Monoclonal Gammopathy Of Undermined Significance Research Articles

Recommendations for the study of monoclonal gammopathies in the clinical laboratory. A consensus of the Spanish Society of Laboratory Medicine and the Spanish Society of Hematology and Hemotherapy. Part II: Methodological and clinical recommendations for the diagnosis and follow-up of monoclonal gammopathies

Abstract Monoclonal gammopathies (MG) are a group of clinical entities characterized by the clonal expansion of monoclonal immunoglobulin (M-protein) secreting plasma cells (PC). This document presents the consensus recommendations of the Spanish Society of Laboratory Medicine (SEQCML) and the Spanish Society of Hematology and Hemotherapy (SEHH) for the study of MG. The recommendations were established based on scientific evidence and the opinion of experts in MG from the clinical laboratory and clinical hematology fields. Recommendations are proposed for the diagnosis of MG and for patient follow-up according to the type of MG and whether or not the patient is undergoing treatment, and to monitor the disease stability, response to therapy and disease progression. With respect to the diagnosis, we describe the most recent criteria and classification established by the International Myeloma Working Group (IMWG) for multiple myeloma (MM), smoldering MM, monoclonal gammopathy of undermined significance (MGUS) and other related entities. Indications are given about the analytical requirements and application of the different serum and urine laboratory tests (study, detection, identification and measurement of M-protein) and the bone marrow study. Recommendations on the clinical laboratory results report model are established to harmonize and ensure that all relevant information is available, including its content, expression, and interpretive comments.

Kappa Free Light Chain Drift Prompts the Need for a New Upper Limit of Normal Free Light Chain Ratio to Avoid an Epidemic of Kappa Light Chain Monoclonal Gammopathy of Undermined Significance.

Multiple laboratory tests are employed for detection of monoclonal proteins in patients and include serum protein electrophoresis (SPEP), immunofixation electrophoresis, free light chain (FLC) immunoassay, and mass spectrometry (Mass-Fix). Recently, reports on a drift in FLC quantitation results have been brought to light. We studied a cohort of 16 887 patients whose sera were tested for a monoclonal protein by a FLC assay, serum protein electrophoresis, and Mass-Fix. This is a retrospective study designed to assess the impact of a drift on the performance of FLC ratio (rFLC) in groups of patients with and without detectable plasma cell disorders (PCDs). The results demonstrated that 63% of patients with monoclonal protein equal or higher than 2 g/L (by SPEP) had an abnormal rFLC (reference range 0.26-1.65). Conversely, 16% of patients with undetectable monoclonal protein by other methods (i.e., SPEP and Mass-Fix) who also had no record of treated PCD had an abnormal rFLC. In these cases, there was an imbalance in the number of kappa high rFLCs to lambda low rFLCs of 201 to 1. The results of this study suggest decreased specificity of rFLC for a monoclonal kappa FLC in the 1.65 to 3.0 range.

Elevated Prothrombin Time: An unusual presentation of Monoclonal Gammopathy of Undermined Significance – A Case Report and literature review

Monoclonal Gammopathy of Undetermined Significance (MGUS) is one of the plasma cell dyscrasias. An isolated finding of a monoclonal para-protein in serum or urine is the hallmark finding in MGUS. Most often it is found incidentally during an unrelated medical evaluation and/or investigation to find a cause for neuropathy, anaemia, rashes, vasculitis or elevated Erythrocyte Sedimentation Rate (ESR). This case report illustrates an evaluation of a patient with persistently elevated prothrombin time has eventually lead to a diagnosis of MGUS.

Defining Genomic Probability of Progression to Identify Low-Risk Smoldering Multiple Myeloma

On an average, 1% of monoclonal gammopathy of undermined significance (MGUS) and 10% of smoldering Multiple Myeloma (SMM) progress to symptomatic MM every year within the first five years of diagnosis. The probability of progression significantly decreases for SMM patients after first 5 years. However, a distinct subset of SMM patients progress within 2 years and are re-classified as high-risk patients based on risk markers such as 20/2/20 or certain genomic features. Although recent studies have evaluated the high-risk genomic features for SMM but genomic background of SMM patients who do not progress to MM after long-term follow-up (>= 5 years) has not been described.Here, we evaluated transcriptomic and genomic changes enriched in non-progressor (NP) (no progression after 5 years of follow-up) precursor conditions (N=31) with those progressed within short period of time (N=71) and compared them with changes observed in newly diagnosed MM (N=192). Additionally, using transcriptome, epigenome and whole genome profiling we also studied additional unique samples from 18 patients at their precursor stage as well as when progressed to MM.Overall, we have observed significantly lower mutational load for NP SMM from progressor SMM (median SNV 4900 vs. 7881 p < 3e-04) with high sensitivity (0.83) and specificity (0.65) to separate NP from progressors. We have further developed a deep learning model by using more than 4500 genome wide features using ten-fold cross validation. This model indicated that not only the load but also the patterns of mutations (type, location, frequency) are different between two conditions. We also found that NP samples have significantly lower heterogeneity (p < 0.05). However, progressed samples showed similar mutational load and heterogeneity at precursor stage and MM. Among CNA differences, absence of gain or deletion of chr8 (not involving MYC region) were strong predictor of NP (OR=7.2 95% CI 2.2-24). Focal genomic loss was also significantly lower for NP (p=0.004) which was also reflected by low genome scar score (GSS) (p=0.07). Structural variant and copy number signature analysis also showed that NPs were showing significantly low exposure to non-clustered variable size genomic deletions. We observed similar frequency of primary translocations [t(11;14), t(4;14), and t(14;16)] in both progressor and NP samples as well as newly diagnosed MM. MYC translocation with any partner was not observed in NP samples, whereas 37% of progressor samples had a MYC translocations (OR=12.8). Adding all these differences including chr8 CNAs, MYC translocations, mutation burden, GSS, focal deletions, all driver mutations as well as primary translocations into recursive partitioning model to predict non-progressor SMM, we have identified a simple genomic model only involving chr8 CN changes and overall mutational burden to achieve a high sensitivity (0.82) and specificity (74%).Our transcriptomic analysis measured the distance between progressor and NP SMM as well as MM and found that NP SMM has greater difference with MM which is closer to progressor SMM. We quantified transcriptomic heterogeneity by using molecular degree of perturbation. This analysis showed that consistent with DNA changes, DNA repair pathway and MYC target genes are expressed similarly in NP SMM as in normal plasma cells compared to progressor SMM. Epigenomic analysis yielded 75 SEs regions differentially utilized between precursor and symptomatic MM stage using paired samples. The targeted genes included BMP6, PRDM1, STAT1, SERTAD2 and RAB21 and possibly regulating genes related to oncogenic KRAS activities.In conclusion, we define genomic characterization of non-progressor SMM and our results now provide the basis to develop molecular definition of SMM as well as risk driving features. DisclosuresMunshi: Janssen: Consultancy; Pfizer: Consultancy; Legend: Consultancy; Novartis: Consultancy; Adaptive Biotechnology: Consultancy; Oncopep: Consultancy, Current equity holder in publicly-traded company, Other: scientific founder, Patents & Royalties; Takeda: Consultancy; Abbvie: Consultancy; Karyopharm: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Bristol-Myers Squibb: Consultancy.

Does Your Smoldering Myeloma Patient Need Treatment? Evidence Based Recommendations

Introduction: The IMWG defined smoldering multiple myeloma (SMM) as presence of 10-60% plasma cells in bone marrow and M-protein (IgG, IgA) ≥3 g/dL without end organ damage (increased calcium level, renal failure, anemia, destructive bone lesions). Patients considered to have SMM should not have any myeloma defining events or amyloidosis. Risks factors classify SMM into low, intermediate, or high risk categories. Rate of progression from SMM to symptomatic myeloma is ~10% per year during the first 5 years of diagnosis. SMM requires frequent follow up, ~ every 3 months during the first 5 years compared to monoclonal gammopathy of undermined significance (MGUS) which requires follow-up every 6 to 12 months. This review presents literature and available data that support or do not support early treatment of high risk SMM and provides evidence-based recommendations for SMM management.Materials and Methods: A literature search was performed using electronic bibliographic databases: MEDLINE (Ovid SP and PubMed), EMBASE, The Cochrane Library (Cochrane Database of Systematic Reviews (CDSR), and Cochrane Central Register of Controlled Trials (CENTRAL), as well as annual meetings abstracts from inception till May 2017. The literature search focused mainly on randomized clinical trials, phase II/III, and retrospective studies. Different search terms like Smoldering Multiple Myeloma, Smoldering Myeloma, early treatment. and asymptomatic myeloma treatment were used to find the relevant material for this review article.We selected 51 articles from the literature search.Discussion: Experts in the field of myeloma have differing opinions about the management of SMM. There is growing number of data (summarized in attached table ) that provides some rationale for the early treatment of high risk SMM, supported by the logic that it has a very high rate of conversion to myeloma and, therefore, it is in the best interest of the patient to control the disease before it causes end organ damage. Early treatment of high risk SMM carries the risk of development of resistance to current therapies. There are other concerns like toxicities of currently available therapies, questionable long term effectiveness of current therapies, and cost of therapies for SMM.Patients with SMM are asymptomatic and have a good quality of life in general; therefore, subjecting an asymptomatic patient to medication related side effects and potentially impairing their quality of life should be taken into consideration before recommending treatment for high risk SMM. There is also considerable concern for patient compliance and clinical follow up, especially with parenteral therapy. Oral therapy potentially should solve this issue.Conclusion: Based on current literature review and current practices, SMM should be managed with close follow up at 3 to 6 months interval and outside a clinical trial, treatment should only be initiated if patient develops active MM or myeloma defining events(MDE), because of the risk of developing resistance to current myeloma therapies, cost, treatment related toxicities, and psychological implications for patients and their families. With more sensitive imaging such as MRI and 18F-FDG PET/CT, many patients who were previously considered high risk SMM were actual cases of myeloma meeting the IMGW 2014 criteria. SMM is a spectrum, bridging MGUS on one extreme and multiple myeloma on the other. We foresee that this entity (SMM) will disappear in the near future with the use of better diagnostic criteria, utilizing sensitive radiological testing and incorporating molecular profile based on genomics of plasma cell disorders. Patients will be either MGUS, not needing any treatment or multiple myeloma, requiring therapy. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

High Throughput Genomic Analysis Identifies Low-Risk Smoldering Multiple Myeloma

Multiple Myeloma is preceded by precursor states of monoclonal gammopathy of undermined significance (MGUS) and smoldering multiple myeloma (SMM). Studies have shown that progression to symptomatic MM five years after diagnosis is 1% for MGUS and 10% for SMM. However, based on the genomic background, this rate is highly variable, especially for SMM patients. Recent studies have evaluated the high-risk genomic features for SMM, but the genomic background of SMM patients who do not progress to MM after long-term follow-up (&amp;gt;= 5 years) has not been described. Here, we evaluated genomic changes enriched in non-progressor (NP) (no progression after 5 years of follow-up) precursor conditions (N=31) with those progressed within a short time (N=71) as well as newly diagnosed Myeloma (N=192). We also studied additional unique samples from 18 patients at their precursor stage as well as when progressed to Myeloma. We report a similar large-scale CN alteration in non-progressor SMM compared to progressor SMMs or MM at diagnosis. However, whole-genome sequencing data showed that the overall mutational load for non-progressor SMM samples was lower than Progressor MGUS/SMM (median SNV 5460 vs. 7018). This difference significantly increased for mutations affecting the coding regions. NP samples at diagnosis had 26% and 53% less coding mutations (missense, nonsense, and frameshift mutations) compared to progressor MGUS/SMM (p=0.008) and newly diagnosed MM (p &amp;lt; 0.001) respectively. We observed very low NRAS (3%, OR=8.86) and BRAF (3%, OR=2.17), mutation frequency in non-progressor SMM samples compared to newly diagnosed MM. We did not observe driver mutations in FAM46C, TTN, CYLD, TP53, KMT2C, IRF4, HIST1H1E that are otherwise frequently mutated in high-risk SMM or symptomatic MM. None of the non-progressor SMM samples had MYC alteration. We observed t(11;14), t(4;14), and t(14;16) translocations at similar frequency compared to newly diagnosed MM samples. We also observed a significant difference in non-recurrent focal deletions. Based on our recent data in newly-diagnosed MM, we quantified genomic scar score, and observed that non-progressor SMM have lower GSS (median=3,IQR=[1-9]) compared to progressor MGUS/SMM (median=11,IQR=[5-15] / median=9,IQR=[9-15], respectively) as well as MM samples at diagnosis (median=9, IQR= [5-16],p=0.002). We further validated this observation in an independent cohort with 69 SMM samples in whom progressor SMM patients had high GSS (median =4, IQR=[2-7.75]), compared to delayed progressor (&amp;gt; four years) or non-progressor SMM (median =1.5, IQR= [0-3.5]; p=0.029). Moreover, non-progressor SMM had significantly low utilization of APOBEC and DNA repair mutational processes. Next, we compared non- progressor SMM with progressor SMM using RNAseq data. We identified 1653 differentially expressed genes (DEG) (762 up-regulated and 891 down-regulated). Genes that were upregulated in non-progressor SMM samples were enriched in IL6/JAK/STAT3 and IL2/STAT5 signaling and the regulation of cytokine secretion. Whereas genes up-regulated in progressor SMM were enriched in MYC targets, DNA repair, and mTOR pathways. Moreover, genes that control the translational initiation, translational elongation, mitochondrial translation, and ATP control were among the top highly expressed genes in progressor SMM. We used our MGUS/SMM to MM paired samples and showed that the E2F target, MYC target, and G2/M checkpoint pathways are more active at MM. We measured the distance between progressor and non-progressor SMM as well as MM and found that non-progressor SMM is less similar to MM compared to progressor SMM. In conclusion, the global CNA and translocations are similar between progressor and non-progressor SMM and symptomatic MM and confirm their role in the development of precursor condition but not adequate for progression to MM, which requires additional hits. On the other hand, lower GSS score reflecting genomic stability along with lower SNVs, low DNA damage and APOBEC mutational processes, down-regulated MYC target genes, and low DNA repair activation define low-risk SMM. These results now provide the basis to develop a genomic definition of SMM. Disclosures Fulciniti: NIH: Research Funding. Parmigiani:Phaeno Biotehnologies: Current equity holder in publicly-traded company; CRA Health: Current equity holder in publicly-traded company; Foundation Medicine Institute: Consultancy; Delphi Diagnostics: Consultancy; BayesMendel Laboratory: Other: Co-lead. Munshi:Janssen: Consultancy; Adaptive: Consultancy; Legend: Consultancy; Amgen: Consultancy; AbbVie: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy; C4: Current equity holder in private company; BMS: Consultancy; OncoPep: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents &amp; Royalties.

Abstract IA39: Investigating malignant transformation in Waldenstrom's macroglobulinemia

Abstract Waldenström's macroglobulinemia (WM) is an uncommon B-cell lymphoma that corresponds to the histopathologic classification of IgM-secreting lymphomplasmacytic lymphoma. It is also a disease characterized by a series of highly recurrent mutations. Whole-genome sequencing of CD19+ bone marrow cells from patients with WM led to the discovery of a somatic heterozygous c.978T&amp;gt;C mutation in Toll-like receptor adaptor protein MYD88, resulting in a leucine-to-proline substitution p.Leu265Pro (L265P) in over 90% of WM patients. Somatic activating mutations in MYD88 induce constitutive homodimerization and downstream signaling through the nuclear factor kappa-light-chain-enhancer of activated B cells (NFKB) pathway independent of receptor activation. Other somatic events characteristic of WM include deletions in chromosome 6q21-23 and activating nonsense and/or frameshift mutations in the carboxyl-terminal tail of CXCR4, found in 40-60% and over 30% of WM patients, respectively. Both of these events are found predominantly in MYD88 mutant WM and are frequently restricted to a subclonal population. Similar to related lymphomas, WM is thought to evolve from IgM-secreting monoclonal gammopathy of undermined significance (MGUS). The MYD88 mutations are easily detectible IgM MGUS stage, suggesting that it is a very early event in clonal development but may predate the malignant transformation into WM. This theory is support by several transgenic mouse models of mutant MYD88 that have demonstrated that p.Leu265Pro MYD88 mutation in B cells alone is not sufficient for lymphomagenesis (Knittel et al., Blood 2016; Sewastianik et al., Blood Adv 2019). Mutations in CXCR4 have been detected in IgM MGUS, though at lower rates than are typical of WM. Given that this and the transcriptional profile of CXCR4 activating mutations in WM are consistent with a pattern of suppression of tumor suppressors upregulated by mutant MYD88, it has been proposed as a possible transformation event from IgM MGUS to asymptomatic WM. Likewise, a number of careful genetic studies of IgM MGUS have suggested the emergence of somatic copy number alterations, particularly the deletions in 6q, to be related to the malignant transformation of WM (Schop et al., Cancer Genet Cytogenet 2006; Paiva et al., Blood 2015). We therefore reanalyzed our whole-genome sequencing data of WM patients and performed allele-specific PCR and 6q copy number assays to study the rates and relationship of CXCR4 mutations and chromosome 6q deletions in untreated MYD88 mutated WM. Both our 30-patient whole-genome and our 25-patient PCR cohort found no relationship between symptomatic and asymptomatic WM and the somatic events, indicating that they both were occurring at an earlier stage of WM development. Both studies also found that the large clonal deletions in chromosome 6q were not observed in the presence of CXCR4 mutations (p&amp;lt;0.01 for both). Using our previous RNASeq data of 55 WM patients, we compared the transcriptional signatures for CXCR4-mutated and 6q-deleted WM relative to WM patients with the MYD88 mutation alone, revealing an overlapping signature of 19 genes. Notably, the magnitude and relative direction of the changes were similar for CXCR4-mutated and 6q-deleted WM. Impacted genes included biologically relevant targets such as FAM110C, WNK2, CDK14, FOXO3, IGF2R, and HRK. Preliminary validation studies using qPCR and immunohistochemistry have confirmed these findings. We therefore propose that CXCR4 mutations and 6q deletions are not only appearing during the transformation from MGUS to WM but target a related set of genes that may play a critical role in the pathogenesis of MYD88 mutant WM. Functional studies to further characterize these genes and evaluate their potential as therapeutic targets for WM are ongoing. Citation Format: Zachary R. Hunter, Maria Luisa Guerrera, Guang Yang, Nicholas Tsakmaklis, Xia Lu, Steven P. Treon. Investigating malignant transformation in Waldenstrom's macroglobulinemia [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr IA39.

Therapeutic Advances in the Management of Smoldering Myeloma.

The International Myeloma Working Group has defined smoldering multiple myeloma (SMM) as the presence of 10%-60% plasma cells in the bone marrow and M-protein (IgG, IgA) ≥3 g/dL without end-organ damage (an increased calcium level, renal failure, anemia, and destructive bone lesions). Patients considered to have SMM should not have any myeloma-defining events or amyloidosis. Different risks factors classify SMM into low-, intermediate-, or high-risk categories. The rate of progression from SMM to symptomatic myeloma is ∼10% per year during the first 5 years of diagnosis. SMM requires frequent follow-up ∼every 3 months during the first 5 years as compared to monoclonal gammopathy of undermined significance, which usually requires follow-up every 6-12 months after the first year of diagnosis. A literature search was performed from electronic bibliographic databases: MEDLINE (Ovid SP/PubMed), EMBASE, the Cochrane Library (Cochrane Database of Systematic Reviews), and Cochrane Central Register of Controlled Trials and from annual meeting abstracts from inception to May 2017. This review presents the literature and available data that support or do not support early treatment of high-risk SMM (HR-SMM) and provides evidence-based recommendations for management of SMM patients. Despite emerging data recommending early treatment of HR-SMM, we predict the SMM category may disappear in the near future and patients will be diagnosed with either multiple myeloma or monoclonal gammopathy of undermined significance. Success with early therapy trials for HR-SMM is largely due to patients meeting current criteria for multiple myeloma that may have been classified as SMM and, therefore, benefitted from therapy. Based on current practices and the literature, SMM should be managed with close follow-up. Based on available data, we suggest SMM to only be treated in clinical trial settings.

IgA plasma cell neoplasms are characterized by poorer long-term survival and increased genomic complexity compared to IgG neoplasms

The characteristics of the IgA plasma cell neoplasms are not clearly reported in the literature. The main goal of this study is to examine IgA plasma cell neoplasms (PCN) and to compare them to IgG lesions. After at least 5 years from the identification of an M protein, 98 cases were selected, the presentation and clinical evolution of 45 IgA neoplasms were compared to 43 cases of IgG gammopathies. The classification at presentation as monoclonal gammopathy of undermined significance (MGUS)-22 of 45 IgA and 20 of 43 IgG (49 vs 46%), plasma cell myeloma (PCM)-22 of 45 IgA and 22 of 43 IgG (49 vs 51%) and smoldering PCM (SPCM)-1 each (2% for both) was essentially identical. No solitary plasmacytomas were identified. At presentation, IgA patients were younger (66.5 ± 11.3 vs. 69.2 ± 10.7 years), less likely to have bone lesions (12/45 vs 18/43, p < 0.14) or immunoparesis (51% vs. 63%), differences statistically insignificant. Cases with normal fluorescence in-situ hybridization (FISH) results, 27% for IgA vs 61% for IgG (p < 0.037) were statistically different. The IgA patients had worse survival (80 vs 108 months median IgA vs IgG, p < 0.013), difference not detectable in the first 5 years, but substantial after 10. In conclusion, poorer long-term survival and increased genomic complexity by FISH are characteristics of IgA PCNs.

Smoldering Multiple Myeloma: To Treat or Not to Treat.

Smoldering multiple myeloma (SMM) is an asymptomatic, intermediate stage positioned between the plasma cell disorders of monoclonal gammopathy of undermined significance and overt multiple myeloma (MM). Although the patients with SMM have a higher risk of progression to MM in comparison to their counterparts with monoclonal gammopathy of undermined significance, their clinical course can be highly variable. The standard of care for SMM, irrespective of the risk status, continues to be observation due to paucity of high-level evidence demonstrating survival or quality-of-life benefit with early intervention. With the expanded 2014 criteria for MM utilizing biomarkers, the subset of SMM patients with 70% to 80% risk of progression at 2 years (ultra-high risk SMM) is now categorized as active MM and treated prior to the development of end-organ damage. After exclusion of this group, patients with approximately 50% risk of progression in 2 years are now considered high-risk SMM, and the value of early treatment in this subset can be established only through clinical trials. Despite its limitations, a recent phase III trial (QuiRedex) has shown survival advantage to using lenalidomide and dexamethasone doublet over observation in high-risk SMM. In this article, we review the evolving concepts in the diagnosis, risk stratification, and management of SMM.

Deciphering the Chronology of Copy Number Alterations in Multiple Myeloma (MM): What Comes First?

Deciphering the Chronology of Copy Number Alterations in Multiple Myeloma (MM): What Comes First?

Impact of CRAB Symptoms in Survival of Patients with Symptomatic Myeloma in Novel Agent Era.

The acronym CRAB summarizes the most typical clinical manifestations of multiple myeloma, these being hypercalcemia, renal failure, anemia, and bone disease. CRAB can be used to distinguish between active, symptomatic multiple myeloma and monoclonal gammopathy of undermined significance or smoldering myeloma. The distinction is relevant not only for classification and diagnosis but also for therapy. CRAB factors influence the prognosis of multiple myeloma. However, it is unclear whether the presence of CRAB factors has an influence on the prognosis of myeloma treated with novel agents. In the current study, patients with hypercalcemia and bone disease showed a significantly worse prognosis, whereas anemia and renal failure showed no difference in survival. Novel agents used for treatment of patients with renal failure suggested a favorable outcome compared with conventional therapy. Bone disease was the most common factor and may have the strongest prognostic value in symptomatic myeloma patients using novel agents.

How I treat smoldering multiple myeloma

AbstractSmoldering myeloma is a heterogeneous clinical entity where a subset of patients has an indolent course of disease that mimics monoclonal gammopathy of undermined significance, whereas others have a more aggressive course that has been described as “early myeloma.” It is defined as either serum M-protein ≥3 g/L or ≥10% monoclonal plasma cells in the bone marrow. There are currently no molecular factors to differentiate risks of progression for these patients. Current recommendations of therapy continue to be patient observation or patient enrollment in clinical trials. However, new definitions of active multiple myeloma recently agreed upon by the International Myeloma Working Group may alter the timing of therapy. On the basis of emerging data of therapy in these patients, it seems reasonable to believe that future recommendations for therapy of patients with smoldering myeloma will become an increasingly important topic. In this article, we review the current knowledge of this disease and risk factors associated with progression. We also examine biological insights and alterations that occur in the tumor clone and the surrounding bone marrow niche. Finally, we review clinical trials that have been performed in these patients and provide recommendations for follow-up of patients with this unique disease entity.

Co-occurrence of monoclonal gammopathy and myelodysplasia: a retrospective study of fourteen cases

We report a series of 14 patients with myelodysplastic syndrome (MDS) accompanied by a monoclonal gammopathy unrelated to therapy. Twelve of these had monoclonal gammopathy of undermined significance (MGUS) and two had smoldering multiple myeloma. These cases represent 10.2 % of all MDS cases seen at our institution over a 14-year period (January 2000 to December 2013). The incidence of MGUS was determined to be significantly higher in MDS than in age-matched concurrent controls by χ(2) test. Absence of prior chemotherapy and simultaneous presentation of MDS and MGUS in most cases suggest true co-occurrence of the two disorders. MGUS was found in all WHO subtypes of MDS with a wide range of risk factors. However, 11 out of the 12 MDS cases accompanied with MGUS had relatively low karyotypic risks. In addition, serum M protein levels remained largely unchanged in 4 cases of MGUS for which serial determinations were performed. These findings indicate that MGUS may not affect the prognosis of MDS.

Comparative miRNA Expression Profiling of Circulating Exosomes From MGUS and Smoldering Multiple Myeloma Patients

AbstractAbstract 3975 Introduction.Exosomes are small vesicles (50–100 nm) of endocytic origin, which are released in the extra-cellular milieu by several cell types. It is known that cell-to-cell communication is partially mediated by exosomes. The role of exosomes has been shown in tumor progression, due to their ability to carry and transfer microRNAs (miRNAs) to the recipient cells. In this study, we sought to examine the role of circulating exosomes in modulating transition from a monoclonal gammopathy of undermined significance (MGUS) stage to a smoldering myeloma (SMM) stage. Method.Exosomes were collected from peripheral blood obtained from healthy individuals (n=4), MGUS patients (n=4) and SMM patients (n=4), using ultracentrifugation; and further studied by using electron microscopy and immunogold labeling for the detection of CD63 and CD81. miRNA profiling has been performed using nCounter miRNA expression assay (Nanostring® Technologies, Seattle WA). Bioinformatic software tools (TargetScan, MIRDB) were used to predict the target genes of identified miRNA and define their function. Results.Circulating exosomes were studied at ultrastructural level showing positivity for CD81 and CD63, as demonstrated by immunogold labeling and electron microscopy. We identified 16 miRNAs differentially expressed in circulating exosome obtained from MGUS patients compared to healthy subjects (p < 0.05): specifically, higher expression of miR-450a, -30e, -125a, -300 and lower expression of miR-185, -150, -98 were observed in MGUS- compared to heatly individual-derived circulating exosomes. Interestingly, miR-30e and -150 are important for modulation of NK cell activity by targeting perforin and c-Myb, respectively. We furthermore compared the miRNA expression profiling between MGUS and SMM circulating exosomes; and found 11 miRNAs differentially expressed (p < 0.05). Specifically, higher expression of miR-107 and lower expression of miR-28, -32, -548a, -939, -99a, -345, -125a, -587, -323b and -92a were observed in SMM- compared to MGUS-derived circulating exosomes. Among the de-regulated miRNAs, miR-99a, -345, -92a and -28 are known to act as tumor suppressors in prior publications. Moreover, predicted targets for miR-107 include genes involved in molding the bone marrow microenvironment. Indeed, miR-107 is known to decrease hypoxia-inducible factor-1 β (HIF-1β), miR-125a correlated with the expression level of matrix metalloproteinase 11 (MMP11), and vascular endothelial growth factor A (VEGF-A) and miR-548a regulates the expression of MMP2. Conclusion.These findings indicate that circulating exosomes differ between normal, MGUS and SMM patients, and could potentially be involved in modulating the host microenvironment for specific homing of clonal plasma cells to the bone marrow; thus providing a better understanding of the epigenetic changes responsible for the transition from an MGUS stage to a SMM stage. Disclosures:Ghobrial:Millennium: Advisory Board Other; Novartis: Advisory Board, Advisory Board Other.

Bortezomib combined with thalidomide and dexamethasone is effective for patient with crystal‐storing histiocytosis associated with monoclonal gammopathy of undermined significance

European Journal of HaematologyVolume 89, Issue 2 p. 183-184 Letter to the Editor Bortezomib combined with thalidomide and dexamethasone is effective for patient with crystal-storing histiocytosis associated with monoclonal gammopathy of undermined significance Xiaoxia Hu, Xiaoxia Hu Department of Hematology, Changhai Hospital, Shanghai, ChinaSearch for more papers by this authorJiaxiang Liu, Jiaxiang Liu Department of Hematology, Changhai Hospital, Shanghai, ChinaSearch for more papers by this authorChenguang Bai, Chenguang Bai Department of Pathology, Changhai Hospital, Shanghai, ChinaSearch for more papers by this authorJianmin Wang, Jianmin Wang Department of Hematology, Changhai Hospital, Shanghai, ChinaSearch for more papers by this authorXianmin Song, Corresponding Author Xianmin Song Department of Hematology, Changhai Hospital, Shanghai, ChinaCorrespondence Xianmin Song, MD, Department of Hematology, Changhai Hospital, 168 Changhai Road, Shanghai 200433, China. Tel: 86-21-8187-3223; Fax: 86-21-8187-3223l; e-mail: [email protected]Search for more papers by this author Xiaoxia Hu, Xiaoxia Hu Department of Hematology, Changhai Hospital, Shanghai, ChinaSearch for more papers by this authorJiaxiang Liu, Jiaxiang Liu Department of Hematology, Changhai Hospital, Shanghai, ChinaSearch for more papers by this authorChenguang Bai, Chenguang Bai Department of Pathology, Changhai Hospital, Shanghai, ChinaSearch for more papers by this authorJianmin Wang, Jianmin Wang Department of Hematology, Changhai Hospital, Shanghai, ChinaSearch for more papers by this authorXianmin Song, Corresponding Author Xianmin Song Department of Hematology, Changhai Hospital, Shanghai, ChinaCorrespondence Xianmin Song, MD, Department of Hematology, Changhai Hospital, 168 Changhai Road, Shanghai 200433, China. Tel: 86-21-8187-3223; Fax: 86-21-8187-3223l; e-mail: [email protected]Search for more papers by this author First published: 09 May 2012 https://doi.org/10.1111/j.1600-0609.2012.01800.xCitations: 8Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article.Citing Literature Volume89, Issue2August 2012Pages 183-184 RelatedInformation

Plasma Mir-92a Levels in Multiple Myeloma Correlate with T-Cell-Derived Mir-92a and Restored in Bortezomib Responder

Abstract 2871 Background and Aim:The oncomir micro-RNA (miR) 17–92a, especially miR-92a, is highly expressed in multiple myeloma (MM) and possibly affects neoplastic proliferation resulting from inhibition of apoptotic effect of BIM. Recent studies have demonstrated that circulating miRNAs can be detected in the plasma and serum of healthy subjects and cancer patients. Therefore, circulating miRNAs are thought to be possible diagnostic or prognostic biomarkers in human diseases. In order to gain more insight into biological and clinical relevance of plasma miR-92a expression, we sought to evaluate plasma miR-92a levels in MM patients at various phases and related disorders. Experimental design:We evaluated peripheral blood obtained from 168 patients with monoclonal gammopathies; 138 patients with symptomatic MM, 8 smoldering MM (SMM), and 22 monoclonal gammopathy of undermined significance (MGUS). The plasma miR-92a expression was measured by Q-RTPCR, and normalized to miR-638 expression, as reported previously (Ohyashiki K, et al. PloS ONE, 2011 6(2) :e16408). The CD4+ or CD8+ T-cell fractions were separated with an isolation kit for humans (Miltenyi Biotec, Bergisch Gladbach, Germany) and AutoMACS Pro Separator (Miltenyi Biotec), according to the supplier's instruction. Cellular miR-92a expression level was also determined as reported previously (Ohyashiki JH, et al. BMC Res Notes, 2010, 3 :347). Results and Discussion:MiR-17-92a clusters (miR-19b, miR-17, miR-92a, miR-20a, and miR-19a) were significantly decreased in plasma samples obtained from MM patients. The plasma miR-92a level in symptomatic MM patients was significantly down-regulated compared with normal subjects (P < 0.0001), regardless of immunoglobulin subtypes or disease stage at diagnosis. Patients in complete remission (CR: n = 8) had a significant increase in plasma miR-92a compared with those at diagnosis (P < 0.0001), and 7 of 8 patients were normalized (≥ 0.2593 cut-off level).By contrast, cellular miR-92a in circulating CD8+ cells (P = 0.0004) or CD4+ cells (P = 0.0013) from MM patients significantly decreased compared with normal subjects, and the patients' values tended to correlate with plasma miR-92a levels. The plasma miR-92a level in complete remission group became normalized, whereas the partial response and very good partial response groups did not reach to the normal range. Of particular interest is that some MM bortezomib-responder patients and non-responders sustained low levels of plasma miR-92a level after short-courses of the therapy, and then the plasma miR-92a levels up-regulated at 8 or more injections in the responder group. Therefore, the down-regulated plasma miR-92a level elevated after bortezomib therapy in therapy responders but not in non-responders. Our observation suggests that measurement of the plasma miR-92a level in MM patients is a useful indicator for monitoring therapeutic response, and the level may represent, in part, the T-cell immunity status of patients with MM. Disclosures:No relevant conflicts of interest to declare.

Respiratory failure with diffuse bronchiectases and cryoglobulinaemia

A 48-yr-old nonsmoking female presented with a 5-yr history of recurrent bronchitis with progressive exercise dyspnoea. She had been diagnosed with a small monoclonal gammopathy of undermined significance (MGUS) 6 yrs previously. Inspiratory vital capacity was 4.7 L (125% predicted) and forced expiratory volume in one second/forced vital capacity (FVC) ratio was 79%. Carbon monoxide transfer factor was markedly impaired (35% pred), and arterial oxygen tension ( P a,O2) decreased from 9.2 to 6.0 kPa at exercise (40 W, 10 min). A thoracic computed tomography (CT) scan was performed (fig. 1⇓). Fibreoptic bronchoscopy found inflammation of the bronchial mucosa with candle stain-like deposits on the trachea and large bronchi, without any purulent secretion within the respiratory tract (fig. 2⇓). The histopathological aspect of bronchial biopsies is shown in figure 3⇓. Blood tests disclosed type I cryoglobulinaemia composed of a 32 g·L−1 monoclonal immunoglobulin (Ig)Mκ serum component (at 37°C). Blood cell count was normal. Bone marrow examination showed malignant lymphoplasmacytic cells representing 30% of total cells, with a monotypic surface expression of IgMκ. The C-reactive protein level was 21 mg·L−1. Extensive renal, cardiac and hepatic evaluations were normal. As severe hypoxaemia and reduction of carbon monoxide transfer factor were unexplained, the patient underwent videothoracoscopic lung biopsies. Fig. 1— Thoracic computed tomography scan. Fig. 2— Fibreoptic bronchoscopy. Arrow shows candle stain-like deposits. Fig. 3— a) Bronchial biopsy of candle-stain like lesions stained by haematoxylin-eosin-saffron. Submucosal abnormal deposits with concentric pattern around the vessels (black arrow), arranging in cords or ribbon-like structures in the interstitium (black dashed arrow) or in an organoid, raspberry-like fashion in smooth muscle fascicles (black arrowhead). b) Bronchial biopsy; perivascular deposits with negative Congo red dye staining. c) Direct anti-κ-light chain immunofluorescence in bronchial biopsy showing positivity of perivascular (white arrow) and interstitial (white dashed arrow) deposits, and epithelial …

Roles of CD19 Molecules That Suppress Proliferation and Induce Apoptosis in Human Myeloma Cells.

CD19 is a B cell-specific membrane protein belonging to immunoglobulin superfamily, and acts as a positive or negative regulator in B cell signaling. Although plasma cells still express CD19, CD19 expression is lost in malignant plasma cells with the progression of multiple myeloma (MM) including monoclonal gammopathy of undermined significance (MGUS). To understand the pathological significance of loss of CD19 in human myelomas, we examined the biological effect of CD19 expression on myeloma cells by generating CD19 transfectants of a myeloma cell line, U266. CD19 transfectants showed slower growth rate in vitro than controls, such as mock and ΔCD19 transected with a truncated form of CD19. The growth-inhibitory effect was CD19-specific and presumably due to the intracellular signaling events via CD19 because this effect was not observed in ΔCD19. Furthermore, serum withdrawal rapidly induced the apoptosis of the CD19-transfectants that was rescued by insulin-like growth factor (IGF-I) as compared with CD19− controls. These may suggest that the CD19 transfectants are likely to be dependent on the growth factors, such as IGF-I, to survive and proliferate, and thus, susceptible to the serum deprivation-induced apoptosis. IGF-I activates extracellular signal-regulated kinase (ERK) 1/2 and phosphatidylinositol-3-kinase (PI-3K) that are important for proliferation of myeloma cells. Western bolt analysis showed that IGF-1-induced activation of ERK1/2 was reduced in the CD19 transfectants, although the similar levels of IGF-I receptors were expressed in the CD19 transfectants and CD19− controls. In contract, CD19 failed to inhibit the IGF-I-mediated PI-3K/AKT activation, whereas a downstream target in the PI-3K pathway, p70S6 kinase activation was decreased in the CD19 transfectants. However, the p70S6 kinase activity could be influenced by both ERK1/2 and PI-3K pathways after IGF-1 stimulation, and the MAPK pathway seems to be a major regulator for myeloma cell growth. Our results, therefore, suggest that the recovering expression of CD19 molecules and genes in human myeloma cells may be an important consideration in therapeutic approaches in human MM.