Search Results (1,698)

Multiple myeloma (MM) is predominantly a disease of the elderly. In recent years, a surge of highly effective plasma cell therapies has revolutionized the care of elderly multiple myeloma (MM) patients, for whom frailty and age-related competing causes of mortality determine management. Traditionally, the treatment of newly diagnosed elderly patients has centered on doublet or triplet combinations composed of immunomodulators (IMIDs), proteasome inhibitors (PIs), anti-CD38 monoclonal antibodies (mAbs), and corticosteroids producing median progression-free survival (PFS) rates between 34 and 62 months. However, recently, a series of large phase III clinical trials examining quadruplet regimens of PIs, IMIDs, corticosteroids, and anti-CD38 mAbs have shown exceptional outcomes, with median PFS exceeding 60 months, albeit with higher rates of peripheral neuropathy (≥Grade 2: 27% vs. 10%) when PIs and IMIDs are combined, and infections (≥Grade 3: 40% vs. 29–41%) with the addition of anti-CD38mAbs. The development of T-cell redirecting therapies including T-cell engagers (TCEs) and CAR-T cells has further expanded the therapeutic arsenal. TCEs have shown exceptional activity in relapsed disease and are being explored in the newly diagnosed setting with promising early results. However, concerns remain regarding the logistical challenges of step-up dosing, which often necessitates inpatient admission, the infectious risks, and the financial burden associated with TCEs in elderly patients. CAR-T, the most potent commercially available therapy for MM, offers the potential of a ‘one and done’ approach. However, its application to elderly patients has been tempered by significant concerns of cytokine release syndrome, early and delayed neurological toxicity, and its overall tolerability in frail patients. Robust data in frail patients are still needed. How CAR-T and TCEs will be sequenced among the growing therapeutic armamentarium for elderly MM patients remains to be determined. This review explores the safety, efficacy, cost, and logistical barriers associated with the above treatments in elderly MM patients. Full article

Despite significant advancements in understanding the pathogenesis and treatment of hematological malignancies, including leukemia and multiple myeloma, the majority of patients continue to experience poor long-term outcomes. This is partly due to the difficulty of accurately recapitulating the malignant microenvironment in vitro, particularly the bone marrow niche. The complexity of the bone marrow microenvironment poses a challenge for the in vitro examination of hematological malignancies. Traditionally, 2D culture and animal models have been utilized, but these representations are limited and have been criticized for their lack of human physiological relevance. In an attempt to overcome this, 3D models have been developed that more accurately recapitulate the in vivo microenvironment. Herein, we present an overview of recent developments in 2D and 3D models used for studying the bone marrow niche in hematological malignancies, highlighting their advantages and limitations. Full article

Background and Objectives: Extramedullary plasmacytoma (EMP) is a rare monoclonal B-cell neoplasm that typically affects the head and neck region, with a predilection for the sinonasal tract. Clinical presentation is often nonspecific, leading to delayed diagnosis. This study aims to improve our understanding of sinonasal EMP by reviewing the recent literature and presenting a case series from our clinical experience. Materials and Methods: A systematic review of published cases of sinonasal EMP from 2000 to 2023 was conducted using the PubMed database, yielding 28 eligible cases. Additionally, we retrospectively analyzed three patients diagnosed and treated at our institutions. Inclusion criteria included histologically and immunohistochemically confirmed EMP without evidence of systemic multiple myeloma. Data on demographics, tumor location, symptoms, treatment, and outcomes were collected and analyzed descriptively. Results: Sinonasal EMP most commonly presented with unilateral nasal obstruction and epistaxis. Tumors were primarily located in the nasal cavity and paranasal sinuses, often extending beyond a single anatomical site. In the literature cohort, the most frequent treatment was combined surgery and radiotherapy (35.71%), followed by radiotherapy alone (17.86%). Recurrence was reported in 10.71% of cases, and 7.14% of patients died due to disease progression. All three patients in our case series underwent surgical excision; two received postoperative radiotherapy. No recurrences or progression to multiple myeloma were observed during follow-up (12–24 months). Conclusions: Sinonasal EMP is a rare but radiosensitive tumor with a favorable prognosis when treated with surgery and/or radiotherapy. Early diagnosis, histopathological confirmation, and exclusion of systemic disease are essential. Multidisciplinary management and long-term follow-up are critical due to the risk of recurrence and transformation into multiple myeloma. Full article

Monoclonal Gammopathy of Undetermined Significance (MGUS) is a precursor to hematologic malignancies such as Multiple Myeloma (MM) and Waldenström Macroglobulinemia (WM). Accurate risk stratification of MGUS patients remains a clinical and computational challenge, with existing models often misclassifying both high-risk and low-risk individuals, leading to inefficient healthcare resource allocation. This study presents a machine learning (ML)-based approach for early prediction of MM/WM progression, using routinely collected hematological data, which are selected based on clinical relevance. A retrospective cohort of 292 MGUS patients, including 7 who progressed to malignancy, was analyzed. For each patient, a feature descriptor was constructed incorporating the latest biomarker values, their temporal trends over the previous year, age, and immunoglobulin subtype. To address the inherent class imbalance, data augmentation techniques were applied. Multiple ML classifiers were evaluated, with the Support Vector Machine (SVM) achieving the highest performance (94.3% accuracy and F1-score). The model demonstrates that a compact set of clinically relevant features can yield robust predictive performance. These findings highlight the potential of ML-driven decision-support systems in electronic health applications, offering a scalable solution for improving MGUS risk stratification, optimizing clinical workflows, and enabling earlier interventions. Full article

Multiple myeloma (MM) is an incurable malignancy characterized by the proliferation of abnormal plasma cells within the bone marrow, followed by potential dissemination to extramedullary sites. The bone marrow barrier (BMB) plays a pivotal role in plasma cell homing and disease progression. Bone marrow endothelial cells (BMECs) and bone marrow stromal cells (BMSCs), through their interactions with MM cells, secrete adhesion molecules, angiogenic cytokines, anti-apoptotic factors, and growth-promoting signals that support MM cell survival and proliferation. This review examines the components of the BMB and the major pathways involved in MM pathogenesis. Targeting the interactions between MM cells and the BMB may offer novel therapeutic opportunities. Full article

Light-chain (AL) amyloidosis is a rare clonal plasma cell disorder that, if left untreated, carries a high risk of organ damage and mortality. Due to the rarity of the disease and the vulnerability of affected organ systems, treatment requires significant caution and nuance. As a plasma cell dyscrasia, AL amyloidosis treatment regimens are often adapted from those used for related disorders, particularly multiple myeloma. Despite substantial progress in research and drug development, optimal treatment strategies for relapsed/refractory (RR) AL amyloidosis remain unclear, and no FDA-approved therapies currently exist for this setting. B-cell maturation antigen (BCMA) has emerged as a promising immunotherapy target, with associated drug classes including antibody–drug conjugates, bispecific antibodies, and CAR-T cell therapies. These therapies have been extensively studied in relapsed/refractory multiple myeloma (RRMM) and are now being explored in the context of RR AL amyloidosis. This review summarizes the current literature on the efficacy and tolerability of BCMA-directed therapies in AL amyloidosis, with a particular emphasis on CAR-T cell therapy and offers comparisons to outcomes observed in RRMM. Full article

Introduction: Despite the approval of novel agents that have significantly improved long-term survival rates for multiple myeloma (MM) patients undergoing autologous stem cell transplant (ASCT), most patients eventually relapse. The failure to achieve or maintain bone marrow (BM) minimal residual disease (MRD) negativity is a recognised adverse prognostic factor for progression-free survival (PFS) and overall survival (OS). Contamination of stem cell apheresis by clonal plasma cells may also affect prognosis, though data remain limited. Methods: We conducted a prospective, single-centre observational study including 100 newly diagnosed MM patients eligible for ASCT and treated with bortezomib-based triplet induction. MRD was assessed both on BM and apheresis samples using multiparameter flow cytometry (MFC-MRD) with a sensitivity of 10⁻⁵. Results: Clonal plasma cells were detected in 22 apheresis samples (aMRD+), all of which were associated with BM MRD positivity. Patients with aMRD+ had inferior pre-ASCT responses (≥VGPR: 10% vs. 63%, p = 0.005) and worse post-ASCT BM MRD negativity rates (4% vs. 49%, p = 0.048). After a median follow-up of 52.4 months, aMRD+ was associated with shorter progression-free survival (median 38.5 vs. not reached, p = 0.007) and overall survival (median 60 months vs. not reached, p = 0.003). Conclusions: Contamination of the apheresis product is associated with persistent BM disease and poorer outcomes. Combined MRD assessment in both bone marrow and apheresis may improve risk stratification in MM patients undergoing ASCT. Full article

Background: Studies have suggested a synergism between lenalidomide (LEN) and ibrutinib (IBR) in multiple myeloma (MM). Both downregulate IRF4, a key target and master transcriptional factor regulating myeloma cell survival. Method: A 3 + 3 phase I trial was conducted to determine the maximum tolerated dose (MTD) of IBR in combination with LEN + dexamethasone (DEX) in patients with relapsed/refractory (RR) MM who had at least one prior line of therapy. Three dose levels (DLs) were planned. The cycle length was 28 days. IBR was administered orally daily in doses of 560 mg on DL1-2 and 840 mg on DL3, LEN was administered orally on days 1–21 in doses of 15 mg on DL1 and 25 mg on DL2-3, and DEX was administered orally on days 1, 8, 15, and 22 in a dose of 40 mg if age < 75 years or in a dose of 20 mg if it was ≥75 years for DL1-3. Patients with a glomerular filtration rate (GFR) <60 but ≥30 mL/min were treated in accordance with the manufacturer’s instructions with LEN 10 mg. Dose-limiting toxicities (DLTs) included the following: grade 4 neutropenia lasting more than 5 days, thrombocytopenia, febrile neutropenia, nausea, vomiting or diarrhea; grade 3 thrombocytopenia with bleeding or platelet transfusion; and grade 3–4 hyperglycemia or a thrombotic/embolic event, and other nonhematologic toxicities. The overall response rate (ORR) was defined as the percentage of patients with a partial response (PR), very good partial response (VGPR), or complete response (CR) according to IMWG criteria on two consecutive evaluations at least 4 weeks apart. The clinical benefit rate (CBR) was defined as the percentage of patients with stable disease (SD) or a better outcome on two consecutive evaluations at weeks apart. Results: Fourteen patients (DL1: six patients; DL2: three patients; DL3: five patients) were registered for the study from March 2019 to May 2023, prior to its closure due to limited accrual. Thirteen patients are included in the summary of toxicities and response as one patient on DL3 halted participation prior to the start of the treatment. Two patients on DL3 were excluded from the determination of MTD: one having discontinued cycle 1 treatment due to COVID-19 infection and the another having mistakenly taken 280 mg/day of IBR instead of the assigned 840 mg/day dose during cycle 1. Only one patient developed a DLT, on DL1 with grade 3 non-viral hepatitis. The median number of cycles administered was 4 (range: 1–56). Severe toxicities reported included grade 4 lymphocytopenia (1), grade 4 thrombocytopenia (1), and grade 5 sepsis in the setting of PD (1). Disease responses included a VGPR on DL1 and CR on DL3. Thus, the ORR was 15.4% (90% CI: 2.8–41.0%). One patient on DL1 maintained SD for 4.6 years before discontinuing the treatment to undergo an alternative therapy. Another five patients maintained SD for ≥ 2 consecutive cycles. Thus, the CBR was 61.5% (90% CI: 35.5–83.4%). Conclusions: The combination of LEN with IBR in RR MM proved feasible, with manageable toxicities and the majority of discontinuations being due to disease progression. Full article

Background: Belantamab mafodotin (belamaf) is a BCMA-targeting antibody–drug conjugate used in triple-class refractory multiple myeloma. Despite its efficacy, keratopathy remains a significant dose-limiting toxicity. Following its withdrawal from the U.S. market in 2022, its use in Austria is limited to clinical trials or compassionate use. Methods: In this real-world, retrospective study, we analyzed 36 relapsed/refractory, BCMA-naïve multiple myeloma patients treated at the University Hospital of Vienna (January 2020–June 2024); 42% received a reduced dose (1.9 mg/kg) throughout all treatment cycles. The primary objective was to assess adverse events, particularly keratopathy, and the impact of dose modifications on toxicity and efficacy. Results: The overall response rate was 64%, with responders having significantly fewer prior therapy lines (median 3 vs. 4.5, p = 0.015). Median PFS was 7.3 months, significantly longer in responders (11.1 vs. 1.6 months, p < 0.0001); median OS was 20.1 months, also longer in responders (not reached vs. 18 months, p = 0.031). Keratopathy occurred in 75% of patients; 33% experienced grade 3–4 events. Dose reduction significantly decreased grade 3–4 keratopathy (7% vs. 52%, p = 0.004) and thrombocytopenia (33% vs. 67%, p = 0.048) without compromising efficacy. Conclusions: Belamaf dose reductions improved tolerability without loss of efficacy, supporting reduced dosing in practice. Full article

Background: Carfilzomib (CFZ) is a proteasome inhibitor with known cardiotoxic effects used in multiple myeloma (MM) treatment. Cardio-oncology guidelines recommend cardiovascular risk assessment via echocardiography. Left atrial strain (LAS) is not yet included as a marker of cardiotoxicity, but it is emerging as a potential indicator of cardiac dysfunction. Objective: This study evaluates LAS as a predictor of CFZ-related hypertensive cardiovascular adverse events (CVAEs) in MM patients, with or without prior hypertension. Methods: A total of 125 MM patients treated with CFZ at the Hypertension Center, “Città della Salute e della Scienza” in Turin, were enrolled. Baseline assessments included transthoracic echocardiography for LAS analysis via Philips QLAB software. Results: During CFZ therapy, 52% of patients experienced hypertensive events. LAS conduit was significantly impaired in those who experienced CVAEs (−16.20 [−20.75; −12.65] vs. −20.80 [−26.30; −15.40], p = 0.006) and LAS conduit > −22 acted as a predictor of hypertensive adverse events in the normotensive population (OR 2.37 [1.02; 5.50]). Conclusion: These findings indicate that alterations in LAS conduit are linked to an increased risk of hypertensive adverse events during CFZ treatment. Incorporating LAS measurement into cardiovascular risk assessments may improve personalized risk stratification for MM patients, especially those without pre-existing hypertension. Full article

Background/Objectives: The treatment of multiple myeloma (MM) remains a challenge, as almost all patients will eventually relapse. Proteasome inhibitors are a cornerstone in the management of MM. Unfortunately, validated biomarkers predicting drug response are largely missing. Therefore, we aimed to identify genes associated with drug resistance or sensitization to proteasome inhibitors. Methods: We performed genome-wide CRISPR-Cas9 knockout (KO) screens in human KMS-28-BM myeloma cells to identify genetic determinants associated with resistance or sensitization to proteasome inhibitors. Results: We show that KO of KLF13 and PSMC4 induces drug resistance, while NUDCD2, OSER1 and HERC1 KO cause drug sensitization. Subsequently, we focused on top sensitization hit, NUDCD2, which acts as a co-chaperone of Hsp90 to regulate the LIS1/dynein complex. RNA sequencing showed downregulation of genes involved in the ERAD pathway and in ER-associated ubiquitin-dependent protein catabolic processes in both untreated and carfilzomib-treated NUDCD2 KO cells, suggesting that NUDCD2 depletion alters protein degradation. Furthermore, bortezomib-treated NUDCD2 KO cells showed a decreased expression of genes that have a function in oxidative phosphorylation and the mitochondrial membrane, such as Carnitine Palmitoyltransferase 1A (CPT1A). CPT1A catalyzes the uptake of long chain fatty acids into mitochondria. Mitochondrial lipid metabolism has recently been reported as a possible therapeutic target for MM drug sensitivity. Conclusions: These results contribute to the search for therapeutic targets that can sensitize MM patients to proteasome inhibitors. Full article

Background/Objectives: Selinexor is a selective nuclear-export inhibitor approved for hematologic malignancies, characterized by extensive plasma protein binding (>95%). However, a validated analytical method to accurately measure the clinically relevant unbound fraction of selinexor in human plasma has not yet been established. This study aimed to develop a fully validated bioanalytical assay for simultaneous quantification of total and unbound selinexor concentrations in human plasma. Methods: We established and fully validated an analytical method based on liquid chromatography–tandem mass spectrometry (LC-MS/MS) capable of quantifying total and unbound selinexor concentrations in human plasma. Unbound selinexor was separated using ultrafiltration, and selinexor was efficiently extracted from 50 μL of plasma by liquid–liquid extraction. Chromatographic separation was achieved on a C18 column using an isocratic mobile phase (0.1% formic acid:methanol, 12:88 v/v) with a relatively short runtime of 2.5 min. Results: Calibration curves showed excellent linearity over a range of 5–2000 ng/mL for total selinexor (r² ≥ 0.998) and 0.05–20 ng/mL for unbound selinexor (r² ≥ 0.995). The precision (%CV ≤ 10.35%) and accuracy (92.5–104.3%) for both analytes met the regulatory criteria. This method successfully quantified selinexor in plasma samples from renally impaired patients with multiple myeloma, demonstrating potential inter-individual differences in unbound drug concentrations. Conclusions: This validated bioanalytical assay enables precise clinical pharmacokinetic assessments in a short runtime using a small plasma volume and, thus, assists in individualized dosing of selinexor, particularly for renally impaired patients with altered protein binding. Full article

Background: Despite the inference about the cardiotoxicity induced by Carfilzomib, no validated risk prediction models for adverse cardiovascular events in a real-life population are available. Objectives: The aim of this study was to evaluate the performance of the risk stratification score for Carfilzomib-induced cardiotoxicity of the Heart Failure Association of the European Society of Cardiology and the International Cardio-Oncology Society (HFA-ICOS) in patients with multiple myeloma (MM). Methods: This is a prospective, real-world study including MM patients consecutively enrolled prior to starting Carfilzomib, divided into levels of risk according to the HFA-ICOS proforma. Results: Of 169 patients, 11.8% were classified as ‘low risk’, 38.5% as ‘medium risk’, 45.6% as ‘high risk’ and 4.1% as ‘very high risk’ at baseline. A total of 89 (52.7%) patients experienced one of the following events: 36 (21.3%) had at least one cardiovascular event and 77 (45.6%) had almost one hypertension-related event. No significant differences were observed for the incidence of any cardiovascular events between the different levels of risk (p > 0.05), even considering the HFA-ICOS score as a continuous variable. The integration of the score with the baseline systolic blood pressure and pulse wave velocity enhanced the accuracy of the score (AUC 0.557 vs. 0.736). Conclusions: The HFA-ICOS score did not discriminate between patients at low, medium and high risk, showing a limited discriminatory power in predicting the risk of events in our population. The integration of other parameters in the HFA-ICOS score, such as systolic blood pressure and pulse wave velocity, improved the performance of the score. Full article

B-cell maturation antigen (BCMA)-targeted therapies including both chimeric antigen receptor (CAR) T-cell therapies and bispecific antibodies (BsAbs), have revolutionized the treatment landscape for relapsed/refractory multiple myeloma (MM), offering both deep and durable responses, even in heavily pretreated patients. Despite these advances, most patients ultimately experience relapse. This is likely related to the development of resistance mechanisms that limit the long-term efficacy and durability of BCMA-targeted approaches. In this review, we examine the current landscape of BCMA-directed therapies, including Idecabtagene Vileucel, Ciltacabtagene Autoleucel, Teclistamab, and Elranatamab and explore the multifactorial mechanisms driving resistance. These mechanisms include tumor-intrinsic factors, host-related and tumor-extrinsic factors, and factors related to the tumor-microenvironment itself. We outline emerging strategies to overcome resistance, such as dual-targeting therapies, γ-secretase inhibitors, immune-checkpoint blockade, armored CAR T constructs, and novel combination regimens. Additionally, we discuss the role of therapy sequencing, emphasizing how prior exposure to BsAbs or CAR T-cell therapies may influence the efficacy of subsequent treatments. A deeper understanding of resistance biology, supported by integrated immune and genomic profiling, is essential to optimizing therapeutic durability and ultimately improve patient outcomes for patients with MM. Full article