Smoldering multiple myeloma in the United States: a population-based analysis.

Multiple myeloma (MM) remains incurable, necessitating development of novel therapeutic targets. Deregulated PRKCN is implicated in solid tumors, while its role in MM remains elusive. Here, PRKCN is identified as a super-enhancer-driven gene associated with adverse prognosis in MM. PRKCN is transactivated by NF-κB signaling intrinsically existing or exogenously provoked. Constitutive or inducible knockdown of PRKCN significantly impairs cell growth and tumorigenicity, while overcoming drug resistance. PRKCN harnesses IRF4 to exert its effect, and in turn, IRF4 directly induces PRKCN transcription, establishing a feed-forward IRF4-PRKCN circuit. Furthermore, PRKCN fosters IRF4 expression by activating mTORC1/C2 signaling pathways via physical interaction with mTOR. Surprisingly, PRKCN modulates mTOR-IRF4 axis and cell growth independently of its acknowledged kinase activity yet requiring activation loop phosphorylation. Intriguingly, PRKCN silencing evokes interferon signaling and confers increased sensitivity to interferon. Finally, targeting PRKCN with an orally bioavailable inhibitor suppresses MM cell growth and overcomes drug resistance in vitro, and elicits robust efficacy in cell line-derived xenografts and a patient-derived xenograft, which is connected with the mitigated PRKCN expression and activation loop phosphorylation as well as blunted mTOR-IRF4 axis. Collectively, our study delineates PRKCN function that links aberrant NF-κB signaling and mTOR-IRF4 axis, supporting clinically targeting PRKCN in MM.

Patients with multiple myeloma (MM) often use cardiovascular medications due to their increased risk of cardiovascular diseases. This study investigated the associations of baseline use of these drugs with survival and adverse events in MM patients initiating daratumumab, lenalidomide, or bortezomib combination treatments. Data from Phase III trials (CASTOR, MAIA, and POLLUX) were analysed, focusing on beta-blockers, calcium channel blockers, ACE inhibitors (ACEI), angiotensin II receptor blockers (ARBs), diuretics, and statins. Cox proportional hazard analysis and logistic regression were used to assess associations with survival and grade ≥ 3 adverse events. Among 1804 patients, ACEI/ARBs were most common (31%), followed by beta-blockers (23%), statins (21%), calcium channel blockers (17%), and diuretics (16%). ACEI/ARBs was associated with better progression-free survival (adjusted hazard ratio (aHR) [95% CI] = 0.84 [0.71-0.99], P = 0.034) but also higher odds of grade ≥ 3 adverse events (adjusted odds ratio (aOR) = 1.45 [1.06-1.97], P = 0.019). Diuretics were similarly associated with grade ≥ 3 adverse events (aOR = 1.53 [1.01-2.34], P = 0.047). Other cardiovascular drugs showed no significant associations. While ACEI/ARBs may improve progression-free survival, they pose safety concerns. It is reassuring that other cardiovascular drugs were not significantly associated with MM treatment outcomes. Further research is essential to fully understand the implications of these medications.

Surveillance, Epidemiology, and End Results (SEER) multiple myeloma (MM) survival statistics (https://seer.cancer.gov/statfacts/html/mulmy.html) that have been used to guide MM management and control have been systematically overestimated due to the inclusion of smoldering multiple myeloma (SMM), a premalignant condition of MM. Using the latest SEER release, we estimated the extent of such overestimation in the survival statistics. In 2016, 77.9% out of 5,495 patients reported as overall MM were symptomatic MM and 10.9% were SMM. Median survival was 65.8 months for overall MM versus 56.8 months for symptomatic MM (p < .001). Inclusion of SMM overestimated MM survival by 9 months. Five-year relative survival estimates from 2015-2021 were 61.6% for overall MM, 57.9% for symptomatic MM, and 88.3% for SMM, versus SEER's reported 62.4%. Survival statistics for symptomatic MM and SMM should be reported separately to guide MM management and prevention at the population level.

Multiple myeloma (MM) health disparities are well-documented, with non-Hispanic Black (NHB) and male individuals experiencing higher disease burdens than their non-Hispanic White (NHW) or female counterparts. However, no studies have shown that how these disparities translate into differences in life expectancy, particularly for monoclonal gammopathy of undetermined significance (MGUS), a precursor to MM. This study quantified the remaining life years and life years lost associated with MGUS and MM to inform MM prevention and control priorities. We developed a discrete-event simulation (DES) model of the natural history of MM, calibrated using nationally representative data on serologic-detected MGUS and registry-based MM. The model was stratified by race and gender (NHB/NHW men and women). Life years lost was computed as the difference in life years between populations without and with MGUS/MM. Remaining life years for MGUS/MM were 17.8/6.3 (95% prediction interval [PI]: 17.4-18.2/5.9-6.9) for NHB men, 20.1/7.7 (95% PI : 19.7-20.5/7.1-8.3) for NHB women, 20.9/7.3 (95% PI: 20.3-21.4/6.7-8.0) for NHW men, and 23.0/8.5 (95% PI: 22.5-23.6/7.7-9.4) for NHW women. Corresponding life years lost associated with MGUS/MM was 7.6/14.2 (95% PI: 7.3-8.0/13.3-15.1), 8.0/16.0 (95% PI: 7.7-8.4/15.0-17.0), 8.4/16.0 (95% PI: 8.0-8.9/14.7-17.3), and 8.8/18.1 (95% PI: 8.4-9.2/16.9-19.4), respectively. Substantial racial and gender differences were identified and quantified in disease burden associated with MGUS and MM, which provides concrete targets for MM prevention and control efforts. Our findings underscore the need for tailored strategies to reduce MM disparities, e.g., enhancing disease monitoring among NHB populations and improving treatment adherence among men with MM.

The proteostatic decline in Alzheimer's disease is well established, and improvement in proteostasis could potentially delay cognitive impairment. One emerging entry point to modulate proteostasis is the regulation of nucleo-cytoplasmic partitioning of proteins across the nuclear pore via karyopherins. The nuclear exportin XPO1 is a key regulator of proteostasis by driving the assembly of ribosomes and by modulating the process of autophagy. We recently found that the XPO1 inhibitor KPT-330 (Selinexor), an FDA-approved drug against multiple myelomas, enhances proteostasis, leading to benefits in models of neurodegenerative diseases in C. elegans and Drosophila. Here, we find that KPT-330 increases autophagy in murine neuronal cells. In a murine model of Alzheimer's disease (5XFAD), KPT-330 improved spatial memory performance. Unexpectedly, general amyloid deposition in several brain regions was significantly increased by KPT-330, but specific regions, especially the thalamus, displayed significantly lower deposition, suggesting that XPO1 inhibition has regional-specific effects on proteostasis and amyloid plaque formation. Altogether, we conclude that, despite overall increases in amyloid plaque burden, XPO1 inhibition can improve cognition via spatially-specific reductions in amyloid deposition.

Immune heterogeneity at diagnosis influences treatment response and survival in multiple myeloma.

When using real-world data to construct an external comparator arm for a single-arm trial, there may be differences in how and when patients are assessed for disease between trial and real-world settings. Such differences can generate outcome measurement error when comparing time to event endpoints and lead to biased findings. Recent methods have been developed to mitigate measurement error bias in real-world endpoints; however, they rely on the existence of a validation sample, ie, data on a set of patients where both the "true" trial-like and "mis-measured" real-world measures are collected. We demonstrate how novel statistical methods can be leveraged as quantitative bias analyses (QBA) to contextualize real-world evidence findings when outcome measurement error is of concern, but validation samples are infeasible to collect. QBA allows researchers to set plausible ranges for the amount of error when not directly measurable. We highlight how to conduct QBA with two recent methods, Cumulative Incidence Curve Correction and Survival Regression Calibration, and illustrate how to generate plausible parameter values through simulation. We provide an illustrative QBA example in a cohort of real-world patients with Newly Diagnosed Multiple Myeloma and provide practical guidance to apply QBA for outcome measurement error and interpret results.

Real-world outcomes of SLiM-only multiple myeloma: Korean Multicenter Retrospective analysis (KMM2401 study).

Multiple myeloma (MM) is associated with skewed T cell activation and function which is present in asymptomatic myeloma precursor conditions, but underlying mechanisms of progression remain undefined. Here, we assemble a large single-cell RNA sequencing dataset of the bone marrow and blood from patients with MM, precursor conditions, and non-cancer controls. We demonstrate that, unlike solid cancers, MM is not characterized by T cell exhaustion, but by antigen-driven terminal memory differentiation. This is influenced by tumour-intrinsic features including tumour burden and expression of antigen-presentation genes. Expanded TCR clones accumulating in MM are not enriched with viral specificities but accumulate in effector states in highly-infiltrated marrows. Additionally, we identify a role for T cell dynamics in patients treated with autologous stem cell transplantation and demonstrate T cell features predict progression from precursor to symptomatic MM. Together, these results suggest that anti-tumour immunity drives a distinctive form of cancer-associated T cell differentiation in MM.

Multiple myeloma remains a therapeutic challenge despite recent advances with proteasome inhibitors, immunomodulatory drugs (IMiDs), and monoclonal antibodies. Among new approaches, the combination of IMiDs and histone deacetylase inhibitors has shown promise in relapsed or refractory multiple myeloma. Here, we elucidate the molecular basis of their synergy and its role in overcoming drug resistance in myeloma cells. We demonstrate that these agents converge to downregulate the master oncogene MYC, resulting in synergistic cytotoxicity. Importantly, this effect persists even in models intrinsically resistant to IMiDs, where the canonical IKZF1/3-IRF4/MYC axis is functionally uncoupled. In this context, the combination engages an alternative ARID2-MYC axis, mediated by the synergistic downregulation of the IMiD neosubstrate ARID2. This finding highlights the functional relevance of IMiD's inherent polypharmacology in circumventing primary resistance mechanisms at the cellular level. Together, our results identify the ARID2-containing PBAF complex as a critical vulnerability in resistant myeloma cells and provide a mechanistic rationale for designing combination strategies that co-target this complex, with the potential to enhance therapeutic efficacy by overcoming drug resistance.

BackgroundShortening chemotherapy infusion times is associated with improvements in resource use and patient satisfaction, as well as reductions in nursing workload and clinic wait times. Cyclophosphamide package inserts mention that the drug should be injected or infused very slowly, but the exact duration of infusion is not specified. Per literature review, there is heterogeneity in infusion times among regimens for various conditions.MethodsThe aim was to analyze the incidence of documented adverse events (AEs) temporally related to cyclophosphamide when it was administered as either a 60- or 30-minute infusion. We performed a retrospective chart review of records between January 1, 2023, and January 31, 2024, including adult patients (age >= 18 years) who received at least one cyclophosphamide infusion over 60- or 30-minutes within selected chemotherapy regimens for lymphoma (CHOP +/- R; EPOCH +/- R; CHOEP +/- R) or multiple myeloma (MM) (CyBorD or VCD +/- Dara; KCyD +/- Dara) at any inpatient or outpatient site within Mount Sinai Health System (MSHS).ResultsAmong 200 consecutive doses evaluated per disease-based group (n = 400 total doses), there were more numerical occurrences of documented AEs in the 60-minute groups compared to 30-minutes groups (n = 4 vs. n = 2), but this finding was not statistically significant (2% vs. 1%; p > 0.05). There were no documented Grade 3 or higher AEs temporally related to cyclophosphamide infusion.ConclusionThe shortening of cyclophosphamide infusion times for selected chemotherapy regimens was determined to be a safe practice change.

Hematologic malignancies pose significant global health burdens, with programmed cell death protein-1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors revolutionizing treatment in subtypes like classical Hodgkin lymphoma (cHL) and primary mediastinal large B-cell lymphoma (PMBCL), achieving high objective response rates (ORR). However, efficacy varies widely, with limited success in multiple myeloma (&amp;lt; 10% ORR) and leukemias, underscoring the need for better predictors beyond tumor-intrinsic biomarkers. This review highlights pre-treatment endocrine–nutritional signatures as key host factors influencing immunotherapy outcomes. Dysregulated hormones (cortisol, thyroid, sex steroids, insulin/insulin-like growth factor-1, adipokines) and nutritional status (vitamin D, zinc, protein-energy malnutrition, iron metabolism) modulate T-cell exhaustion, myeloid suppression, and tumor microenvironment dynamics, often leading to resistance. Evidence from cohorts shows hypercortisolism, hypothyroidism, insulin resistance, vitamin D deficiency, and hypoalbuminemia correlate with inferior ORR, progression-free survival, and overall survival, while thyroid immune-related adverse events and moderate obesity predict benefit. In hematologic contexts, marrow infiltration exacerbates these imbalances, explaining heterogeneous responses. Integrated signatures (e.g., Glasgow Prognostic Score, Prognostic Nutritional Index) offer superior prognostic value, enabling targeted interventions like vitamin D supplementation, metformin, or nutritional support to enhance immune checkpoint inhibitor efficacy. Mechanistic insights reveal convergence on mTOR/IFN-γ pathways and microbiome modulation. Translating these to clinical panels could personalize immunotherapy, addressing gaps in hematologic malignancies literature and improving outcomes in relapsed/refractory settings.

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The Characteristic “Tunnel Sign” on MRI as a Diagnostic Marker of Tunneling Abscesses in Listeria Rhombencephalitis in a Patient With Multiple Myeloma: A Case Report

Burixafor, a CXCR4 inhibitor with a differentiated kinetics profile: results of a phase 2 study for rapid cell mobilization in multiple myeloma and lymphoma patients undergoing transplant.

Preclinical and clinical insights are reshaping how immune-based therapies are used in multiple myeloma. This review explores how optimizing the integration of natural and synthetic immunity can support a shift from disease control to deep, durable immune eradication, paving the way for personalized immune strategies tailored to individual immune profiles.

Super-resolution microscopy in combination with genetic labeling methods allows imaging of single proteins in cells. However, visualizing endogenous proteins on primary cells remains challenging due to the use of sterically demanding antibodies for labeling. Here, we demonstrate how immunolabeling conditions and antibody cross-linking influence the quantification and identification of membrane receptor stoichiometry on cells using single-molecule localization microscopy. We developed an optimized immunolabeling and analysis protocol and demonstrate the performance of the approach by resolving the molecular organization of endogenous CD45, CD69, and CD38 on Jurkat T cells. To demonstrate the usefulness of the method for immunotherapy applications, we investigated the interaction of primary multiple myeloma cells with the therapeutic monoclonal antibodies daratumumab and isatuximab and a polyclonal anti-CD38 antibody. Our approach might lay the foundation for improved personalized diagnostics and treatment with therapeutic antibodies.

Optimizing bridging radiotherapy prior to CAR-T cell therapy: An evidence-based approach.