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Background/Objectives: Monoclonal gammopathies, such as Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering Multiple Myeloma (SMM), are conditions marked by the overproduction of specific monoclonal proteins. Patients with these conditions are known to have a higher risk of fractures compared to the general population, yet there are no established guidelines for assessing or managing their skeletal health. The Trabecular Bone Score (TBS), which can be calculated from DXA images of the lumbar spine, provides additional insights into bone microarchitecture. Methods: This study aimed to determine whether TBS can serve as a supplementary tool in assessing bone loss in MGUS and SMM patients. Conducted from 2020 to 2023, the study involved 148 participants—74 diagnosed with a myeloma precursor state and 74 healthy controls—who underwent simultaneous DXA and TBS measurements. Results: The results indicated a weak positive correlation (R = 0.405) between DXA and TBS T-scores, suggesting that other factors may influence the measurements. When analyzed separately, the correlations remained weak for both MGUS (R = 0.250) and SMM (R = 0.485). Interestingly, discrepancies were noted in T-score classifications; for instance, a patient classified as normal via DXA could be deemed osteopenic or osteoporotic with TBS. Conclusions: Overall, the findings suggest that incorporating TBS alongside DXA can enhance the accuracy of bone density assessments, facilitating earlier diagnosis and treatment initiation for osteoporosis in asymptomatic patients with monoclonal gammopathies. [ABSTRACT FROM AUTHOR]

Monoclonal antibodies (MoAbs) targeting several cellular receptors have significantly improved the prognosis of multiple myeloma (MM). Their high effectiveness and safety raise the question of whether earlier therapeutic intervention in monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) influences the natural course of the disease. MM is preceded by clinically recognized conditions such as MGUS and SMM. Numerous studies are investigating the disease biology and immune profile of SMM and MGUS to unravel the intricate relationship between immunosurveillance and disease progression. The standard approach to MGUS and SMM remains close observation. Early studies indicate benefits in terms of progression or even survival for promptly treating high-risk SMM patients. Ongoing debates are focused on which patients with SMM and MGUS to treat, as well as on determining the optimal therapeutic approach. The first approach aims to cure by attempting to eliminate the pathological clone, while the second approach is preventive, aiming to manage disease progression to active MM and restore the immune system. In this review, we focus on the available and emerging data on early treatment, particularly with MoAbs alone or in combination with other therapies, in SMM and MGUS patients. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a cancer of plasma cells. Normal (NL) cells are considered to pass through a precancerous state, such as monoclonal gammopathy of undetermined significance (MGUS), before transitioning to MM. In the present study, we acquired Raman spectra at three stages—834 NL, 711 MGUS, and 970 MM spectra—and applied the dynamical network biomarker (DNB) theory to these spectra. The DNB analysis identified MGUS as the unstable pre-disease state of MM and extracted Raman shifts at 1149 and 1527–1530 cm − 1 as DNB variables. The distribution of DNB scores for each patient showed a significant difference between the mean values for MGUS and MM patients. Furthermore, an energy landscape (EL) analysis showed that the NL and MM stages were likely to become stable states. Raman spectroscopy, the DNB theory, and, complementarily, the EL analysis will be applicable to the identification of the pre-disease state in clinical samples. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is an incurable hematological cancer. It is preceded by monoclonal gammopathy of uncertain significance (MGUS)—an asymptomatic phase. It has been demonstrated that early detection increases the 5-year survival rate. However, blood-based biomarkers that enable early disease detection are lacking. Metabolomic and lipoprotein subfraction variable profiling is gaining traction to expand our understanding of disease states and, more specifically, for identifying diagnostic markers in patients with hematological cancers. This study aims to enhance our understanding of multiple myeloma (MM) and identify candidate metabolites, allowing for a more effective preventative treatment. Serum was collected from 25 healthy controls, 20 patients with MGUS, and 30 patients with MM. 1H-NMR (Nuclear Magnetic Resonance) spectroscopy was utilized to evaluate serum samples. The metabolite concentrations were examined using multivariate, univariate, and pathway analysis. Metabolic profiles of the MGUS patients revealed lower levels of alanine, lysine, leucine but higher levels of formic acid when compared to controls. However, metabolic profiling of MM patients, compared to controls, exhibited decreased levels of total Apolipoprotein-A1, HDL-4 Apolipoprotein-A1, HDL-4 Apolipoprotein-A2, HDL Free Cholesterol, HDL-3 Cholesterol and HDL-4 Cholesterol. Lastly, metabolic comparison between MGUS to MM patients primarily indicated alterations in lipoproteins levels: Total Cholesterol, HDL Cholesterol, HDL Free Cholesterol, Total Apolipoprotein-A1, HDL Apolipoprotein-A1, HDL-4 Apolipoprotein-A1 and HDL-4 Phospholipids. This study provides novel insights into the serum metabolic and lipoprotein subfraction changes in patients as they progress from a healthy state to MGUS to MM, which may allow for earlier clinical detection and treatment. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a hematologic malignancy with a multistep evolutionary pattern, in which the pro-inflammatory and immunosuppressive microenvironment and genomic instability drive tumor evolution. MM microenvironment is rich in iron, released by pro-inflammatory cells from ferritin macromolecules, which contributes to ROS production and cellular damage. In this study, we showed that ferritin increases from indolent to active gammopathies and that patients with low serum ferritin had longer first line PFS (42.6 vs. 20.7 months and, p = 0.047, respectively) and OS (NR vs. 75.1 months and p = 0.029, respectively). Moreover, ferritin levels correlated with systemic inflammation markers and with the presence of a specific bone marrow cell microenvironment (including increased MM cell infiltration). Finally, we verified by bioinformatic approaches in large transcriptomic and single cell datasets that a gene expression signature associated with ferritin biosynthesis correlated with worse outcome, MM cell proliferation, and specific immune cell profiles. Overall, we provide evidence of the role of ferritin as a predictive/prognostic factor in MM, setting the stage for future translational studies investigating ferritin and iron chelation as new targets for improving MM patient outcome. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is an incurable hematologic malignancy characterized by a multistep evolutionary pathway, with an initial phase called monoclonal gammopathy of undetermined significance (MGUS), potentially evolving into the symptomatic disease, often preceded by an intermediate phase called “smoldering” MM (sMM). From a biological point of view, genomic alterations (translocations/deletions/mutations) are already present at the MGUS phase, thus rendering their role in disease evolution questionable. On the other hand, we currently know that changes in the bone marrow microenvironment (TME) could play a key role in MM evolution through a progressive shift towards a pro-inflammatory and immunosuppressive shape, which may drive cancer progression as well as clonal plasma cells migration, proliferation, survival, and drug resistance. Along this line, the major advancement in MM patients’ survival has been achieved by the introduction of microenvironment-oriented drugs (including immunomodulatory drugs and monoclonal antibodies). In this review, we summarized the role of the different components of the TME in MM evolution from MGUS as well as potential novel therapeutic targets/opportunities. [ABSTRACT FROM AUTHOR]

Simple Summary: It is being increasingly recognized that patients with monoclonal gammopathy (MG) who do not meet criteria for malignant disease and treatment initiation may have other manifestations that are linked to the unique properties of the monoclonal protein that are clinically significant and could provide a rationale for treatment. It has been recognized that patients with MG are at higher risk for thrombosis and a number of rare entities that include venous, arterial and micro-thrombotic events have been described. The hemostatic profile of patients with MG has not been ascertained yet and the major challenge is to identify patients with MG at high risk for thrombotic events and apply appropriate preventive measures. We propose a new umbrella term, monoclonal gammopathy of thrombotic significance, that creates a link between the M-protein and thrombotic events, posing the question of whether treatment initiation and/or long term anticoagulation is indicated for these, otherwise asymptomatic patients. The current review provides an overview of the thrombotic risk observed in patients with MG who do not otherwise require treatment. We discuss clinical and biomarker studies that highlight the heterogenous hemostatic profile observed in these patients and how knowledge has evolved over the past 20 years. Biomarker studies suggest shared biologic features between multiple myeloma and monoclonal gammopathy of undetermined significance (MGUS), which involves both hypercoagulability and platelet activation. Hemostatic abnormalities identified in MGUS patients cannot be translated into clinical practice as they lack correlation to clinical events. The prothrombotic phenotype of MGUS patients has not been ascertained yet, but novel data on coagulation markers are promising. We also review rare conditions associated with the thrombogenic properties of the monoclonal protein that predispose to arterial, venous or microthrombotic events and demonstrate that the M-protein can be linked to clinically significant thrombotic events. Cryoglobulinemia, cryofibrinogenemia, cryo-crystaloglobulinemia and MG-related antiphospholipid syndrome are reviewed. We propose the new umbrella term "monoclonal gammopathy of thrombotic significance" (MGTS) to refer to significant, recurrent thrombotic events in patients with MGUS that provide a rationale for targeting the underlying plasma cell clone. Identifying MGUS patients at high risk for thrombotic events is currently a challenge. [ABSTRACT FROM AUTHOR]

Simple Summary: This review highlights the potential of differential scanning calorimetry for multiple myeloma diagnosis and monitoring of the treatment outcome. The thermodynamic signatures of blood sera from patients with multiple myeloma are strongly dependent on the concentration and isotype of the secreted monoclonal immunoglobulins. Mathematical methods developed to analyze the biocalorimetry data and distinguish "diseased" from "healthy" thermogram to stratify plasma calorimetric profiles and determine specific interrelations between calorimetric and biochemical/clinical data are discussed. This review summarizes data obtained thus far on the application of differential scanning calorimetry (DSC) for the analysis of blood sera from patients diagnosed with multiple myeloma (MM) with the secretion of the most common isotypes of monoclonal proteins (M-proteins), free light chains (FLC) and non-secretory MM, as well as Waldenström macroglobulinemia and the premalignant state monoclonal gammopathy of undetermined significance. The heterogeneous nature of MM is reflected in the thermal stability profiles of the blood serum proteome of MM patients found to depend on both the level and the isotype of the secreted M-proteins or FLC. Common calorimetric markers feature the vast majority of the different myeloma types, i.e., stabilization of the major serum proteins and decrease in the albumin/globulin heat capacity ratio. A unique calorimetric fingerprint of FLC molecules forming amorphous aggregates is the low-temperature transition centered at 57 °C for a calorimetric set of FLC MM and at 46–47 °C for a single FLC MM case for which larger aggregates were formed. The calorimetric assay proved particularly advantageous for non-secretory MM and is thus a suitable tool for monitoring such patients during treatment courses. Thus, DSC provides a promising blood-based approach as a complementary tool for MM detection and monitoring. [ABSTRACT FROM AUTHOR]

Gaucher disease (GD, OMIM 230800) is one of the most common lysosomal disorders, being caused by the deficient activity of the enzyme acid β-glucocerebrosidase (Gcase). Three clinical forms of Gaucher's disease (GD) are classified based on neurological involvement. Type 1 (GD1) is non-neuronopathic, while types 2 (GD2) and 3 (GD3) are neuronopathic forms. Gcase catalyzes the conversion of glucosylceramide (GlcCer) into ceramide and glucose. As GlcCer accumulates in lysosomal macrophages, it undergoes deacylation to become glycosylsphingosine (lyso-Gb1), which has shown to be a useful and reliable biomarker for the diagnosis and monitoring of treated and untreated patients with GD. Multiple myeloma (MM) is one of the leading causes of cancer-related death among patients with GD and monoclonal gammopathy of undetermined significance (MGUS) is a non-neoplastic condition that can be a telltale sign of a B clonal proliferation caused by the chronic activation of B cells. This study aimed to quantify Lyso-Gb1 levels in dried blood spots (DBS) and cerebrospinal fluid (CSF) as biomarkers for Gaucher disease (GD) and discuss the association of this biomarker with other clinical parameters. This is a mixed-methods study incorporating both cross-sectional and longitudinal elements within a cohort design with a convenience-sampling strategy. Data collection took place from January 2012 to March 2023. Lyso-Gb1 extraction from DBS involved the use of a methanol-acetonitrile-water mixture, followed by incubation and centrifugation. Analysis was performed using UPLC-MS/MS with MassLynx software version 4.2 and the control group for the DBS measurements included general newborns. CSF Lyso-Gb1 was extracted using ethyl acetate, analyzed by UPLC-MS/MS with a calibration curve, and expressed in pmol/L. Lysosomal activity in CSF was assessed by measuring chitotriosidase (Cht), and other lysosomal enzyme activities were assessed as previously described in the literature. Patients with metachromatic leukodystrophy (MLD) were used as controls. Thirty-two treated patients (twenty-nine GD1 and three GD3, all on ERT except for one GD type on SRT with eliglustat) and three untreated patients (one GD1, one GD2, and one GD3) were included. When analyzing only the treated GD1 group, a significant correlation was found between lyso-Gb1 and age (rho = -0.447, p = 0.001), ChT, and IgG levels (rho = 0.73, p < 0.001; and rho = 0.36, p = 0.03, respectively). Five GD1 patients (three females, mean age 40 years) also had their CSF collected and analyzed. The average measurement of lyso-Gb1 in CSF was 94 pmol/L (range: 57.1-157.9 pmol/L) versus <6.2 pmol/L in the control group (MLD). This is the first time, to the best of our knowledge, that lyso-Gb1 has been associated with IgG levels. While this finding reflects a risk for MGUS or MM and not only chronic plasma B-cell activation, it still requires further studies. Moreover, the analysis of CSF lyso-Gb1 levels in GD1 patients was demonstrated to be significantly higher than the control group. This raises the hypothesis that CSF lyso-Gb1 may serve as a valuable indicator for neurological involvement in GD, providing insights into the potential implications for neurological manifestations in GD, including GD1. The correlation between lyso-Gb1 and ChT levels in treated GD1 patients further underscores the interconnectedness of lysosomal markers and their relevance in monitoring.

The Lymphocyte-Activation Protein 3 (LAG-3) inhibitory receptor is expressed on regulatory plasma cells (PCs). Micro-environmental cells that express LAG-3 were found to be increased during the progression of smoldering multiple myeloma (SMM). To assess the possible role of LAG-3 expression on regulatory PCs in patients with plasma cell dyscrasia. Purified Cluster of Differentiation 138 (CD138 +) PCs from patients with premalignant conditions, active multiple myeloma (MM), and controls were analyzed for the expression of LAG-3 by flow cytometry. Autologous CD8 + T cells were incubated with sorted LAG-3 pos or LAG-3 neg PCs for 24 h. The expression of granzyme (Grz) in CD8 + T cells was assessed by flow cytometry. LAG-3 expression on PCs in active MM (newly diagnosed and relapse refractory MM) was significantly increased compared to monoclonal gammopathy of undetermined significance (MGUS)/ SMM. Grz expression was significantly decreased in CD8 + T cells incubated with CD138 + LAG-3 pos PCs, compared to CD138 + LAG-3 neg PCs in patients with plasma cell dyscrasia, n = 31, p = 0.0041. LAG-3 expression on malignant PCs can be involved in the development of MM from MGUS by decreasing the expression of Grz in CD8 + T cells.

A 66 years old Caucasian woman with pneumococcal meningitis was treated and discharged after an uncomplicated course. Five months later she was readmitted with fever and right side abdominal pain and diagnosed with pneumococcal spondylodiscitis. One year later she was treated for a severe chest X-ray confirmed left lobar pneumonia. Two years later she was diagnosed with a pneumococcal pneumonia in her left lung with septic shock. An immune deficiency screen revealed slightly reduced IgA levels, low IgG2 levels, low IgG3 levels and high IgG1 levels. No other immune defects were identified. She did not respond serologically on vaccination with 13-valent conjugate and 23-valent polysaccharide pneumococcal vaccines. Further evaluations revealed a positive M-component in her blood and a bone marrow biopsy diagnosed her to have monoclonal gammopathy of undetermined significance. To protect her against future life threatening pneumococcal infections she was started on treatment with intravenous immunoglobulin. The case report illustrates the importance of thorough evaluation of patients with unusual infectious disease entities or unusual frequency of infections in individual patients. To optimize prophylactic measures and active treatment options in the individual patient, it is important to identify underlying causes of diseases and immune deficiencies that potentially can lead to life threatening infections. This is illustrated in our case by an undiagnosed monoclonal gammopathy of undetermined significance in an apparently healthy woman with at least three life threatening documented pneumococcal infections in a two-year period and poor pneumococcal vaccine response. [ABSTRACT FROM AUTHOR]

Simple Summary: Multiple myeloma (MM), characterized by the expansion of plasma cells in the bone marrow, is the second most common hematological malignancy. This incurable cancer is consistently preceded by non-malignant asymptomatic precursor conditions known as monoclonal gammopathy of undetermined significance (MGUS) and/or smoldering multiple myeloma (SMM). These pre-stages are relatively frequent, but only a select percentage of them will progress to MM. However, it is still not possible to individually predict when and which patients will develop MM. Therefore, this study aimed to investigate the mutational profile in the progression in serial bone marrow samples with a custom targeted sequencing panel, designed to detect variants in myeloma-related genes. Remarkably, almost all variants identified in the MM samples were also already present in the pre-stages, sometimes even many years before the progression. These results provide new important insights into the molecular mechanisms of the precursor conditions and progression to MM. Multiple myeloma (MM), or Kahler's disease, is an incurable plasma cell (PC) cancer in the bone marrow (BM). This malignancy is preceded by one or more asymptomatic precursor conditions, monoclonal gammopathy of undetermined significance (MGUS) and/or smoldering multiple myeloma (SMM). The molecular mechanisms and exact cause of this progression are still not completely understood. In this study, the mutational profile underlying the progression from low–intermediate risk myeloma precursor conditions to MM was studied in serial BM smears. A custom capture-based sequencing platform was developed, including 81 myeloma-related genes. The clonal evolution of single nucleotide variants and short insertions and deletions was studied in serial BM smears from 21 progressed precursor patients with a median time of progression of six years. From the 21 patients, four patients had no variation in one of the 81 studied genes. Interestingly, in 16 of the 17 other patients, at least one variant present in MM was also detected in its precursor BM, even years before progression. Here, the variants were present in the pre-stage at a median of 62 months before progression to MM. Studying these paired BM samples contributes to the knowledge of the evolutionary genetic landscape and provides additional insight into the mutational behavior of mutant clones over time throughout progression. [ABSTRACT FROM AUTHOR]

Simple Summary: Multiple myeloma (MM) is the second most common haematologic malignancy, and it remains an incurable disease despite the advances of novel therapies. It is characterised by a multistep process that arises from a pre-malignant asymptomatic status-defined monoclonal gammopathy of undetermined significance (MGUS), evolves to a middle stage named smouldering myeloma phase (SMM), and culminates in the active disease (MM). Identification of early and non-invasive markers of the disease progression is currently an active field of investigation. In this review, we discuss the role and significance of microRNAs (miRNAs) as potential diagnostic biomarkers to predict the clinical transition from MGUS/SMM status to MM. Multiple myeloma (MM) is a hematological malignancy characterised by proliferation of clonal plasma cells (PCs) within the bone marrow (BM). Myelomagenesis is a multi-step process which goes from an asymptomatic phase, defined as monoclonal gammopathy of undetermined significance (MGUS), to a smouldering myeloma (SMM) stage, to a final active MM disease, characterised by hypercalcemia, renal failure, bone lesions anemia, and higher risk of infections. Overall, microRNAs (miRNAs) have shown to significantly impact on MM tumorigenesis, as a result of miRNA-dependent modulation of genes involved in pathways known to be crucial for MM pathogenesis and disease progression. We aim to revise the literature related to the role of miRNAs as potential diagnostic and prognostic biomarkers, thus highlighting their key role as novel players within the field of MM and related premalignant conditions. [ABSTRACT FROM AUTHOR]

Simple Summary: Multiple myeloma (MM) remains an incurable blood cancer. One of the current challenges in patient management is the risk assessment and subsequent treatment management for each patient with MM. Patients with an identical diagnosis may present very different disease courses and outcomes. This challenge of MM is a current focus of the scientific and medical communities. In our research, we have used an imaging approach to determine the risk of MM patients to progressive/aggressive disease. Using three-dimensional (3D) imaging of telomeres, the ends of chromosomes, we report that specific telomeric profiles are associated with aggressive disease. The prognosis of multiple myeloma (MM), an incurable B-cell malignancy, has significantly improved through the introduction of novel therapeutic modalities. Myeloma prognosis is essentially determined by cytogenetics, both at diagnosis and at disease progression. However, for a large cohort of patients, cytogenetic analysis is not always available. In addition, myeloma patients with favorable cytogenetics can display an aggressive clinical course. Therefore, it is necessary to develop additional prognostic and predictive markers for this disease to allow for patient risk stratification and personalized clinical decision-making. Genomic instability is a prominent characteristic in MM, and we have previously shown that the three-dimensional (3D) nuclear organization of telomeres is a marker of both genomic instability and genetic heterogeneity in myeloma. In this study, we compared in a longitudinal prospective study blindly the 3D telomeric profiles from bone marrow samples of 214 initially treatment-naïve patients with either monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), or MM, with a minimum follow-up of 5 years. Here, we report distinctive 3D telomeric profiles correlating with disease aggressiveness and patient response to treatment in MM patients, and also distinctive 3D telomeric profiles for disease progression in smoldering multiple myeloma patients. In particular, lower average intensity (telomere length, below 13,500 arbitrary units) and increased number of telomere aggregates are associated with shorter survival and could be used as a prognostic factor to identify high-risk SMM and MM patients. [ABSTRACT FROM AUTHOR]

Cancer dissemination and distant metastasis most frequently require the release of tumor cells into the blood circulation, both in solid tumors and most hematological malignancies, including plasma cell neoplasms. However, detection of blood circulating tumor cells in solid tumors and some hematological malignancies, such as the majority of mature/peripheral B-cell lymphomas and monoclonal gammopathies, has long been a challenge due to their very low frequency. In recent years, the availability of highly-sensitive and standardized methods for the detection of circulating tumor plasma cells (CTPC) in monoclonal gammopathies, e.g., next-generation flow cytometry (NGF), demonstrated the systematic presence of CTPC in blood in virtually every smoldering (SMM) and symptomatic multiple myeloma (MM) patient studied at diagnosis, and in the majority of patients with newly-diagnosed monoclonal gammopathies of undetermined significance (MGUS). These methods set the basis for further detailed characterization of CTPC vs. their bone marrow counterpart in monoclonal gammopathies, to investigate their role in the biology of the disease, and to confirm their strong impact on patient outcome when measured both at diagnosis and after initiating therapy. Here, we review the currently available techniques for the detection of CTPC, and determine their biological features, physiopathological role and clinical significance in patients diagnosed with distinct diagnostic categories of plasma cell neoplasms. [ABSTRACT FROM AUTHOR]

Both multiple myeloma (MM) and its precursor state of monoclonal gammopathy of undetermined significance (MGUS) are characterized by an infiltration of plasma cells into the bone marrow, but the mechanisms underlying the disease progression remain poorly understood. Previous research has indicated that 3D nuclear telomeric and centromeric organization may represent important structural indicators for numerous malignancies. Here we corroborate with previously noted differences in the 3D telomeric architecture and report that modifications in the nuclear distribution of centromeres may serve as a novel structural marker with potential to distinguish MM from MGUS. Our findings improve the current characterization of the two disease stages, providing two structural indicators that may become altered in the progression of MGUS to MM. [ABSTRACT FROM AUTHOR]

Almost all multiple myeloma (MM) cases have been demonstrated to be linked to earlier monoclonal gammopathy of undetermined significance (MGUS). Nevertheless, there are no identified characteristics in the diagnosis of MGUS that have been helpful in differentiating subjects whose cancer may progress to a malignant situation. Regarding malignancy, the role of lymphocyte subsets and cytokines at the beginning of neoplastic diseases is now incontestable. In this review, we have concentrated our attention on the equilibrium between the diverse lymphocyte subsets and the cytokine system and summarized the current state of knowledge, providing an overview of the condition of the entire system in MGUS and MM. In an age where the therapy of neoplastic monoclonal gammopathies largely relies on drugs capable of acting on the immune system (immunomodulants, immunological checkpoint inhibitors, CAR-T), detailed knowledge of the the differences existing in benign and neoplastic forms of gammopathy is the main foundation for the adequate and optimal use of new drugs. [ABSTRACT FROM AUTHOR]

Multiple myeloma is an invariably fatal cancer of plasma cells. Despite tremendous advances in treatment, this malignancy remains incurable in most individuals. We postulate that strategies aimed at prevention have the potential to be more effective in preventing myeloma-related death than additional pharmaceutical strategies aimed at treating advanced disease. Here, we present a rationale for the development of prevention therapy and highlight potential target areas of study. [ABSTRACT FROM AUTHOR]