolving treatment algorithms. Following the introduction of daratumumab, which improved outcomes in AL amyloidosis patients, it remains unclear whether HDCT/ASCT still confers additional benefit. Methods: Our retrospective, single-center study aimed to compare patients diagnosed between January 2003–December 2024 and consolidated in first remission with HDCT/ASCT vs. without HDCT/ASCT, both before and within the era of CD38-targeting daratumumab. Results: In our cohort of 106 AL systemic amyloidosis patients, 57 patients underwent HDCT/ASCT after induction therapy, while 49 had chemoimmunotherapy regimens alone. The two groups differed at initial diagnosis by age (p = 0.0028), renal function (eGFR, p = 0.0054), Troponin T levels (p < 0.0001) and NT-proBNP (p = 0.038). Patients treated with HDCT/ASCT had considerably better outcomes than patients without HDCT/ASCT. The median overall survival (OS) was 157 vs. 36 months (p < 0.0001), and median progression-free survival (PFS) was 81 vs. 24 months (p < 0.0001). Daratumumab was given to 45 patients (41.7%) during first line treatment, and patients were divided into additional subgroups: HDCT/ASCT ± daratumumab and chemotherapy ± daratumumab. OS and PFS were longer in patients treated with HDCT/ASCT, regardless of whether daratumumab was added to induction. The 5-year OS was 88%/86% in patients treated with HDCT with/without daratumumab and 37%/47% in the chemoimmunotherapy group with/without daratumumab (n.s.). The 5-year PFS in patients receiving HDCT was 63%/78% and in the group without HDCT/ASCT 38%/22% each with/without daratumumab. Conclusions: Thus, regardless of daratumumab use during induction treatment, our results strongly suggest that patients with AL amyloidosis undergoing HDCT/ASCT consolidation achieve superior PFS and OS compared with those treated with chemoimmunotherapy alone. Full article

Background and Clinical Significance: Kidney transplant recipients have a 2–4-fold higher cancer risk than the general population. The sequential occurrence of multiple myeloma (MM) and native-kidney renal cell carcinoma (RCC) is rare and creates competing priorities between anti-myeloma efficacy and allograft preservation. Case Presentation: A 54-year-old woman with a 2020 living-donor kidney transplant presented in 2024 with bone pain and shoulder swelling. Low-dose whole-body CT showed multiple punched-out osteolytic lesions. Work-up revealed IgG-κ M-protein 38.5 g/L and 25% clonal plasma cells; cytogenetics showed a complex karyotype (R-ISS III). First-line bortezomib/cyclophosphamide/dexamethasone (VCd) was given while maintaining tacrolimus plus low-dose steroid. After four cycles, she achieved very good partial response (M-protein 42.3 to 5.6 g/L) with stable graft function. Follow-up imaging detected a large exophytic mass in the native right kidney; nephrectomy confirmed papillary RCC, type II. Later, the myeloma progressed with epidural extension causing cord compression. Second-line daratumumab/carfilzomib/dexamethasone (DKd) and palliative spine radiotherapy were initiated. The course was complicated by opportunistic infection and pancytopenia, and the patient died in January 2025. Conclusions: Vigilant post-transplant cancer surveillance—including native-kidney RCC—tailored immunosuppression, and multidisciplinary coordination are critical. VCd with tacrolimus may be feasible when graft preservation is prioritized; however, relapsed high-risk MM on DKd carries substantial infectious risk and a guarded prognosis. Full article

Background/Objectives: Despite therapeutic advances, managing relapsed/refractory multiple myeloma (RRMM) remains challenging. For patients with frailty, comorbidities, mobility limitations, or when treatment preference and drug accessibility are key considerations, the all-oral ixazomib–lenalidomide–dexamethasone (IRd) regimen offers a practical alternative. Methods: We performed a multicenter retrospective study of RRMM patients treated with IRd in Hungary between 1 January 2020 and 30 June 2025. Results: The median age at treatment initiation was 73.7 years. Treatment was initiated for clinical progression in 38.2%, biochemical progression in 53.3%, and for intolerance or toxicity of prior therapy in 8.6%. Median progression-free survival (PFS) was 18.7 months, and median overall survival (OS) was 34.7 months. Patients treated at biochemical progression had significantly longer PFS than those treated at clinical progression (24.3 vs. 15.6 months; p = 0.004), with additional benefit when IRd was initiated owing to intolerance or toxicity of previous therapy (p = 0.04). In the second-line setting, median PFS was 24.5 months, and median OS was not reached. Adverse events occurred in 68.3% of patients; dose reductions were required in 18.4%, and 21.6% discontinued treatment because of intolerance or toxicity. Most common toxicities were neutropenia (32.9%), thrombocytopenia (27.6%), diarrhoea (25%), peripheral neuropathy (25.3%), and infections (22.4%). Conclusions: IRd initiation at biochemical progression was associated with superior PFS compared with treatment at clinical progression. When compared with a recent Hungarian multicenter cohort treated with second-line daratumumab, lenalidomide, and dexamethasone, outcomes with IRd are not significantly inferior (36-month OS calculated from 2nd line treatment initiation: 65.5% for DRd vs. 60% in our cohort; p = 0.56). These real-world data support IRd as an effective, convenient, all-oral option for appropriately selected RRMM patients. Full article

Background: Although anti-CD38 monoclonal antibody-based regimens are standard care for newly diagnosed multiple myeloma (NDMM), direct comparative efficacy and comprehensive real-world safety data remain scarce. Methods: We conducted a systematic review and Bayesian network meta-analysis (NMA) of randomized controlled trials (RCTs). Efficacy was assessed using hazard ratios (HRs) for progression-free survival and odds ratios (ORs) for response rates, with treatment rankings evaluated by Surface Under the Cumulative Ranking (SUCRA) values. Separately, adverse event reports for daratumumab, bortezomib, lenalidomide, and dexamethasone (D_VRd) regimens were extracted from the US FDA Adverse Event Reporting System (FAERS) (Q1 2015–Q2 2025). Statistical analyses were performed using R (4.3.3) and STATA (16.0). Results: The NMA included 33 RCTs. For the primary efficacy endpoints, compared to the standard bortezomib, lenalidomide, and dexamethasone (VRd) regimen, both D_VRd (OR = 3.21, 95% CI: 2.46–4.26; HR = 0.48, 95% CI: 0.38–0.63) and isatuximab plus VRd (Isa_VRd) (OR = 1.71, 95% CI: 1.25–2.32; HR = 0.66, 95% CI: 0.51–0.85) regimens demonstrated superior efficacy. Subsequent pharmacovigilance analysis of D_VRd identified 11,714 FAERS reports, yielding 197 significant adverse drug event signals (64 unlabeled). These signals primarily affected elderly males and showed a bimodal distribution pattern. Conclusions: Combination regimens containing anti-CD38 monoclonal antibodies demonstrate superiority in achieving deep remission and survival benefits, with D_VRd and Isa_VRd regimens showing particularly outstanding performance. However, efficacy and safety profiles vary across different combination regimens. Real-world data analysis further indicates that the D_VRd regimen carries several safety risk signals that remain underappreciated and exhibits a bimodal time distribution pattern. These findings provide new evidence to guide clinical decision-making and risk-stratified monitoring. Full article

Host-modulating therapies and oral microbiome-targeted approaches are emerging options in periodontal care and are especially relevant for patients undergoing immunotherapy for hematologic malignancies. Immune dysregulation induced by immune checkpoint inhibitors or CAR-T cell therapy may worsen periodontal inflammation and alter the composition and functions of the oral microbiota. Beyond these, other immunomodulatory treatments commonly employed in hematologic malignancies—including monoclonal antibodies (e.g., rituximab, daratumumab), immunomodulatory drugs (e.g., lenalidomide, thalidomide), cytokine-based therapies (e.g., interferon-α), and targeted small-molecule inhibitors (e.g., BTK inhibitors, JAK inhibitors) may also influence periodontal homeostasis and oral microbial ecology by altering neutrophil function, cytokine profiles, and mucosal immune surveillance. The oral microbiota is functionally connected with the intestinal microbial ecosystem through the oral–gut axis, by periodontal pathogens may colonize the gut and modulate systemic immune responses, with potential repercussions on the efficacy and safety of immunotherapy. This narrative review examines the mechanisms and clinical applicability of host-modulating therapies, including subantimicrobial-dose doxycycline, omega-3 fatty acids, and microbiome-targeted interventions, such as oral probiotics, prebiotics and other antimicrobials in patients treated with immunotherapy. Full article

Background/Objectives: Therapeutic monoclonal antibodies, including bispecifics (t-mAbs), can interfere with serum protein electrophoresis (SPEP) and immunofixation electrophoresis (IFE), mimicking residual M-protein. We evaluated a mass spectrometry (MS; EXENT^®)-based workflow supported by an m/z reference library to discriminate drug from disease and assess concordance with IFE. Methods: Fifty-eight serum samples from 29 multiple myeloma patients were analyzed at baseline and after 3 months. Targeted enrichment of t-mAbs followed by MS enabled detection of peaks annotated through matching to a theoretical m/z panel and correlation with SPEP/IFE results. Results: Comparison of IFE versus MS showed 11/29 (38%) double positives, 15/29 (52%) double negatives, and 3/29 (10%) IFE−/MS+; no IFE+/MS− cases were observed. Using MS as a reference, IFE exhibited 78.6% sensitivity and 100% specificity. The m/z library enabled attribution of interference to linvoseltamab (n = 9), daratumumab (n = 6), and teclistamab (n = 3); in 16 patients treated with other bispecifics, no drug-related peaks were detected after 3 months. Longitudinal analysis discriminated therapeutic from endogenous immunoglobulins, identified baseline M-protein, and prevented false residual signals. Conclusions: MS (EXENT^®)-based characterization of t-mAbs improves response monitoring accuracy in multiple myeloma and supports integration of MS into routine laboratory practice. Full article

Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy, characterized by the clonal proliferation of immature lymphoid precursors. The distinction between B-cell ALL (B-ALL) and T-cell ALL (T-ALL) is fundamental, as each subtype exhibits distinct cytomorphological, genetic, and clinical features influencing prognosis and therapeutic strategies. Conventional multi-phase chemotherapy has significantly improved survival rates, yet its efficacy is limited by severe short- and long-term toxicities, highlighting the need for more selective therapeutic approaches. Advances in molecular profiling have enabled the identification of key oncogenic pathways, paving the way for targeted therapies such as tyrosine kinase inhibitors (TKIs), JAK-STAT pathway inhibitors, BCL-2 antagonists, and agents modulating epigenetic and cell cycle regulators. Concurrently, immunotherapeutic strategies have transformed the therapeutic landscape of pediatric ALL. Bispecific antibodies such as blinatumomab (anti-CD19), antibody–drug conjugates like inotuzumab ozogamicin (anti-CD22), and monoclonal antibodies such as daratumumab (anti-CD38) have demonstrated efficacy in relapsed or refractory disease with improved safety profiles. Moreover, CAR-T-cell therapy, particularly CD19-directed products, has shown unprecedented remission rates in refractory B-ALL. The integration of targeted and immune-based therapies into conventional regimens represents a decisive step toward precision medicine, aiming to enhance survival outcomes while reducing treatment-related toxicity and improving quality of life in ALL children. This review aims to provide a comprehensive overview of the current understanding of ALL pathobiology and therapeutic approaches, with particular emphasis on the expanding role of immunotherapeutic strategies in pediatric disease. Full article

Thrombosis is a common complication in multiple myeloma (MM) patients treated with immunomodulatory drugs (IMiDs), including thalidomide, lenalidomide, and pomalidomide. When combined with anti-CD38 monoclonal antibodies, these agents are highly effective but may increase thrombotic events (TE), potentially delaying therapy. This exploratory, hypothesis-generating analysis, conducted within the MMVision mono-institutional prospective study, included 53 MM patients who initiated IMiD plus anti-CD38 therapy between May 2021 and December 2022 (median follow-up: 18 months). Treatment regimens comprised lenalidomide (n = 36) or thalidomide (n = 15) with daratumumab, and pomalidomide (n = 2) with isatuximab. Most patients (n = 38) received frontline therapy, and all were given thromboprophylaxis according to guidelines, mainly aspirin (73%). Five patients (9.4%) developed VTE after a median of 48 days, managed with short-term low-molecular-weight heparin (LMWH). Exploratory analysis of 27 clinical/laboratory parameters suggested possible associations between VTE and low levels of beta-2 microglobulin, ferritin, intact/free lambda light chains, and monocyte-to-lymphocyte ratio. Notably, four of the five VTEs occurred in patients without lytic bone disease, typically associated with bone-driven inflammation in MM. Although all patients received aspirin prophylaxis from treatment initiation, it remains unclear whether thrombosis would also have occurred among those with higher inflammatory burden. These preliminary observations may indicate that in patients with relatively lower inflammation, aspirin prophylaxis could be less effective, potentially favoring VTE onset. In two VTE cases, cytokine profiling showed decreased M-CSF, SCLF-β, and MIP-1α, with increased G-CSF, raising the hypothesis of distinct immune-inflammatory pathways contributing to TEs. Given the limited number of patients and thrombotic events, and the cytokine data available for only two VTE cases, these associations should be regarded as exploratory and interpreted with caution. Overall, these exploratory findings warrant validation in larger, independent cohorts and may help generate hypotheses on how inflammatory signatures influence thrombotic risk and prophylaxis efficacy in MM patients receiving IMiD/anti-CD38-based regimens. Full article

Background/Objectives: The role of daratumumab, lenalidomide, and dexamethasone (DRd) in autologous stem cell transplantation (ASCT)-eligible patients with multiple myeloma (MM) after first-line bortezomib, cyclophosphamide, and dexamethasone (VCd) treatment is not yet established. Methods: We retrospectively evaluated ASCT-eligible patients with MM who received second-line therapy with DRd after initial induction therapy with VCd between 2017 and 2023 (salvage group). For comparison, patients who successfully underwent per-protocol treatment with VCd induction, followed by ASCT during the same period, were selected (control group). Results: Eight patients with a median age of 61 years (range, 36–68 years) were included in the salvage group. After a median of 5 DRd cycles, the best response was partial response (PR) in two patients (25%) and a very good partial response (VGPR) in six (75%). All patients underwent ASCT, resulting in PR in one (13%), VGPR in four (50%), and stringent complete response in three (38%). Measurable residual disease (MRD) assessed using multicolor flow cytometry was negative in four patients (50%). The controls included thirteen patients with a median age of 60 years (range, 44–64 years). While most patients in both groups received various post-ASCT therapies, the post-ASCT 2-year time to the next treatment rate was slightly better in the salvage group than in the control group (88% vs. 49%, p = 0.089). However, hypogammaglobulinemia was more common in the salvage group (75% vs. 15%, p = 0.018). Conclusions: This small case series suggests that DRd is promising for ASCT-eligible patients with MM after VCd failure. Full article

Background: Treatment for transplant-ineligible (TIE) newly diagnosed multiple myeloma (NDMM) has improved with anti-CD38 monoclonal antibodies. Among them, daratumumab, combined with standard therapies, has shown promising results in clinical trials. This meta-analysis consolidates evidence on the effectiveness and safety of daratumumab-based treatments for this patient group from all available randomized controlled trials (RCTs). Methods: We systematically searched PubMed, Embase, Cochrane Central Register of Controlled Trials, and clinical trial registries from inception to September 2025 for phase II and III RCTs comparing daratumumab-containing regimens to non-daratumumab controls in TIE NDMM patients. Primary outcomes were progression-free survival (PFS) and overall survival (OS). Secondary outcomes included minimal residual disease (MRD) negativity rate and adverse events (AEs). Heterogeneity was assessed using I² statistics, and subgroup analyses were performed to explore potential sources of heterogeneity. Results: Six RCTs involving 2478 patients were included. Daratumumab-based regimens significantly improved PFS (hazard ratio [HR] = 0.544, 95% confidence interval [CI]: 0.483–0.612, p < 0.001; I² = 28.6%) and OS (HR = 0.693, 95% CI: 0.606–0.791, p < 0.001; I² = 30.6%). The MRD negativity rate was significantly higher with daratumumab (risk ratio [RR] = 2.322, 95% CI: 1.486–3.627, p < 0.001). Furthermore, daratumumab-based regimens yielded a four-fold increase in the rate of sustained MRD negativity (≥12 months) (RR = 3.999, 95% CI: 1.094–8.403, p < 0.001). However, these regimens were associated with increased risks of serious adverse events (SAEs) (RR = 1.146, 95% CI: 1.064–1.233, p < 0.001), overall grade 3/4 AEs (RR = 1.075, 95% CI: 1.038–1.115, p < 0.001), neutropenia, lymphopenia, infections, pneumonia, and fatal AEs. No significant differences were observed in thrombocytopenia or anemia. Conclusions: Daratumumab-based regimens significantly improve survival outcomes and the depth/durability of treatment response in TIE NDMM patients, supporting their use as first-line therapy. However, the increased risk of specific AEs necessitates careful patient selection, proactive infection prevention, and vigilant monitoring. These findings provide robust evidence for clinical practice guidelines and underscore the need to balance efficacy with safety in this vulnerable population. Full article

Background/Objectives: CD38-targeting monoclonal antibodies isatuximab and daratumumab have revolutionized multiple myeloma (MM) treatment, but a deeper understanding of their distinct mechanisms is crucial for therapeutic optimization. Methods: We used flow cytometry to assess isatuximab and daratumumab binding competition in MM cell lines and patient-derived bone marrow cells. The dynamics of CD38 expression were evaluated at different time points before and after antibody-mediated removal. The effects of IMiDs (pomalidomide, lenalidomide) on CD38 expression and isatuximab-induced apoptosis, either alone or in combination with IMiDs, were also examined. Moreover, MM cell migration was assessed through CXCR4-mediated assays, and cell adhesion was evaluated via CD49d-dependent assays. Results: Isatuximab and daratumumab did not compete for CD38 binding, confirming distinct epitope recognition. Following depletion with either antibody, CD38 expression on the MM cell surface began to recover within 2 h, suggesting a dynamic regulation of CD38 availability. While daratumumab lacked direct apoptosis, isatuximab induced significant direct cell death. Pomalidomide enhanced isatuximab-induced apoptosis by increasing CD38 expression, whereas lenalidomide had no significant effect. Additionally, both antibodies effectively inhibited MM cell migration and significantly reduced cell adhesion. Conclusions: Their non-competitive binding and shared impact on cell dynamics suggest opportunities for optimizing treatment strategies through combinatorial or sequential approaches in MM therapy. Full article

Background: Cardiac amyloidosis (CA) is an increasingly recognized but historically underdiagnosed cause of restrictive cardiomyopathy and heart failure with preserved ejection fraction (HFpEF). It results from the extracellular deposition of misfolded protein fibrils, most commonly transthyretin (ATTR) or immunoglobulin light chains (AL), leading to progressive myocardial dysfunction and multi-organ involvement. Objective: This review provides a comprehensive, cardiology-centered overview of cardiac amyloidosis, with an emphasis on early recognition, diagnostic strategies, subtype differentiation, and the evolving therapies. Content: We summarize the epidemiology, pathophysiology, and clinical manifestations of both ATTR and AL subtypes. Key diagnostic tools, including echocardiography, cardiac magnetic resonance imaging, bone scintigraphy, monoclonal protein screening, and endomyocardial biopsy, are reviewed in the context of a stepwise diagnostic approach. Special attention is given to clinical presentation, electrocardiographic and imaging “red flags,” and to differentiating CA from mimickers such as hypertrophic cardiomyopathy, hypertension-induced left ventricular hypertrophy, and aortic stenosis. Staging systems are detailed, highlighting the prognostic role of cardiac biomarkers. Therapeutic strategies are explored, including subtype-specific regimens (e.g., daratumumab-based therapy for AL; tafamidis and gene silencers for ATTR), the judicious use of conventional heart failure medications, and emerging therapies such as CRISPR-based gene editing. Conclusions: Timely recognition and accurate diagnosis of cardiac amyloidosis are critical to improving outcomes. As diagnostic tools and disease-modifying therapies evolve rapidly, cardiologists must remain at the forefront of multidisciplinary care. A structured biomarker- and imaging-guided approach can enhance diagnostic yield, inform prognosis, and optimize patient-specific management. Full article