Imaging in multiple myeloma.

Multiple myeloma is a type of blood cancer arising from the uncontrolled clonal proliferation of malignant plasma cells resulting in impaired hematopoiesis, hyper production of monoclonal protein, bone tissue destruction leading and renal system alterations up to kidney failure. The aim is to review the state-of-the-art of radiological imaging in multiple myeloma. Radiological techniques as well as the advancements in imaging technology have been reviewed and summarized. The main radiological findings of different imaging techniques in patients suffering from multiple myeloma are also illustrated. Different radiological techniques provide structural and functional data. In the last years, conventional skeletal survey has gradually lost its utility and it has been replaced by whole body low-dose computed tomography which allows to identify also small lytic lesions, the medullary and the extramedullary involvement. Nowadays, magnetic resonance is the most sensitive imaging technique for detecting of skeletal as well as medullary involvement in patients with multiple myeloma. Thanks to the multiparametric evaluation (morphological, diffusion weighted and perfusion imaging sequences) and to the quantitative analysis, magnetic resonance imaging is proved to be useful in the early evaluation of response to therapy. Finally, positron emission tomography has greater sensibility compared to computed tomography as it provides quantitative data; however, the lower expression levels of the specific gene involved in the glycolysis pathway are associated with false-negative results with consequent underestimation of the disease. The only use of the advanced combined multimodal imaging allows a better evaluation, staging and early assessment of treatment response in patients with multiple myeloma.

Multiple myeloma is a malignant bone marrow neoplasia in which a monoclonal strain of atypical plasma cells proliferates and typically secretes paraproteins. It typically affects the elderly population with a peak incidence in the eighth decade. The atypical plasma cells are distributed in the bone marrow either focally or in a diffuse manner and may result in bone destruction, but may also occur in soft tissue. Bone marrow aspirates or bone marrow biopsies are essential for the diagnosis. Due to various therapeutic options and the large variability in survival, the sensitive detection of myeloma involvement of the skeleton is mandatory to enable accurate disease staging. Various imaging methods are employed in assessing the disease burden in multiple myeloma. The following chapter reviews the findings in multiple myeloma in conventional radiography, computed tomography (CT), positron-emission tomography (PET)/CT, and magnetic resonance imaging (MRI) and compares the various methods. Whole-body MRI is superior to the skeletal survey and whole-body multidetector CT (MDCT). On the other hand, MDCT is the method of choice for displaying osteolytic lesions and determining fracture risk. PET-CT has a high sensitivity and specificity in detecting myeloma involvement and has been shown to be more sensitive than other modalities for detecting extramedullary sites of disease. The increased sensitivity of these imaging techniques has led to further refinement of the classic Durie and Salmon staging system. We review the role of the various imaging methods in the staging, assessment of prognosis, and evaluation of relapse/response to therapy in multiple myeloma. Knowledge of the use and limitations of the various imaging modalities, imaging findings, staging, and treatment-related changes is essential for the accurate assessment of the disease burden in multiple myeloma by the radiologist.KeywordsMultiple MyelomaFocal LesionOsteolytic LesionPercutaneous VertebroplastySolitary PlasmacytomaThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Multiple myeloma (MM) is a malignant disease with abnormal proliferation of clonal plasma cells. The development of the disease shows a vast heterogeneity, which is closely related to the interaction between MM cells and bone marrow microenvironment (BMM). The interleukin-6 (IL-6)/interleukin-6 receptor (IL-6R)/Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway can regulate the transcription of related soluble factors in BMM, promote the proliferation, anti-apoptosis, drug resistance and guide related bone destruction of MM cells. This article reviews the research progress on the effect of BMM regulated by IL-6/IL-6R/JAK2/STAT3 pathway on the biological behavior of MM, in order to provide new research ideas for targeted therapy and precise therapy of MM.

Findings of Whole Body Computed Tomography Compared to Conventional Skeletal Survey in Patients with Monoclonal Plasma Cell Disorders - a Study of the International Myeloma Working Group

This study evaluated the anti-myeloma activity of nuvisertib using in vitro and in vivo preclinical models. Multiple myeloma (MM) is a hematologic malignancy characterized by the clonal proliferation of plasma cells within the bone marrow, leading to the production of monoclonal immunoglobulin and progressive marrow failure. Despite significant therapeutic advances, MM remains largely incurable, with many patients eventually relapsing or developing resistance to treatment. PIM-1 is frequently overexpressed in hematologic malignancies and contributes to malignant cell growth and resistance mechanisms. Nuvisertib (TP-3654), an oral PIM-1 kinase inhibitor currently under clinical investigation for myelofibrosis (NCT04176198), may be a potential therapeutic candidate for MM due to its role in modulating cell survival and proliferation pathways, particularly through the JAK/STAT signaling axis. While pan-PIM inhibitors have demonstrated anti-tumor activity in relapsed/refractory MM patients with acceptable tolerability, there are no published preclinical or clinical data on the anti-MM effects of nuvisertib. In this study, in vitro assays were conducted using bone marrow cells from MM patients and human MM LAGλ-1 cells. Cells were treated with nuvisertib alone or in combination with standard MM therapies. Cell viability was assessed using MTS assays after 48 hours of treatment. In vivo efficacy was evaluated in SCID mice implanted with LAGκ-2 or LAGλ-1 MM patient-derived xenografts (PDXs) in the gluteal muscle of the left hind limb. Once tumors became palpable, mice were randomized (n=10 per group) and treated orally with nuvisertib or vehicle control and tumor volumes measured during treatment. After 2–4 weeks, depending on tumor progression, mice were sacrificed and tumors harvested for weight analysis. Nuvisertib demonstrated potent, dose-dependent cytotoxicity in vitro, with an IC30 value of 1.11 µM, comparable to those of established MM drugs including dexamethasone (1.32 µM), cyclophosphamide (1.01 mM), lenalidomide (95.1 µM), and pomalidomide (16.5 µM). When combined with other agents, nuvisertib exhibited additive anti-proliferative effects, particularly in samples from patients with progressive disease (>50% malignant plasma cells). In contrast, samples from patients in complete response (<5% plasma cells) showed less pronounced effects. These findings suggest nuvisertib may be potentially active in drug-resistant or relapsed/refractory MM patients. In vivo, nuvisertib reduced tumor volume in both LAGκ-2 and LAGλ-1 models compared to controls, with final tumor volumes of 1385 mm3 and 2838 mm3 in treated groups versus 2789 mm3 and 6258 mm3 in vehicle groups, respectively (p<0.013). Tumor weights were also lower in nuvisertib-treated mice (p<0.04). These results support nuvisertib as a potential therapeutic agent for MM, both as a monotherapy and in combination with currently used treatments. Further studies using preclinical human MM PDX models are warranted to evaluate drug interactions and impact on overall survival. Citation Format: Zakir Khan, Stacy Behare, Mingjie Li, Jason M. Foulks, Steven L. Warner, James R. Berenson. Nuvisertib shows single-agent anti-tumor activity in multiple myeloma nonclinical models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A098.

Multiple myeloma (MM) is a hematologic malignancy characterized by the proliferation of clonal plasma cells in the bone marrow (BM). It is known that early genetic mutations in post-germinal center B/plasma cells are the cause of myelomagenesis. The acquisition of additional chromosomal abnormalities and distinct mutations further promote the outgrowth of malignant plasma cell populations that are resistant to conventional treatments, finally resulting in relapsed and therapy-refractory terminal stages of MM. In addition, myeloma cells are supported by autocrine signaling pathways and the tumor microenvironment (TME), which consists of diverse cell types such as stromal cells, immune cells, and components of the extracellular matrix. The TME provides essential signals and stimuli that induce proliferation and/or prevent apoptosis. In particular, the molecular pathways by which MM cells interact with the TME are crucial for the development of MM. To generate successful therapies and prevent MM recurrence, a thorough understanding of the molecular mechanisms that drive MM progression and therapy resistance is essential. In this review, we summarize key mechanisms that promote myelomagenesis and drive the clonal expansion in the course of MM progression such as autocrine signaling cascades, as well as direct and indirect interactions between the TME and malignant plasma cells. In addition, we highlight drug-resistance mechanisms and emerging therapies that are currently tested in clinical trials to overcome therapy-refractory MM stages.

Simple SummaryMultiple myeloma (MM) is a frequent hematological malignancy characterized by the uncontrolled growth of clonal plasma cells, primarily in the bone marrow. Over the past years, novel therapies have been discovered and introduced into clinical practice that have dramatically changed the treatment landscape of MM. Despite the tremendous advances, MM remains incurable, with poor outcomes particularly in patients with relapsed/refractory disease, emphasizing the need for new therapeutic approaches. In this review we discuss the current treatment paradigm of multiple myeloma and focus on promising future approaches.Multiple myeloma (MM) is a complex hematologic malignancy characterized by the uncontrolled proliferation of clonal plasma cells in the bone marrow that secrete large amounts of immunoglobulins and other non-functional proteins. Despite decades of progress and several landmark therapeutic advancements, MM remains incurable in most cases. Standard of care frontline therapies have limited durable efficacy, with the majority of patients eventually relapsing, either early or later. Induced drug resistance via up-modulations of signaling cascades that circumvent the effect of drugs and the emergence of genetically heterogeneous sub-clones are the major causes of the relapsed-refractory state of MM. Cytopenias from cumulative treatment toxicity and disease refractoriness limit therapeutic options, hence creating an urgent need for innovative approaches effective against highly heterogeneous myeloma cell populations. Here, we present a comprehensive overview of the current and future treatment paradigm of MM, and highlight the gaps in therapeutic translations of recent advances in targeted therapy and immunotherapy. We also discuss the therapeutic potential of emerging preclinical research in multiple myeloma.

Multiple myeloma (MM) is a blood cancer caused by the unlimited proliferation of intramedullary plasma cells. The presence of focal lesions (FLs) is presumed to be a more relevant factor for patient outcomes and risk distribution than diffuse bone marrow signal abnormalities. Signal changes in these FLs also have a good correlation with prognosis. As the cell density increased, a lower apparent diffusion coefficient (ADC) value was found with the diffusion-weighted imaging (DWI) sequence. Therefore, whole-body magnetic resonance imaging (MRI) with DWI sequences is sensitive to cell density and viability and may be vital for disease detection and therapy response assessments. However, the correlation between the DWI signal and the degree of bone destruction and the proportion of bone marrow plasma cells (BMPC) was still unclear in patients with MM. Water-fat separation MRI is used mainly for evaluating liver and bone marrow fat quantification, and fat quantification in other diseases. Meanwhile, it is also possible to assess the extent of bone marrow invasion in medullary lesions. This study aimed to investigate the correlation between ADC values from whole-body DWI and water/fat MRI signals from T1-weighted water-fat separation in evaluating bone marrow infiltration in patients with MM. The study included 35 patients with MM who underwent whole-body DWI and T1-weighted water-fat separation Dixon examinations before therapy. The ADC values, normalized fat signal intensity (nMfat), normalized water molecular signal intensity (nMwater), and normalized fat fraction (nFF) of the thoracolumbar spine was measured in FLs and the normal-appearing bone marrow (NABM). The differences in values were compared using the independent-samples t-test. The correlation between ADC values and water-fat MRI signals was estimated using the Pearson or Spearman correlation test. The correlation between the MRI above parameters and proportions of BMPC was also explored. Statistically significant differences were found between the mean ADC values in FLs and NABM (0.72 vs. 0.33 mm2/s, P<0.0001). Significantly elevated nMwater values and decreased nMfat and nFF values were observed in FLs; no correlations were found in NABM (P>0.05). The ADC value highly correlated with nMfat and nFF values and moderately with the nMwater value in FLs (r=-0.899, -0.834, 0.642, respectively, P<0.0001). Correlations were also observed between the proportion of BMPC and MRI parameters in MM (r=0.984, 0.716, -0.938, and -0.905, respectively, P<0.05). The ADC value combined with water-fat separation parameters could be used for evaluating thoracolumbar bone marrow infiltration in MM. All parameters correlated with the proportion of BMPC, which helped assess the early response in MM therapy.

Downregulation of MDM2 Leads to Anti-Proliferative Effects through Activation of p53-Associated Pathway Mediated By Both Dual Inhibitor MX69 and Mir-548c-3p in Multiple Myeloma

Thalidomide Therapy and Deep Venous Thrombosis in Multiple Myeloma

DDX3X Promotes Multiple Myeloma Cell Survival and Proteasome Inhibitor Resistance through Modulation of Stress Granule Assembly and MAPKAPK2 Translation

Simple SummaryAdvances in treatment, especially with novel drugs, have dramatically improved the survival of multiple myeloma (MM) patients recently. However, frequent relapses and drug resistance remain unsolved issues. Endoplasmic reticulum stress (ERS) is elevated in MM compared to normal plasma cells, and is regarded as the Achilles’ heel of MM. This review summarizes the current knowledge of how ERS response influences the pathogenesis and drug-resistance of MM, and provides inspiration for novel therapeutic strategies to improve clinical outcomes of MM patients by targeting ERS.Multiple myeloma (MM) is the second most common hematologic malignancy, resulting from the clonal proliferation of malignant plasma cells within the bone marrow. Despite significant advances that have been made with novel drugs over the past two decades, MM patients often develop therapy resistance, especially to bortezomib, the first-in-class proteasome inhibitor that was approved for treatment of MM. As highly secretory monoclonal protein-producing cells, MM cells are characterized by uploaded endoplasmic reticulum stress (ERS), and rely heavily on the ERS response for survival. Great efforts have been made to illustrate how MM cells adapt to therapeutic stresses through modulating the ERS response. In this review, we summarize current knowledge on the mechanisms by which ERS response pathways influence MM cell fate and response to treatment. Moreover, based on promising results obtained in preclinical studies, we discuss the prospect of applying ERS modulators to overcome drug resistance in MM.

Novel therapies for multiple myeloma.

Multiple myeloma (MM) is a plasma cell dyscrasia characterized by the clonal proliferation of antibody producing plasma cells. Despite the use of next generation proteasome inhibitors (PI), immunomodulatory agents (IMiDs) and immunotherapy, the development of therapy refractory disease is common, with approximately 20% of MM patients succumbing to aggressive treatment-refractory disease within 2 years of diagnosis. A large emphasis is placed on understanding inter/intra-tumoral genetic, epigenetic and transcriptomic changes contributing to relapsed/refractory disease, however, the contribution of cellular metabolism and intrinsic/extrinsic metabolites to therapy sensitivity and resistance mechanisms is less well understood. Cancer cells depend on specific metabolites for bioenergetics, duplication of biomass and redox homeostasis for growth, proliferation, and survival. Cancer therapy, importantly, largely relies on targeting cellular growth, proliferation, and survival. Thus, understanding the metabolic changes intersecting with a drug’s mechanism of action can inform us of methods to elicit deeper responses and prevent acquired resistance. Knowledge of the Warburg effect and elevated aerobic glycolysis in cancer cells, including MM, has allowed us to capitalize on this phenomenon for diagnostics and prognostics. The demonstration that mitochondria play critical roles in cancer development, progression, and therapy sensitivity despite the inherent preference of cancer cells to engage aerobic glycolysis has re-invigorated deeper inquiry into how mitochondrial metabolism regulates tumor biology and therapy efficacy. Mitochondria are the sole source for coupled respiration mediated ATP synthesis and a key source for the anabolic synthesis of amino acids and reducing equivalents. Beyond their core metabolic activities, mitochondria facilitate apoptotic cell death, impact the activation of the cytosolic integrated response to stress, and through nuclear and cytosolic retrograde crosstalk maintain cell fitness and survival. Here, we hope to shed light on key mitochondrial functions that shape MM development and therapy sensitivity.

PO-165 Estetrol reduce cell migration and proliferation in two/three-dimensional T47D breast cancer cell model