RARE DISEASE
Plasma cell leukemia
Plasma cell leukemia
Plasma cell leukemia
Synonyms: PCL
Synonyms: PCL
Synonyms: PCL
Drug discovery
4
drugs
With orphan designations
Overview
Plasma cell leukemia (PCL) is a rare, aggressive plasma cell neoplasm characterized by ≥5% circulating clonal plasma cells (≥20% by older criteria) or >2×10⁹/L in peripheral blood. It presents de novo (primary PCL) or evolves from multiple myeloma (secondary PCL), marked by severe cytopenias, extramedullary involvement, and high-risk cytogenetics (e.g., TP53 deletion). Prognosis remains poor (median survival 8–30 months), though proteasome inhibitors, immunomodulatory drugs, and stem cell transplantation have modestly improved outcomes.
Burden
Median survival: 8–12 months with conventional therapy; 16–30 months with novel agents/ASCT [5][10][19].
High relapse rates (≥70% post-ASCT) [5][9]; frequent hospitalizations due to infections, organ damage, and cytopenias [6][7].
Aggressive biology: 30–50% exhibit TP53 mutations or complex karyotypes, driving chemoresistance [4][9][11].
Therapies
Induction: Proteasome inhibitor (bortezomib, carfilzomib) and immunomodulatory drug (lenalidomide) combinations ± chemotherapy (e.g., hyper-CVAD) [3][5][14].
Transplant: Autologous stem cell transplantation (ASCT) for eligible patients; allogeneic options in select cases [3][10][14].
Novel agents: Venetoclax for t(11;14), CAR-T therapy (BCMA-targeted), and monoclonal antibodies under investigation [5][13][14].
Categories: rare hematological diseases, rare neoplastic diseases, rare transplant-related disorders
Research Papers
1,079 drug discovery papers about Plasma cell leukemia, with 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,079 drug discovery papers about Plasma cell leukemia, with 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-26 | Multiple Myeloma-Derived Cellular Lipids Enhance Targeting and Efficacy of Nanoliposome Formulations In Vitro.
Multiple myeloma (MM) is a blood cancer characterized by the accumulation of abnormal plasma cells within the bone marrow (BM). The neoplastic expansion progressively disrupts normal blood cell production by outcompeting healthy hematopoietic cells. The disease is characterized by terminally differentiated B cells that secrete antibodies as part of an adaptive immune response. A serious threat confronting small drug molecule therapy for MM is the lack of selective drug targeting, ultimately resulting in insufficient accumulation of drugs to target cells, and harmful off-target drug effects. We now report on the use of cellular lipid extracts (LEs) originating from two different human multiple myeloma (target) cell lines, RPMI 8226 and NCI H929, to develop RPMI 8226 LE- and NCI H929 LE-modified nanoliposomes, respectively. Other ingredients included phospholipid DOPC (dioleoyl-phosphatidylcholine) and/or Chol (cholesterol). Additional cell lines included non-target (Y79-retinoblastoma, U937-lymphoma, K562-GFP-chronic myeloid leukemia) and (off-target) normal healthy PBMCs-peripheral blood mononuclear cells. The LE-modified nanoliposomes stably incorporated various cytotoxic agents, demonstrating novel formulation characteristics and cell-interaction profiles. RPMI 8226 LE enhanced nanoliposome targeting to source-originating RPMI 8226 cells, with diminished uptake by Y79 and PBMCs. The inclusion of Chol reduced targeting to RPMI 8226 cells. The RPMI 8226 LE enhanced nano-formulation effects against RPMI 8226 cells, but not against the Y79 control. Consistent with these findings, RPMI 8226 LE-modified nano-formulations enhanced extracellular lactate dehydrogenase release against RPMI 8226 cells, but not against the Y79 control. NCI H929 LE material also enhanced targeting and nano-formulation effects against source and non-originating source tumor cells from the BM. Designing nanoliposomes to mimic tumor cell membranes may represent a powerful strategy to treat multiple myeloma. Significance: Cellular membrane lipid extracts derived from multiple myeloma cells enhanced targeting and cytotoxicity while limiting damage to normal healthy cells. The inclusion of LE materials in drug delivery systems may represent a promising strategy to enhance cellular targeting and drug therapy for multiple myeloma.
2026-08-12 | USP8 controls proteostasis pathways in B cells and multiple myeloma.
Ubiquitin-specific protease 8 (USP8) plays a pivotal role in the regulation of endosomal and lysosomal trafficking and is critically involved in the pathogenesis of various tumor entities. USP8 represents a vulnerability gene in multiple myeloma (MM), suggesting a functional role in the B- and plasma cell compartment. Here we analyzed mice with stage-specific Usp8 deletion during B-cell development and investigated its role in patient-derived MM cells that are sensitive or resistant to the proteasome inhibitor Bortezomib (BTZ) using USP8 depletion and treatment with DUB-IN-2, a reported USP8 inhibitor. Usp8 depletion in Usp8f/fCd19-Cre mice affected B-cell survival and development favoring immature, innate-like B cells, and germinal center and plasma cells, while also elevating immune-responses and causing Roquin depletion. Cells expressing catalytically inactive USP8 accumulated proteins modified with mixed ubiquitin/NEDD8 chains indicative of proteotoxic stress, which we identified as preferred USP8 substrates. In MM cells, USP8 knockdown reduced survival via lysosomal dysfunction. In contrast, DUB-IN-2 induced an enhanced ER stress response to treatment with BTZ questioning DUB-IN-2 function as a USP8 inhibitor, as confirmed by biochemical analysis. Thus, our results highlight the therapeutic potential of targeting USP8 and identify the combination of DUB-IN-2 and BTZ as a novel strategy for treating BTZ-resistant MM.
2026-08-03 | O-GlcNAc transferase as an oncogenic regulator in hematologic malignancies: Mechanisms, disease contexts, and therapeutic perspectives.
O-GlcNAc transferase (OGT) catalyzes the addition of N-acetylglucosamine to serine and threonine residues of nuclear and cytoplasmic proteins, coupling cellular metabolic state to the post-translational regulation of hundreds of substrates. Hematologic malignancies exhibit the highest OGT and O-GlcNAcase (OGA) expression levels among all cancer lineages, making this system a unique oncobiological axis in leukemias, lymphomas, and plasma cell dyscrasias. This review provides a disease-specific and mechanistically integrated account of OGT as an oncogenic regulator across the major hematologic entities. We examine the structural biology of the OGT/OGA cycle, its role in normal hematopoiesis, and its coupling to the hexosamine biosynthetic pathway, features that define the primary on-target safety limitation for therapeutic intervention. Disease-specific evidence is addressed for AML, CLL, DLBCL, MCL, multiple myeloma, and associated myeloid malignancies. Four mechanistic axes are identified: immune evasion via PD-L1 stabilization; crosstalk with the phosphoproteome; proteostatic stabilization of MYC, p53, and STAT5; and epigenetic reprogramming via TET/H3K4me3 and EZH2/H3K27me3 circuits. These axes underpin a unified amplifier model explaining why elevated O-GlcNAcylation associates with indolent disease in p53-intact CLL, drives oncogenesis in ASXL1-intact AML, and exerts tumor-suppressive activity in ASXL1-mutant disease. The therapeutic landscape, encompassing OSMI-series inhibitors, HBP-targeting agents, TPR-directed polypeptides, and combination strategies, is reviewed within this framework. ASXL1 mutation status and p53 pathway integrity are identified as the leading stratification biomarkers for clinical translation. Key open questions, including substrate-selective TPR inhibition, phase separation biology, and O-GlcNAcome profiling, are outlined as field priorities.
2026-07-10 | Severe hypereosinophilia and eosinophilic myocarditis during secondary plasma cell leukemia: evidence of a paraneoplastic manifestation of aggressive myeloma evolution.
Secondary plasma cell leukemia (sPCL) represents one of the most aggressive forms of Multiple Myeloma (MM) progression and remains associated with poor outcomes despite the availability of novel immunotherapeutic approaches. Severe hypereosinophilia is exceptionally rare in plasma cell neoplasms and may occasionally occur as a paraneoplastic manifestation of aggressive disease biology. In selected cases, eosinophilic infiltration can result in life-threatening organ damage, particularly involving the cardiovascular system. We report the case of a 40-year-old woman with IgG lambda MM who achieved complete remission following daratumumab-based induction therapy, autologous stem cell transplantation, and lenalidomide maintenance. Approximately one year after transplantation, she developed rapidly progressive relapse characterized by constitutional symptoms, circulating clonal plasma cells, extensive bone marrow involvement, severe hypereosinophilia, and marked cardiac biomarker elevation. Comprehensive infectious, autoimmune, and molecular investigations excluded alternative causes of eosinophilia. Cardiac magnetic resonance imaging revealed diffuse myocardial edema, increased myocardial wall thickness, extensive subendocardial late gadolinium enhancement, regional wall motion abnormalities, and left ventricular mural thrombosis, findings highly suggestive of eosinophilic myocarditis with endomyocardial involvement consistent with Loeffler syndrome. Urgent cytoreductive therapy with cyclophosphamide and dexamethasone resulted in rapid normalization of eosinophil counts, substantial clinical improvement, and reduction of cardiac symptoms, strongly supporting a pathogenetic relationship between eosinophilia and plasma cell disease burden. Despite subsequent salvage therapies, including isatuximab-based treatment and the BCMA-directed bispecific antibody elranatamab, disease control remained transient and the patient ultimately died from refractory sPCL. This case highlights severe hypereosinophilia as a rare paraneoplastic manifestation of aggressive clonal evolution in MM and emphasizes the importance of prompt recognition of eosinophilic cardiac involvement. The close correlation between eosinophil kinetics and disease activity further suggests that hypereosinophilia may represent a potential clinical indicator of aggressive plasma cell disease evolution and warrants further investigation.
2026-06-04 | Patterns of Progression and Clinical Outcomes After First Progression in Patients With Primary Plasma Cell Leukemia.
Primary plasma cell leukemia (pPCL) is a rare and aggressive plasma cell disorder with inferior outcomes compared with multiple myeloma (MM). However, studies describing outcomes after first progression and subsequent lines of therapy remain limited. We retrospectively analyzed 104 patients with pPCL who progressed after first-line therapy treated at one comprehensive cancer center between 2006 and 2024. Clinical characteristics, treatments, time to next treatment (TTNT), and overall survival (OS) were assessed using Kaplan-Meier methods. All pPCL patients received novel agent-based induction. At the time of analysis, 63% had died; median OS was 39 months. High-risk cytogenetics were present in 71%. The median TTNT after first-line therapy was 10 months. Symptomatic progression occurred in 29% of patients and was associated with significantly inferior subsequent OS (13 vs. 34 months) compared with those experiencing asymptomatic biochemical progression. The TTNT progressively shortened with subsequent lines of therapy (3rd line: 6 months; 4th line: 4 months; 5th line: 3 months). Notable exceptions included pPCL patients with t(11;14) treated with anti-BCL-2-based regimens, who achieved a median TTNT of 13 months. Additionally, 24 patients received anti-BCMA CAR T-cell therapy. With a median follow-up of 21 months, their median TTNT was 32 months. pPCL is characterized by frequent disease progression and diminishing response duration with successive therapeutic lines. Symptomatic progression portends particularly poor outcomes. Anti-BCL-2-based therapy in t(11;14) disease and anti-BCMA CAR T-cell therapy appear to provide more durable disease control and represent important advances for the management of progressed pPCL.
cell therapies
2026-09-24 | Real-world outcomes for multiple myeloma patients after apheresis for planned chimeric antigen receptor T-cell therapy.
Chimeric antigen receptor T-cell (CAR-T) therapy is highly active in relapsed/refractory multiple myeloma (RRMM), but manufacturing creates an obligatory waiting period between apheresis and infusion. Patients may deteriorate, progress or die during this window. Analyses that begin follow-up at infusion exclude these patients entirely and cannot describe the experience of all patients who enter the CAR-T pathway. To describe, in an intention-to-collect fashion, the outcomes of all RRMM patients who underwent T-cell apheresis for planned CAR-T therapy; to characterise the apheresis-to-infusion interval and the reasons for, and correlates of, failure to reach infusion; and to report progression-free survival (PFS) and overall survival (OS) anchored at the date of apheresis. The study was descriptive; it was not designed to estimate the causal effect of CAR-T infusion on survival. Retrospective single-centre cohort of all RRMM patients undergoing T-cell apheresis for CAR-T at Hackensack University Medical Center between 1 January 2021 and 30 April 2024. PFS and OS were calculated from apheresis by the Kaplan-Meier method with Greenwood 95% confidence intervals (CIs) and numbers at risk. Groups were compared with the log-rank test; baseline characteristics with the Wilcoxon rank-sum and Fisher exact tests. Because infusion is a post-baseline, time-dependent event, the association between infusion and survival was additionally examined using a Mantel-Byar time-dependent Cox model and a 60-day landmark analysis. Correlates of non-infusion were examined by univariable logistic regression; multivariable modelling was not performed owing to the small number of events. Of 99 patients undergoing apheresis, 87 (87.9%, 95%CI: 79.8-93.6) were infused and 12 (12.1%, 95%CI: 6.4-20.2) were not. Median follow-up was 14.0 months [interquartile range (IQR): 8.2-20.7]. Median apheresis-to-infusion interval was 54 days (IQR 46-62; range 37-202; n = 84 evaluable). Contrary to our preliminary report, baseline disease phenotype differed significantly between groups: Extramedullary disease was present in 9/12 (75.0%) non-infused vs 17/87 (19.5%) infused patients (P < 0.001), and plasma cell leukaemia in 3/12 (25.0%) vs 3/87 (3.4%) (P = 0.017). Age, prior lines of therapy (median 5 in both), high-risk cytogenetics (36.4% vs 34.1%) and Revised International Staging System distribution did not differ. The commonest reasons for non-infusion were progressive disease or myeloma-related death (7/12, 58.3%), non-myeloma death (2/12, 16.7%), manufacturing or collection failure (2/12, 16.7%) and infection (1/12, 8.3%). The median time from apheresis to the attrition event was 44 days (IQR 30-72). Median PFS from apheresis was 17.5 months (95%CI: 12.7-21.6) in infused patients vs 1.5 months (95%CI: 0.8-2.3) in non-infused patients; median OS was not reached vs 1.9 months (95%CI: 1.0-6.2) (both log-rank P < 0.001). In the time-dependent Cox model the hazard ratio for death associated with infusion was 0.24 (95%CI: 0.11-0.53), substantially closer to the null than the unadjusted comparison, illustrating how much of the apparent difference reflects the time-dependent nature of the exposure and confounding by disease phenotype. In this descriptive cohort, roughly one in eight patients who underwent apheresis never received CAR-T, and attrition clustered before the median time to infusion and among patients with extramedullary disease or plasma cell leukaemia. These data support shortening manufacturing turnaround, prioritising patients with aggressive phenotypes for expedited slots and intensified bridging, and reporting outcomes from apheresis using analytic methods that respect the time-dependent nature of infusion.
2026-09-16 | Early deep response to cilta-cel as 2nd CAR T-Cell therapy after CELMoD-based bridging for advanced multiple myeloma.
AbstractChimeric antigen receptor (CAR) T-cell therapy has emerged as an innovative and highly effective treatment option for patients with relapsed/refractory multiple myeloma (RRMM). This effect is based on redirecting modified T-cells towards plasma cells expressing target antigens, specifically B cell maturation antigen (BCMA). Despite high initial response rates, disease relapse remains a major clinical challenge. Therapeutic options after progression following prior BCMA-directed CAR T-cell therapy are limited, and prognosis is often poor. We report on a 58-year-old male with high-risk IgA kappa multiple myeloma who was heavily pretreated and received idecabtagene vicleucel as sixth-line therapy, achieving a deep response lasting for approximately one year. Following disease progression, the patient received bridging therapy with mezigdomide,carfilzomib, and dexamethasone, followed by a second BCMA-directed CAR T-cell infusion using ciltacabtagene autoleucel. Previous whole genome sequencing had confirmed preserved BCMA expression.Early post-infusion assessment showed a rapid and profound response, with marked declines in serum IgA and free kappa light chains, accompanied by robust CAR T-cell expansion. Treatment-related toxicities were manageable, including grade II cytokine release syndrome and prolonged cytopenias, without evidence of neurotoxicity.This case provides additional knowledge that retreatment with BCMA-directed CAR T-cell therapy may be feasible and clinically effective in heavily pretreated multiple myeloma, particularly after a durable response to initial CAR T-cell therapy. Bridging therapy and the use of an alternative CAR T-cell construct may further improve outcomes. Prospective studies are needed to define optimal patient selection and treatment sequencing in this setting.
2026-09-12 | Transplantation Strategies in Treatment of Primary Plasma Cell Leukemia in Germany-A Multi-Center Analysis.
Primary plasma cell leukemia (pPCL) is a rare disease with poor outcomes. As data on randomized phase-III trials are lacking, treatment recommendations are predominately based on retrospective analyses incorporating time periods with outdated therapies. Thus, the optimal consolidation strategy remains to be defined. We conducted a retrospective, multi-center analysis with 49 transplant-eligible patients diagnosed with pPCL between 2011 and 2025 focusing on different stem cell transplantation (SCT) strategies as consolidation treatment in first remission: single autologous (auto) or single allogeneic (allo) SCT versus patients with tandem cell therapy strategies (auto-auto, allo-auto, auto-chimeric antigen receptor therapy). The median follow-up after first SCT was 31 months. The cumulative incidence of initiating next treatment was lower after tandem cell therapy compared to single SCT (at 12 months: 42% vs. 57%, p = 0.006). Moreover, in a multivariable analysis incorporating cytogenetic risk and response to induction therapy, tandem transplantation strategies tended to be the only independent predictor for prolonged time to next treatment (TTNT, p = 0.077). Noteworthy, differences in TTNT between patients with a single SCT and patients with tandem cell therapy did not translate into an improved overall survival, possibly due to potent salvage therapies. Our data support recent recommendations advising treating patients with tandem transplantation regimes.
2026-07-24 | Role of Autologous Haematopoietic Transplantation in Leukaemias: When to Consider It in 2026.
Background: This review aims to provide a comprehensive and practical overview of the evolving role of autologous transplantation in leukaemias, a strategy that was once largely abandoned but has recently regained interest in selected clinical settings. Methods: We reviewed the historical development of autologous transplantation in acute leukaemias, including the early period during which autologous transplantation was considered inferior to allogeneic approaches because of limited graft purification techniques and the inability to induce effective graft-versus-leukaemia (GVL)-like immune responses. We further summarise more recent experimental strategies aimed at improving stem cell purification and enhancing anti-leukaemic immune activity in autologous settings. In addition, we discuss how advances in measurable residual disease (MRD) assessment and molecular risk stratification have contributed to the renewed interest in autologous transplantation in selected subgroups of leukaemia patients. Results: This review identifies clinical situations in which autologous transplantation remains an important therapeutic option, including plasma cell leukaemia, where it continues to represent a standard first-line approach. We also discuss well-defined patient subgroups, particularly selected AML subtypes with intermediate-risk molecular profiles and acute promyelocytic leukaemia (APL) in second remission, in which outcomes following autologous transplantation may be comparable to, or occasionally superior to, those achieved with allogeneic transplantation. In contrast, autologous transplantation currently plays only a limited role in diseases such as chronic lymphocytic leukaemia (CLL) and chronic myeloid leukaemia (CML). Although attempts to induce potent anti-leukaemic immune effects in autologous settings have so far shown limited clinical efficacy, several emerging strategies appear promising and may further expand the role of autologous transplantation, particularly in elderly or frail patients. Discussion: Overall, current molecular and MRD-based risk stratification strategies, together with emerging immunological and graft-manipulation approaches, may redefine the role of autologous transplantation as a personalised therapeutic option in selected subgroups of leukaemia patients.
2026-06-12 | Development of Genetically Modified ARH-77 Feeder Cells for Efficient Expansion of Natural Killer Cells with Potent Anti-Tumor Activity.
Background/Objectives: Adoptive transfer of allogeneic natural killer (NK) cells represents a promising off-the-shelf immunotherapy for cancer, offering advantages in safety and availability over autologous T cell therapies. However, generating therapeutically sufficient NK cell numbers remains challenging due to their low frequency in blood sources. Engineered feeder cell co-cultures have enabled substantial expansions of NK cells to clinically relevant doses. Methods: We evaluated the plasma cell leukemia-derived ARH-77 cell line as a feeder for ex vivo NK cell expansion from healthy donor peripheral blood mononuclear cells (PBMCs). Unmodified ARH-77 was compared to K562, followed by engineering both lines to co-express B7-H6 (NKp30 ligand), CD137L (4-1BBL), IL-15, and IL-15Rα via sequential lentiviral transduction. PBMCs were co-cultured with irradiated feeders in cytokine-supplemented (IL-2, IL-21, and later IL-15) RPMI-1640 or DMEM/F-12 medium for up to 28 days. Expansion (fold change in CD3-CD56+ cells), purity, surface receptor expression, and cytotoxicity (against K562 targets) were quantified. Results: Unmodified ARH-77 supported significantly greater NK cell expansion than K562 (model-estimated 681-fold vs. 155-fold at week 4 in RPMI; p = 0.0018), with higher purity but comparable cytotoxicity and receptor profiles. Engineered ARH-77 cells achieved robust expansion in RPMI, comparable to that of engineered K562 cells. In optimized DMEM/F-12 medium, engineered ARH-77 drove superior expansion (up to model-estimated 101,241-fold; 95% CI 46,771-219,146 at week 4), significantly outperforming engineered K562 (4.4-fold greater; 95% CI 1.01 to 18.54; p = 0.0479) while maintaining high purity and equivalent cytotoxicity. Substantial inter-donor variability influenced expansion magnitude, though relative feeder performance remained consistent across donors. Conclusions: Genetically modified ARH-77 feeder cells provide a potent platform for large-scale ex vivo expansion of functional NK cells.
antibodies
2026-09-25 | Retraction: Recurrent Radiculopathy Caused by an Epidural Cervical Plasmacytoma Revealing Plasma Cell Leukemia: A Case Report and Literature Review.
[This retracts the article DOI: 10.7759/cureus.114134.].
2026-09-07 | Induction and extended consolidation with daratumumab, cyclophosphamide, bortezomib, lenalidomide, and dexamethasone in patients with high-risk multiple myeloma (OPTIMUM/MUKnine): 5-year follow-up of a multicentre, externally controlled, phase 2 trial.
High-risk multiple myeloma, defined by two or more high-risk cytogenetic abnormalities (HRCAs), high-risk gene expression profiling (GEP), or plasma cell leukaemia, remains associated with poor long-term outcomes despite quadruplet induction therapy. OPTIMUM showed that intensified induction, extended consolidation, and maintenance therapy after autologous stem-cell transplantation (ASCT) improved progression-free survival for patients with high-risk multiple myeloma. Here we report the 5-year follow-up of survival outcomes across molecular subgroups. The multicentre, externally controlled, phase 2 OPTIMUM trial was conducted at 22 centres in the UK and enrolled patients aged 18 or older with newly diagnosed high-risk multiple myeloma or plasma cell leukaemia, measurable disease according to IMWG criteria, up to two previous induction cycles, and an Eastern Cooperative Oncology Group Performance Status of 2 or less. Participants received intravenous or subcutaneous daratumumab, oral cyclophosphamide, subcutaneous bortezomib, oral lenalidomide, and oral or intravenous dexamethasone induction at protocol specified doses before and after ASCT; melphalan-bortezomib during ASCT; consolidation part 1: daratumumab, bortezomib, lenalidomide, and dexamethasone; consolidation part 2: bortezomib, lenalidomide, and daratumumab; and maintenance lenalidomide and daratumumab until disease progression, unacceptable toxicity, or withdrawal. The trial used a Bayesian design and activity of treatment was compared with a molecularly matched external control cohort from the Myeloma XI trial. The primary endpoint was 18-month progression-free survival and has been previously reported. In this analysis, we report progression-free survival, progression-free survival 2 (time from registration until second disease progression or death, whichever occurred first), and overall survival at 5 years follow-up; and subgroup analyses by high-risk multiple myeloma features at entry (≥2 HRCAs, high-risk GEP, ≥2 HRCAs and high-risk GEP; and plasma cell leukaemia; subgroups selected post-hoc). OPTIMUM was registered with ClinicalTrials.gov (NCT03188172; active [not recruiting], with ongoing follow-up and maintenance). Between Sept 29, 2017, and Sept 24, 2019, 108 participants with high-risk multiple myeloma were recruited to OPTIMUM and 107 were included in the analysis, with 120 genetically matched patients from the Myeloma XI trial (external control). Median follow-up was 71·1 months (IQR 66·9-77·7) for OPTIMUM and 117·8 months (98·3-128·6) for Myeloma XI. Progression-free survival (not reached [NR; 70·6-NR] vs 24·4 months [19·7-30·4]; HR 0·32 [95% CI 0·22-0·45]; p<0·0001) and overall survival (NR [NR-NR] vs 57·4 months [47·3-74·2]; HR 0·43 [95% CI 0·28-0·65]; p<0·0001) was longer in OPTIMUM than in Myeloma XI. Median progression-free survival 2 was NR (NR-NR) in OPTIMUM and 43·9 months (38·3-51·5) in Myeloma XI (HR 0·26 [95% CI 0·17-0·41]; p<0·0001). The survival benefit was consistent across high-risk multiple myeloma subgroups, except for patients with three or more HRCAs. OPTIMUM shows sustained progression-free survival and overall survival improvement with risk-stratified extended therapy, supporting implementation of molecular diagnostics and tailored treatment in patients with newly diagnosed high-risk multiple myeloma. Myeloma UK, BMS, and Johnson & Johnson.
2026-08-06 | Multilineage lymphoid clonal hematopoiesis: a cross-sectional, correlative analysis of plasma cell dyscrasias and large granular lymphocytic leukemia.
Clonal expansions in large granular lymphocytic leukemia (LGLL) may arise in response to immune dysregulation in the context of other hematologic malignancies. This study aimed to investigate the co-occurrence of LGLL and plasma cell dyscrasias (PCDs) to assess its prevalence, features, and potential underlying mechanisms. We conducted a cross-sectional study involving 2064 PCD cases and 534 LGLL cases. Of the 534 LGLL cases, 20% co-occurred with PCD, while LGLL was present in 2% of the 2064 PCD cases. Among 117 patients with both conditions, PCDs were predominantly associated with IgM M-protein, while LGLL patients had increased NK-cell proliferation and fewer mutations in STAT3/5B. The co-occurrence was linked to a higher incidence of autoimmune conditions, B-cell neoplasms, and more severe immune-mediated cytopenias. In symptomatic PCD/LGLL patients with low plasma-cell infiltration, B-cell-targeted therapies outperformed immunosuppression, suggesting humoral involvement. Correlation with biological parameters revealed elevated interleukin-6 and inhibitory effects of sera of symptomatic PCD/LGLL patients on hematopoietic cells. Our findings suggest an association between PCD and LGLL, characterized by distinct features that may have significant implications for clinical management. These results highlight the importance of considering hematologic co-occurrences in clinical practice and warrant further investigation into the molecular mechanisms linking these conditions.
2026-07-03 | Real-World Outcomes with BCMA- and GPRC5D-Targeting Bispecific Antibodies in Plasma Cell Leukemia.
Patients with plasma cell leukemia (PCL) are generally excluded from pivotal T-cell redirecting bispecific antibody (BsAb) trials. We evaluated real-world outcomes in a multicenter retrospective study of 122 patients with primary or secondary PCL across 15 academic centers, categorized as 'active' (≥5% circulating plasma cells within 30 days of BsAb initiation) or 'historical'. In a heavily pretreated population, patients received teclistamab (37%), elranatamab (11%), talquetamab as a line of therapy (Tal LOT, 42%), or talquetamab as bridging therapy to CAR-T (Tal Bridge, 11%). Cytokine release syndrome (CRS) was grade 1-2 in 56% and grade 3-4 in 4%, whereas neurotoxicity was grade 1-2 in 16% and grade 3-4 in 5%. Among 110 evaluable patients, the overall response rate (ORR) was 55%, including 61% with Tal LOT, 58% with Tal Bridge, 46% with elranatamab, and 33% with teclistamab. With a median follow-up of 8.3 months, talquetamab demonstrated superior survival. Tal LOT showed a median progression-free survival (mPFS) of 5.5 months and a median overall survival (mOS) of 11.5 months, and both were unreached in the Tal Bridge cohort. In contrast, teclistamab and elranatamab showed a mPFS of 1.2 and 1.6 months and mOS of 8.1 and 3.6 months, respectively (P=0.007, P=0.023). In active PCL, Tal LOT achieved mPFS/mOS of 6.9/12.2 months versus 0.7/1.4 months with teclistamab and 1.0/3.1 months with elranatamab, respectively (P<0.001, P=0.002). Multivariable analysis associated active PCL with worse survival and Tal LOT with improved outcomes. BsAbs were safe in PCL, with talquetamab showing superior outcomes compared with BCMA-directed BsAbs.
2026-06-11 | Multiple Myeloma Cells Resistant to T-cell Therapies Exhibit a CD45+ Immunoevasive Phenotype.
Multiple myeloma is a plasma cell malignancy that is mostly incurable, even with recent advances in treatment such as B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR) T cells and bispecific T cell-engaging (TCE) antibodies. To better understand this treatment resistance, we examined multiple myeloma cells that persisted after these treatments and consistently observed CD45 upregulation as part of a resistance program. Bone marrow samples were treated ex vivo with BCMA CAR T cells, TCE antibodies (elranatamab, SAR442257), or activated T cells and analyzed via flow cytometry. CD45 upregulation was validated in patient samples before and after idecabtagene vicleucel therapy (anti-BCMA CAR T-cell therapy) and using an in vivo mouse model of disseminated multiple myeloma. Persisting multiple myeloma cells exhibited focal CD45 surface patches. Mechanistic studies implicated secreted HSP70, whereas bulk RNA sequencing revealed increased LAG-3, IFNγ signaling, and PD-L1 expression. These findings suggest that T cell-redirecting therapy (TCRT) drives an immunoevasive phenotype defined by CD45 upregulation and immune checkpoint activation, supporting combination strategies of TCRT with checkpoint inhibitors to overcome resistance in relapsed/refractory multiple myeloma.
oligonucleotides
2026-04-12 | Transforming tumor cells into professional antigen-presenting cells using poly(β-amino ester) nanoparticles to deliver CD80-encoding mRNA.
Effective T-cell activation requires both antigen recognition and co-stimulatory signaling. However, tumor cells typically lack the necessary co-stimulatory molecules, rendering T-cell receptor engagement with tumor antigens insufficient to induce potent anti-tumor immune responses. To overcome this limitation, we converted tumor cells into professional antigen-presenting cell (APC)-like cells by equipping them with the co-stimulatory molecule CD80. Electroporation of melanoma and lung cancer cell lines with CD80-encoding mRNA significantly increased their ability to stimulate tumor-antigen-specific T cells, as indicated by increased activation markers and cytokine secretion. Most importantly, CD80 expression converted melanoma cells into APC-like cells capable of priming and expanding naïve T cells that recognize endogenous tumor antigens. To enable clinical application, we subsequently used poly-(beta aminoester) (pBAE) polymers, which efficiently encapsulate mRNA into nanometric polyplexes. As previously reported, pBAE nanoparticles (NPs) efficiently penetrate plasma membranes and escape endosomal degradation both in vitro and in vivo. Here, we evaluated pBAE NPs encapsulating GFP-encoding mRNA in human cell lines derived from melanoma, lung cancer, leukemia, adenocarcinoma, uveal melanoma, and Merkel cell carcinoma. The pBAE NPs effectively transfected adherent tumor cells, and tumor spheroids in vitro and in ovo. When delivering CD80 mRNA, NPs achieved expression rates of more than 50% in most cell lines, which lasted for at least 72 h. Here as well, nanoparticle-mediated CD80 expression enabled melanoma cells to prime and expand naïve T cells recognizing endogenous tumor antigens. Importantly, T cells primed by CD80-expressing tumor cells were also capable of killing tumor cells that had not been transfected. In line with these findings, T cells stimulated with untransfected tumor cells showed high levels of checkpoint receptors CTLA-4 and PD-1, whereas the expression was significantly lower when using CD80-transfected tumor cells. This proof-of-concept study indicates that conversion of tumor cells into professional APC-like cells with CD80 mRNA is feasible and results in potent anti-tumor CD8+ T-cell responses. With the use of mRNA-loaded pBAEs, the prerequisites for a future application in vivo are given. Therefore, the application of pBAE NPs encapsulating CD80 mRNA to specifically transfect tumor cells presents a new promising strategy for the in vivo treatment of various cancers.
2026-01-27 | Immunogenicity and safety of a third and subsequent COVID-19 vaccine doses in patients with plasma cell dyscrasias.
Plasma cell dyscrasias (PCD) are a group of hematologic disorders associated with immune dysfunction from underlying disease and/or treatment. With the continued circulation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), optimizing and maintaining durable protection in this vulnerable population through vaccination remains important. A prospective cohort study was conducted between August 2021 and January 2023 across 12 sites in Canada to evaluate humoral immunity to COVID-19 vaccination in participants with hematologic malignancies. Participants were monitored longitudinally, and finger-prick dried blood spot cards were obtained at specific intervals based on vaccination. Serum antibodies against SARS-CoV-2 proteins after the third, fourth, and fifth dose were measured by high-throughput enzyme-linked immunosorbent assay. Differences in antispike (anti-S) seropositivity by vaccine dose number and clinical risk factors were analyzed by logistic regression. A total of 262 unique participants with 983 samples were included for analysis, among which 66% were diagnosed with PCD. Analysis of the predicted probability of immunity showed consistently higher proportions of participants with PCD with vaccine (anti-S) immunity compared with those with infection-derived (antinucleocapsid) immunity throughout the study. Although vaccine responses appeared to wane 6 months after dose 3 and, to a lesser extent, after dose 4, subsequent doses cumulatively increased anti-S immunity. Seropositivity decreased with anti-CD38 therapy and older age, although the receipt of additional vaccine doses significantly improved anti-S immunity. Overall, this study demonstrated that the third and subsequent COVID-19 vaccine doses could safely improve humoral immunity in participants with PCD. Although anti-CD38 therapy and age reduced seropositivity, antibody responses could still be enhanced with vaccine doses beyond the primary 3-dose series.
2023-10-09 | Anti-nucleolin aptamer AS1411: an advancing therapeutic.
Targeted therapy is highly desirable, as it allows for selective cytotoxicity on diseased cells without off-target side effects. Nucleolin is a remarkable target for cancer therapy given its high abundance, selective presence on the plasma membrane, and multifaceted influence on the initiation and progression of cancer. Nucleolin is a protein overexpressed on the cell membrane in many tumors and serves as a binding protein for several ligands implicated in angiogenesis and tumorigenesis. Nucleolin is present in the cytoplasm, nucleoplasm, and nucleolus and is used by selected pathogens for cell entry. AS1411 is a guanosine-rich oligonucleotide aptamer that binds nucleolin and is internalized in the tumor cells. AS1411 is well tolerated at therapeutic doses and localizes to tumor cells overexpressing nucleolin. AS1411 has a good safety profile with efficacy in relapsed acute myeloid leukemia and renal cell carcinoma producing mild or moderate side effects. The promising potential of AS1411 is its ability to be conjugated to drugs and nanoparticles. When a drug is bound to AS1411, the drug will localize to tumor cells leading to targeted therapy with fewer systemic side effects than traditional practices. AS1411 can also be bound to nanoparticles capable of detecting nucleolin at concentrations far lower than lab techniques used today for cancer diagnosis. AS1411 has a promising potential to change cancer diagnoses and treatment.
2022-10-13 | DAZAP1 facilitates the alternative splicing of KITLG to promote multiple myeloma cell proliferation via ERK signaling pathway
Multiple myeloma (MM) is an incurable plasma cell malignancy, in which alternative pre-mRNA splicing (AS) acts as one of the key transcriptome modifier. The Deleted in Azoospermia-Associated Protein 1 (DAZAP1) is a splicing factor that has been identified as an oncogene in multiple cancers, yet its role in MM proliferation remains unclear. We first analyzed MM clinical databases and found that MM patients with elevated DAZAP1 had a poor survival. Furthermore, we overexpressed DAZAP1 by lentiviral transfection and utilized siRNA silencing the expression of DAZAP1 in MM cells. DAZAP1 promoted MM cell proliferation in vitro and accelerated MM xenograft tumor growth in vivo. KEGG pathway enrichment analysis showed that ERK signaling pathway was activated in DAZAP1-OE MM cells. The analyses of RIP-seq and RIP-qPCR revealed that DAZAP1 activated alternative splicing of KIT proto-oncogene ligand (KITLG) mRNA. Further study validated that DAZAP1 increased ERK phosphorylation via modulating alternative splicing of KITLG mRNA to promote MM cell proliferation. In conclusion, we establish DAZAP1 as a tumor-promoting gene with therapeutic potential and provide mechanistic insights into targeting DAZAP1 as a new strategy for the diagnosis and treatment of MM.
2022-05-30 | Hypermethylation of the Promoter Region of miR-23 Enhances the Metastasis and Proliferation of Multiple Myeloma Cells via the Aberrant Expression of uPA
Multiple myeloma has a long course, with no obvious symptoms in the early stages. However, advanced stages are characterized by injury to the bone system and represent a severe threat to human health. The results of the present work indicate that the hypermethylation of miR-23 promoter mediates the aberrant expression of uPA/PLAU (urokinase plasminogen activator, uPA) in multiple myeloma cells. miR-23, a microRNA that potentially targets uPA’s 3’UTR, was predicted by the online tool miRDB. The endogenous expressions of uPA and miR-23 are related to disease severity in human patients, and the expression of miR-23 is negatively related to uPA expression. The hypermethylation of the promoter region of miR-23 is a promising mechanism to explain the low level of miR-23 or aberrant uPA expression associated with disease severity. Overexpression of miR-23 inhibited the expression of uPA by targeting the 3’UTR of uPA, not only in MM cell lines, but also in patient-derived cell lines. Overexpression of miR-23 also inhibited in vitro and in vivo invasion of MM cells in a nude mouse model. The results therefore extend our knowledge about uPA in MM and may assist in the development of more effective therapeutic strategies for MM treatment.
other
2026-03-05 | Cancer Susceptibility to Stapled Oncolytic Peptides Is Dictated by Membrane Cholesterol and Inflammatory Signaling.
Relapsed and refractory cancers effectively overcome diverse treatment modalities that primarily target nucleic acids and proteins. The plasma membranes of cancer cells represent an alternative and underutilized target, with the potential for membrane lysis to induce rapid, proinflammatory cell death that circumvents the challenges of intratumor heterogeneity and immune evasion. In this study, we repurposed StAMP51.2, a stapled magainin 2 peptide previously optimized for selective membrane lysis of Gram-negative bacteria, to target cancer cell membranes. The Profiling Relative Inhibition Simultaneously in Mixtures (PRISM) assay, a high-throughput cancer cytotoxicity screen, revealed cancer cells most vulnerable to StAMP51.2 and biomarkers of susceptibility, specifically reduced cholesteryl esters and elevated triacylglycerols. This signature was validated in pairs of sensitive (OCI-AML3 and THP-1) and resistant (K562 and KMS-11) leukemia cell lines, with their differential responses correlated to distinct lipidomic profiles. Susceptibility of OCI-AML3 cells in culture extended to the in vivo context, in which StAMP51.2 suppressed leukemic growth in orthotopic and intraperitoneal models. To further characterize the mechanism of action, StAMP51.2-resistant OCI-AML3 cells were generated, which required 4 months of low-level exposure. Strikingly, drug-resistant OCI-AML3 cells recapitulated the lipidomic phenotype of naturally resistant K562 cells. Transcriptomic analyses further revealed that lipid reprogramming was accompanied by pervasive downregulation of inflammatory signaling. Thus, in advancing StAMP51.2 as an oncolytic prototype, this study uncovered an immunoregulatory axis that links membrane integrity to inflammatory signaling. A stapled oncolytic peptide targets cancer cell membranes and induces a lipid-inflammation axis that underlies susceptibility, offering a promising therapeutic strategy beyond traditional nucleic acid and protein targets.
2025-12-28 | Nogo-A-cleaved amino-terminal fragment but not Nogo-B regulates STAT3 activation.
Nogo family protein contains splice variants Nogo-A and Nogo-B, which differ in their expression patterns and functions. Ectopic overexpression of Nogo-A in HEK293T cells causes multiple fragmentation of the Nogo-A protein. Herein, we focused on the posttranslational production of a Nogo-A amino-terminal fragment with a molecular weight of approximately 45 kDa, which we term NogoA-213. Comparing endogenous Nogo protein expression among mouse organs, we detected full-length Nogo-A protein migrating at approximately 200 kDa and a smaller protein of approximately 45 kDa using an anti-Nogo-A N-terminal antibody. Interestingly, this 45 kDa band was recognized by an anti-NogoA-F antibody that detects human Nogo-A aa 186-213, which is specific to full-length Nogo-A and the Nogo-A N-terminal fragment but not Nogo-B, and completely overlapped with the bands detected by anti-NogoA N-terminal antibody. Therefore, we concluded that the 45 kDa band represents the Nogo-A N-terminal fragment rather than Nogo-B. Nogo proteins contain a hydrophobic domain in their C-terminal region and localize to membrane organelles such as the endoplasmic reticulum (ER) and plasma membrane. Following overexpression, Nogo-B localized to the ER and plasma membrane in HeLa cells, whereas Nogo-213 diffused throughout the cell because of lacking the C-terminal hydrophobic domain. Furthermore, following overexpression, NogoA-213 colocalized with signal transducer and activator of transcription 3 (STAT3) and enhanced leukemia inhibitory factor (LIF)-induced STAT3 phosphorylation, whereas Nogo-B did not. Importantly, LIF treatment promoted the generation of the Nogo-A N-terminal fragment in HEK293T cells. Taken together the NogoA-N-terminal fragment NogoA-213 but not Nogo-B plays a role in STAT3 activation.
2025-11-25 | Microbiome modulation uncouples efficacy and toxicity induced by immune checkpoint blockade in mouse multiple myeloma.
Smoldering multiple myeloma (SMM), which is in principle curable, may develop into life-threatening MM. Intestinal microbiota and gut-born T helper-17 (Th17) lymphocytes may contribute to this development, but the mechanisms are unclear. Here we demonstrate that administering the human commensal Prevotella melaninogenica to transgenic Vk*MYC mice that exhibit SMM-like phenotypes delays the evolution to full-blown MM. Mechanistically, P. melaninogenica increases the production of short-chain fatty acids (SCFA), thereby preventing the skewing of dendritic cells towards a pro-Th17 phenotype and subsequently accumulation of Th17 cells in the bone marrow of treated mice. P. melaninogenica or butyrate synergizes with anti-PD-L1 or anti-TIGIT to suppress myeloma progression by restraining Th17 cell expansion while inducing effector CD8+ T cells. P. melaninogenica also attenuates IL-17-mediated skin lesions that mimic anti-PD-L1-induced adverse events. Our results thus suggest that gut microbiota modulation or SCFAs administration may represent treatment options for patients affected by plasma cell dyscrasias.
2024-10-17 | Cytosolic delivery of monobodies using the bacterial type III secretion system inhibits oncogenic BCR: ABL1 signaling.
The inability of biologics to pass the plasma membrane prevents their development as therapeutics for intracellular targets. To address the lack of methods for cytosolic protein delivery, we used the type III secretion system (T3SS) of Y. enterocolitica, which naturally injects bacterial proteins into eukaryotic host cells, to deliver monobody proteins into cancer cells. Monobodies are small synthetic binding proteins that can inhibit oncogene signaling in cancer cells with high selectivity upon intracellular expression. Here, we engineered monobodies targeting the BCR::ABL1 tyrosine kinase for efficient delivery by the T3SS, quantified cytosolic delivery and target engagement in cancer cells and monitored inhibition of BCR::ABL1 signaling. In vitro assays were performed to characterize destabilized monobodies (thermal shift assay and isothermal titration calorimetry) and to assess their secretion by the T3SS. Immunoblot assays were used to study the translocation of monobodies into different cell lines and to determine the intracellular concentration after translocation. Split-Nanoluc assays were performed to understand translocation and degradation kinetics and to evaluate target engagement after translocation. Phospho flow cytometry and apoptosis assays were performed to assess the functional effects of monobody translocation into BCR:ABL1-expressing leukemia cells. To enable efficient translocation of the stable monobody proteins by the T3SS, we engineered destabilized mutant monobodies that retained high affinity target binding and were efficiently injected into different cell lines. After injection, the cytosolic monobody concentrations reached mid-micromolar concentrations considerably exceeding their binding affinity. We found that injected monobodies targeting the BCR::ABL1 tyrosine kinase selectively engaged their target in the cytosol. The translocation resulted in inhibition of oncogenic signaling and specifically induced apoptosis in BCR::ABL1-dependent cells, consistent with the phenotype when the same monobody was intracellularly expressed. Hence, we establish the T3SS of Y. enterocolitica as a highly efficient protein translocation method for monobody delivery, enabling the selective targeting of different oncogenic signaling pathways and providing a foundation for future therapeutic application against intracellular targets.
2023-09-08 | Acquired Isolated Factor VII Deficiency in Plasma Cell Dyscrasias: A Brief Presentation of Two Plasma-Cell-Leukemia-Related Cases and Review of Literature
Acquired isolated factor VII (FVII) deficiency is a rare but important discovery in patients with plasma cell disorders with significant therapeutic and prognostic implications. The present analysis and review of cases reported in the literature is intended to highlight disease-related characteristics associated with this rare clotting defect, clinical manifestations and outcome, and potential underlying mechanisms, and to provide guidance on how to manage these patients in terms of prophylactic and therapeutic measures. The discovery of acquired FVII deficiency in a patient with multiple myeloma (MM) or monoclonal gammopathy of uncertain significance (MGUS) should prompt an evaluation for AL amyloidosis, particularly for amyloid hepatosplenic involvement, whenever not previously documented. Acquired FVII deficiency in patients with MM and AL amyloidosis is frequently associated with severe bleeding diathesis, also related to a number of concomitant predisposing factors, adversely affecting the outcome. The prompt institution of a rapidly acting therapy is crucial to prevent severe bleeding complications and positively impact outcome. Recombinant activated factor VII (rVIIa) may represent a useful supportive care measure, both in treating active bleeding and in the peri-procedural setting. However, further clinical experience is needed to optimize the therapeutic management of this rare disorder.
small molecules
2026-09-26 | Multiple Myeloma-Derived Cellular Lipids Enhance Targeting and Efficacy of Nanoliposome Formulations In Vitro.
Multiple myeloma (MM) is a blood cancer characterized by the accumulation of abnormal plasma cells within the bone marrow (BM). The neoplastic expansion progressively disrupts normal blood cell production by outcompeting healthy hematopoietic cells. The disease is characterized by terminally differentiated B cells that secrete antibodies as part of an adaptive immune response. A serious threat confronting small drug molecule therapy for MM is the lack of selective drug targeting, ultimately resulting in insufficient accumulation of drugs to target cells, and harmful off-target drug effects. We now report on the use of cellular lipid extracts (LEs) originating from two different human multiple myeloma (target) cell lines, RPMI 8226 and NCI H929, to develop RPMI 8226 LE- and NCI H929 LE-modified nanoliposomes, respectively. Other ingredients included phospholipid DOPC (dioleoyl-phosphatidylcholine) and/or Chol (cholesterol). Additional cell lines included non-target (Y79-retinoblastoma, U937-lymphoma, K562-GFP-chronic myeloid leukemia) and (off-target) normal healthy PBMCs-peripheral blood mononuclear cells. The LE-modified nanoliposomes stably incorporated various cytotoxic agents, demonstrating novel formulation characteristics and cell-interaction profiles. RPMI 8226 LE enhanced nanoliposome targeting to source-originating RPMI 8226 cells, with diminished uptake by Y79 and PBMCs. The inclusion of Chol reduced targeting to RPMI 8226 cells. The RPMI 8226 LE enhanced nano-formulation effects against RPMI 8226 cells, but not against the Y79 control. Consistent with these findings, RPMI 8226 LE-modified nano-formulations enhanced extracellular lactate dehydrogenase release against RPMI 8226 cells, but not against the Y79 control. NCI H929 LE material also enhanced targeting and nano-formulation effects against source and non-originating source tumor cells from the BM. Designing nanoliposomes to mimic tumor cell membranes may represent a powerful strategy to treat multiple myeloma. Significance: Cellular membrane lipid extracts derived from multiple myeloma cells enhanced targeting and cytotoxicity while limiting damage to normal healthy cells. The inclusion of LE materials in drug delivery systems may represent a promising strategy to enhance cellular targeting and drug therapy for multiple myeloma.
2026-08-12 | USP8 controls proteostasis pathways in B cells and multiple myeloma.
Ubiquitin-specific protease 8 (USP8) plays a pivotal role in the regulation of endosomal and lysosomal trafficking and is critically involved in the pathogenesis of various tumor entities. USP8 represents a vulnerability gene in multiple myeloma (MM), suggesting a functional role in the B- and plasma cell compartment. Here we analyzed mice with stage-specific Usp8 deletion during B-cell development and investigated its role in patient-derived MM cells that are sensitive or resistant to the proteasome inhibitor Bortezomib (BTZ) using USP8 depletion and treatment with DUB-IN-2, a reported USP8 inhibitor. Usp8 depletion in Usp8f/fCd19-Cre mice affected B-cell survival and development favoring immature, innate-like B cells, and germinal center and plasma cells, while also elevating immune-responses and causing Roquin depletion. Cells expressing catalytically inactive USP8 accumulated proteins modified with mixed ubiquitin/NEDD8 chains indicative of proteotoxic stress, which we identified as preferred USP8 substrates. In MM cells, USP8 knockdown reduced survival via lysosomal dysfunction. In contrast, DUB-IN-2 induced an enhanced ER stress response to treatment with BTZ questioning DUB-IN-2 function as a USP8 inhibitor, as confirmed by biochemical analysis. Thus, our results highlight the therapeutic potential of targeting USP8 and identify the combination of DUB-IN-2 and BTZ as a novel strategy for treating BTZ-resistant MM.
2026-08-03 | O-GlcNAc transferase as an oncogenic regulator in hematologic malignancies: Mechanisms, disease contexts, and therapeutic perspectives.
O-GlcNAc transferase (OGT) catalyzes the addition of N-acetylglucosamine to serine and threonine residues of nuclear and cytoplasmic proteins, coupling cellular metabolic state to the post-translational regulation of hundreds of substrates. Hematologic malignancies exhibit the highest OGT and O-GlcNAcase (OGA) expression levels among all cancer lineages, making this system a unique oncobiological axis in leukemias, lymphomas, and plasma cell dyscrasias. This review provides a disease-specific and mechanistically integrated account of OGT as an oncogenic regulator across the major hematologic entities. We examine the structural biology of the OGT/OGA cycle, its role in normal hematopoiesis, and its coupling to the hexosamine biosynthetic pathway, features that define the primary on-target safety limitation for therapeutic intervention. Disease-specific evidence is addressed for AML, CLL, DLBCL, MCL, multiple myeloma, and associated myeloid malignancies. Four mechanistic axes are identified: immune evasion via PD-L1 stabilization; crosstalk with the phosphoproteome; proteostatic stabilization of MYC, p53, and STAT5; and epigenetic reprogramming via TET/H3K4me3 and EZH2/H3K27me3 circuits. These axes underpin a unified amplifier model explaining why elevated O-GlcNAcylation associates with indolent disease in p53-intact CLL, drives oncogenesis in ASXL1-intact AML, and exerts tumor-suppressive activity in ASXL1-mutant disease. The therapeutic landscape, encompassing OSMI-series inhibitors, HBP-targeting agents, TPR-directed polypeptides, and combination strategies, is reviewed within this framework. ASXL1 mutation status and p53 pathway integrity are identified as the leading stratification biomarkers for clinical translation. Key open questions, including substrate-selective TPR inhibition, phase separation biology, and O-GlcNAcome profiling, are outlined as field priorities.
2026-07-10 | Severe hypereosinophilia and eosinophilic myocarditis during secondary plasma cell leukemia: evidence of a paraneoplastic manifestation of aggressive myeloma evolution.
Secondary plasma cell leukemia (sPCL) represents one of the most aggressive forms of Multiple Myeloma (MM) progression and remains associated with poor outcomes despite the availability of novel immunotherapeutic approaches. Severe hypereosinophilia is exceptionally rare in plasma cell neoplasms and may occasionally occur as a paraneoplastic manifestation of aggressive disease biology. In selected cases, eosinophilic infiltration can result in life-threatening organ damage, particularly involving the cardiovascular system. We report the case of a 40-year-old woman with IgG lambda MM who achieved complete remission following daratumumab-based induction therapy, autologous stem cell transplantation, and lenalidomide maintenance. Approximately one year after transplantation, she developed rapidly progressive relapse characterized by constitutional symptoms, circulating clonal plasma cells, extensive bone marrow involvement, severe hypereosinophilia, and marked cardiac biomarker elevation. Comprehensive infectious, autoimmune, and molecular investigations excluded alternative causes of eosinophilia. Cardiac magnetic resonance imaging revealed diffuse myocardial edema, increased myocardial wall thickness, extensive subendocardial late gadolinium enhancement, regional wall motion abnormalities, and left ventricular mural thrombosis, findings highly suggestive of eosinophilic myocarditis with endomyocardial involvement consistent with Loeffler syndrome. Urgent cytoreductive therapy with cyclophosphamide and dexamethasone resulted in rapid normalization of eosinophil counts, substantial clinical improvement, and reduction of cardiac symptoms, strongly supporting a pathogenetic relationship between eosinophilia and plasma cell disease burden. Despite subsequent salvage therapies, including isatuximab-based treatment and the BCMA-directed bispecific antibody elranatamab, disease control remained transient and the patient ultimately died from refractory sPCL. This case highlights severe hypereosinophilia as a rare paraneoplastic manifestation of aggressive clonal evolution in MM and emphasizes the importance of prompt recognition of eosinophilic cardiac involvement. The close correlation between eosinophil kinetics and disease activity further suggests that hypereosinophilia may represent a potential clinical indicator of aggressive plasma cell disease evolution and warrants further investigation.
2026-06-04 | Patterns of Progression and Clinical Outcomes After First Progression in Patients With Primary Plasma Cell Leukemia.
Primary plasma cell leukemia (pPCL) is a rare and aggressive plasma cell disorder with inferior outcomes compared with multiple myeloma (MM). However, studies describing outcomes after first progression and subsequent lines of therapy remain limited. We retrospectively analyzed 104 patients with pPCL who progressed after first-line therapy treated at one comprehensive cancer center between 2006 and 2024. Clinical characteristics, treatments, time to next treatment (TTNT), and overall survival (OS) were assessed using Kaplan-Meier methods. All pPCL patients received novel agent-based induction. At the time of analysis, 63% had died; median OS was 39 months. High-risk cytogenetics were present in 71%. The median TTNT after first-line therapy was 10 months. Symptomatic progression occurred in 29% of patients and was associated with significantly inferior subsequent OS (13 vs. 34 months) compared with those experiencing asymptomatic biochemical progression. The TTNT progressively shortened with subsequent lines of therapy (3rd line: 6 months; 4th line: 4 months; 5th line: 3 months). Notable exceptions included pPCL patients with t(11;14) treated with anti-BCL-2-based regimens, who achieved a median TTNT of 13 months. Additionally, 24 patients received anti-BCMA CAR T-cell therapy. With a median follow-up of 21 months, their median TTNT was 32 months. pPCL is characterized by frequent disease progression and diminishing response duration with successive therapeutic lines. Symptomatic progression portends particularly poor outcomes. Anti-BCL-2-based therapy in t(11;14) disease and anti-BCMA CAR T-cell therapy appear to provide more durable disease control and represent important advances for the management of progressed pPCL.
cell therapies
2026-09-24 | Real-world outcomes for multiple myeloma patients after apheresis for planned chimeric antigen receptor T-cell therapy.
Chimeric antigen receptor T-cell (CAR-T) therapy is highly active in relapsed/refractory multiple myeloma (RRMM), but manufacturing creates an obligatory waiting period between apheresis and infusion. Patients may deteriorate, progress or die during this window. Analyses that begin follow-up at infusion exclude these patients entirely and cannot describe the experience of all patients who enter the CAR-T pathway. To describe, in an intention-to-collect fashion, the outcomes of all RRMM patients who underwent T-cell apheresis for planned CAR-T therapy; to characterise the apheresis-to-infusion interval and the reasons for, and correlates of, failure to reach infusion; and to report progression-free survival (PFS) and overall survival (OS) anchored at the date of apheresis. The study was descriptive; it was not designed to estimate the causal effect of CAR-T infusion on survival. Retrospective single-centre cohort of all RRMM patients undergoing T-cell apheresis for CAR-T at Hackensack University Medical Center between 1 January 2021 and 30 April 2024. PFS and OS were calculated from apheresis by the Kaplan-Meier method with Greenwood 95% confidence intervals (CIs) and numbers at risk. Groups were compared with the log-rank test; baseline characteristics with the Wilcoxon rank-sum and Fisher exact tests. Because infusion is a post-baseline, time-dependent event, the association between infusion and survival was additionally examined using a Mantel-Byar time-dependent Cox model and a 60-day landmark analysis. Correlates of non-infusion were examined by univariable logistic regression; multivariable modelling was not performed owing to the small number of events. Of 99 patients undergoing apheresis, 87 (87.9%, 95%CI: 79.8-93.6) were infused and 12 (12.1%, 95%CI: 6.4-20.2) were not. Median follow-up was 14.0 months [interquartile range (IQR): 8.2-20.7]. Median apheresis-to-infusion interval was 54 days (IQR 46-62; range 37-202; n = 84 evaluable). Contrary to our preliminary report, baseline disease phenotype differed significantly between groups: Extramedullary disease was present in 9/12 (75.0%) non-infused vs 17/87 (19.5%) infused patients (P < 0.001), and plasma cell leukaemia in 3/12 (25.0%) vs 3/87 (3.4%) (P = 0.017). Age, prior lines of therapy (median 5 in both), high-risk cytogenetics (36.4% vs 34.1%) and Revised International Staging System distribution did not differ. The commonest reasons for non-infusion were progressive disease or myeloma-related death (7/12, 58.3%), non-myeloma death (2/12, 16.7%), manufacturing or collection failure (2/12, 16.7%) and infection (1/12, 8.3%). The median time from apheresis to the attrition event was 44 days (IQR 30-72). Median PFS from apheresis was 17.5 months (95%CI: 12.7-21.6) in infused patients vs 1.5 months (95%CI: 0.8-2.3) in non-infused patients; median OS was not reached vs 1.9 months (95%CI: 1.0-6.2) (both log-rank P < 0.001). In the time-dependent Cox model the hazard ratio for death associated with infusion was 0.24 (95%CI: 0.11-0.53), substantially closer to the null than the unadjusted comparison, illustrating how much of the apparent difference reflects the time-dependent nature of the exposure and confounding by disease phenotype. In this descriptive cohort, roughly one in eight patients who underwent apheresis never received CAR-T, and attrition clustered before the median time to infusion and among patients with extramedullary disease or plasma cell leukaemia. These data support shortening manufacturing turnaround, prioritising patients with aggressive phenotypes for expedited slots and intensified bridging, and reporting outcomes from apheresis using analytic methods that respect the time-dependent nature of infusion.
2026-09-16 | Early deep response to cilta-cel as 2nd CAR T-Cell therapy after CELMoD-based bridging for advanced multiple myeloma.
AbstractChimeric antigen receptor (CAR) T-cell therapy has emerged as an innovative and highly effective treatment option for patients with relapsed/refractory multiple myeloma (RRMM). This effect is based on redirecting modified T-cells towards plasma cells expressing target antigens, specifically B cell maturation antigen (BCMA). Despite high initial response rates, disease relapse remains a major clinical challenge. Therapeutic options after progression following prior BCMA-directed CAR T-cell therapy are limited, and prognosis is often poor. We report on a 58-year-old male with high-risk IgA kappa multiple myeloma who was heavily pretreated and received idecabtagene vicleucel as sixth-line therapy, achieving a deep response lasting for approximately one year. Following disease progression, the patient received bridging therapy with mezigdomide,carfilzomib, and dexamethasone, followed by a second BCMA-directed CAR T-cell infusion using ciltacabtagene autoleucel. Previous whole genome sequencing had confirmed preserved BCMA expression.Early post-infusion assessment showed a rapid and profound response, with marked declines in serum IgA and free kappa light chains, accompanied by robust CAR T-cell expansion. Treatment-related toxicities were manageable, including grade II cytokine release syndrome and prolonged cytopenias, without evidence of neurotoxicity.This case provides additional knowledge that retreatment with BCMA-directed CAR T-cell therapy may be feasible and clinically effective in heavily pretreated multiple myeloma, particularly after a durable response to initial CAR T-cell therapy. Bridging therapy and the use of an alternative CAR T-cell construct may further improve outcomes. Prospective studies are needed to define optimal patient selection and treatment sequencing in this setting.
2026-09-12 | Transplantation Strategies in Treatment of Primary Plasma Cell Leukemia in Germany-A Multi-Center Analysis.
Primary plasma cell leukemia (pPCL) is a rare disease with poor outcomes. As data on randomized phase-III trials are lacking, treatment recommendations are predominately based on retrospective analyses incorporating time periods with outdated therapies. Thus, the optimal consolidation strategy remains to be defined. We conducted a retrospective, multi-center analysis with 49 transplant-eligible patients diagnosed with pPCL between 2011 and 2025 focusing on different stem cell transplantation (SCT) strategies as consolidation treatment in first remission: single autologous (auto) or single allogeneic (allo) SCT versus patients with tandem cell therapy strategies (auto-auto, allo-auto, auto-chimeric antigen receptor therapy). The median follow-up after first SCT was 31 months. The cumulative incidence of initiating next treatment was lower after tandem cell therapy compared to single SCT (at 12 months: 42% vs. 57%, p = 0.006). Moreover, in a multivariable analysis incorporating cytogenetic risk and response to induction therapy, tandem transplantation strategies tended to be the only independent predictor for prolonged time to next treatment (TTNT, p = 0.077). Noteworthy, differences in TTNT between patients with a single SCT and patients with tandem cell therapy did not translate into an improved overall survival, possibly due to potent salvage therapies. Our data support recent recommendations advising treating patients with tandem transplantation regimes.
2026-07-24 | Role of Autologous Haematopoietic Transplantation in Leukaemias: When to Consider It in 2026.
Background: This review aims to provide a comprehensive and practical overview of the evolving role of autologous transplantation in leukaemias, a strategy that was once largely abandoned but has recently regained interest in selected clinical settings. Methods: We reviewed the historical development of autologous transplantation in acute leukaemias, including the early period during which autologous transplantation was considered inferior to allogeneic approaches because of limited graft purification techniques and the inability to induce effective graft-versus-leukaemia (GVL)-like immune responses. We further summarise more recent experimental strategies aimed at improving stem cell purification and enhancing anti-leukaemic immune activity in autologous settings. In addition, we discuss how advances in measurable residual disease (MRD) assessment and molecular risk stratification have contributed to the renewed interest in autologous transplantation in selected subgroups of leukaemia patients. Results: This review identifies clinical situations in which autologous transplantation remains an important therapeutic option, including plasma cell leukaemia, where it continues to represent a standard first-line approach. We also discuss well-defined patient subgroups, particularly selected AML subtypes with intermediate-risk molecular profiles and acute promyelocytic leukaemia (APL) in second remission, in which outcomes following autologous transplantation may be comparable to, or occasionally superior to, those achieved with allogeneic transplantation. In contrast, autologous transplantation currently plays only a limited role in diseases such as chronic lymphocytic leukaemia (CLL) and chronic myeloid leukaemia (CML). Although attempts to induce potent anti-leukaemic immune effects in autologous settings have so far shown limited clinical efficacy, several emerging strategies appear promising and may further expand the role of autologous transplantation, particularly in elderly or frail patients. Discussion: Overall, current molecular and MRD-based risk stratification strategies, together with emerging immunological and graft-manipulation approaches, may redefine the role of autologous transplantation as a personalised therapeutic option in selected subgroups of leukaemia patients.
2026-06-12 | Development of Genetically Modified ARH-77 Feeder Cells for Efficient Expansion of Natural Killer Cells with Potent Anti-Tumor Activity.
Background/Objectives: Adoptive transfer of allogeneic natural killer (NK) cells represents a promising off-the-shelf immunotherapy for cancer, offering advantages in safety and availability over autologous T cell therapies. However, generating therapeutically sufficient NK cell numbers remains challenging due to their low frequency in blood sources. Engineered feeder cell co-cultures have enabled substantial expansions of NK cells to clinically relevant doses. Methods: We evaluated the plasma cell leukemia-derived ARH-77 cell line as a feeder for ex vivo NK cell expansion from healthy donor peripheral blood mononuclear cells (PBMCs). Unmodified ARH-77 was compared to K562, followed by engineering both lines to co-express B7-H6 (NKp30 ligand), CD137L (4-1BBL), IL-15, and IL-15Rα via sequential lentiviral transduction. PBMCs were co-cultured with irradiated feeders in cytokine-supplemented (IL-2, IL-21, and later IL-15) RPMI-1640 or DMEM/F-12 medium for up to 28 days. Expansion (fold change in CD3-CD56+ cells), purity, surface receptor expression, and cytotoxicity (against K562 targets) were quantified. Results: Unmodified ARH-77 supported significantly greater NK cell expansion than K562 (model-estimated 681-fold vs. 155-fold at week 4 in RPMI; p = 0.0018), with higher purity but comparable cytotoxicity and receptor profiles. Engineered ARH-77 cells achieved robust expansion in RPMI, comparable to that of engineered K562 cells. In optimized DMEM/F-12 medium, engineered ARH-77 drove superior expansion (up to model-estimated 101,241-fold; 95% CI 46,771-219,146 at week 4), significantly outperforming engineered K562 (4.4-fold greater; 95% CI 1.01 to 18.54; p = 0.0479) while maintaining high purity and equivalent cytotoxicity. Substantial inter-donor variability influenced expansion magnitude, though relative feeder performance remained consistent across donors. Conclusions: Genetically modified ARH-77 feeder cells provide a potent platform for large-scale ex vivo expansion of functional NK cells.
antibodies
2026-09-25 | Retraction: Recurrent Radiculopathy Caused by an Epidural Cervical Plasmacytoma Revealing Plasma Cell Leukemia: A Case Report and Literature Review.
[This retracts the article DOI: 10.7759/cureus.114134.].
2026-09-07 | Induction and extended consolidation with daratumumab, cyclophosphamide, bortezomib, lenalidomide, and dexamethasone in patients with high-risk multiple myeloma (OPTIMUM/MUKnine): 5-year follow-up of a multicentre, externally controlled, phase 2 trial.
High-risk multiple myeloma, defined by two or more high-risk cytogenetic abnormalities (HRCAs), high-risk gene expression profiling (GEP), or plasma cell leukaemia, remains associated with poor long-term outcomes despite quadruplet induction therapy. OPTIMUM showed that intensified induction, extended consolidation, and maintenance therapy after autologous stem-cell transplantation (ASCT) improved progression-free survival for patients with high-risk multiple myeloma. Here we report the 5-year follow-up of survival outcomes across molecular subgroups. The multicentre, externally controlled, phase 2 OPTIMUM trial was conducted at 22 centres in the UK and enrolled patients aged 18 or older with newly diagnosed high-risk multiple myeloma or plasma cell leukaemia, measurable disease according to IMWG criteria, up to two previous induction cycles, and an Eastern Cooperative Oncology Group Performance Status of 2 or less. Participants received intravenous or subcutaneous daratumumab, oral cyclophosphamide, subcutaneous bortezomib, oral lenalidomide, and oral or intravenous dexamethasone induction at protocol specified doses before and after ASCT; melphalan-bortezomib during ASCT; consolidation part 1: daratumumab, bortezomib, lenalidomide, and dexamethasone; consolidation part 2: bortezomib, lenalidomide, and daratumumab; and maintenance lenalidomide and daratumumab until disease progression, unacceptable toxicity, or withdrawal. The trial used a Bayesian design and activity of treatment was compared with a molecularly matched external control cohort from the Myeloma XI trial. The primary endpoint was 18-month progression-free survival and has been previously reported. In this analysis, we report progression-free survival, progression-free survival 2 (time from registration until second disease progression or death, whichever occurred first), and overall survival at 5 years follow-up; and subgroup analyses by high-risk multiple myeloma features at entry (≥2 HRCAs, high-risk GEP, ≥2 HRCAs and high-risk GEP; and plasma cell leukaemia; subgroups selected post-hoc). OPTIMUM was registered with ClinicalTrials.gov (NCT03188172; active [not recruiting], with ongoing follow-up and maintenance). Between Sept 29, 2017, and Sept 24, 2019, 108 participants with high-risk multiple myeloma were recruited to OPTIMUM and 107 were included in the analysis, with 120 genetically matched patients from the Myeloma XI trial (external control). Median follow-up was 71·1 months (IQR 66·9-77·7) for OPTIMUM and 117·8 months (98·3-128·6) for Myeloma XI. Progression-free survival (not reached [NR; 70·6-NR] vs 24·4 months [19·7-30·4]; HR 0·32 [95% CI 0·22-0·45]; p<0·0001) and overall survival (NR [NR-NR] vs 57·4 months [47·3-74·2]; HR 0·43 [95% CI 0·28-0·65]; p<0·0001) was longer in OPTIMUM than in Myeloma XI. Median progression-free survival 2 was NR (NR-NR) in OPTIMUM and 43·9 months (38·3-51·5) in Myeloma XI (HR 0·26 [95% CI 0·17-0·41]; p<0·0001). The survival benefit was consistent across high-risk multiple myeloma subgroups, except for patients with three or more HRCAs. OPTIMUM shows sustained progression-free survival and overall survival improvement with risk-stratified extended therapy, supporting implementation of molecular diagnostics and tailored treatment in patients with newly diagnosed high-risk multiple myeloma. Myeloma UK, BMS, and Johnson & Johnson.
2026-08-06 | Multilineage lymphoid clonal hematopoiesis: a cross-sectional, correlative analysis of plasma cell dyscrasias and large granular lymphocytic leukemia.
Clonal expansions in large granular lymphocytic leukemia (LGLL) may arise in response to immune dysregulation in the context of other hematologic malignancies. This study aimed to investigate the co-occurrence of LGLL and plasma cell dyscrasias (PCDs) to assess its prevalence, features, and potential underlying mechanisms. We conducted a cross-sectional study involving 2064 PCD cases and 534 LGLL cases. Of the 534 LGLL cases, 20% co-occurred with PCD, while LGLL was present in 2% of the 2064 PCD cases. Among 117 patients with both conditions, PCDs were predominantly associated with IgM M-protein, while LGLL patients had increased NK-cell proliferation and fewer mutations in STAT3/5B. The co-occurrence was linked to a higher incidence of autoimmune conditions, B-cell neoplasms, and more severe immune-mediated cytopenias. In symptomatic PCD/LGLL patients with low plasma-cell infiltration, B-cell-targeted therapies outperformed immunosuppression, suggesting humoral involvement. Correlation with biological parameters revealed elevated interleukin-6 and inhibitory effects of sera of symptomatic PCD/LGLL patients on hematopoietic cells. Our findings suggest an association between PCD and LGLL, characterized by distinct features that may have significant implications for clinical management. These results highlight the importance of considering hematologic co-occurrences in clinical practice and warrant further investigation into the molecular mechanisms linking these conditions.
2026-07-03 | Real-World Outcomes with BCMA- and GPRC5D-Targeting Bispecific Antibodies in Plasma Cell Leukemia.
Patients with plasma cell leukemia (PCL) are generally excluded from pivotal T-cell redirecting bispecific antibody (BsAb) trials. We evaluated real-world outcomes in a multicenter retrospective study of 122 patients with primary or secondary PCL across 15 academic centers, categorized as 'active' (≥5% circulating plasma cells within 30 days of BsAb initiation) or 'historical'. In a heavily pretreated population, patients received teclistamab (37%), elranatamab (11%), talquetamab as a line of therapy (Tal LOT, 42%), or talquetamab as bridging therapy to CAR-T (Tal Bridge, 11%). Cytokine release syndrome (CRS) was grade 1-2 in 56% and grade 3-4 in 4%, whereas neurotoxicity was grade 1-2 in 16% and grade 3-4 in 5%. Among 110 evaluable patients, the overall response rate (ORR) was 55%, including 61% with Tal LOT, 58% with Tal Bridge, 46% with elranatamab, and 33% with teclistamab. With a median follow-up of 8.3 months, talquetamab demonstrated superior survival. Tal LOT showed a median progression-free survival (mPFS) of 5.5 months and a median overall survival (mOS) of 11.5 months, and both were unreached in the Tal Bridge cohort. In contrast, teclistamab and elranatamab showed a mPFS of 1.2 and 1.6 months and mOS of 8.1 and 3.6 months, respectively (P=0.007, P=0.023). In active PCL, Tal LOT achieved mPFS/mOS of 6.9/12.2 months versus 0.7/1.4 months with teclistamab and 1.0/3.1 months with elranatamab, respectively (P<0.001, P=0.002). Multivariable analysis associated active PCL with worse survival and Tal LOT with improved outcomes. BsAbs were safe in PCL, with talquetamab showing superior outcomes compared with BCMA-directed BsAbs.
2026-06-11 | Multiple Myeloma Cells Resistant to T-cell Therapies Exhibit a CD45+ Immunoevasive Phenotype.
Multiple myeloma is a plasma cell malignancy that is mostly incurable, even with recent advances in treatment such as B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR) T cells and bispecific T cell-engaging (TCE) antibodies. To better understand this treatment resistance, we examined multiple myeloma cells that persisted after these treatments and consistently observed CD45 upregulation as part of a resistance program. Bone marrow samples were treated ex vivo with BCMA CAR T cells, TCE antibodies (elranatamab, SAR442257), or activated T cells and analyzed via flow cytometry. CD45 upregulation was validated in patient samples before and after idecabtagene vicleucel therapy (anti-BCMA CAR T-cell therapy) and using an in vivo mouse model of disseminated multiple myeloma. Persisting multiple myeloma cells exhibited focal CD45 surface patches. Mechanistic studies implicated secreted HSP70, whereas bulk RNA sequencing revealed increased LAG-3, IFNγ signaling, and PD-L1 expression. These findings suggest that T cell-redirecting therapy (TCRT) drives an immunoevasive phenotype defined by CD45 upregulation and immune checkpoint activation, supporting combination strategies of TCRT with checkpoint inhibitors to overcome resistance in relapsed/refractory multiple myeloma.
oligonucleotides
2026-04-12 | Transforming tumor cells into professional antigen-presenting cells using poly(β-amino ester) nanoparticles to deliver CD80-encoding mRNA.
Effective T-cell activation requires both antigen recognition and co-stimulatory signaling. However, tumor cells typically lack the necessary co-stimulatory molecules, rendering T-cell receptor engagement with tumor antigens insufficient to induce potent anti-tumor immune responses. To overcome this limitation, we converted tumor cells into professional antigen-presenting cell (APC)-like cells by equipping them with the co-stimulatory molecule CD80. Electroporation of melanoma and lung cancer cell lines with CD80-encoding mRNA significantly increased their ability to stimulate tumor-antigen-specific T cells, as indicated by increased activation markers and cytokine secretion. Most importantly, CD80 expression converted melanoma cells into APC-like cells capable of priming and expanding naïve T cells that recognize endogenous tumor antigens. To enable clinical application, we subsequently used poly-(beta aminoester) (pBAE) polymers, which efficiently encapsulate mRNA into nanometric polyplexes. As previously reported, pBAE nanoparticles (NPs) efficiently penetrate plasma membranes and escape endosomal degradation both in vitro and in vivo. Here, we evaluated pBAE NPs encapsulating GFP-encoding mRNA in human cell lines derived from melanoma, lung cancer, leukemia, adenocarcinoma, uveal melanoma, and Merkel cell carcinoma. The pBAE NPs effectively transfected adherent tumor cells, and tumor spheroids in vitro and in ovo. When delivering CD80 mRNA, NPs achieved expression rates of more than 50% in most cell lines, which lasted for at least 72 h. Here as well, nanoparticle-mediated CD80 expression enabled melanoma cells to prime and expand naïve T cells recognizing endogenous tumor antigens. Importantly, T cells primed by CD80-expressing tumor cells were also capable of killing tumor cells that had not been transfected. In line with these findings, T cells stimulated with untransfected tumor cells showed high levels of checkpoint receptors CTLA-4 and PD-1, whereas the expression was significantly lower when using CD80-transfected tumor cells. This proof-of-concept study indicates that conversion of tumor cells into professional APC-like cells with CD80 mRNA is feasible and results in potent anti-tumor CD8+ T-cell responses. With the use of mRNA-loaded pBAEs, the prerequisites for a future application in vivo are given. Therefore, the application of pBAE NPs encapsulating CD80 mRNA to specifically transfect tumor cells presents a new promising strategy for the in vivo treatment of various cancers.
2026-01-27 | Immunogenicity and safety of a third and subsequent COVID-19 vaccine doses in patients with plasma cell dyscrasias.
Plasma cell dyscrasias (PCD) are a group of hematologic disorders associated with immune dysfunction from underlying disease and/or treatment. With the continued circulation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), optimizing and maintaining durable protection in this vulnerable population through vaccination remains important. A prospective cohort study was conducted between August 2021 and January 2023 across 12 sites in Canada to evaluate humoral immunity to COVID-19 vaccination in participants with hematologic malignancies. Participants were monitored longitudinally, and finger-prick dried blood spot cards were obtained at specific intervals based on vaccination. Serum antibodies against SARS-CoV-2 proteins after the third, fourth, and fifth dose were measured by high-throughput enzyme-linked immunosorbent assay. Differences in antispike (anti-S) seropositivity by vaccine dose number and clinical risk factors were analyzed by logistic regression. A total of 262 unique participants with 983 samples were included for analysis, among which 66% were diagnosed with PCD. Analysis of the predicted probability of immunity showed consistently higher proportions of participants with PCD with vaccine (anti-S) immunity compared with those with infection-derived (antinucleocapsid) immunity throughout the study. Although vaccine responses appeared to wane 6 months after dose 3 and, to a lesser extent, after dose 4, subsequent doses cumulatively increased anti-S immunity. Seropositivity decreased with anti-CD38 therapy and older age, although the receipt of additional vaccine doses significantly improved anti-S immunity. Overall, this study demonstrated that the third and subsequent COVID-19 vaccine doses could safely improve humoral immunity in participants with PCD. Although anti-CD38 therapy and age reduced seropositivity, antibody responses could still be enhanced with vaccine doses beyond the primary 3-dose series.
2023-10-09 | Anti-nucleolin aptamer AS1411: an advancing therapeutic.
Targeted therapy is highly desirable, as it allows for selective cytotoxicity on diseased cells without off-target side effects. Nucleolin is a remarkable target for cancer therapy given its high abundance, selective presence on the plasma membrane, and multifaceted influence on the initiation and progression of cancer. Nucleolin is a protein overexpressed on the cell membrane in many tumors and serves as a binding protein for several ligands implicated in angiogenesis and tumorigenesis. Nucleolin is present in the cytoplasm, nucleoplasm, and nucleolus and is used by selected pathogens for cell entry. AS1411 is a guanosine-rich oligonucleotide aptamer that binds nucleolin and is internalized in the tumor cells. AS1411 is well tolerated at therapeutic doses and localizes to tumor cells overexpressing nucleolin. AS1411 has a good safety profile with efficacy in relapsed acute myeloid leukemia and renal cell carcinoma producing mild or moderate side effects. The promising potential of AS1411 is its ability to be conjugated to drugs and nanoparticles. When a drug is bound to AS1411, the drug will localize to tumor cells leading to targeted therapy with fewer systemic side effects than traditional practices. AS1411 can also be bound to nanoparticles capable of detecting nucleolin at concentrations far lower than lab techniques used today for cancer diagnosis. AS1411 has a promising potential to change cancer diagnoses and treatment.
2022-10-13 | DAZAP1 facilitates the alternative splicing of KITLG to promote multiple myeloma cell proliferation via ERK signaling pathway
Multiple myeloma (MM) is an incurable plasma cell malignancy, in which alternative pre-mRNA splicing (AS) acts as one of the key transcriptome modifier. The Deleted in Azoospermia-Associated Protein 1 (DAZAP1) is a splicing factor that has been identified as an oncogene in multiple cancers, yet its role in MM proliferation remains unclear. We first analyzed MM clinical databases and found that MM patients with elevated DAZAP1 had a poor survival. Furthermore, we overexpressed DAZAP1 by lentiviral transfection and utilized siRNA silencing the expression of DAZAP1 in MM cells. DAZAP1 promoted MM cell proliferation in vitro and accelerated MM xenograft tumor growth in vivo. KEGG pathway enrichment analysis showed that ERK signaling pathway was activated in DAZAP1-OE MM cells. The analyses of RIP-seq and RIP-qPCR revealed that DAZAP1 activated alternative splicing of KIT proto-oncogene ligand (KITLG) mRNA. Further study validated that DAZAP1 increased ERK phosphorylation via modulating alternative splicing of KITLG mRNA to promote MM cell proliferation. In conclusion, we establish DAZAP1 as a tumor-promoting gene with therapeutic potential and provide mechanistic insights into targeting DAZAP1 as a new strategy for the diagnosis and treatment of MM.
2022-05-30 | Hypermethylation of the Promoter Region of miR-23 Enhances the Metastasis and Proliferation of Multiple Myeloma Cells via the Aberrant Expression of uPA
Multiple myeloma has a long course, with no obvious symptoms in the early stages. However, advanced stages are characterized by injury to the bone system and represent a severe threat to human health. The results of the present work indicate that the hypermethylation of miR-23 promoter mediates the aberrant expression of uPA/PLAU (urokinase plasminogen activator, uPA) in multiple myeloma cells. miR-23, a microRNA that potentially targets uPA’s 3’UTR, was predicted by the online tool miRDB. The endogenous expressions of uPA and miR-23 are related to disease severity in human patients, and the expression of miR-23 is negatively related to uPA expression. The hypermethylation of the promoter region of miR-23 is a promising mechanism to explain the low level of miR-23 or aberrant uPA expression associated with disease severity. Overexpression of miR-23 inhibited the expression of uPA by targeting the 3’UTR of uPA, not only in MM cell lines, but also in patient-derived cell lines. Overexpression of miR-23 also inhibited in vitro and in vivo invasion of MM cells in a nude mouse model. The results therefore extend our knowledge about uPA in MM and may assist in the development of more effective therapeutic strategies for MM treatment.
other
2026-03-05 | Cancer Susceptibility to Stapled Oncolytic Peptides Is Dictated by Membrane Cholesterol and Inflammatory Signaling.
Relapsed and refractory cancers effectively overcome diverse treatment modalities that primarily target nucleic acids and proteins. The plasma membranes of cancer cells represent an alternative and underutilized target, with the potential for membrane lysis to induce rapid, proinflammatory cell death that circumvents the challenges of intratumor heterogeneity and immune evasion. In this study, we repurposed StAMP51.2, a stapled magainin 2 peptide previously optimized for selective membrane lysis of Gram-negative bacteria, to target cancer cell membranes. The Profiling Relative Inhibition Simultaneously in Mixtures (PRISM) assay, a high-throughput cancer cytotoxicity screen, revealed cancer cells most vulnerable to StAMP51.2 and biomarkers of susceptibility, specifically reduced cholesteryl esters and elevated triacylglycerols. This signature was validated in pairs of sensitive (OCI-AML3 and THP-1) and resistant (K562 and KMS-11) leukemia cell lines, with their differential responses correlated to distinct lipidomic profiles. Susceptibility of OCI-AML3 cells in culture extended to the in vivo context, in which StAMP51.2 suppressed leukemic growth in orthotopic and intraperitoneal models. To further characterize the mechanism of action, StAMP51.2-resistant OCI-AML3 cells were generated, which required 4 months of low-level exposure. Strikingly, drug-resistant OCI-AML3 cells recapitulated the lipidomic phenotype of naturally resistant K562 cells. Transcriptomic analyses further revealed that lipid reprogramming was accompanied by pervasive downregulation of inflammatory signaling. Thus, in advancing StAMP51.2 as an oncolytic prototype, this study uncovered an immunoregulatory axis that links membrane integrity to inflammatory signaling. A stapled oncolytic peptide targets cancer cell membranes and induces a lipid-inflammation axis that underlies susceptibility, offering a promising therapeutic strategy beyond traditional nucleic acid and protein targets.
2025-12-28 | Nogo-A-cleaved amino-terminal fragment but not Nogo-B regulates STAT3 activation.
Nogo family protein contains splice variants Nogo-A and Nogo-B, which differ in their expression patterns and functions. Ectopic overexpression of Nogo-A in HEK293T cells causes multiple fragmentation of the Nogo-A protein. Herein, we focused on the posttranslational production of a Nogo-A amino-terminal fragment with a molecular weight of approximately 45 kDa, which we term NogoA-213. Comparing endogenous Nogo protein expression among mouse organs, we detected full-length Nogo-A protein migrating at approximately 200 kDa and a smaller protein of approximately 45 kDa using an anti-Nogo-A N-terminal antibody. Interestingly, this 45 kDa band was recognized by an anti-NogoA-F antibody that detects human Nogo-A aa 186-213, which is specific to full-length Nogo-A and the Nogo-A N-terminal fragment but not Nogo-B, and completely overlapped with the bands detected by anti-NogoA N-terminal antibody. Therefore, we concluded that the 45 kDa band represents the Nogo-A N-terminal fragment rather than Nogo-B. Nogo proteins contain a hydrophobic domain in their C-terminal region and localize to membrane organelles such as the endoplasmic reticulum (ER) and plasma membrane. Following overexpression, Nogo-B localized to the ER and plasma membrane in HeLa cells, whereas Nogo-213 diffused throughout the cell because of lacking the C-terminal hydrophobic domain. Furthermore, following overexpression, NogoA-213 colocalized with signal transducer and activator of transcription 3 (STAT3) and enhanced leukemia inhibitory factor (LIF)-induced STAT3 phosphorylation, whereas Nogo-B did not. Importantly, LIF treatment promoted the generation of the Nogo-A N-terminal fragment in HEK293T cells. Taken together the NogoA-N-terminal fragment NogoA-213 but not Nogo-B plays a role in STAT3 activation.
2025-11-25 | Microbiome modulation uncouples efficacy and toxicity induced by immune checkpoint blockade in mouse multiple myeloma.
Smoldering multiple myeloma (SMM), which is in principle curable, may develop into life-threatening MM. Intestinal microbiota and gut-born T helper-17 (Th17) lymphocytes may contribute to this development, but the mechanisms are unclear. Here we demonstrate that administering the human commensal Prevotella melaninogenica to transgenic Vk*MYC mice that exhibit SMM-like phenotypes delays the evolution to full-blown MM. Mechanistically, P. melaninogenica increases the production of short-chain fatty acids (SCFA), thereby preventing the skewing of dendritic cells towards a pro-Th17 phenotype and subsequently accumulation of Th17 cells in the bone marrow of treated mice. P. melaninogenica or butyrate synergizes with anti-PD-L1 or anti-TIGIT to suppress myeloma progression by restraining Th17 cell expansion while inducing effector CD8+ T cells. P. melaninogenica also attenuates IL-17-mediated skin lesions that mimic anti-PD-L1-induced adverse events. Our results thus suggest that gut microbiota modulation or SCFAs administration may represent treatment options for patients affected by plasma cell dyscrasias.
2024-10-17 | Cytosolic delivery of monobodies using the bacterial type III secretion system inhibits oncogenic BCR: ABL1 signaling.
The inability of biologics to pass the plasma membrane prevents their development as therapeutics for intracellular targets. To address the lack of methods for cytosolic protein delivery, we used the type III secretion system (T3SS) of Y. enterocolitica, which naturally injects bacterial proteins into eukaryotic host cells, to deliver monobody proteins into cancer cells. Monobodies are small synthetic binding proteins that can inhibit oncogene signaling in cancer cells with high selectivity upon intracellular expression. Here, we engineered monobodies targeting the BCR::ABL1 tyrosine kinase for efficient delivery by the T3SS, quantified cytosolic delivery and target engagement in cancer cells and monitored inhibition of BCR::ABL1 signaling. In vitro assays were performed to characterize destabilized monobodies (thermal shift assay and isothermal titration calorimetry) and to assess their secretion by the T3SS. Immunoblot assays were used to study the translocation of monobodies into different cell lines and to determine the intracellular concentration after translocation. Split-Nanoluc assays were performed to understand translocation and degradation kinetics and to evaluate target engagement after translocation. Phospho flow cytometry and apoptosis assays were performed to assess the functional effects of monobody translocation into BCR:ABL1-expressing leukemia cells. To enable efficient translocation of the stable monobody proteins by the T3SS, we engineered destabilized mutant monobodies that retained high affinity target binding and were efficiently injected into different cell lines. After injection, the cytosolic monobody concentrations reached mid-micromolar concentrations considerably exceeding their binding affinity. We found that injected monobodies targeting the BCR::ABL1 tyrosine kinase selectively engaged their target in the cytosol. The translocation resulted in inhibition of oncogenic signaling and specifically induced apoptosis in BCR::ABL1-dependent cells, consistent with the phenotype when the same monobody was intracellularly expressed. Hence, we establish the T3SS of Y. enterocolitica as a highly efficient protein translocation method for monobody delivery, enabling the selective targeting of different oncogenic signaling pathways and providing a foundation for future therapeutic application against intracellular targets.
2023-09-08 | Acquired Isolated Factor VII Deficiency in Plasma Cell Dyscrasias: A Brief Presentation of Two Plasma-Cell-Leukemia-Related Cases and Review of Literature
Acquired isolated factor VII (FVII) deficiency is a rare but important discovery in patients with plasma cell disorders with significant therapeutic and prognostic implications. The present analysis and review of cases reported in the literature is intended to highlight disease-related characteristics associated with this rare clotting defect, clinical manifestations and outcome, and potential underlying mechanisms, and to provide guidance on how to manage these patients in terms of prophylactic and therapeutic measures. The discovery of acquired FVII deficiency in a patient with multiple myeloma (MM) or monoclonal gammopathy of uncertain significance (MGUS) should prompt an evaluation for AL amyloidosis, particularly for amyloid hepatosplenic involvement, whenever not previously documented. Acquired FVII deficiency in patients with MM and AL amyloidosis is frequently associated with severe bleeding diathesis, also related to a number of concomitant predisposing factors, adversely affecting the outcome. The prompt institution of a rapidly acting therapy is crucial to prevent severe bleeding complications and positively impact outcome. Recombinant activated factor VII (rVIIa) may represent a useful supportive care measure, both in treating active bleeding and in the peri-procedural setting. However, further clinical experience is needed to optimize the therapeutic management of this rare disorder.
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Drug Discovery Landscape
4 orphan drug designations for Plasma cell leukemia.
4 orphan drug designations for Plasma cell leukemia.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Roneparstat | — | EMA | — | Leadiant GmbH |
Melphalan flufenamide [Pepaxti] | small molecules | EMA | [INACTIVE] Oncopeptides AB | |
Selinexor [Nexpovio] | small molecules | EMA | Karyopharm Europe GmbH | |
Isatuximab [Sarclisa] | antibodies | EMA | Sanofi-Aventis Groupe |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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