Search Results (240)

In the last few decades, chimeric antigen receptor (CAR) T-cell therapy has led to a paradigm shift in the treatment of hematological malignancies, including various subtypes of B-cell non-Hodgkin’s lymphoma, B-cell acute lymphoblastic leukemia, and multiple myeloma. However, most patients experience refractoriness to CAR T-cells or relapse after treatment. Many efforts are underway to understand the mechanisms behind CAR T-cell failure, which are mainly related to CAR T-cell dysfunction, tumor-intrinsic resistance, an immunosuppressive tumor microenvironment, manufacturing issues, or patient-related factors. Several strategies are being developed to overcome these resistance mechanisms, including the engineering of more functional allogeneic CAR T-cell products, the targeting of alternative tumor antigens, and combination therapies with other drugs such as checkpoint inhibitors or small molecules to enhance CAR T-cell efficacy. In this review, we will provide an updated overview of the mechanisms of CAR T-cell failure and the therapeutic advances currently under development to address them. Full article

Background/objectives: MDG1011 is a Preferentially Expressed Antigen in Melanoma (PRAME)-specific autologous T cell receptor (TCR) T cell therapy for HLA-A*02:01-positive patients. Data from the first-in-human (FIH) clinical trial, CD-TCR-001, are reported here regarding treatment feasibility, safety, tolerability, and clinical activity of MDG1011 in patients with relapsed/refractory (r/r) acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and multiple myeloma (MM). Methods: Nine of thirteen enrolled patients received MDG1011 at dose levels ranging from 0.1 to 5 × 10⁶ TCR-T cells per kg body weight. In addition to clinical assessments, immune monitoring of cytokines associated with cytokine release syndrome (CRS), presence and persistence of MDG1011, and changes in levels of PRAME mRNA were used to assess safety and potential biological activity at defined time points. Results: The treatment was well tolerated. No dose-limiting toxicities (DLTs) were observed, and the most common serious adverse events were associated with lymphodepleting chemotherapy and/or disease progression. Various parameters, such as measurable clinical responses in two patients, the occurrence of CRS in two additional patients, and reductions in PRAME mRNA levels in bone marrow (BM) or peripheral blood (PB) in seven patients, served as signs of the clinical and biological activity of MDG1011 TCR-T therapy. Conclusions: Patients enrolled in the phase 1 part of CD-TCR-001 displayed signs of potential clinical and biological activity of MDG1011 among the small number of patients studied. Advanced disease stage and rapid progression in the r/r AML patients limited clinical impact. The acceptable safety profile of MDG1011 merits further investigation of this TCR-T therapy, potentially in patients at an earlier stage of their disease and with lower tumor burden. Full article

Background: Multiple myeloma (MM) is an incurable plasma cell dyscrasia with particularly adverse prognosis in relapsed, multi-drug refractory settings. The management of those patients is challenging as treatment options are limited. In this context, bispecific antibodies (BsAbs) have recently emerged as promising therapeutic agents, and several have gained regulatory approval. To better understand their impact in MM landscape, we performed a systematic review and meta-analysis assessing their efficacy and safety in patients with relapsed/refractory MM (RRMM). Methods: A systematic search was conducted in the PubMed, ScienceDirect, Scopus and ClinicalTrials.gov databases for clinical trials investigating BsAbs for RRMM. Pooled estimates in terms of proportions along with 95% confidence intervals were calculated with random-effects models. The present meta-analysis was performed following PRISMA guidelines and was registered in PROSPERO (ID: CRD420251028553). Results: Based on data from six clinical trials involving 850 patients, the pooled overall response and complete response or better rates were 69% and 42%, respectively, whereas the pooled rate of duration of response for at least one year was 71%. The estimated one-year progression-free survival and overall survival were 56% and 72%, respectively. Neutropenia was the most frequently observed severe hematological toxicity, with a pooled incidence of 46%. Grade ≥3 infections occurred in 29%, while any-grade CRS occurred in 69%, as per pooled analysis. Finally, an exploratory minimal residual disease (MRD) analysis in four of the six studies yielded a pooled MRD-negativity rate of 24%. Conclusions: BsAbs demonstrated commendable efficacy in heavily pretreated RRMM patients, in terms of response rates and survival outcomes. However, notable rates of hematologic toxicity, infections, and CRS were recorded. These findings support the clinical utility of BsAbs in RRMM, while highlighting the need for comprehensive toxicity management. Full article

Multiple myeloma (MM) is a malignant plasma cell disorder that evolves from precursor conditions including monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). Understanding the biological continuum and the molecular drivers of disease progression is crucial for early diagnosis and risk-adapted therapy. Recent advances in next-generation sequencing have identified recurrent mutations in the RAS/MAPK, TP53, and MYC pathways, along with epigenetic alterations that contribute to clonal evolution and therapeutic resistance. Novel diagnostic tools including minimal residual disease (MRD) assessment, gene expression profiling, and advanced imaging have improved risk stratification. Therapeutically, the integration of proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies has dramatically improved patient outcomes. In parallel, emerging immunotherapies such as CAR-T cells, bispecific T-cell engagers, and antibody–drug conjugates are expanding treatment options, especially in relapsed or refractory settings. Future directions aim to personalize treatment using genomics, target the tumor microenvironment, and leverage synthetic lethality and epigenetic vulnerabilities. This review highlights the evolving landscape of plasma cell disorders from molecular pathogenesis to cutting-edge therapeutic innovations, emphasizing the need for precision medicine approaches to improve survival and quality of life for patients with MM and its precursors. Full article

This report presents the case of a seven-year-old West Highland White Terrier diagnosed with relapsed and refractory multiple myeloma (MM), managed using multiple treatment approaches, including conventional chemotherapy (melphalan, vincristine, doxorubicin, and dexamethasone), radiation therapy (RT), and novel agents such as the selective inhibitor of nuclear export (verdinexor), proteasome inhibitors (bortezomib, carfilzomib, and ixazomib), and tyrosine kinase inhibitors (TKIs; toceranib and sorafenib). Treatment response was monitored using serum globulin concentration and imaging studies. Verdinexor achieved the longest period of stable remission with minimal toxicity post-RT. Bortezomib + dexamethasone was effective in controlling hyperglobulinemia at doses ≥ 1.45 mg/m², although cumulative hematologic and gastrointestinal toxicity limited its prolonged use. Second-line proteasome inhibitors and TKIs demonstrated limited efficacy. Despite initial therapeutic response, the patient’s condition deteriorated due to persistent hyperglobulinemia and hyperviscosity syndrome. The absence of advanced supportive options, including plasmapheresis, contributed to a fatal outcome. This case highlights the potential utility of novel therapies such as verdinexor and bortezomib in managing refractory canine MM. Timely intervention, individualized dosing, and supportive care are essential for optimizing treatment outcomes. Further research is required to define effective combinations and integrate advanced care options, including stem cell transplantation and targeted antibody therapies, in veterinary MM. Full article

Chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising treatment for relapsed or refractory multiple myeloma (RRMM), with high response rates of 80–95%. Serum immunoglobulin changes have been observed throughout conventional multiple myeloma treatment, including after immunomodulatory drugs, proteasome inhibitors, and autologous stem cell transplantation. However, the clinical significance of new abnormal protein bands (APBs) following CAR T-cell therapy is largely unexplored. We retrospectively analyzed consecutive multiple myeloma (MM) patients who received CAR T-cell therapy at the University Hospital Bern between May 2021 and February 2024. Serum paraprotein (M-protein) patterns were assessed using immuno-fixation electrophoresis (IFE) before and after CAR T-cell treatment. Patients were grouped based on serum immunoglobulin changes. Among 46 patients, 9 (19.6%) developed new APBs following CAR T-cell therapy. No significant differences in overall survival (OS) or progression-free survival (PFS) were observed between patients with and without APBs. Immunoglobulin changes occurred in both relapsed and non-relapsed patients, suggesting that the appearance of new APBs does not indicate disease progression. This observation aligns with previous reports of paraprotein changes following conventional MM therapies. This report suggests that new APBs following CAR T-cell therapy are a relatively common finding but do not correlate with inferior clinical outcomes. Our results highlight the need for larger, multi-center studies to further investigate this phenomenon in MM patients undergoing CAR T-cell therapy. 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

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

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

Background: Cytokine release syndrome (CRS) is a life-threatening systemic inflammatory condition marked by excessive cytokine production, leading to multi-organ dysfunction. It is commonly associated with T-cell-engaging therapies such as chimeric antigen receptor (CAR) T cells, T-cell receptor bispecific molecules, and monoclonal antibodies. Carfilzomib, a proteasome inhibitor, is known to cause a range of adverse effects, primarily hematologic and cardiovascular. However, multiorgan failure grade 5 (fatal), resembling CRS has not been previously reported in association with Carfilzomib. Case Report: A 74-year-old male with relapsed multiple myeloma developed grade 5 multiorgan failure 60 min after the third dose of Carfilzomib, resulting in death within 24 h of symptom onset. The patient tolerated the first doses of Carfilzomib well with only fever and headache developing post infusion. Before the second dose, the patient developed worsening pancytopenia, prompting the discontinuation of Lenalidomide. After the second Carfilzomib infusion, he experienced fever and transient encephalopathy, which resolved with acetaminophen, corticosteroids, and supportive care. However, following the third dose, he rapidly deteriorated—developing fever, tachycardia, hypotension, hypoxia, and encephalopathy. Despite aggressive management with intravenous fluids, broad-spectrum antibiotics, corticosteroids, and tocilizumab, the patient progressed to refractory shock and multi-organ failure, culminating in death within 24 h. A comprehensive infectious workup was negative, ruling out sepsis and suggesting possible Carfilzomib-induced CRS. Conclusion: Grade 5 multiorgan failure with signs and symptoms similar with CRS following Carfilzomib administration is a rare but potentially fatal adverse drug reaction. Further research is needed to better define the risk factors and optimal management strategies for Carfilzomib-induced multiorgan failure and possible CRS. Full article

Serum cereblon (CRBN) has been proposed as a target protein for immunomodulatory drugs (IMiDs). IMiDs are one of the backbone treatment options in multiple myeloma (MM), rendering CRBN an intriguing candidate for use as a biomarker in clinical settings. Ninety-two (92) MM patients, mostly relapsed/refractory and a few at diagnosis, were included in the study, from lenalidomide–dexamethasone (LD) initiation until last follow-up or death. Median CRBN at LD initiation (N = 68) treatment was 247 pg/mL (range, 0–9760 pg/mL), at the time of best response (BR) status (N = 59) 142.5 pg/mL (range, 0–9940 pg/mL) and in patients with relapse/refractory MM to LD regimen (N = 54) 298 pg/mL (range, 0–9840 pg/mL). CRBN in healthy individuals was almost undetectable and significantly lower compared to the CRBN at LD initiation (p = 0.003), at BR to LD (p = 0.012) and at relapse to LD (p = 0.002). CRBN was significantly lower at BR in contrast to LD initiation and relapse to LD (p = 0.04, p = 0.028). High levels of CRBN at treatment initiation correlated with early relapse to LD (≤12 months) (p = 0.03). Seven-year survival was improved in patients with CRBN levels below median measured at the time of LD initiation (p = 0.013) as well as at BR (p = 0.032). CRBN was associated with treatment response and is predictive of survival after LD. Full article

Multiple myeloma (MM or plasma cell myeloma) is a heterogenous B-cell malignant tumor that typically exhibits a high recurrence rate, resistance to drugs, and molecular diversity of tumor subclones. Given the limited efficacy of standard therapy options, cellular immunotherapy featuring a chimeric antigen receptor (CAR) has proven tangible potential in treatment for relapsed and refractory forms of MM. The rational choice of a tumor target which shows high selectivity, stable expression, and biological significance is key to the successful implementation of CAR therapy. This review has summarized and analyzed data from the literature on biological properties, the features of expression, and the clinical development stages of CAR cell products for MM treatment which target BCMA, GPRC5D, FcRH5, SLAMF7, CD38, CD138, TACI, APRIL, CD19, TNFR2, CD44v6, CD70, NKG2D ligands, etc. Special focus is on strategic approaches to overcoming antigenic escape, such as multi-specific CAR constructs, logical activation sequences, and controlled safety systems. The analysis underscores the need for integrating the molecular selection of targets with cutting-edge bioengineering solutions as a key trend for raising the efficacy, stability, and safety of cellular therapy in the case of MM. Full article

Introduction: In the past decade, chimeric antigen receptor T-cell therapy (CAR-T) has revolutionized the treatment of relapsed refractory multiple myeloma (RRMM) and lymphoma, but it is associated with significant cardiovascular adverse effects. We aim to analyze the incidence, patterns, and outcomes of cardiac events in RRMM and lymphoma patients undergoing CAR-T therapy utilizing the FDA Adverse Event Reporting System (FAERS) database, paving the way for future research and being more vigilant in treating high-risk populations. Methods: We conducted a retrospective post-marketing pharmacovigilance inquiry using the FDA Adverse Event Reporting System (FAERS) database and the Medical Dictionary for Regulatory Activities (MEDRA). We examined the adverse effects associated with CAR-T and TCE since their FDA approval in US and non-US populations (accessed 5 January 2024), and we analyzed the incidence of cardiac events related to six CAR-T products: Idecabtagene vicleucel, Ciltacabtagene autoleucel, Axicabtagene ciloleucel, Tisagenlecleucel, Lisocabtagene maraleucel, and Brexucabtagene autoleucel since FDA approval. Cardiotoxicities were assessed, including coronary artery disease (CAD), myocardial infarction (MI), arrhythmia, heart failure, and hypotension. Results: Out of 12,949 adverse events, we identified 675 (5.2%) cardiac events irrespective of severity. Almost 440 (65%) cardiac events were associated with cytokine release syndrome (CRS). The most common cardiotoxic event was atrial fibrillation (122), followed by the development of heart failure (113), ventricular arrhythmia (108), hypotension (87), and bradyarrhythmia (41). The mortality rate was highest among Brexucabtagene autoleucel recipients (n = 26, 2.3%), followed by Tisagenlecleucel (n = 71, 2.1%) and Lisocabtagene maraleucel (n = 10, 2.1%). Conclusions: CAR-T therapy can result in fatal adverse events due to its cardiotoxic properties. Timely monitoring, such as screening echocardiography and electrocardiograms, can help identify the at-risk population and allow for early intervention—particularly in patients with high baseline cardiovascular risk or previous exposure to cardiotoxic agents—thereby improving outcomes by enabling risk stratification and supportive management. Full article

Background: The remarkable efficacy of B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T-cell therapy (CAR-T) has had a significant impact on treatment strategies for relapsed/refractory multiple myeloma (RRMM). However, response durability remains a concern, necessitating the optimization of CAR-T procedures. Therapies preceding CAR-T therapy are crucial for disease control and preserving T-cell fitness. Methods: This review summarizes the evidence supporting the potential of selinexor-based regimens as holding or bridging therapy with preclinical research, demonstrating selinexor’s ability to foster an anti-inflammatory tumor microenvironment. Results: Selinexor enhances CD8+ T-lymphocyte and NK cell activation, re-polarizes macrophages, and inhibits immunosuppressive cells. Bone marrow samples from patients in clinical studies show that selinexor increases CD8 and granzyme B expression in T-cells. Selinexor also disrupts NK cell inhibition, enhances anti-tumor activity, and reduces pro-inflammatory cytokines. Selinexor may upregulate BCMA expression and increase myeloma cell immunogenicity. Real-world data suggests selinexor as bridging therapy does not compromise CAR-T outcomes and may even improve them. Conclusions: Overall, the evidence indicates selinexor’s potential to optimize CAR-T outcomes, warranting further investigation as a holding or bridging therapy for CAR-T. Full article