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After a hospital-wide formulary change resulted in the replacement of filgrastim with TBO-filgrastim for all on- and off-label indications, we performed a retrospective comparison of patients with myeloma receiving 200 mg/m² melphalan with autologous hematopoietic stem cell transplantation to see whether the type of growth factor used post-transplant made a difference. One hundred and eighty-two consecutive patients with myeloma were studied, 91 receiving filgrastim immediately prior to the change and 91 receiving TBO-filgrastim afterward. The CD34+ cell dose was comparable, as were other characteristics. Although the overall time to neutrophil recovery was similar for both groups, early engraftment (≤12 d) occurred more often (p = 0.05), and late engraftment (≥14 d) less often (p = 0.09) in filgrastim-treated patients. The number of documented infections was significantly less in the TBO-filgrastim group. Day 100 mortality and hospital stay were similar for the two groups. These data indicate that there is no material difference between filgrastim and TBO-filgrastim in this clinical setting. [ABSTRACT FROM AUTHOR]

In contrast to the upfront setting in which the role of high-dose therapy with autologous hematopoietic cell transplantation (HCT) as consolidation of a first remission in patients with multiple myeloma (MM) is well established, the role of high-dose therapy with autologous or allogeneic HCT has not been extensively studied in MM patients relapsing after primary therapy. The International Myeloma Working Group together with the Blood and Marrow Transplant Clinical Trials Network, the American Society of Blood and Marrow Transplantation, and the European Society of Blood and Marrow Transplantation convened a meeting of MM experts to: (1) summarize current knowledge regarding the role of autologous or allogeneic HCT in MM patients progressing after primary therapy, (2) propose guidelines for the use of salvage HCT in MM, (3) identify knowledge gaps, (4) propose a research agenda, and (5) develop a collaborative initiative to move the research agenda forward. After reviewing the available data, the expert committee came to the following consensus statement for salvage autologous HCT: (1) In transplantation-eligible patients relapsing after primary therapy that did NOT include an autologous HCT, high-dose therapy with HCT as part of salvage therapy should be considered standard; (2) High-dose therapy and autologous HCT should be considered appropriate therapy for any patients relapsing after primary therapy that includes an autologous HCT with initial remission duration of more than 18 months; (3) High-dose therapy and autologous HCT can be used as a bridging strategy to allogeneic HCT; (4) The role of postsalvage HCT maintenance needs to be explored in the context of well-designed prospective trials that should include new agents, such as monoclonal antibodies, immune-modulating agents, and oral proteasome inhibitors; (5) Autologous HCT consolidation should be explored as a strategy to develop novel conditioning regimens or post-HCT strategies in patients with short (less than 18 months remissions) after primary therapy; and (6) Prospective randomized trials need to be performed to define the role of salvage autologous HCT in patients with MM relapsing after primary therapy comparing it to “best non-HCT” therapy. The expert committee also underscored the importance of collecting enough hematopoietic stem cells to perform 2 transplantations early in the course of the disease. Regarding allogeneic HCT, the expert committee agreed on the following consensus statements: (1) Allogeneic HCT should be considered appropriate therapy for any eligible patient with early relapse (less than 24 months) after primary therapy that included an autologous HCT and/or high-risk features (ie, cytogenetics, extramedullary disease, plasma cell leukemia, or high lactate dehydrogenase); (2) Allogeneic HCT should be performed in the context of a clinical trial if possible; (3) The role of postallogeneic HCT maintenance therapy needs to be explored in the context of well-designed prospective trials; and (4) Prospective randomized trials need to be performed to define the role salvage allogeneic HCT in patients with MM relapsing after primary therapy. [ABSTRACT FROM AUTHOR]

The prognosis of patients with multiple myeloma has improved markedly over the last two decades. Despite that, allogeneic hematopoietic stem cell transplantation remains the only treatment option with curative potential. Therefore it should be considered for younger patients, especially those with high-risk disease as defined based on revised international scoring system. A decision to use transplantation, as well as the choice of conditioning regimen should be personalized, taking into account a particular center's experience. [ABSTRACT FROM AUTHOR]

CD4+ T cells contribute to tumor eradication, even in the absence of CD8+ T cells. Cytotoxic CD4+ T cells can directly kill MHC class II positive tumor cells. More surprisingly, CD4+ T cells can indirectly eliminate tumor cells that lack MHC class II expression. Here, we review the mechanisms of direct and indirect CD4+ T cell-mediated elimination of tumor cells. An emphasis is put on T cell receptor (TCR) transgenic models, where anti-tumor responses of naïve CD4+ T cells of defined specificity can be tracked. Some generalizations can tentatively be made. For both MHCIIPOS and MHCIINEG tumors, presentation of tumor specific antigen by host antigen presenting cells (APCs) appears to be required for CD4+ T cell priming. This has been extensively studied in a myeloma model (MOPC315), where host APCs in tumor-draining lymph nodes are primed with secreted tumor antigen. Upon antigen recognition, naïve CD4+ T cells differentiate into Th1 cells and migrate to the tumor. At the tumor site, the mechanisms for elimination of MHCIIPOS and MHCIINEG tumor cells differ. In a TCR transgenic B16 melanoma model, MHCIIPOS melanoma cells are directly killed by cytotoxic CD4+ T cells in a perforin/granzyme B-dependent manner. By contrast, MHCIINEG myeloma cells are killed by IFN-g stimulated M1-like macrophages. In summary, while the priming phase of CD4+ T cells appears similar for MHCIIPOS and MHCIINEG tumors, the killing mechanisms are different. Unresolved issues and directions for future research are addressed.

Background. Some patients who are stable or in remission from a myeloma secreting intact monoclonal immunoglobulin (+/− associated free light-chains (FLCs)) relapse with production of FLC. This FLC escape is one of the illustrations of the intraclonal heterogeneity of multiple myeloma. Results. We report FLC escape in a patient with IgD myeloma characterized by a severe outcome. We discuss parameters that negatively impacted prognosis in this patient, including bone lesions, biochemical parameters, and genomic abnormalities. Conclusion. This case illustrates the selective pressure exerted by therapeutic drugs and the variable sensitivity of subclones to these drugs; it also highlights the importance of FLC monitoring in treated MM patients. [ABSTRACT FROM AUTHOR]

Background: Comorbidity increases overall mortality in patients diagnosed with hematological malignancies. The impact of comorbidity on cancer-specific mortality, taking competing risks into account, has not been evaluated.Methods: Using the Swedish Cancer Register, we identified patients aged >18 years with a first diagnosis of acute myeloid leukemia (AML, N = 2,550), chronic myeloid leukemia (CML, N = 1,000) or myeloma (N = 4,584) 2002-2009. Comorbid disease history was assessed through in- and out-patient care as defined in the Charlson comorbidity index. Mortality rate ratios (MRR) were estimated through 2012 using Poisson regression. Probabilities of cancer-specific death were computed using flexible parametric survival models.Results: Comorbidity was associated with increased all-cause as well as cancer-specific mortality (cancer-specific MRR: AML = 1.27, 95 % CI: 1.15-1.40; CML = 1.28, 0.96-1.70; myeloma = 1.17, 1.08-1.28) compared with patients without comorbidity. Disorders associated with higher cancer-specific mortality were renal disease (in patients with AML, CML and myeloma), cerebrovascular conditions, dementia, psychiatric disease (AML, myeloma), liver and rheumatic disease (AML), cardiovascular and pulmonary disease (myeloma). The difference in the probability of cancer-specific death, comparing patients with and without comorbidity, was largest among AML patients <70 years, whereas in myeloma the difference did not vary by age among the elderly. The probability of cancer-specific death was generally higher than other-cause death even in older age groups, irrespective of comorbidity.Conclusion: Comorbidities associated with organ failure or cognitive function are associated with poorer prognosis in several hematological malignancies, likely due to lower treatment tolerability. The results highlight the need for a better balance between treatment toxicity and efficacy in comorbid and elderly AML, CML and myeloma patients. [ABSTRACT FROM AUTHOR]

The combination of metabolomics, lipidomics, and phosphoproteomics that incorporates triple stable isotope labeling by amino acids in cell culture (SILAC) protein labeling, as well as 13C in vivo metabolite labeling, was demonstrated on BCR-ABL-positive H929 multiple myeloma cells. From 11x880 phosphorylation sites, we confirm that H929 cells are primarily signaling through the BCR-ABL-ERK pathway, and we show that imatinib treatment not only downregulates phosphosites in this pathway but also upregulates phosphosites on proteins involved in RNA expression. Metabolomics analyses reveal that BCR-ABL-ERK signaling in H929 cells drives the pentose phosphate pathway (PPP) and RNA biosynthesis, where pathway inhibition via imatinib results in marked PPP impairment and an accumulation of RNA nucleotides and negative regulation of mRNA. Lipidomics data also show an overall reduction in lipid biosynthesis and fatty acid incorporation with a significant decrease in lysophospholipids. RNA immunoprecipitation studies confirm that RNA degradation is inhibited with short imatinib treatment and transcription is inhibited upon long imatinib treatment, validating the triomics results. These data show the utility of combining mass spectrometry-based "-omics" technologies and reveals that kinase inhibitors may not only downregulate phosphorylation of their targets but also induce metabolic events via increased phosphorylation of other cellular components. [ABSTRACT FROM AUTHOR]

In this study, we established stable cell lines producing 1.5 mg/mL recombinant human prothrombin in 400-L fed-batch culture, using CHO DG44 cells as a host cell line. And we also established a recombinant human α-thrombin purification process that produces a purified product suitable for use as a biopharmaceutical, by using recombinant ecarin from CHO DG44 cells, achieving a total yield of approximately 27% of prothrombin in culture medium. The establishment of stable cell lines with high expression levels, long-term passage stability and satisfactory scale-up are essential to ensure the stable supply of biopharmaceuticals. Furthermore, biopharmaceuticals must be of high quality to assure safety and effectiveness in target applications. We had previously reported that recombinant human prethrombin-2 expression level in a stable cell line established using the mouse myeloma cells, Sp2/0-Ag14, reached 200 μg/mL using animal-free materials in 50-L fed-batch culture. However, the productivity was insufficient to completely replace α-thrombin in human plasma preparations. By employing CHO DG44 cells as a host cell line, we had established a stable cell line and achieved significant improvements in quality, productivity of recombinant human α-thrombin manufacture suitable for use as a biopharmaceutical. [ABSTRACT FROM AUTHOR]

The treatment of patients with myeloma has dramatically changed over the past decade due in part to the development of new agents and myeloma-specific targets. Despite these advancements, a group for whom the long-term benefit remains less clear are patients with genetically or clinically defined high-risk myeloma. In order to successfully treat these patients, it is important to first identify these patients, treat them with aggressive combination therapy, and employ the use of aggressive long-term maintenance therapy. Future directions include the use of new immunebased treatments (antibodies or cellular-based therapies) as well as target-driven approaches. Until these treatment approaches are better defined, this review will provide a potential treatment approach for standard- and high-risk myeloma that can be followed using agents and strategies that are currently available with the goal of improving progression-free and overall survival for these patients today. [ABSTRACT FROM AUTHOR]

Prior studies report that 9-27% of persons receiving a hematopoietic cell transplant develop arrhythmias, but the effect on outcomes is largely unknown. We reviewed data from 1177 consecutive patients ⩾40 years old receiving a hematopoietic cell transplant at one center during 1999-2009. Transplant indication was predominately leukemia, lymphoma and multiple myeloma. Overall, 104 patients were found to have clinically significant arrhythmia: 43 before and 61 after transplant. Post-transplant arrhythmias were most frequently atrial fibrillation (N=30), atrial flutter (N=7) and supraventricular tachycardia (N=11). Subjects with an arrhythmia post transplant were more likely to have longer median hospital stays (32 days vs 23, P=<0.001), a greater probability of an intensive care unit admission (52% vs 7%; P<0.001), greater probability of in-hospital deaths (28% vs 3%, P<0.001), and greater probability of death within 1 year of transplant (41% vs 15%; P<0.001) compared with patients without arrhythmia at any time. In a multivariate model including age at transplant, diagnosis, history of pretransplant arrhythmia, and transplant-related variables, post-transplant arrhythmia was associated with a greater risk for death within a year of transplant (odds ratio 3.5, 95% confidence interval: 2.1, 5.9; P<0.001). Our data suggest that arrhythmias after transplants are associated with significant morbidity and mortality. A prospective study of arrhythmia in the transplant setting is warranted. [ABSTRACT FROM AUTHOR]

Nicotinamide adenine dinucleotide (NAD+) is an essential co-enzyme reported to operate both intra- and extracellularly. In the extracellular space, NAD+ can elicit signals by binding purinergic P2 receptors or it can serve as the substrate for a chain of ectoenzymes. As a substrate, it is converted to adenosine (ADO) and then taken up by the cells, where it is transformed and reincorporated into the intracellular nucleotide pool. Nucleotide-nucleoside conversion is regulated by membrane-bound ectoenzymes. CD38, the main mammalian enzyme that hydrolyzes NAD+, belongs to the ectoenzymatic network generating intracellular Ca2+-active metabolites. Within this general framework, the extracellular conversion of NAD+ can vary significantly according to the tissue environment or pathological conditions. Accumulating evidence suggests that tumor cells exploit such a network for migrating and homing to protected areas and, even more importantly, for evading the immune response. We report on the experience of this lab to exploit human multiple myeloma (MM), a neoplastic expansion of plasma cells, as a model to investigate these issues. MM cells express high levels of surface CD38 and grow in an environment prevalently represented by closed niches hosted in the bone marrow (BM). An original approach of this study derives from the recent use of the clinical availability of therapeutic anti-CD38 monoclonal antibodies (mAbs) in perturbing tumor viability and enzymatic functions in conditions mimicking what happens in vivo. [ABSTRACT FROM AUTHOR]

Tumors cells can escape cytotoxic CD8+ T cells by preventing MHC I display of tumor antigens. It is unknown how tumors evade CD4+ T-cell responses, but because many tumor cells lack MHC II expression, novel mechanisms would be required. We have investigated this issue in a model in which MHC IINEG myeloma cells secrete a monoclonal Ig containing a V region L chain (VL) epitope recognized by CD4+ T cells. Infiltrating macrophages process and present the secreted tumor antigen to Th1 cells, resulting in induction of macrophage cytotoxicity and apparent rejection of the tumor. Despite long-term tumor protection in VL-specific T-cell receptor transgenic mice, we here describe that some myeloma cells persisted in a dormant state and, eventually, formed expanding tumors. Escape tumor cells maintained their secretion of complete (H+L) monoclonal Ig with unchanged sequence, while secretion of surplus free L chain was severely diminished. Although free L chains were efficiently processed and presented by tumor-infiltrating macrophages to CD4+ T cells, complete (H+L) monoclonal Ig was not. Forced overexpression of free L chain secretion reinstated tumor rejection. These results show that tumors can escape CD4+ T-cell--mediated rejection by impairing indirect presentation of tumor antigen by infiltrating macrophages. This occurs through a novel mechanism of immunoediting, in which modulation of the quaternary structure of the secreted tumor-specific antigen reduces its immunogenicity. [ABSTRACT FROM AUTHOR]

Group A Streptococcus (GAS) strains are lately classified on the basis of sequence variations in the emm gene encoding the M protein, but despite the high number of distinct emm genotypes, the spectrum of phenotypes varying from invasive suppurative to non-suppurative GAS-related disorders has still to be defined. The relationship of GAS types with the uprising of acute rheumatic fever (ARF), a multisystemic disease caused by misdirected anti-GAS response in predisposed people, is also obscure. Studies published over the last 15 years were retrieved from PubMed using the keywords: “ Streptococcus pyogenes ” or “group A Streptococcus ” and “acute rheumatic fever”: the prevalence of peculiar emm types across different countries of the world is highly variable, depending on research designs, year of observation, country involved, patients' age, and gender. Most studies revealed that a relatively small number of specific emm /M protein types can be considered “rheumatogenic”, as potentially characterized by the possibility of inducing ARF, with remarkable differences between developing and developed countries. The association between emm types and post-streptococcal manifestations is challenging, however surveillance of disease-causing variants in a specific community with high rate of ARF should be reinforced with the final goal of developing a potential primary prophylaxis against GAS infections. [ABSTRACT FROM AUTHOR]

Proteasome inhibitors have a 20 year history in cancer therapy. The first proteasome inhibitor, bortezomib (Velcade, PS-341), a break-through multiple myeloma treatment, moved rapidly through development from bench in 1994 to first approval in 2003. Bortezomib is a reversible boronic acid inhibitor of the chymotrypsin-like activity of the proteasome. Next generation proteasome inhibitors include carfilzomib and oprozomib which are irreversible epoxyketone proteasome inhibitors; and ixazomib and delanzomib which are reversible boronic acid proteasome inhibitors. Two proteasome inhibitors, bortezomib and carfilzomib are FDA approved drugs and ixazomib and oprozomib are in late stage clinical trials. All of the agents are potent cytotoxics. The disease focus for all the proteasome inhibitors is multiple myeloma. This focus arose from clinical observations made in bortezomib early clinical trials. Later preclinical studies confirmed that multiple myeloma cells were indeed more sensitive to proteasome inhibitors than other tumor cell types. The discovery and development of the proteasome inhibitor class of anticancer agents has progressed through a classic route of serendipity and scientific investigation. These agents are continuing to have a major impact in their treatment of hematologic malignancies and are beginning to be explored as potential treatment agent for non-cancer indications. [ABSTRACT FROM AUTHOR]

In preclinical studies, pomalidomide mediated both direct antitumor effects and immune activation by binding cereblon. However, the impact of drug-induced immune activation and cereblon/ikaros in antitumor effects of pomalidomide in vivo is unknown. Here we evaluated the clinical and pharmacodynamic effects of continuous or intermittent dosing strategies of pomalidomide/dexamethasone in lenalidomide-refractory myeloma in a randomized trial. Intermittent dosing led to greater tumor reduction at the cost of more frequent adverse events. Both cohorts experienced similar event-free and overall survival. Both regimens led to a distinct pattern but similar degree of mid-cycle immune activation, manifested as increased expression of cytokines and lytic genes in T and natural killer (NK) cells. Pomalidomide induced poly-functional T-cell activation, with increased proportion of coinhibitory receptor BTLA+ T cells and Tim-3+ NK cells. Baseline levels of ikaros and aiolos protein in tumor cells did not correlate with response or survival. Pomalidomide led to rapid decline in Ikaros in T and NK cells in vivo, and therapy-induced activation of CD8+ T cells correlated with clinical response. These data demonstrate that pomalidomide leads to strong and rapid immunomodulatory effects involving both innate and adaptive immunity, even in heavily pretreated multiple myeloma, which correlates with clinical antitumor effects. [ABSTRACT FROM AUTHOR]

The progression of multiple myeloma (MM) is governed by a network of molecular signals, the majority of which remain to be identified. Recent studies suggest that Runt-related transcription factor 2 (Runx2), a well-known bone-specific transcription factor, is also expressed in solid tumors, where expression promotes both bone metastasis and osteolysis. However, the function of Runx2 in MM remains unknown. The current study demonstrated that (1) Runx2 expression in primary human MM cells is significantly greater than in plasma cells from healthy donors and patients with monoclonal gammopathy of undetermined significance; (2) high levels of Runx2 expression in MM cells are associated with a high-risk population of MM patients; and (3) overexpression of Runx2 in MM cells enhanced tumor growth and disease progression in vivo. Additional studies demonstrated that MM cell-derived Runx2 promotes tumor progression through a mechanism involving the upregulation of Akt/β-catenin/Survivin signaling and enhanced expression of multiple metastatic genes/proteins, as well as the induction of a bone-resident cell-like phenotype in MM cells. Thus, Runx2 expression supports the aggressive phenotype of MM and is correlated with poor prognosis. These data implicate Runx2 expression as a major regulator of MM progression in bone and myeloma bone disease. [ABSTRACT FROM AUTHOR]

Recent studies indicate that lipid metabolic changes affect the survival of multiple myeloma (MM) cells. Time-of-flight secondary ion mass spectrometry (TOF-SIMS), an imaging mass spectrometry technique, is used to visualize the subcellular distribution of biomolecules including lipids. We therefore applied this method to human clinical specimens to analyze the membrane fatty acid composition and determine candidate molecules for MM therapies. We isolated MM cells and normal plasma cells (PCs) from bone marrow aspirates of MM patients and healthy volunteers, respectively, and these separated cells were analyzed by TOF-SIMS. Multiple ions including fatty acids were detected and their ion counts were estimated. In MM cells, the mean intensity of palmitic acid was significantly lower than the mean intensity in PCs. In a cell death assay, palmitic acid reduced U266 cell viability dose-dependently at doses between 50 and 1000 μM. The percentage of apoptotic cells increased from 24 h after palmitic acid administration. In contrast, palmitic acid had no effect on the viability of normal peripheral blood mononuclear cells (PBMCs). The results of this study indicated that palmitic acid is a potential candidate for novel therapeutic agents that specifically attack MM cells. [ABSTRACT FROM AUTHOR]

High-dose chemotherapy (HDT) followed by autologous peripheral blood progenitor cell transplant (PBPCT) has become a standard intervention in certain clinical settings of hematologic malignancies, particularly multiple myeloma and relapsed/refractory lymphoma. While the minimal required PBPCs infused, as defined by number of CD34 + cells, has been relatively well delineated for adequate hematopoietic recovery post-HDT, optimal PBPC dose has not been clearly defined. This is particularly relevant in the context of retrospective data suggesting improved survival outcomes with increased PBPC doses. The potential confounding of these data as they relate to disease risk is discussed within this review. Additionally, other retrospective data have suggested that enhanced quantitative lymphocyte subset reconstitution post-HDT-PBPCT may confer progression-free and overall survival advantage. These reported series herein reviewed may inform discussion of future, prospective clinical trials with the intent of defining optimal autologous PBPC dose following HDT, especially as it may relate to metrics beyond hematopoietic recovery. [ABSTRACT FROM AUTHOR]

Glycosphingolipids (GSLs) are essential constituents of cell membranes and lipid rafts and can modulate signal transduction events. The contribution of GSLs in osteoclast (OC) activation and osteolytic bone diseases in malignancies such as the plasma cell dyscrasia multiple myeloma (MM) is not known. Here, we tested the hypothesis that pathological activation of OCs in MM requires de novo GSL synthesis and is further enhanced by myeloma cell-derived GSLs. Glucosylceramide synthase (GCS) inhibitors, including the clinically approved agent N-butyl-deoxynojirimycin (NB-DNJ), prevented OC development and activation by disrupting RANKL-induced localization of TRAF6 and c-SRC into lipid rafts and preventing nuclear accumulation of transcriptional activator NFATc1. GM3 was the prevailing GSL produced by patient-derived myeloma cells and MM cell lines, and exogenous addition of GM3 synergistically enhanced the ability of the pro-osteoclastogenic factors RANKL and insulin-like growth factor 1 (IGF-1) to induce osteoclastogenesis in precursors. In WT mice, administration of GM3 increased OC numbers and activity, an effect that was reversed by treatment with NB-DNJ. In a murine MM model, treatment with NB- DNJ markedly improved osteolytic bone disease symptoms. Together, these data demonstrate that both tumor-derived and de novo synthesized GSLs influence osteoclastogenesis and suggest that NB-DNJ may reduce pathological OC activation and bone destruction associated with MM. [ABSTRACT FROM AUTHOR]

Hepatocyte growth factor (HGF) is a pro-angiogenic cytokine activated by tissue-type plasminogen activator (tPA) that might play a role in the progression of multiple myeloma (MM). Preliminary studies indicated that serum HGF levels were higher in patients with AL amyloidosis (AL) compared to those with MM. The aim of the present study was to determine whether HGF is a relevant marker of diagnosis and prognosis in AL. HGF serum levels were measured at diagnosis in patients with monoclonal gammopathy (MG) without AL (76 controls), or with biopsy-proven systemic AL (69 patients). HGF serum levels were significantly higher in patients with AL compared to controls, respectively, 11.2 ng/mL [min: 0.95-max: 200.4] versus 1.4 ng/mL [min: 0.82-max: 6.2] ( p < 0.0001). The threshold value of 2.2 ng/mL conferred optimal sensitivity (88%) and specificity (95%) to differentiate AL and monoclonal gammopathy of undetermined significance (MGUS) patients. Serum HGF concentrations were correlated positively with the severity of cardiac involvement and the serum level of monoclonal light chains. These data suggest that HGF measurement could be used in patients with MG to detect AL or to reinforce a clinical suspicion of AL and to guide indications for diagnostic tissue biopsies. [ABSTRACT FROM AUTHOR]

We have recently reported on the outcome of autologous transplantation in the rare myelomas (IgD, IgE, IgM, and nonsecretory [NS]) but there is no real information on the outcome of these conditions after allogeneic transplantation. We used the European Group for Blood and Marrow Transplantation myeloma database to compare the outcomes after allogeneic transplantation of 1354 common myelomas (IgG, IgA, and light chain myeloma) with the outcome in 26 IgD myelomas and 52 NS myelomas. There was little difference between common and the IgD and NS myeloma patients with respect to prognostic factors although the IgD group had a higher beta 2 microglobulin at diagnosis, shorter time to transplantation, and more T cell depletion. IgD and NS patients had a significantly greater achievement of complete remission at conditioning but this did not translate into equivalent progression-free survival and overall survival for the IgD patients although the NS outcome was very similar to that of common myeloma. The PFS and OS of IgD, common, and NS myelomas appear similar after allogeneic transplantation, despite a tendency for higher early relapse rate in IgD myeloma. Allogeneic transplantation may, therefore, be an option to investigate in prospective observational studies. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is an incurable hematologic malignancy caused by the autonomous growth of malignant plasma cells. In the last decade, the introduction of novel targeted agents such as thalidomide, bortezomib, and lenalidomide has dramatically improved the clinical outcome of MM patients in both the frontline and recurrent settings. Lenalidomide is a synthetic derivative of thalidomide, which has been shown to significantly improve overall survival, time to progression, and overall response rates in patients with MM. The China Food and Drug Administration approved the use of lenalidomide in patients with MM in 2013. In a Phase II trial, lenalidomide plus low-dose dexamethasone was associated with a high response rate and acceptable safety profile in heavily pretreated Chinese patients with relapsed/refractory MM, including those with renal impairment and IgD subtype. However, lenalidomide will remain as a second-line antimyeloma drug in the near future because of its high price and the policy of health insurance reimbursement in People's Republic of China. In this review, we summarize the clinical utility and patient considerations in the use of lenalidomide for MM in Chinese patients. Further studies with larger sample sizes are required to investigate the better quality, longer duration, and more clinically meaningful outcomes of lenalidomide in the treatment of MM in Chinese patients. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the efficacy and safety of bortezomib-based vs non-bortezomib-based post-transplantation therapy in patients with multiple myeloma. Methods: Data of relevant randomized controlled trials assessing the effect of bortezomib as post-transplantation consolidation or maintenance therapy was obtained through a comprehensive search. The outcome measures included response rate, progression-free survival, overall survival, and adverse events (AEs). The hazard ratio (HR), Cochran-Mantel-Haenszel odds ratio (OR), and 95% confidence interval (95% CI) were applied to evaluate the effect of bortezomib in relation to the end points such as progression-free survival, overall survival, response rate, and AEs. Results: Three randomized controlled trials comprising 1,518 participants were included in this study. Pooled ORs for the rates of overall response, and complete response and near complete response, were 1.85 and 1.75, respectively. Pooled HR for progression-free survival favored bortezomib-based therapy over non-bortezomib-based therapy (0.73, 95% CI: 0.67-0.81), while no statistically significant difference could be found between the two groups regarding the pooled HR for 3-year overall survival. Moreover, incidence rates of overall adverse events and grade 3 and 4 peripheral neuropathy were similar in the bortezomib-based groups and the non-bortezomib-based groups (P=0.12 and P=0.41, respectively). The corresponding cumulative meta-analyses of the rates of overall response rate, complete response and near complete response, and grades 3 and 4 peripheral neuropathy supported the superiority of bortezomibbased maintenance therapy over consolidation therapy. Conclusion: Bortezomib-based therapy after autologous stem cell transplantation, with tolerable AEs, could obviously improve the response as well as the outcome of multiple myeloma patients, particularly when bortezomib was administered as maintenance therapy. [ABSTRACT FROM AUTHOR]

Aim To estimate and compare the extent of myeloma bone disease by skeletal region using whole-body diffusion-weighted imaging (WB-DWI) and skeletal survey (SS) and record interobserver agreement, and to investigate differences in imaging assessments of disease extent and apparent diffusion coefficient (ADC) between patients with pathological high versus low disease burden. Materials and methods Twenty patients with relapsed myeloma underwent WB-DWI and SS. Lesions were scored by number and size for each skeletal region by two independent observers using WB-DWI and SS. Observer scores, ADC, and ADC-defined volume of tumour-infiltrated marrow were compared between patients with high and low disease burden (assessed by serum paraproteins and marrow biopsy). Results Observer scores were higher on WB-DWI than SS in every region ( p <0.05) except the skull, with greater interobserver reliability in rating the whole skeleton (WB-DWI: ICC = 0.74, 95% CI: 0.443–0.886; SS: ICC = 0.44, 95% CI: 0.002–0.730) and individual body regions. WB-DWI scores were not significantly higher in patients with high versus low disease burden (observer 1: mean ± SD: 48.8 ± 7, 38.6 ± 14.5, observer 2: mean ± SD: 37.3 ± 13.5, 30.4 ± 15.5; p = 0.06, p = 0.35). Conclusion WB-DWI demonstrated more lesions than SS in all regions except the skull with greater interobserver agreement. Sensitivity is not a limiting factor when considering WB-DWI in the management pathway of patients with myeloma. [ABSTRACT FROM AUTHOR]

Background. Previously we established two cell lines (SNU_MM1393_BM and SNU_MM1393_SC) from different tissues (bone marrow and subcutis) of mice which were injected with single patient’s myeloma sample. We tried to define genetic changes specific for each cell line using whole exome sequencing (WES). Materials and Methods. We extracted DNA from SNU_MM1393_BM and SNU_MM1393_SC and performed WES. For single nucleotide variants (SNV) calling, we used Varscan2. Annotation of mutation was performed using ANNOVAR. Results. When calling of somatic mutations was performed, 68 genes were nonsynonymously mutated only in SNU_MM1393_SC, while 136 genes were nonsynonymously mutated only in SNU_MM1393_BM. KIAA1199, FRY, AP3B2, and OPTC were representative genes specifically mutated in SNU_MM1393_SC. When comparison analysis was performed using TCGA data, mutational pattern of SNU_MM1393_SC resembled that of melanoma mostly. Pathway analysis using KEGG database showed that mutated genes specific of SNU_MM1393_BM were related to differentiation, while those of SNU_MM1393_SC were related to tumorigenesis. Conclusion. We found out genetic changes that underlie tropism of myeloma cells using WES. Genetic signature of cutaneous plasmacytoma shares that of melanoma implying common mechanism for skin tropism. KIAA1199, FRY, AP3B2, and OPTC are candidate genes for skin tropism of cancers. [ABSTRACT FROM AUTHOR]

Incorporation of novel agents into auto-SCT for patients with multiple myeloma has led to improvement in their outcomes. However, the effects of new drugs, either single or combined, on PBSC mobilization have not been fully evaluated, particularly in phase 3 clinical studies. We analyzed the impact of two novel agent-based induction treatments in patients enrolled in the GIMEMA MMY-3006 study comparing bortezomib, thalidomide and dexamethasone (VTD) versus thalidomide and dexamethasone (TD) in preparation for double auto-SCT. Results showed that a short-term induction therapy with VTD did not adversely affect CD34+ cell yields as compared with TD (9.75 vs 10.76 × 106 CD34+ cells/kg, P=0.220). For poor mobilizers (<4 × 106 CD34+ cells/kg), 5-year rates of time to progression (TTP), progression-free survival (PFS) and overall survival (OS) were significantly shorter than for successful mobilizers (TTP:17 vs 48%, P<0.0001; PFS: 16 vs 46%, P<0.0001; OS: 50 vs 80%, P<0.0001). These differences were retained across patients randomized to the TD arm; conversely, no differences in outcomes were seen in patients treated with VTD, irrespective of the number of harvested CD34+ cells. The number of collected PBSCs predicted better outcomes after auto-SCT and VTD overcame the negative impact of a poor stem cell mobilization. [ABSTRACT FROM AUTHOR]

MDX-1097 is an antibody specific for a unique B cell antigen called kappa myeloma antigen ( KMA) that consists of cell membrane-associated free kappa light chain (κ FLC). KMA was detected on kappa human multiple myeloma cell lines (κ HMCLs), on plasma cells ( PCs) from kappa multiple myeloma (κ MM) patients and on κ PC dyscrasia tissue cryosections. In primary κ MM samples, KMA was present on CD38+ cells that were CD138 and CD45 positive and/or negative. MDX-1097 exhibited a higher affinity for KMA compared to κ FLC and the latter did not abrogate binding to KMA. MDX-1097-mediated antibody-dependent cellular cytotoxicity ( ADCC) and in vitro exposure of target cells to the immunomodulatory drug lenalidomide resulted in increased KMA expression and ADCC. Also, in vitro exposure of peripheral blood mononuclear cells ( PBMCs) to lenalidomide enhanced MDX-1097-mediated ADCC. PBMCs obtained from myeloma patients after lenalidomide therapy elicited significantly higher levels of MDX-1097-mediated ADCC than cells obtained prior to lenalidomide treatment. These data establish KMA as a relevant cell surface antigen on MM cells that can be targeted by MDX-1097. The ADCC-inducing capacity of MDX-1097 and its potentiation by lenalidomide provide a powerful rationale for clinical evaluation of MDX-1097 alone and in combination with lenalidomide. [ABSTRACT FROM AUTHOR]

In order to quantify the association between use of statins and the risk of all hematological malignancies and of subtypes, we performed a meta-analysis of observational studies. We achieved a MEDLINE/ EMBASE comprehensive search for studies published up to August 2014 investigating the association between use of statins and the risk of hematological malignancies, including Hodgkin- and non-Hodgkin lymphoma, leukemia, and myeloma. Fixed- and random-effect models were fitted to estimate the summary relative risk ( RR) based on adjusted study-specific results. Between-study heterogeneity was assessed using the Q and I2 statistics and the sources of heterogeneity were investigated using Deeks' test. Moreover, an influence analysis was performed. Finally, publication bias was evaluated using funnel plot and Egger's regression asymmetry test. Fourteen studies (10 case-control and four cohort studies) contributed to the analysis. Statin use, compared to nonuse of statins, was negatively associated with all hematological malignancies taken together (summary RR 0.86; 95% CI: 0.77-0.96), with leukemia (0.83; 0.74-0.92), and non-Hodgkin lymphoma (0.81; 0.68 to 0.96), but it was not related to the risk of myeloma (0.89; 0.53-1.51). Long-term users of statins showed a statistically significant reduction in the risk of all hematological malignancies taken together (0.78; 0.71-0.87). Statistically significant between-studies heterogeneity was observed for all outcome except for leukemia. Heterogeneity was caused by differences confounding-adjustment level of the included studies only for Myeloma. No significant evidence of publication bias was found. [ABSTRACT FROM AUTHOR]

The article describes the case of a 72-year-old Caucasian male patient with a history of a violaceous nodule with hemorrhagic dots, and who was diagnosed with plasmablastic lymphoma. The diagnosis was confirmed after performing neurological examination, computed tomography (CT) of the brain, histopathology and immunohistochemical analysis and serologic test. A discussion on the similarities between plasmablastic lymphoma and plasmablastic plasma cell myeloma is offered.

CD99 is a transmembrane glycoprotein expressed in physiological conditions by cells of different tissues, including osteoblasts (OBs). High or low CD99 levels have been detected in various pathological conditions, and the supernatant of some carcinoma cell lines can modulate CD99 expression in OB-like cells. In the present work we demonstrate for the first time that two different human myeloma cell lines (H929 and U266) and, in a less degree, their conditioned media significantly downregulate CD99 expression in normal human OBs during the differentiation process. In the same experimental conditions the OBs display a less differentiated phenotype as demonstrated by the decreased expression of RUNX2 and Collagen I. On the contrary, when CD99 was activated by using a specific agonist antibody, the OBs become more active as demonstrated by the upregulation of Alkaline Phosphatase, Collagen I, RUNX2, and JUND expression. Furthermore, we demonstrate that the activation of CD99 is able to induce the phosphorylation of ERK 1/2 and AKT intracellular signal transduction molecules in the OBs. [ABSTRACT FROM AUTHOR]

In multiple myeloma (MM), mast cells (MCs) modify bone marrow microenvironment. In order to estimate whether MC density (MCD) in active MM bone marrows relates to the proliferative activity of plasma cells, we estimated in 42 patients MCD, microvascular density (MVD), and the Ki-67 proliferation index (PI) (immunohistochemical expression of tryptase, CD31, and Ki-67). MCD correlated with Ki-67 PI ( p < .001), suggesting the important participation of MCs in MM biology and growth; MCs enhance angiogenesis and produce cytokines with growth effects on myeloma cells. Therefore, MCs could be valuable targets for therapeutic interventions. [ABSTRACT FROM AUTHOR]

Background: Gene expression profiling (GEP) via microarray analysis is a widely used tool for assessing risk and other patient diagnostics in clinical settings. However, non-biological factors such as systematic changes in sample preparation, differences in scanners, and other potential batch effects are often unavoidable in long-term studies and meta-analysis. In order to reduce the impact of batch effects on microarray data, Johnson, Rabinovic, and Li developed ComBat for use when combining batches of gene expression microarray data. We propose a modification to ComBat that centers data to the location and scale of a pre-determined, 'gold-standard' batch. This modified ComBat (M-Combat) is designed specifically in the context of meta-analysis and batch effect adjustment for use with predictive models that are validated and fixed on historical data from a 'gold-standard' batch. Results: We combined data from MIRT across two batches ('Old' and 'New' Kit sample preparation) as well as external data sets from the HOVON-65/GMMG-HD4 and MRC-IX trials into a combined set, first without transformation and then with both ComBat and M-ComBat transformations. Fixed and validated gene risk signatures developed at MIRT on the Old Kit standard (GEP5, GEP70, and GEP80 risk scores) were compared across these combined data sets. Both ComBat and M-ComBat eliminated all of the differences among probes caused by systematic batch effects (over 98% of all untransformed probes were significantly different by ANOVA with 0.01 q-value threshold reduced to zero significant probes with ComBat and M-ComBat). The agreement in mean and distribution of risk scores, as well as the proportion of high-risk subjects identified, coincided with the 'gold-standard' batch more with M-ComBat than with ComBat. The performance of risk scores improved overall using either ComBat or M-Combat; however, using M-ComBat and the original, optimal risk cutoffs allowed for greater ability in our study to identify smaller cohorts of high-risk subjects. Conclusion: M-ComBat is a practical modification to an accepted method that offers greater power to control the location and scale of batch-effect adjusted data. M-ComBat allows for historical models to function as intended on future samples despite known, often unavoidable systematic changes to gene expression data. [ABSTRACT FROM AUTHOR]

Aim: To study the bone marrow changes in elderly patients (above 60 years of age). Material and methods: Bone marrow records from the pathology laboratory in the Department of Pathology, Bangalore Medical College, Bangalore, from March 2012 to June 2013, were searched, and cases from all patients at least 60 years old at the time of bone marrow study were retrospectively reviewed. Results: During the 16 months period, 164 bone marrow examinations were performed, and out of these, 50 patients were at least 60 years old. The age range of the patients was 60 to 82 years, 27 were males and 23 were females. 47 cases (94%) yielded specific diagnosis. 27 cases (54%) had nutritional anemia, 6 cases (12%) were diagnosed as myeloma, 3 cases (6%) had aplastic anemia, 3 cases (6%) had chronic lymphocytic leukemia! small lymphocytic leukemia infiltrating the bone marrow; 2 cases (4%) had acute myeloid leukemia, 2 cases (4%) had hypocellular marrow with myelofibrosis - grade 3, 2 cases were diagnosed to have monoclonal gammopathy of undetermined significance (4%), 1 case (2%) had metastatic deposits from prostatic carcinoma and 1 case (2%) had metastatic deposits from renal cell carcinoma - clear cell variant; 1 case (2%) of myelodysplastic syndrome - refractory cytopenia with multi lineage dysplasia and ringed side roblasts was diagnosed. Conclusions: In this study we found that after nutritional anemia, plasma cell dyscrasias were the most common findings in bone marrow studies in elderly patients. Diagnosis of plasma cell dyscrasias prompt for early institution of treatment resulting in reduced morbidity and mortality in such patients. [ABSTRACT FROM AUTHOR]

Background Serum lactate dehydrogenase ( LDH) has been an adverse prognostic factor for myeloma but does not feature in the International Staging System ( ISS). We examined whether elevated serum LDH at diagnosis remains an adverse risk factor independent of ISS for survivals transplant-eligible myeloma patients receiving early/frontline bortezomib-based induction, followed by autologous stem cell transplantation ( ASCT). Patients Seventy-seven transplant-eligible Chinese patients received three induction regimens [staged approach ( N = 25), PAD ( N = 19), VTD ( N = 33)], followed by ASCT and thalidomide maintenance. Results Five-year overall ( OS) and event-free ( EFS) survivals were 66.4% and 36.2%. There was no difference in demographics, complete remission/near complete remission ( CR/ nCR rates postinduction or ASCT, and survivals among patients induced by the three induction regimens. Elevated LDH was associated with male gender ( P = 0.006), ISS III ( P = 0.042) and serum β2-microglobulin ( P = 0.040). Univariate analysis showed that elevated LDH, ISS III, high β2-microglobulin, and failure to attain CR/ nCR post- ACST were risk factors adversely impacting both OS and EFS. Multivariate analysis showed that elevated LDH was the only factor impacting both OS ( P = 0.007) and EFS ( P = 0.008). Conclusion In this uniformly treated cohort of transplant-eligible myeloma patients, elevated serum LDH is an adverse risk factor independent of ISS for both OS and EFS. Bortezomib-based induction/ ASCT regimen had not abolished the adverse impact of elevated LDH. [ABSTRACT FROM AUTHOR]

The detection of minimal residual disease (MRD) in myeloma using a 0.01% threshold (10-4) after treatment is an Independent predictor of progression-free survival (PFS), but not always of overall survival (OS). However, MRD level is a continuous variable, and the predictive value of the depth of tumor depletion was evaluated In 397 patients treated intensively in the Medical Research Council Myeloma IX study. There was a significant improvement in OS for each log depletion In MRD level (median OS was 1 year for 210%, 4 years for 1% to <10%, 5.9 years for 0.1% to <1%, 6.8 years for 0.01% to <0.1%,and more than 7.5 years for <0.01% MRD). MRD level as a continuous variable determined by flow cytometry independently predicts both PFS and OS, with approximately 1 year median OS benefit per log depletion. [ABSTRACT FROM AUTHOR]

Patients with light-chain deposition disease (LCDD) frequently do not meet criteria for myeloma. In such cases, despite low tumor burden, the circulating monoclonal immunoglobulins cause renal damage, are responsible for post-transplant recurrence, and are rightly categorized as monoclonal gammopathy of renal significance (MGRS) requiring chemotherapy. A 65-year male with uncharacterized nodular glomerulopathy presented with proteinuria 3 years postrenal transplant. His allograft biopsies were diagnostic of light-chain deposition disease (likely recurrent), and in the absence of myeloma, he was labeled as MGRS. Based on the limited literature available, he was treated with bortezomib which resulted in normalization of serum-free light-chain ratios and resolution of proteinuria. He, however, later succumbed to complications of chemotherapy. This case highlights the diagnostic difficulties in LCDD, the importance of an accurate pretransplant diagnosis, and treatment of the malignant clone, in the absence of which posttransplant management of recurrence is challenging with poor outcomes. [ABSTRACT FROM AUTHOR]

Myeloma is characterized by a highly variable clinical outcome. Despite the effectiveness of high-dose therapy, 15% of patients relapse within 1 year. We show that these cases also have a significantly shorter post-relapse survival compared to the others (median 14.9 months vs. 40 months, p = 8.03 × 10− 14). There are no effective approaches to define this potentially distinct biological group such that treatment could be altered. In this work a series of uniformly treated patients with myeloma were used to develop a gene expression profiling (GEP)-based signature to identify this high risk clinical behavior. Gene enrichment analyses applied to the top differentially expressed genes showed a significant enrichment of epigenetic regulators as well as 'stem cell' myeloma genes. A derived 17-gene signature effectively identifies patients at high risk of early relapse as well as impaired overall survival. Integrative genomic analyses showed that epigenetic mechanisms may play an important role on transcription of these genes. [ABSTRACT FROM AUTHOR]

The development of resistance to therapy is unavoidable in the history of multiple myeloma patients. Therefore, the study of its characteristics and mechanisms is critical in the search for novel therapeutic approaches to overcome it. This effort is hampered by the absence of appropriate preclinical models, especially those mimicking acquired resistance. Here we present an in vivo model of acquired resistance based on the continuous treatment of mice bearing subcutaneous MM1S plasmacytomas. Xenografts acquired resistance to two generations of immunomodulatory drugs (IMiDs; lenalidomide and pomalidomide) in combination with dexamethasone, that was reversible after a wash-out period. Furthermore, lenalidomide-dexamethasone (LD) or pomalidomide-dexamethasone (PD) did not display cross-resistance, which could be due to the differential requirements of the key target Cereblon and its substrates Aiolos and Ikaros observed in cells resistant to each combination. Differential gene expression profiles of LD and PD could also explain the absence of cross-resistance. Onset of resistance to both combinations was accompanied by upregulation of the mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK pathway and addition of selumetinib, a small-molecule MEK inhibitor, could resensitize resistant cells. Our results provide insights into the mechanisms of acquired resistance to LD and PD combinations and offer possible therapeutic approaches to addressing IMiD resistance in the clinic. [ABSTRACT FROM AUTHOR]