Multiple Myeloma Therapy: Emerging Trends and Challenges

Novel therapies for multiple myeloma.

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

Characterization of Germline Variants in Multiple Myeloma

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

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.

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.

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 hematological malignancy of aberrant clonal plasma cells that reside within the bone marrow (BM).1 The disease course differs from other BM malignancies essentially in 2 features. First, there are 2 precursor stages, monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM), that can transition into MM over time.2 Second, once clinical MM develops, the disease remains largely incurable, and despite significant therapeutic improvements, relapse and refractoriness usually cannot be prevented. The interactions between MM cells and the BM microenvironment (BM-ME) are an area of particularly intense research, as tumor evasion and suppression of the host immune system constellate main factors of MM progression.3 Single-cell sequencing technologies that have emerged over the last years have the potential to significantly advance the field because they enable the evaluation of alterations in cell numbers and states as well as interactions between MM cells and the BM-ME. Recent studies have applied single-cell techniques at different precursor and MM stages to determine the comprehensive changes in the BM-ME and to identify mechanisms that foster oncogenesis.4–11 This article briefly summarizes these studies and proposes how the dissection of the BM-ME on a single-cell level can improve our understanding of MM pathogenesis, thereby advancing prognostication and the therapeutic landscape. We would like to emphasize that single-cell analyses are a rapidly expanding field and the number of published studies investigating the BM-ME in MM and its precursors is likely to grow exponentially in the next few years given the increased interest in and access to single-cell technologies. Thus, this perspective does not cover all available articles. THE IMMUNE MICROENVIRONMENT IN THE EARLY EVOLUTION OF MYELOMA Progression from precursor stages to clinical MM is highly heterogeneous, with some patients progressing quickly, while the others remain stable for decades.2 Treatment is hence not justified solely on the premise of a precursor diagnosis. Hence, recent research has focused on identifying SMM patients, who would benefit from early therapeutic interventions. Current risk classifiers are mainly based on clinical parameters and tumor aberrations (translocation t[4;14], t[14;16], gain1q and/or del13q), yet are only able to capture up to ~60% of patients who progress to MM within 2 years.12 Further molecular characterization of the BM-ME could improve the accuracy of prognostication and also pave the way for better therapeutic avenues. In that regard, Zavidij et al8 performed single-cell RNA sequencing (scRNA-seq) of the immune-ME from 5 MGUS, 11 SMM and 7 MM patients compared with 9 healthy individuals. The authors show that substantial alterations of the immune-ME are already present at the MGUS stage. These include increased populations of natural killer (NK) cells, T cells, particularly Tregs, and nonclassical CD16+ monocytes. CD14+ monocytes showed dysregulated expression of major histocompatibility complex (MHC) type II genes, which resulted in T-cell suppression in in vitro cultures. The progression from MGUS to SMM was associated with the loss of granzyme K+ memory cytotoxic T cells leading to reduced immunosurveillance in in vivo models. Symptomatic MM was characterized by an increased INF-alpha response across all immune cell types, which has been shown to promote immunosuppression, favoring expansion of MM cells. Similarly, using scRNA-seq and mass cytometry, Bailur et al11 showed that precursor stages already harbor BM-ME alterations compared with healthy donors, including early changes in NK and myeloid cells as well as increased terminal effector differentiation and enrichment of stem-like T cells in MGUS. Another scRNA-seq study with 8 MGUS, 7 SMM, and 10 MM patients showed substantial alterations in the immune-ME of MM compared with its precursor stages.5 Symptomatic MM was enriched for CD14+ and CD16+ monocyte populations, memory B and CD8 effector cells compared with early stages with a transitional decrease of CD4-positive T cells and MAIT cells. However, there was no differential expression of exhaustion markers such as PD1, TIGIT, and LAG-3 when comparing stages. Importantly, cell proportions were heterogeneous even across the same disease stage, emphasizing the need for larger datasets and also underscoring the existence of an individual immune phenotype, which is likely influenced by other factors than the aberrant plasma cells. THE IMMUNE MICROENVIRONMENT DURING MYELOMA THERAPY AND IN RELAPSING DISEASE Established therapeutic strategies yield high complete remission rates, but disease relapse will ensue in the vast majority of patients. Yet, the disease course remains very heterogeneous with some patients relapsing within months of treatment initiation and others experiencing deep remission for >10 years. This observation has led to the hypothesis that MM cells can enter a dormant state with regrowth over time when conditions become permissive, particularly when immune surveillance falters.13 Although many MM therapies try to stimulate the immune-ME to fight the disease, it has been also shown that therapy causes immunosuppression with ensuing cytopenias and hypogammaglobulinemia, emphasizing that the balance of a stimulated or dysfunctioning immune-ME is very delicate. Deciphering the alterations within the immune-ME during therapy will hence be challenging. Tirier et al6 investigated 20 relapsed/refractory MM patients prior and post salvage therapy and compared them to 8 healthy donors. Applying scRNA-seq to the immune-ME and plasma cells, the authors analyzed both compositional changes and alterations in cell–cell interactions. In this population, which was heavily enriched for gain1q, the investigators found depletion of CD4+/CD8+ naïve and CD4+ memory cells with enrichment of CD14+/CD16+ monocytes, effector T-cell populations (CD8+ memory and cytotoxic cells) as well as gamma/delta T cells with an increase of inflammatory markers in the BM that were primarily secreted by CD14+ monocytes and MM cells. In a similar attempt to understand co-evolution of MM cells and their immune-ME, Liu et al4 described longitudinal alterations during disease progression in 14 MM patients. They report that genetic alterations tend to be associated with distinct immune cells clusters, for example, patients with translocation t(11;14) showed separate T-cell clusters with upregulation of lysine methyltransferase genes KMT2A and KMT2C in CD8+ T cells. Other studies addressed the role of the immune-ME in early relapse patients. Pilcher et al7 performed scRNA-seq on the immune-ME in patients with rapidly progressing disease (<18 months) compared with those without progression within 4 years of follow-up. Early relapse patients had significantly higher numbers of exhausted CD8+ T cells (GZMK+ and TIGIT) with decreased expression of cytotoxic markers (PRF1, GZMB, and GNLY). Similar to the study by Tirier et al, there were also alterations within the monocyte/macrophage compartment with an increase of M2 macrophages in rapid progressors. Yao et al combined scRNA-seq with an additional capture of surface markers (Cellular Indexing of Transcriptomes and Epitopes by Sequencing, CITE-Seq) and the mass cytometry approach cytometry by time of flight (CyTOF) to elucidate the biology of early relapse.9 Stratifying 18 MM patients by international staging system (ISS) and by time to progression (<6 months for rapid progressors or 6 months to 5 years for slow progressors), they found aggressive disease (ISS 3) to be associated with a decrease in CD4+ T cells and the CD4/CD8 ratio. Last but not least, recent studies investigated alterations of the BM-ME during immunotherapies, as those heavily rely on a functional immune system for optimal efficacy. Adams III et al determined the effect of the CD38-antibody Daratumumab on immune cells in the BM and peripheral blood (PB) in relapsed MM patients.10 Daratumumab depleted NK cells and reduced the amount of CD38+ basophils. As seen in the previous studies, immune profiling differed between responders and nonresponders with higher granzyme B expression in CD8+ T cells of responders, suggesting treatment induced T-cell activation with increased killing capacity. Friedrich et al determined the immunological single-cell mechanisms of resistance to bispecific BCMAxCD3 T-cell engager (TCE) therapy, a novel immunotherapy leading to unprecedented response rates in refractory MM.14 They show that TCEs lead to clonal expansion of immune cell subsets, particularly effector CD8+ T cells and that primary or acquired failure to TCE therapy is associated with exhaustion of CD8+ T cells. Importantly, treatment failure or loss of response was not solely associated with immune-ME alterations but also MM intrinsic adaptations, such as loss of the target epitope and MHC class I protein. Taken together, current research is rapidly progressing to identifying alterations within the immune-ME of particularly aggressive disease, as these patients are in most need of novel therapeutic approaches. Single-cell sequencing studies so far appear to uniformly show dysregulation of T cells, particularly cytotoxic/effector T cells with increase of exhaustion markers in progressing patients. Furthermore, there appear to be alterations leading to a dysfunctional state in the monocytes/macrophages compartment in more aggressive MM. CHALLENGES AND FUTURE PERSPECTIVES Single-cell techniques have the potential to comprehensively dissect disease mechanisms within the immune-ME and their relationship with MM cells, thereby offering a path to truly individualized medicine leading to improved prognostic measure and therapeutic avenues. Challenges remain in unifying cell subset annotations to better compare studies. The encountered heterogeneity between patients could be accounted for by increasing sample sizes and by stratifying patients based on the parameters such as age, genetic profiles of MM, and treatment received. Age has shown to have a significant impact on immune function and is manifested at multiple levels including reduced production of B and T cells and diminished function of mature lymphocytes.15 It is hence not surprising that increased age has repeatedly shown to be an adverse risk factor for clinical outcome in MM, which is likely not only due to the higher prevalence of comorbidities in this population.16 The notion that molecular subgroups of MM can differ in the surrounding BM-ME has been reported long before the onset of single-cell technologies. For example, patients of the low bone disease molecular subgroup barely show osteolytic lesions, suggesting that this subset spares the stimulation of osteoclasts and the resulting bone resorption.17 The recently discovered associations of an immune-ME signature and +1q MM and the distinct clustering of immune cells in patients with translocation t(11;14) further corroborate the hypothesis that the MM genotype and phenotype influences its surrounding or vice versa. Hence, analyzing MM in its BM-ME on a single-cell level will offer the unique opportunity to associate alterations in the ME to intrinsic MM cell features, which could revolutionize our understanding of MM biology. Treatment has a significant effect on the immune-ME, and can lead to alterations in cell populations and expression patterns, which will need to be taken into account when analyzing single-cell data.10,18,19 These alterations are associated with immune cell cytotoxicity, exhaustion, and senescence, which can influence the further disease course.20 Conversely, comprehensive immune profiling before therapy could determine which treatment modalities would yield best responses. The use of single-cell techniques before and during therapy would enable us to dissect mechanisms of response versus resistance and could tailor therapeutic approaches based on the patients' individualized immune profile. Additional challenges to single-cell technologies are based on the current limitations of these techniques and are unlikely to be overcome by merely increasing the number of samples. This includes the limited number of analyzed cells due to the high costs. As an alternative or complementary approach, multidimensional flow cytometry allows for a cost-effective assessment of immune-phenotypes in the BM-ME and yields prognostic information in MM and its precursor stages.19,21,22 A particular hindrance to single-cell technologies is the lack of spatial resolution as they are performed on BM aspirates or PB. Although the current algorithms can predict interactions between cell populations based on the surface markers, the BM-ME architecture remains elusive. Furthermore, aspirates contain very small numbers of adherent cells, such as stromal cells, osteoblasts, and osteoclasts. Hence, to determine the structure and composition of the BM and its relationship with MM in great detail, it will be important to combine single-cell technologies with multiplex immunohistochemistry studies.23 Of note, BM-ME single-cell data are usually derived from a random BM site and might not be representative of the whole disease process. This is particularly important for MM, as the vast majority of patients present with focal lesions where genetic profiles of MM cells have been shown to be distinct from the random BM site.24,25 First reports suggest that this also holds true for the BM-ME at these sites.26,27 There is growing awareness that MM cell heterogeneity is, to at least some degree, reflected by circulating tumor cells, which are thought to originate from all affected MM sites and have prognostic impact.22 Thus, paired profiling of the BM and PB could unravel alterations that are not evident at the random BM site. A summary of the anticipated comprehensive analysis of MM and its BM-ME in the future is presented in Figure 1.Figure 1.: Summary of the anticipated future comprehensive analysis of myeloma and its microenvironment at a single-cell level.In conclusion, single-cell technologies have already influenced the MM field by identifying mechanisms underlying treatment resistance and they have the potential to further advance our current understanding of risk classification, prognostication, and individualized treatment approaches. While high costs currently limit their application, it is anticipated that technical advances and broader use will significantly reduce the costs and allow for larger sample collections. Hence, comprehensive and longitudinal profiling of the immune-ME using multiomic single-cell approaches with integration of the spatial BM architecture and genomic profiling of MM cells could soon be a reality for our MM patients and will eventually lead to improved clinical outcomes and cure. ACKNOWLEDGMENTS As a result of the space constraints, we apologize that we were unable to cite all our colleagues that have made an impact in defining our current knowledge on this topic. DISCLOSURES NW was supported by the Dietmar-Hopp Foundation. The authors declare no conflicts of interest. SOURCES OF FUNDING NW was supported by the Dietmar-Hopp Foundation.

Systematic Review of Currently Available Predictive Machine Learning Models for Multiple Myeloma

다발성 골수종은 골수에서 클론 형질 세포의 증식으로 인한 악성 혈액 질환으로 최근 우리나라에서도 발병률이 증가하고 있다. 다발성 골수종의 치료법이 발전하면서 질환의 조기 진단과 조기 치료의 필요성이 대두되었고 International Myeloma Working Group (이하 IMWG) 중심으로 질병의 진단의학적, 영상의학적 진단 기준이 여러 차례 개정되고 있다. 또한 다발성 골수종 환자의 진단과 치료 반응 평가에 전신 자기공명영상(whole body MR; 이하 WBMR)의 사용량이 증가하면서 WBMR의 영상 획득 기법이나 영상 결과 해석, 반응평가법을 표준화하기 위해 Myeloma Response Assessment and Diagnosis System (이하 MY-RADS)가 만들어졌다. 이 종설에서는 다발성 골수종의 정확한 진단을 위해 영상의학과 의사로서 알아야 할 최신 지견으로 IMWG의 최신 가이드라인에 따른 다발성 골수종의 영상검사법 및 MY-RADS에 따른 WBMR에서의 영상 획득 기법 및 반응 평가 기법에 대해 설명하였다.

Suppression of Multiple Myeloma Via Inhibition of EFNB2 Reverse Signaling

Background: Multiple myeloma (MM) is an incurable hematological malignancy characterized by a proliferation of clonal plasma cells in bone marrow. MM progresses from precursor stages, named monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM), to the symptomatic myeloma, MM. MYC abnormalities play a critical role in the disease progression. However, MYC is not therapeutically targetable due to its nuclear localization and the short half-life of the protein. Aims: To overcome this, we hypothesized that the proliferative advantage promoted by MYC overexpression induces differential genomic dependencies on other signaling pathways thus creates vulnerabilities that can be exploited therapeutically. Methods: We searched for genetic vulnerabilities associated with MYC overexpression by leveraging genome-scale pooled short hairpin RNA screening data for 236 cancer cell lines from Project Achilles. We generated an isogenic model of MYC overexpression (OE) in U266 cell line using EF1A-C-MYC lentiviral vector. Then, we performed RNA-seq, quantitative proteomics by Tandem Mass Tag mass spectrometry (TMT-MS) and a drug screening with ~2000 compounds. For validation, we performed pharmacological inhibition of glutamine catabolism as well as shRNA-mediated GLS1 knockdown. To determine the functional mechanisms, we used capillary electrophoresis-mass spectrometry (CE-MS) and Agilent Seahorse XF analyzer. Results: Achilles analysis revealed main dependencies associated with MYC overexpression on glutamine metabolism and specifically GLS1 (glutaminase) and SLC1A1 (glutamine transporter). Using a screening of 2000 small molecules, we further observed that inhibitors of NAD synthesis and mTORC1, which rely on the intracellular glutamine pool, had preferential effect on the proliferation of U266/MYC. Both RNA-seq and quantitative proteomics showed no significant upregulation of glutaminolysis related genes, suggesting a non-oncogenic dependency. Our validation tests confirmed this metabolic dependency, MYC OE cell lines failed to proliferate in the context of glutamine starvation and showed higher sensitivity to CB-839 and V-9302 inhibiting GLS1 and SLC1A5, respectively. Using the Seahorse analyzer, we measured the oxygen consumption rate (OCR) induced by glutamine. U266/MYC cells possess the ability to oxidize glutamine at a higher rate compared to U266/Ctrl. Additionally, higher sensitivity of U266/MYC to CB-839 was observed on both baseline and FCCP-induced OCR highlighting the role of glutamine in controlling mitochondrial OXPHOS in MYC OE cells. To understand the differential metabolic rewiring in MYC OE cells, we performed metabolomic analysis and observed higher GLS1 activity in U266/MYC presented by elevated glutamine to glutamate flux. We also identified the enriched metabolic pathways under GLS1 inhibition. Notably, CB-839 in U266/MYC results in more pronounced changes in TCA cycle and energy debt. This effect was blunted by the co-incubation with a-ketoglutarate, in a rescue experiment. Interestingly GLS1 inhibition was not limited to this effect, but extended to redox balance. CB839 significantly decreased glutathione level in U266/MYC. Furthermore, the intracellular concentrations of the glutamate-dependent amino acids were more depleted under GLS1 inhibition in U266/MYC compared to U266/Ctrl. Summary/Conclusion: Combining these observations, we were able to identify vulnerabilities to glutamine metabolism in MYC overexpressing cells. These results may lead to developing new therapeutic strategies to target MYC in clinical practice.

Multiple myeloma (MM) is a neoplastic disorder. It results from proliferation of clonal plasma cells in bone marrow with production of monoclonal proteins, which are detectable in serum or urine. MM is clinically characterized by destructive bone lesions, anemia, hypercalcemia and renal insufficiency. Its prognosis is severe, with a median survival after diagnosis of approximately 3 years due to frequent relapses. Treatments for patients with relapsed/refractory MM include hematopoietic cell transplantation, a rechallenge using a previous chemotherapy regimen or a trial of a new regimen. The introduction of new drugs such as thalidomide, lenalidomide and bortezomib has markedly improved MM outcomes. When relapse occurs, the clinician’s challenge is to select the optimal treatment for each patient while balancing efficacy and toxicity. Patients with indolent relapse can be first treated with a 2-drug or a 3-drug combination. Patients with more aggressive relapse often require therapy with a combination of multiple active agents. Autologous stem cell transplantation should be considered as salvage therapy at first relapse for patients who have cryopreserved stem cells early in the disease course. The aim of this review is to provide an overview on the pharmacological and molecular action of treatments used for patients with relapsed/refractory multiple myeloma.

Imaging in multiple myeloma.

Interleukin-6 Drives Multiple Myeloma Progression By up-Regulating of CD147/Emmprin Expression