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The number and activity of osteoclasts (OCs) are strongly enhanced by myeloma cells, leading to significant bone lesions in patients with multiple myeloma (MM). Mechanisms remain elusive as to whether myeloma-supporting OCs also induce suppressive immune bone marrow (BM) microenvironment. Here, we first show that OCs significantly protect MM cells against T-cell–mediated cytotoxicity via direct inhibition of proliferating CD4+ and CD8+ T cells. The immune checkpoint molecules programmed death ligand 1 (PD-L1), Galectin-9, herpesvirus entry mediator (HVEM), and CD200, as well as T-cell metabolism regulators indoleamine 2, 3-dioxygenase (IDO), and CD38 are significantly upregulated during osteoclastogenesis. Importantly, the levels of these molecules, except CD38, are higher in OCs than in MM cells. Anti–PD-L1 monoclonal antibody (mAb) and IDO inhibitor partly overcome OC-inhibited T-cell responses against MM cells, confirming their roles in OC-suppressed MM cell lysis by cytotoxic T cells. In addition, Galectin-9 and a proliferation-induced ligand (APRIL), secreted by OCs, are significantly upregulated during osteoclastogenesis. Galectin-9 specifically induces apoptosis of T cells while sparing monocytes and MM cells. APRIL induces PD-L1 expression in MM cells, providing additional immune inhibition by OCs. Moreover, CD38 is significantly upregulated during osteoclastogenesis. When targeted by an anti-CD38 mAb, suppressive T-cell function by OCs is alleviated, associated with downregulation of HVEM and IDO. Taken together, these results define the expression of multiple immune proteins and cytokines in OCs essential for suppressive MM BM milieu. These results further support the combination of targeting these molecules to improve anti-MM immunity. [ABSTRACT FROM AUTHOR]

Solitary plasmacytoma and extramedullary plasmocytoma are tumors of malignant character composed of plasma cells, with a mean age of onset at 60 years. They can appear anywhere where the reticuloendothelial system is present. Usually these tumors lead to the development of multiple myeloma in a period of time ranging from 3 to 5 years. We present a rare case handled in our neurosurgery service associated with an unusually long period of evolution. [ABSTRACT FROM AUTHOR]

In this study, targeted sequencing to screen 50 multidrug refractory multiple myeloma (rMM) patients was performed by using the Multiple Myeloma Mutation Panel. Patients were pretreated with both immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs), and 88%, 78%, and 68% were refractory to an IMiD, a PI, or both, respectively. The majority of patients had progressive (82%) or refractory (78%) disease immediately before sampling, with 43% being IMiD refractory and 46% being PI refractory in the most recent line of therapy.Comparedwith newly diagnosedMM,an increased prevalence ofmutations in theRas pathway genesKRAS,NRAS, and/orBRAF(72%), as well as TP53 (26%),CRBN(12%), andCRBNpathwaygenes (10%)wasobserved.Longitudinalanalysesperformed in3 patients with CRBN mutations at time of IMiD resistance confirmed that these mutations were undetectable at earlier, IMiD-sensitive time points. Furthermore, the functional introduction of these mutationsinMMcellsconferredlenalidomideresistanceinvitro.Thesedataindicateadifferential genetic landscape in rMM associated with drug response. [ABSTRACT FROM AUTHOR]

DNArepair activity ofmalignant cells seems to influencetherapeuticoutcomeandpatients' survival. Herein, we investigated the mechanistic basis for the link between DNA repair efficiency and response to antimyeloma therapy. Nucleotide excision repair (NER), interstrand cross-links repair (ICL/R), double-strand breaks repair (DSB/R), and chromatin structure were evaluated in multiple myeloma (MM) cell lines (melphalan-sensitive RPMI8226; melphalan-resistant LR5) and bone marrow plasma cells (BMPCs) from MM patients who responded (n = 17) or did not respond (n = 9) to subsequent melphalan therapy. The effect of DSB/R inhibition was also evaluated. Responders' BMPCs showed slower rates of NER and DSB/R (P < .0022), similar rates of ICL/R, and more condensed chromatin structure compared with nonresponders. Moreover, apoptosis rates of BMPCs were inversely correlated with individual DNA repair efficiency and were higher in responders' cells compared with those of nonresponders (P = .0011). Similarly, RPMI8226 cells showed slower rates of NER and DSB/R, comparable rates of ICL/R, more condensed chromatin structure, and higher sensitivity than LR5 cells. Interestingly, cotreatment of BMPCs or cell lines with DSB/R inhibitors significantly reduced the rates ofDSB/R and increasedmelphalan sensitivity of the cells, with the nonhomologous end-joining inhibitor SCR7 showing the strongest effect. Together, responders' BMPCs are characterized by lower efficiencies of NER and DSB/R mechanisms, resulting in higher accumulation of the extremely cytotoxic ICLs andDSBs lesions,which in turn triggers the induction of the apoptotic pathway. Moreover, the enhancement of melphalan cytotoxicity by DSB/R inhibition offers a promising strategy toward improvement of existing antimyeloma regimens. [ABSTRACT FROM AUTHOR]

Cinnamon is one of the most widely used herbal medicines with diverse bioactive effects. However, there is no report in regard to the potential anti-proliferative effects of cinnamon on myeloma cells. In this study, the authors investigated the anti-proliferative potential of cinnamon bark powder extract (CBPE) on myeloma cells specifically focusing on its anti-angiogenic and anti-inflammatory properties. The authors observed inhibition of myeloma cell proliferation by CBPE along with anti-inflammatory and anti-angiogenic effects in a human myeloma cell line RPMI 8226. After 24 h of treatment, CBPE caused approximately 50% inhibition of cell growth in RPMI 8226 cells at a concentration of 72 μg/mL (IC50), compared with the untreated controls. CBPE treatment strongly inhibited expression of angiogenic factors and cyclooxygenase at mRNA as well as at protein level in a time-dependent manner. Treatment with the CBPE resulted in cell cycle arrest in the G 0 /G 1 phase in a time-dependent manner. CBPE besides altering growth kinetics of cells, induces DNA fragmentation resulting in apoptosis. In the treated group, DNA fragmentation increased in a time dependent manner with maximum intensity of labeled nucleotides in cells treated for 72 h as compared to 24 h and 48 h. In conclusion, the anticancer effects of cinnamon extract appear to be mediated by multiple mechanisms. These include inhibition of angiogenesis, inflammation and induction of apoptosis in myeloma cells. CBPE could be considered as a promising candidate for restricting the growth of myeloma cells. Hence, CBPE could lead to the development of an effective anti-cancer agent or herbal medicine for the treatment of MM. [ABSTRACT FROM AUTHOR]

Background: Although the introduction of novel agents improved the survival outcomes in patients with multiple myeloma (MM), some patients died within one year (early mortality, EM) following diagnosis. In this study, we evaluated the EM rate, and investigated the risk factors associated with EM in MM patients.Methods: Retrospective data from 542 patients who were initially treated with a novel agent-containing regimen were analyzed.Results: The median overall survival (OS) for the entire cohort was 56.5 months. The median OS in the 2010-2014 group was longer than in the 2002-2009 group (59.2 months vs. 49.1 months, P = 0.054). The rate of EM was 13.8 %, and the most common causes of EM were infection and comorbidity. In multivariate analysis, the age-adjusted Charlson comorbidity index (ACCI ≥ 4), low body mass index (BMI < 20 kg/m(2)), thrombocytopenia, and renal failure were significantly associated with EM. The presence of none, 1, or ≥ 2 factors was associated with a 4.1 %, 14.3 %, or 27.4 % risk of EM (P < 0.001), respectively. The median OS times were significantly different depending on the presence of factors associated with EM (P < 0.001).Conclusions: In conclusion, the ACCI (≥ 4), low BMI, thrombocytopenia and renal failure were strong predictors for EM in the novel agent era. The results of this study will help to identify patients at high risk for EM, and may be helpful to more accurately predict prognosis of MM patients in the novel-agent era. [ABSTRACT FROM AUTHOR]

Myeloma immunosurveillance remains incompletely understood. We have demonstrated proteolytic processing of the matrix proteoglycan, versican (VCAN), in myeloma tumors. Whereas intact VCAN exerts tolerogenic activities through Toll-like receptor 2 (TLR2) binding, the immunoregulatory consequences of VCAN proteolysis remain unknown. Here we show that human myeloma tumors displaying CD8+ infiltration/aggregates underwent VCAN proteolysis at a site predicted to generate a glycosaminoglycan-bereft N-terminal fragment, versikine. Myeloma-associated macrophages (MAMs), rather than tumor cells, chiefly produced V1-VCAN, the precursor to versikine, whereas stromal cell-derived ADAMTS1 was the most robustly expressed VCAN-degrading protease. Purified versikine induced early expression of inflammatory cytokines interleukin 1β (IL-1β) and IL-6 by human myelomamarrow-derived MAMs.We show that versikine signals through pathways both dependent and independent of Tpl2 kinase, a key regulator of nuclear factor kB1-mediated MAPK activation in macrophages. Unlike intact VCAN, versikine-induced Il-6 productionwas partially independent of Tlr2. In amodel of macrophage-myeloma cell crosstalk, versikine induced components of "T-cell inflammation," including IRF8-dependent type I interferontranscriptional signatures andT-cell chemoattractantCCL2.Thus the interplay between stromal cells andmyeloid cells in the myeloma microenvironment generates versikine, a novel bioactive damage-associated molecular pattern that may facilitate immune sensing of myeloma tumors and modulate the tolerogenic consequences of intact VCAN accumulation. Therapeutic versikine administration may potentiate T-cell-activating immunotherapies. [ABSTRACT FROM AUTHOR]

Although the antimyeloma effect of lenalidomide is associated with activation of the immune system, the exact in vivo immunomodulatory mechanisms of lenalidomide combined with low-dose dexamethasone (Len-dex) in refractory/relapsed multiple myeloma (RRMM) patients remain unclear. In this study, we analyzed the association between immune cell populations and clinical outcomes in patients receiving Len-dex for the treatment of RRMM. Peripheral blood samples from 90 RRMM patients were taken on day 1 of cycles 1 (baseline), 2, 3, and 4 of Len-dex therapy. Peripheral blood CD3, CD4, and CD8 cell frequencies were significantly decreased by 3 cycles of therapy, whereas NK cell frequency was significantly increased after the 3rd cycle. For the myeloid-derived suppressor cell (MDSC) subset, the frequency of granulocytic MDSCs transiently increased after the 1st cycle, whereas there was an increase in monocytic MDSC (M-MDSC) frequency after the 1st and 3rd cycles. Among 81 evaluable patients, failure to achieve a response of VGPR or greater was associated with a decrease in CD8 cell frequency and increase in M-MDSC frequency after 3 cycles of Len-dex treatment. A high proportion of natural killer T (NKT)-like cells (CD3/CD56) prior to Len-dex treatment might predict a longer time to progression. In addition, patients with a smaller decrease in the frequency of both CD3 cells and CD8 cells by 3 cycles exhibited a longer time to the next treatment. These results demonstrated that early changes in immune cell subsets are useful immunologic indicators of the efficacy of Len-dex treatment in RRMM. [ABSTRACT FROM AUTHOR]

Primary plasma cell leukemia (pPCL) is an uncommon form of plasma cell dyscrasia, and the most aggressive of the human monoclonal gammopathies. The t(11;14)(q13;q32) rearrangement is the most common alteration in pPCL, promoting cyclin D1 (CCND1) gene overexpression caused by its juxtaposition with the immunoglobulin heavy locus chromosome region. The myeloma overexpressed (MYEOV) gene maps very close to the CCND1 gene on chromosome 11, but its overexpression is rarely observed in multiple myeloma. The present study describes a case of pPCL with t(11;14) characterized by a breakpoint on der(11), unlike the one usually observed. Droplet digital polymerase chain reaction analysis revealed overexpression of CCND1 and MYEOV. To the best of our knowledge, MYEOV gene overexpression has never been previously described in pPCL. [ABSTRACT FROM AUTHOR]

The importance of proinflamatory cytokines and acute phase proteins in pathogenesis and progression of MM is well known. However, there are any studies evaluating the role of NT-proCN in management and treatment of MM. The aim of our study was to evaluate the concentration of NT-proCNP and acute phase proteins in patients with MM before and after stem cell transplantation. We involved 40 newly diagnosed MM patients in stage III according to the Durie-Salmon classification and treated with high dose of melphalan (200 mg/m2) prior to ASCT. Concentration of NT-proCNP, hs-CRP and SAA were measured before conditioning treatment and every 4 days until the 24th day after stem cell infusion. We observed low NT-proCNP levels before conditioning treatment (0.121 ± 0.04 pmol/l), the higher in day on ASCT (0.28 ± 0.14 pmol/l). Further we showed significant gradual increase concentration of NT-proCNP up to 12 days after stem cells infusion (1.07 ± 0.72 pmol/l). The kinetics of hs-CRP and SAA levels were similar to NT-proCNP. We showed positive correlation between NT-proCNP levels and absolute neutrophil and platelets count in patients after ASCT. NT-proCNP can be useful parameter to assess effectiveness of treatment and monitoring of hematopoetic recovery time in patients with MM after stem cell transplantations. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to better understand the efficacy and safety of carfilzomib, panobinostat, and elotuzumab combinations in patients with refractory/relapsed multiple myeloma(R/RMM). Methods: We retrieved and reviewed published reports including carfilzomib, panobinostat, and elotuzumab combination regimens for patients with R/RMM. Results: We identified 20 prospective studies that evaluated 2220 patients. Carfilzomib combination regimens produced an overall response rate (ORR ≥ PR) of 61 % in the 1211 relapsed/refractory patients. At least very good partial response (VGPR) was 29 % in patients with carfilzomib combinations. Finally, 49 % of the 597 patients achieved ORR in patients receiving panobinostat-containing combinations. At least VGPR was 16 % in patients with panobinostat combinations. Three hundred twenty-eight of these 449 patients (73 %) receiving elotuzumab-containing combinations achieved ORR. And at least VGPR was 37 %. And, the vital nonhematologic adverse events (AEs) were cardiac events and pneumonia. Conclusion: Carfilzomib, panobinostat, and elotuzumab combination regimens produced clinical benefits in patients with R/RMM. [ABSTRACT FROM AUTHOR]

Combining cytotoxic agents with novel agents is an inferior treatment option for patients with relapsed/refractory myeloma. Not all combination therapies have the same efficacy, and the agents in the combinations do matter. See also pages 2050‐6. [ABSTRACT FROM AUTHOR]

Microfluidic cell culture systems are becoming increasingly useful for studying biology questions, particularly those involving small cell populations that are cultured within microscale geometries mimicking the complex cellular microenvironment. Depending on the geometry and spatial organization of these cell populations, however, paracrine signaling between cell types can depend critically on spatial concentration profiles of soluble factors generated by diffusive transport. In scenarios where single cell data are acquired to study cell population heterogeneities in functional response, uncertainty associated with concentration profiles can lead to interpretation bias. To address this issue and provide important evidence on how diffusion develops within typical microfluidic cell culture systems, a combination of experimental and computational approaches were applied to measure and predict concentration patterns within microfluidic geometries, and characterize the functional response of culture cells based on single-cell resolution transcription factor activation. Using a model coculture system consisting of multiple myeloma cells (MMCs) and neighboring bone marrow stromal cells (BMSCs), we measured concentrations of three cytokines (IL-6, VEGF, and TNFα) in conditioned media collected from separate culture compartments using a multiplex ELISA system. A 3D numerical model was developed to predict biomolecular diffusion and resulting concentration profiles within the tested microsystems and compared with experimental diffusion of 20 kDa FITC-Dextran. Finally, diffusion was further characterized by controlling exogenous IL-6 diffusion and the coculture spatial configuration of BMSCs to stimulate STAT3 nuclear translocation in MMCs. Results showed agreement between numerical and experimental results, provided evidence of a shallow concentration gradient across the center well of the microsystem that did not lead to a bias in results, and demonstrated that microfluidic systems can be tailored with specific geometries to avoid spatial bias when desired. [ABSTRACT FROM AUTHOR]

Background: General practice plays an important role in the cancer care pathway. Patient dissatisfaction with the diagnostic process may be expressed by changing to another general practice.Aim: To compare the frequency of change of practice (COP) in patients with cancer (n = 150 216) with a matched cancer-free control cohort (n = 1 502 114) and to analyse associations with cancer type and patient characteristics.Design and Setting: A population-based matched cohort study using historical and prospectively collected data from Danish nationwide registers.Method: COP was defined as a change of practice list, unrelated to change of address or reorganisation of the practice. Data were analysed monthly in the year before and after a cancer diagnosis.Results: More patients with cancer than controls changed general practice (4.1% versus 2.6%) from 7 months before and until 12 months after diagnosis. The COP rate varied by cancer type (rectal cancer served as reference). Before the diagnosis, COP was most often seen among patients with ovarian cancer (risk ratio [RR] 1.51, 95% confidence interval [CI] = 1.10 to 2.08) and multiple myeloma (RR 1.89, 95% CI = 1.34 to 2.67). After the diagnosis, COP was most frequent among patients with brain cancer (RR 1.38, 95% CI = 1.05 to 1.82) and ovarian cancer (RR 1.51, 95% CI = 1.21 to 1.88).Conclusion: Patients with cancer changed general practice more frequently than the cancer-free controls. COP variations between cancer types may be attributed to lack of diagnostic timeliness due to clinical complexity of the diagnosis and the role of the GP in the diagnostic process. [ABSTRACT FROM AUTHOR]

Carfilzomib, a proteasome inhibitor, is approved in the United States as a single agent, and in combination with dexamethasone or lenalidomide/dexamethasone (KRd) for relapsed or refractory multiple myeloma (MM). Under the single-agent and KRd approvals, carfilzomib is administered as a 10-minute IV infusion on days 1, 2, 8, 9, 15, and 16 of 28- day cycles (20mg/m2 [cycle 1, days 1-2]; 27mg/m2 thereafter).Thismulticenter, single-arm, phase 1/2 study, Community Harmonized Assessment of Myeloma Patients via an Integrated Oncology Network-1 (CHAMPION-1), evaluated once-weekly carfilzomib with dexamethasone in relapsed, or relapsed and refractory MM (1-3 prior therapies). Patients received carfilzomib (30-minute IVinfusion) on days 1, 8, and15 of 28-day cycles. Thephase 1 portion used a 3 1 3 dose-escalation scheme to determine the maximum tolerated dose (MTD) of carfilzomib. During phase 2, patients received carfilzomib on the same schedule at theMTD. Patients received dexamethasone (40mg) on days 1, 8, 15, and 22; dexamethasone was omitted on day 22 for cycles 91. A total of 116 patients were enrolled. The MTD was 70 mg/m2, and 104 patients (phase 1/2) received carfilzomib 70 mg/m2. At 70 mg/m2, the median number of prior regimens was 1; and 52% were bortezomib-refractory. At 70 mg/m2, the most common grade ≥3 adverse events were fatigue (11%) and hypertension (7%). Overall response rate at 70 mg/m2 was 77%. Median progression-free survival was 12.6 months. These findings merit additional evaluation of the once-weekly dosing regimen. This trial was registered at www.clinicaltrials. gov as #NCT01677858. [ABSTRACT FROM AUTHOR]

In the year 2000, Hanahan and Weinberg (1) defined the six Hallmarks of Cancer as: self-sufficiency in growth signals, evasion of apoptosis, insensitivity to antigrowth mechanisms, tissue invasion and metastasis, limitless replicative potential, and sustained angiogenesis. Eleven years later, two new Hallmarks were added to the list (avoiding immune destruction and reprograming energy metabolism) and two new tumor characteristics (tumor-promoting inflammation and genome instability and mutation) (2). In multiple myeloma (MM), a destructive cancer of the plasma cell that grows predominantly in the bone marrow (BM), it is clear that all these hallmarks and characteristics are in play, contributing to tumor initiation, drug resistance, disease progression, and relapse. Bone marrow adipose tissue (BMAT) is a newly recognized contributor to MM oncogenesis and disease progression, potentially affecting MM cell metabolism, immune action, inflammation, and influences on angiogenesis. In this review, we discuss the confirmed and hypothetical contributions of BMAT to MM development and disease progression. BMAT has been understudied due to technical challenges and a previous lack of appreciation for the endocrine function of this tissue. In this review, we define the dynamic, responsive, metabolically active BM adipocyte. We then describe how BMAT influences MM in terms of: lipids/metabolism, hypoxia/angiogenesis, paracrine or endocrine signaling, and bone disease. We then discuss the connection between BMAT and systemic inflammation and potential treatments to inhibit the feedback loops between BM adipocytes and MM cells that support MM progression. We aim for researchers to use this review to guide and help prioritize their experiments to develop better treatments or a cure for cancers, such as MM, that associate with and may depend on BMAT. [ABSTRACT FROM AUTHOR]

Bone marrow mesenchymal stem cells' (BM-MSCs) role in multiple myeloma (MM) pathogenesis is recognized. Recently, we have published that co-culture of MM cell lines with BM-MSCs results in mutual modulation of phenotype and proteome (via translation initiation (TI) factors eIF4E/eIF4GI) and that there are differences between normal donor BM-MSCs (ND-MSCs) and MM BM-MSCs (MM-MSCs) in this crosstalk. Here, we aimed to assess the involvement of soluble BM-MSCs' (ND, MM) components, more easily targeted, in manipulation of MM cell lines phenotype and TI with specific focus on microvesicles (MVs) capable of transferring critical biological material. We applied ND and MM-MSCs 72 h secretomes to MM cell lines (U266 and ARP-1) for 12-72 h and then assayed the cells' (viability, cell count, cell death, proliferation, cell cycle, autophagy) and TI (factors: eIF4E, teIF4GI; regulators: mTOR, MNK1/2, 4EBP; targets: cyclin D1, NFκB, SMAD5, cMyc, HIF1α). Furthermore, we dissected the secretome into > 100 kDa and < 100 kDa fractions and repeated the experiments. Finally, MVs were isolated from the ND and MM-MSCs secretomes and applied to MM cell lines. Phenotype and TI were assessed. Secretomes of BM-MSCs (ND, MM) significantly stimulated MM cell lines' TI, autophagy and proliferation. The dissected secretome yielded different effects on MM cell lines phenotype and TI according to fraction (> 100 kDa- repressed; < 100 kDa- stimulated) but with no association to source (ND, MM). Finally, in analyses of MVs extracted from BM-MSCs (ND, MM) we witnessed differences in accordance with source: ND-MSCs MVs inhibited proliferation, autophagy and TI whereas MM-MSCs MVs stimulated them. These observations highlight the very complex communication between MM and BM-MSCs and underscore its significance to major processes in the malignant cells. Studies into the influential MVs cargo are underway and expected to uncover targetable signals in the regulation of the TI/proliferation/autophagy cascade. [ABSTRACT FROM AUTHOR]

Monoclonal immunoglobulins are markers of plasma cell proliferative diseases and have been described as the first (and perhaps best) serological tumor marker. The unique structure of each monoclonal protein makes them highly specific for each plasma cell clone. The difficulties of using monoclonal proteins for diagnosing and monitoring multiple myeloma, however, stem from the diverse disease presentations and broad range of serum protein concentrations and molecular weights. Because of these challenges, no single test can confidently diagnose or monitor all patients. Panels of tests have been recommended for sensitivity and efficiency. In this review we discuss the various disease presentations and the use of various tests such as protein electrophoresis and immunofixation electrophoresis as well as immunoglobulin quantitation, free light chain quantitation, and heavy-light chain quantitation by immuno-nephelometry. The choice of tests for inclusion in diagnostic and monitoring panels may need to be tailored to each patient, and examples are provided. The panel currently recommended for diagnostic screening is serum protein electrophoresis, immunofixation electrophoresis, and free light chain quantitation. [ABSTRACT FROM AUTHOR]

Objectives: Modern management of myeloma has significantly improved survival, with increasing numbers of patients living beyond a decade. However, little is known about the long-term cardiovascular and respiratory status of intensively treated and multiply relapsed survivors. Methods: We performed detailed cardiovascular and respiratory evaluations in patients with intensively treated, advanced but stable myeloma. All patients had received at least two lines of treatment, including at least one haematopoietic stem cell transplantation procedure, but had stable, controlled disease and were off active treatment at the time of evaluation. Results: Thirty-two patients with a median duration of 6 years (range 2-12) from original diagnosis of myeloma and three lines (range 2-6) of treatment were evaluated. Despite normal physical examination in the majority, there was a high prevalence of sub-clinical cardiac and respiratory dysfunction, reflected by abnormalities of electrocardiography (45%), echocardiography (50%), serum N-terminal pro-B-type natriuretic peptide level (NT-pro-BNP, 50%), and pulmonary function testing (45%). NT-pro-BNP level correlated negatively with quality of life (P = 0.012) and positively with serum ferritin (P = 0.027). Dyspnoea score correlated with BMI (P = 0.001). Risk factors for cardiovascular disease (obesity, hypertension, hyperlipidaemia, and hyperinsulinaemia) were common. Discussion: Even in the absence of overt clinical features, the majority of intensively treated long-term survivors of myeloma have established cardiovascular and/or respiratory dysfunction, above levels expected in the general population of a similar age. Conclusion: This study supports routine screening and lifestyle modification combined with primary and secondary preventive strategies to reduce cardiovascular and respiratory disease and to preserve quality of life in transplanted myeloma patients. [ABSTRACT FROM AUTHOR]

Heparanase is a β-D-glucuronidase which cleaves heparan sulfate chains in the extracellular matrix and on cellular membranes. A dysregulated heparanase activity is intimately associated with cell invasion, tumor metastasis and angiogenesis, making heparanase an attractive target for the development of anticancer therapies. SST0001 (roneparstat; Sigma-Tau Research Switzerland S.A.) is a non-anticoagulant 100% N-acetylated and glycol-split heparin acting as a potent heparanase inhibitor, currently in phase I in advanced multiple myeloma. Herein, the kinetics of heparanase inhibition by roneparstat is reported. The analysis of dose-inhibition curves confirmed the high potency of roneparstat (IC50 ≈ 3 nM) and showed, at higher concentrations, a Hill coefficient consistent with the engagement of two molecules of inhibitor. A homology model of human heparanase GS3 construct was built and used for docking experiments with inhibitor fragments. The model has high structural similarity with the recently reported crystal structure of human heparanase. Different interaction schemes are proposed, which support the hypothesis of a complex binding mechanism involving the recruitment of one or multiple roneparstat chains, depending on its concentration. In particular, docking solutions were obtained in which (i) a single roneparstat molecule interacts with both heparin- binding domains (HBDs) of heparanase or (ii) twofragments of roneparstat interact with either HBD-1 or HBD-2, consistent with the possibility of different inhibitor:enzyme binding stoichiometries. This study provides unique insights into the mode of action of roneparstat as well as clues of its interaction with heparanase at a molecular level, which could be exploited to design novel potential inhibitor molecules. [ABSTRACT FROM AUTHOR]

Summary Proteasome inhibitors have revolutionized outcomes in multiple myeloma, but they are used empirically, and primary and secondary resistance are emerging problems. We have identified TJP1 as a determinant of plasma cell proteasome inhibitor susceptibility. TJP1 suppressed expression of the catalytically active immunoproteasome subunits LMP7 and LMP2, decreased proteasome activity, and enhanced proteasome inhibitor sensitivity in vitro and in vivo. This occurred through TJP1-mediated suppression of EGFR/JAK1/STAT3 signaling, which modulated LMP7 and LMP2 levels. In the clinic, high TJP1 expression in patient myeloma cells was associated with a significantly higher likelihood of responding to bortezomib and a longer response duration, supporting the use of TJP1 as a biomarker to identify patients most likely to benefit from proteasome inhibitors. [ABSTRACT FROM AUTHOR]

Heavy chain diseases are rare variants of B-cell lymphomas that produce one of three classes of immunoglobulin heavy chains, without corresponding light chains. We describe two patients with asymptomatic heavy chain monoclonal gammopathy. The first patient is a 51-year-old woman with alpha paraprotein on serum immunofixation. The second case is a 46-year-old woman with gamma paraprotein on urine immunofixation. Neither patient had corresponding monoclonal light chains. Workup for multiple myeloma and lymphoma was negative in both patients. These two cases illustrate that heavy chain monoclonal gammopathy can exist in the absence of clinically apparent malignancy. Only a few reports of “heavy chain MGUS” have been described before. In the absence of specialized guidelines, we suggest a similar follow-up as for MGUS, while taking into account the higher probability of progression to lymphoma than to myeloma. [ABSTRACT FROM AUTHOR]

Multiple myeloma is an aggressive hematopoietic cancer of plasma cells. The recent emergence of three effective FDA-approved proteasome-inhibiting drugs, bortezomib (Velcade®), carfilzomib (Kyprolis®), and ixazomib (Ninlaro®), confirms that proteasome inhibitors are therapeutically useful against neoplastic disease, in particular refractory multiple myeloma and mantle cell lymphoma. This study describes the synthesis, computational affinity assessment, and preclinical evaluation of TIR-199, a natural product-derived syrbactin structural analog. Molecular modeling and simulation suggested that TIR-199 covalently binds each of the three catalytic subunits (β1,β2, and β5) and revealed key interaction sites. In vitro and cell culturebased proteasome activity measurements confirmed that TIR- 199 inhibits the proteasome in a dose-dependent manner and induces tumor cell death in multiple myeloma and neuroblastoma cells as well as other cancer types in the NCI-60 cell panel. It is particularly effective against kidney tumor cell lines, with >250-fold higher anti-tumor activities than observed with the natural product syringolin A. In vivo studies in mice revealed a maximum tolerated dose of TIR-199 at 25 mg/kg. The anti-tumor activity of TIR-199 was confirmed in hollow fiber assays in mice. Adverse drug reaction screens in a kidney panel revealed no off-targets of concern. This is the first study to examine the efficacy of a syrbactin in animals. Taken together, the results suggest that TIR-199 is a potent new proteasome inhibitor with promise for further development into a clinical drug for the treatment of multiple myeloma and other forms of cancer. [ABSTRACT FROM AUTHOR]

Background: Melphalan has been used in the treatment of various hematologic malignancies for almost 60 years. Today it is part of standard therapy for multiple myeloma and also as part of myeloablative regimens in association with autologous allogenic stem cell transplantation. Melflufen (melphalan flufenamide ethyl ester, previously called J1) is an optimized derivative of melphalan providing targeted delivery of active metabolites to cells expressing aminopeptidases. The activity of melflufen has compared favorably with that of melphalan in a series of in vitro and in vivo experiments performed preferentially on different solid tumor models and multiple myeloma. Melflufen is currently being evaluated in a clinical phase I/II trial in relapsed or relapsed and refractory multiple myeloma.Methods: Cytotoxicity of melflufen was assayed in lymphoma cell lines and in primary tumor cells with the Fluorometric Microculture Cytotoxicity Assay and cell cycle analyses was performed in two of the cell lines. Melflufen was also investigated in a xenograft model with subcutaneous lymphoma cells inoculated in mice.Results: Melflufen showed activity with cytotoxic IC50-values in the submicromolar range (0.011-0.92 μM) in the cell lines, corresponding to a mean of 49-fold superiority (p < 0.001) in potency vs. melphalan. In the primary cultures melflufen yielded slightly lower IC50-values (2.7 nM to 0.55 μM) and an increased ratio vs. melphalan (range 13-455, average 108, p < 0.001). Treated cell lines exhibited a clear accumulation in the G2/M-phase of the cell cycle. Melflufen also showed significant activity and no, or minimal side effects in the xenografted animals.Conclusion: This study confirms previous reports of a targeting related potency superiority of melflufen compared to that of melphalan. Melflufen was active in cell lines and primary cultures of lymphoma cells, as well as in a xenograft model in mice and appears to be a candidate for further evaluation in the treatment of this group of malignant diseases. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a haematologic malignancy characterized by the expansion of monoclonal plasma cells in the bone marrow. It is associated with serum or urine monoclonal protein and organ damage including renal failure, anaemia, hypercalcaemia and bone lesions. Despite recent improvements MM still remains an incurable disease. Previous studies have shown that the adoptive transfer of autologous T-cells modified to express chimeric antigen receptors (CAR) is effective in cases of acute and chronic lymphoid leukaemia. However, the adjustment of CAR-T-cell therapy to MM is hindered by the scarcity of antigens specific to the tumour plasma cells. Most candidate targets are shared by healthy tissues, and entail high risks of toxicity. Therefore several strategies have been proposed to regulate CAR-T-cell function as well as to enhance CAR-T-cell specificity against tumour cells. In this article we summarize the surface markers that have been investigated as targets to eliminate MM plasma cells and the MM-specific CARs that have been developed to date. Then we describe the different CAR-T-cell designs that could be applied in the case of MM to circumvent current problems of toxicity. [ABSTRACT FROM AUTHOR]

Background: The proteasome is a validated anti-cancer target and various small-molecule inhibitors are currently in clinical development or on the market. However, adverse events and resistance associated with those proteasome inhibitors indicate the need for a new generation of drugs. Therefore, we focused on developing an oral proteasome inhibitor with improved efficacy and safety profiles.Method: The in vitro inhibition of the 20S proteasome catalytic activities was determined in human multiple myeloma (MM) cellular lysates with fluorogenic peptide substrates specific for each catalytic subunit. Cell cytotoxicity was assessed with the ATP bioluminescence assay using human cell samples from tumor cell lines, MM patients or normal healthy donors. In mice bearing human MM xenografts, a single dose of LC53-0110 was administered orally, and concentration-time profiles of LC53-0110 and the 20S proteasome catalytic activities in plasma, blood, and tumor were determined. The efficacy of repeat-dose compound with regard to tumor growth inhibition in vivo was also evaluated in the same MM xenograft models.Results: LC53-0110 is far more specific for the chymotrypsin-like proteolytic (β5) site of the 20S proteasome as compared to bortezomib, carfilzomib, or ixazomib. LC53-0110 treatment showed accumulation of ubiquitinated proteins, inhibited cell viability with a low nM range potency in various tumor cell lines, and showed potent activity on CD138(+) cells isolated from MM patients who are resistant/refractory to current FDA-approved drug treatment. When a single dose was administered orally to tumor-bearing mice, LC53-0110 showed both greater maximum and sustained tumor proteasome inhibition as compared with ixazomib in MM xenograft models. The robust pharmacodynamic responses in tumor correlated with tumor growth regression. In addition, LC53-0151, an analog of LC53-0110, in combination with pomalidomide, a third-generation immunomodulatory drug, showed synergistic inhibition of tumor growth both in vitro and in the xenograft mouse model.Conclusions: In view of the in vitro, in vivo, and ex vivo profiles, further investigation of additional LC compounds in preclinical studies is warranted for the nomination of a clinical development candidate. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a hematological malignancy of clonal plasma cells in the bone marrow (BM). The microenvironment plays a key role in MM cell survival and drug resistance through release of soluble factors, expression of adhesion molecules and release of extracellular vesicles (EVs). The aim of this manuscript is to use proteomic profiling of EVs as a tool to identify circulating tumor associated markers in MM patients. First, we characterized the EV protein content obtained from different MM cell lines. Then, we established differences in protein abundance among EVs isolated from MM patient serum and BM and the serum of healthy donors. These data show that the Major Histocompatibility Complex Class I is highly enriched in EVs of MM cell lines and MM patient's serum. Next, we show that CD44 is highly expressed in the EVs isolated from the corticosteroid resistant MM cell line, MM.1R. Furthermore, CD44 was found to be differentially expressed in EVs isolated from newly diagnosed MM patients. Finally through ELISA analysis, we establish the potential of serum CD44 as a predictive biomarker of overall survival. These results support the analysis of EVs as an easily accessible source for MM biomarkers. Biological significance Extracellular vesicles are becoming a research focus due to their roles in cancer cell biology such as immune evasion, therapeutic resistance, proliferation and metastases. While numerous studies of vesicle characterization and biology have been conducted in many cancer models, the role of EV in MM remains relatively unstudied. Here we found that EVs isolated from MM cells are enriched in MHC-1 antigen presenting complex and its binding protein β2-MG, this observation is compatible with the enhanced proteasome activity of MM cells compared to other cancers and the ability of functional MHC-1 to bind and present peptides, generated from protein degradation by the proteasome. Additionally, our experiments show that CD44 is particularly enriched in the EV fraction of corticosteroid resistant MM.1R cells and is differentially expressed in the EV fraction of MM patients. This is of high significance due to the established role of CD44 in adhesion of MM cells to BMSC and induction of IL-6, the primary cytokine for MM cell survival, secretion by the BMSC. Furthermore, ELISA assays for CD44 content from the serum of 254 newly diagnosed MM patients enrolled in a Phase 3 randomized trial show highly variable CD44 levels and those patients with > 280 ng/mL serum CD44 showing a reduced overall survival time. These results suggest the potential use of CD44 as a prognostic biomarker in MM. [ABSTRACT FROM AUTHOR]

Light chain deposition disease (LCDD) is a rare multisystemic disorder associated with plasma cell proliferation. It mainly affects the kidney, but liver and heart involvement may occur, sometimes mimicking the picture of systemic amyloidosis. Liver disease in LCDD is usually asymptomatic and exceptionally manifests with severe cholestatic hepatitis. We report the case of a 66-year-old female with k-LCDD and cast nephropathy in the setting of symptomatic multiple myeloma who, after a first cycle of bortezomib-dexamethasone chemotherapy, developed severe and rapidly worsening intrahepatic cholestasis secondary to liver K-light chain deposition. Intrahepatic cholestasis was attributed to LCDD on the basis of the liver histology and exclusion of possible diagnoses. Chemotherapy was maintained and resulted in progressive resolution of cholestasis. We report here an uncommon presentation of LCDD, with prominent liver involvement that fully recovered with bortezomib-based chemotherapy, and briefly review the relevant literature. [ABSTRACT FROM AUTHOR]

Background: The overall prognosis of multiple myeloma has improved significantly over the last 15 years. We wondered whether the overall improvement would also be seen in unselected patients in an academic center in Northwest Louisiana with a high proportion of minority patients, and if second malignant neoplasms are relevant for our patients. Materials and Methods: Between 1998 and 2009, 215 patients were treated for multiple myeloma at our center and had complete follow-up until May 2013. Results: The mean survival of patients with multiple myeloma increased from 3.25 to 5.34 years, which is comparable to patients treated at larger centers. No prognostic difference was observed in the subgroups of myeloma patients. Among 215 patients followed for the development of secondary cancers, 16 already had a preexisting or concomitant malignancy (7.4%) and 10 developed secondary cancers. Our data indicate a significant background of histologically unrelated cancers and a cumulative incidence of new cancers of about 20% after 10 years of follow-up. Based on SEER data, preexisting or secondary cancers were not statistically increased in our population. Conclusions: The use of autologous transplantation and the introduction of new agents resulted in a significant improvement in the prognosis of multiple myeloma. Other cancers are not statistically increased before or after multiple myeloma is diagnosed and are not prognostically relevant. [ABSTRACT FROM AUTHOR]

Human myeloma cells express CD38 at high levels and grow in hypoxic niches inside the bone marrow. Myeloma cells respond to hypoxia with metabolic changes leading to aerobic glycolysis, thus reducing adenosine triphosphate (ATP) and increasing NAD+. Our hypothesis is that these conditions favor the enzymatic pathways involved in the production of adenosine in the niche. Within the niche, NAD+ is able to activate a discontinuous adenosinergic pathway that relies upon CD38, CD203a and CD73 or TRACP, according to the environmental pH. The observed variability in adenosine concentrations in bone marrow aspirates is a result of the interactions taking place among myeloma and other cells in the bone marrow niche. A pilot study showed that adenosine profiles differ during disease progression. Adenosine levels were significantly higher in the bone marrow plasma of patients with symptomatic myeloma and correlated with ISS staging, suggesting that adenosine is produced in the myeloma niche at micromolar levels by an ectoenzymatic network centered on CD38. Adenosine levels increase with disease aggressiveness, a finding that supports adenosine as a potential marker of myeloma progression. [ABSTRACT FROM AUTHOR]

Extramedullary myeloma (EMM) is defined by the presence of plasma cells (PCs) outside the bone marrow in a patient with multiple myeloma (MM). Using sensitive imaging techniques including magnetic resonance imaging and positron emission tomography/computed tomography, EMM may be found in up to 30% of MM patients across the overall disease course. The molecular mechanisms underlying the hematogenous spread of PCs outside the bone marrow are only partially known and involve hypoxia and an altered expression of adhesion molecules. Extramedullary disease is associated with adverse prognostic factors (ie, high lactate dehydrogenase level, 17p deletion, and high-risk gene expression profile). The prognosis of EMM is poor, and the median overall survival of patientswho experience anextramedullary relapse is <6 months. The adverse prognosis is less pronounced in patients with bone-related plasmacytomas than in those with hematogenous EMM. EMM patients should be considered as having high-risk myeloma and treated accordingly. However, EMM clinical situations are extraordinarily heterogeneous, and their management is particularly challenging. In the present review, a case-and-comment format is used to describe our approach to the management of EMM. [ABSTRACT FROM AUTHOR]

Nuclear receptor SET domain containing protein 2 (NSD2) catalyzes the methylation of histone H3 lysine 36 (H3K36). It is a determinant in Wolf-Hirschhorn syndrome and is overexpressed in human multiple myeloma. Despite the relevance of NSD2 to cancer, there are no potent, selective inhibitors of this enzyme reported. Here, a combination of kinetic isotope effect measurements and quantum chemical modeling was used to provide subangstrom details of the transition state structure for NSD2 enzymatic activity. Kinetic isotope effects were measured for the methylation of isolated HeLa cell nucleosomes by NSD2. NSD2 preferentially catalyzes the dimethylation of H3K36 along with a reduced preference for H3K36 monomethylation. Primary Me-14C and 36S and secondary Me-³H3, Me-²H3, 5'-14C, and 5'-³H2 kinetic isotope effects were measured for the methylation of H3K36 using specifically labeled S-adenosyl-L-methionine. The intrinsic kinetic isotope effects were used as boundary constraints for quantum mechanical calculations for the NSD2 transition state. The experimental and calculated kinetic isotope effects are consistent with an SN2 chemical mechanism with methyl transfer as the first irreversible chemical step in the reaction mechanism. The transition state is a late, asymmetric nucleophilic displacement with bond separation from the leaving group at (2.53 Å) and bond making to the attacking nucleophile (2.10 Å) advanced at the transition state. The transition state structure can be represented in a molecular electrostatic potential map to guide the design of inhibitors that mimic the transition state geometry and charge. [ABSTRACT FROM AUTHOR]

Purpose: Pomalidomide is a distinct immunomodulatory agent approved for the treatment of relapsed and refractory multiple myeloma. QT interval was monitored in prior studies, and although there was no indication that pomalidomide could induce QT prolongation, a formal analysis was not previously conducted. Therefore, we present here the results of a study evaluating the effects of pomalidomide on QT interval corrected for heart rate (QTc) using Fridericia's formula (QTcF) and other electrocardiogram (ECG) parameters.Methods: Healthy male volunteers with normal or clinically acceptable laboratory tests and ECG results were randomized to receive single oral doses of placebo, pomalidomide 4 mg, pomalidomide 20 mg, and moxifloxacin 400 mg (positive control) in different sequences. Subjects were evaluated by digital ECG monitoring and underwent blood sampling and standard safety monitoring.Results: Seventy-two subjects were enrolled. In ECG evaluations performed after dosing with pomalidomide 4 mg (therapeutic dose) or 20 mg (supratherapeutic dose), the upper limit of the two-sided 90 % CI for mean change from baseline and placebo-corrected QTcF was <10 ms at all postdose time points, which is below the defined threshold of regulatory concern. In contrast, moxifloxacin induced a clear prolongation in QT interval. Changes in heart rate and other ECG parameters after pomalidomide dosing were clinically insignificant.Conclusions: Pomalidomide given as a single oral dose of up to 20 mg was not associated with QT prolongation in healthy male subjects. [ABSTRACT FROM AUTHOR]

This article addresses the problem of designing therapies for the myeloma bone disease that optimize in a systematic way a compromise between drug toxicity and tumor repression. For that sake, the techniques of optimal control are applied to the dynamics of tumor growth, and the necessary conditions of Pontryagin's minimum principle are solved using a numerical relaxation algorithm. A therapy to accelerate bone mass recovery is applied in parallel, based on a PI control rule. Since the optimal controller provides an open-loop control, it is turned into a feedback law by following a receding horizon strategy. For that sake, an optimal manipulated variable profile is first computed over a time horizon, but only the initial part of this function is applied. The whole optimization procedure is then repeated starting at a time instant that corresponds to the end of the previously applied control. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study is to explore the antitumor efficacy of lidamycin (LDM) against human multiple myelomas (MM).Materials and Methods: Human MM RPMI 8226 cells and the xenograft model in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice were used to examine the antitumor activity of LDM.Results: Notably, LDM markedly suppressed the growth of human MM RPMI 8226 xenograft in NOD/SCID mice. In vitro, there was a significant reduction in cell proliferation after treatment with LDM. The overall growth inhibition correlated with the increase of apoptotic cells. The apoptosis-related proteins including caspase-3, 7, and 9 were activated, and poly adenosine diphosphate-ribose polymerase was cleaved. Further investigation revealed that cellular Bcl-2 and survivin decreased, whereas the level of Bax increased in the LDM-treated cells.Conclusions: LDM is highly effective against the growth of MM xenograft in NOD/SCID mice. The potent apoptosis.inducing effect of LDM may be mediated through caspase. and mitochondria.dependent pathway. [ABSTRACT FROM AUTHOR]

The 57th American Society of Haematology (ASH) meeting held in Orlando, FL was certainly the year when myeloma management changed for good, with a plethora of newly Food and Drug Administration (FDA)-approved drugs showing impressive outcome improvements and the introduction of new techniques for disease monitoring. Also, chimeric antigen receptor (CAR) T cells continued their triumphal march, consolidating their success in lymphoma and chronic lymhocytic leukaemia (CLL) and venturing into new fields such as again multiple myeloma. Some experimental drugs showed long-awaited results (midostaurin in FLT3-mutated acute myeloid leukaemia (AML)) and some brand new drugs showed promising results in the clinic after extensive preclinical studies, such as those targeting new epigenetic factors (histone methyltransferases) and apoptosis. [ABSTRACT FROM AUTHOR]

Background. Light chain myeloma cast nephropathy (MCN) is the major cause of renal failure in multiple myeloma and strongly impacts patient survival. The role of kidney biopsy in the management of MCN is unclear. Methods. Renal pathological findings were retrospectively studied in 70 patients with multiple myeloma and MCN. Patients were categorized according to the achievement or not of renal response, as defined by estimated glomerular filtration rate (eGFR) =30 mL/min/1.73 m² and/or dialysis independence at 3 months. Results. Thirty-two patients (46%) achieved a renal response. In the whole study population, the following parameters differed significantly between patients with and without renal response, respectively: baseline median eGFR (13.3 versus 9.3 mL/min/1.73 m², P = 0.017), Acute Kidney Injury Network Stage 3 (68.8 versus 92.1%, P = 0.019), haematological response rate (94 versus 34%, P < 0.0001), median percentage of free light chain (FLC) reduction at Day 21 (92 versus 24%, P = 0.006) and median number of casts/10 fields (14 versus 25, P = 0.005). The extent of interstitial fibrosis and tubular atrophy was similar. In multivariate analysis, only FLC reduction at Day 21 was significantly associated with renal response. However, when considering only the subgroup of haematological responders, both median number of casts [odds ratio (OR) = 0.93, 95% confidence interval (95% CI): 0.88-0.98, P = 0.01] and extent of tubular atrophy (OR = 0.03, 95% CI: 0.00-0.52, P = 0.02) were independent predictors of renal response. Conclusions. In MCN, the presence of numerous casts and diffuse tubular atrophy is associated with poor renal prognosis. These data suggest that additional strategies to reduce FLC burden should be considered in patients with extensive cast formation. [ABSTRACT FROM AUTHOR]

The article focuses on autologus hematopoietic stem cell transplantation which is known to provide hematopoietic support after high-dose chemotherapy including means of delivering care for patients suffering from multiple myeloma.

Background Chromosome abnormalities are important prognostic factors in myeloma allowing risk stratification of patients. Different techniques are available for their detection including cytogenetics, Fluorescent In Situ Hybridisation (FISH) and array Competitive Genomic Hybridisation (CGH). This study aimed to assess the validity and usefulness of each technique in a diagnostic setting. Methods 112 myeloma cases were analysed by whole bone marrow cytogenetics and by FISH and array CGH performed on purified plasma cell populations. Results Clonal abnormalities were identified in 30% of cases by cytogenetics and 97% by FISH and array CGH. By combining array and FISH results abnormalities were detected in 99% of cases and, if cytogenetic analysis was also considered, abnormalities were detected in 100% of cases. Conclusions Cytogenetic analysis is of limited value in myeloma. Array CGH and FISH are highly specific tests allowing the identification of aberrations in virtually all cases. The two techniques are complementary and need to be combined in order to provide a comprehensive analysis of all clinically relevant aberrations in myeloma. [ABSTRACT FROM AUTHOR]

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]