Correction: Spectrum of Cerebrovascular Disease in Patients with Multiple Myeloma Undergoing Chemotherapy-Results of a Case Control Study.

[This corrects the article DOI: 10.1371/journal.pone.

Spectrum of Cerebrovascular Disease in Patients with Multiple Myeloma Undergoing Chemotherapy-Results of a Case Control Study.

Objectives: Patients with multiple myeloma (MM) are at increased risk of arterial thrombosis. Our aim was to determine the risk factors, mechanisms and outcome of strokes in these patients.

Methods: We conducted a retrospective matched case-control study from our database of MM patients enrolled in Total Therapy (TT) 2, TT3a and TT3b protocols who developed a vascular event (transient ischemic attack, ischemic stroke, or intracerebral hemorrhage) from October 1998 to January 2014.

Adverse Metaphase Cytogenetics Can Be Overcome by Adding Bortezomib and Thalidomide to Fractionated Melphalan Transplants.

To determine whether a reduction in the intensity of Total Therapy (TT) reduces toxicity and maintains efficacy. A total of 289 patients with gene expression profiling (GEP70)-defined low-risk multiple myeloma were randomized between a standard arm (TT4-S) and a light arm (TT4-L). TT4-L employed one instead of two inductions and consolidations.

Assessment of Total Lesion Glycolysis by F FDG PET/CT Significantly Improves Prognostic Value of GEP and ISS in Myeloma.

Fluorine-18 fluorodeoxyglucose positron emission tomography with CT attenuation correction (F-FDG PET/CT) is useful in the detection and enumeration of focal lesions and in semiquantitative characterization of metabolic activity (glycolytic phenotype) by calculation of glucose uptake. Total lesion glycolysis (TLG) and metabolic tumor volume (MTV) have the potential to improve the value of this approach and enhance the prognostic value of disease burden measures. This study aims to determine whether TLG and MTV are associated with progression-free survival (PFS) and overall survival (OS), and whether they improve risk assessments such as International Staging System (ISS) stage and GEP70 risk.

Fulminant onset of acute leukemia from normal hematopoiesis within 3 months of follow up for multiple myeloma treated with total therapy protocols.

Assiduous surveillance for genetic aberrations is necessary in patients on cytotoxic therapies to detect therapy-related myeloid neoplasms (t-MN). Current modalities include metaphase cytogenetics and FISH. Since t-MN may develop abruptly in cytogenetically normal patients, a discussion exploring additional methods such as SNP-array and targeted-deep-sequencing to detect subchromosomal abnormalities is needed.

Ex vivo-expanded natural killer cells demonstrate robust proliferation in vivo in high-risk relapsed multiple myeloma patients.

Highly activated/expanded natural killer (NK) cells can be generated by stimulation with the human leukocyte antigen-deficient cell line K562, genetically modified to express 41BB-ligand and membrane-bound interleukin (IL)15. We tested the safety, persistence, and activity of expanded NK cells generated from myeloma patients (auto-NK) or haploidentical family donors (allo-NK) in heavily pretreated patients with high-risk relapsing myeloma. The preparative regimen comprised bortezomib only or bortezomib and immunosuppression with cyclophosphamide, dexamethasone, and fludarabine.

Hepatitis B reactivation in patients with multiple myeloma and isolated positive hepatitis B core antibody: a call for greater cognizance.

Hepatitis B virus (HBV) reactivation is a well-established complication of severe immunosuppression in patients with hematologic malignancy and positive hepatitis B surface antigen (HBsAg). Patients who receive high-dose chemotherapy, corticosteroids, rituximab, or have a bone marrow transplant are particularly at increased risk for HBV reactivation. However, limited information is available in the literature regarding HBV reactivation in patients with isolated anti-HBc, particularly in the setting of multiple myeloma (MM).

Jumping translocations of 1q12 in multiple myeloma: a novel mechanism for deletion of 17p in cytogenetically defined high-risk disease.

Multiple myeloma (MM) is a B-cell malignancy driven in part by increasing copy number alterations (CNAs) during disease progression. Prognostically significant CNAs accumulate during clonal evolution and include gains of 1q21 and deletions of 17p, among others. Unfortunately, the mechanisms underlying the accumulation of CNAs and resulting subclonal heterogeneity in high-risk MM are poorly understood.

Patterns of central nervous system involvement in relapsed and refractory multiple myeloma.

Background: Invasion of CNS in MM is an extremely rare occurrence that is associated with advanced disease with poor prognosis.

Patients And Methods: Our MM database identified 35 CNS MM cases presenting between January 1996 and March 2012. Descriptive analyses were performed on available data on patient characteristics, disease course, and outcomes.

Clinical, genomic, and imaging predictors of myeloma progression from asymptomatic monoclonal gammopathies (SWOG S0120).

All cases of clinical myeloma (CMM) are preceded by an asymptomatic monoclonal gammopathy (AMG), classified as either monoclonal gammopathy of undetermined significance (MGUS) or asymptomatic multiple myeloma (AMM). We analyzed data from AMG patients (n = 331) enrolled in a prospective, observational clinical trial (S0120). Baseline data from clinical variables, gene expression profiles (GEP) of purified tumor cells, and findings of magnetic resonance imaging (MRI) were correlated with the risk of progression to CMM requiring therapy.

Metronomic therapy is an effective salvage treatment for heavily pre-treated relapsed/refractory multiple myeloma.

Relapsed/refractory multiple myeloma represents a major challenge in multiple myeloma therapy. For patients with relapsed/refractory multiple myeloma, we developed a treatment schema of metronomically scheduled drug therapy. We identified 186 patients who had been treated with metronomic therapy between March 2004 and January 2012 with a median follow up of 24.

Risk factors for MDS and acute leukemia following total therapy 2 and 3 for multiple myeloma.

Lenalidomide has been linked to myelodysplastic syndrome (MDS) after autotransplants for myeloma. Total therapy trials (TT; TT2(-/+) thalidomide) and TT3 (TT3a with bortezomib, thalidomide; TT3b with additional lenalidomide) offered the opportunity to examine the contribution of these immune-modulatory agents to MDS-associated cytogenetic abnormalities (MDS-CA) and clinical MDS or acute leukemia ("clinical MDS/AL"). Of 1080 patients with serial cytogenetic studies, MDS-CA occurred in 11% and clinical MDS/AL in 3%.

Prognostic implications of serial 18-fluoro-deoxyglucose emission tomography in multiple myeloma treated with total therapy 3.

Prognostic implications of 3 imaging tools, metastatic bone survey, magnetic resonance imaging, and positron emission tomography (PET), were evaluated in 2 consecutive Total Therapy 3 trials for newly diagnosed myeloma. Data including PET at baseline and on day 7 of induction as well as standard prognostic factors were available in 302 patients of whom 277 also had gene expression profiling (GEP)-derived risk information. According to multivariate analysis, more than 3 focal lesions on day 7 imparted inferior overall survival and progression-free survival, overall and in the subset with GEP-risk data.

Thalidomide in total therapy 2 overcomes inferior prognosis of myeloma with low expression of the glucocorticoid receptor gene NR3C1.

Purpose: Because dexamethasone remains a key component of myeloma therapy, we wished to examine the impact of baseline and relapse expression levels of the glucocorticoid receptor gene NR3C1 on survival outcomes in the context of treatment with or without thalidomide.

Experimental Design: We investigated the clinical impact of gene expression profiling (GEP)-derived expression levels of NR3C1 in 351 patients with GEP data available at baseline and in 130 with data available at relapse, among 668 subjects accrued to total therapy 2 (TT2).

Results: Low NR3C1 expression levels had a negative impact on progression-free survival (PFS; HR, 1.

Standard and novel imaging methods for multiple myeloma: correlates with prognostic laboratory variables including gene expression profiling data.

Multiple myeloma causes major morbidity resulting from osteolytic lesions that can be detected by metastatic bone surveys. Magnetic resonance imaging and positron emission tomography can detect bone marrow focal lesions long before development of osteolytic lesions. Using data from patients enrolled in Total Therapy 3 for newly diagnosed myeloma (n=303), we analyzed associations of these imaging techniques with baseline standard laboratory variables assessed before initiating treatment.

Extramedullary disease portends poor prognosis in multiple myeloma and is over-represented in high-risk disease even in the era of novel agents.

Background: Extramedullary disease is an uncommon manifestation in multiple myeloma and can either accompany newly diagnosed disease or develop with disease progression or relapse. We evaluated the impact of this disease feature on patients' outcome in the context of novel agents.

Design And Methods: We analyzed clinical and biological features of extramedullary disease in 936 patients with multiple myeloma enrolled in Total Therapy protocols, 240 patients in non-Total Therapy protocols, and 789 non-protocol patients, all of whom had baseline positron emission tomography scans to document extramedullary disease at diagnosis and its subsequent development at the time of disease progression or relapse.

Second malignancies in total therapy 2 and 3 for newly diagnosed multiple myeloma: influence of thalidomide and lenalidomide during maintenance.

Thalidomide and lenalidomide constitute an important part of effective myeloma therapy. Recent data from the Intergroup Francophone du Myélome, Cancer and Leukemia Group B, and Gruppo Italiano Malattie Ematologiche dell Adulto MM-015 trials suggest that lenalidomide maintenance therapy is associated with a higher incidence of second primary malignancies (SPMs), including both hematologic and solid malignancies. In the present study, we analyzed data from the Total Therapy 2 (TT2) trial, along with the 2 Total Therapy 3 (TT3) trials.

Pharmacogenomics of bortezomib test-dosing identifies hyperexpression of proteasome genes, especially PSMD4, as novel high-risk feature in myeloma treated with Total Therapy 3.

Gene expression profiling (GEP) of purified plasma cells 48 hours after thalidomide and dexamethasone test doses showed these agents' mechanisms of action and provided prognostic information for untreated myeloma patients on Total Therapy 2 (TT2). Bortezomib was added in Total Therapy 3 (TT3), and 48 hours after bortezomib GEP analysis identified 80 highly survival-discriminatory genes in a training set of 142 TT3A patients that were validated in 128 patients receiving TT3B. The 80-gene GEP model (GEP80) also distinguished outcomes when applied at baseline in both TT3 and TT2 protocols.

International staging system and metaphase cytogenetic abnormalities in the era of gene expression profiling data in multiple myeloma treated with total therapy 2 and 3 protocols.

Background: Myeloma survival varies markedly with International Staging System classification, presence of cytogenetic abnormalities, and, especially, gene expression profiling-based risk and delTP53 status, whose collective impact has not been examined in the context of specific therapies.

Methods: The authors examined overall survival (OS), event-free survival (EFS), and complete response duration (CRD) in Total Therapy 2 with randomization to a control or thalidomide arm and in Total Therapy 3 with added bortezomib. Among 612 patients with complete data sets, multivariate analyses were used to investigate the relative contributions to OS, EFS, and CRD of International Staging System stage, cytogenetic abnormalities, and gene expression profiling-derived risk and delTP53 status, in the context of the 3 Total Therapy regimens.

Total Therapy 3 for multiple myeloma: prognostic implications of cumulative dosing and premature discontinuation of VTD maintenance components, bortezomib, thalidomide, and dexamethasone, relevant to all phases of therapy.

The impact of cumulative dosing and premature drug discontinuation (PMDD) of bortezomib (V), thalidomide (T), and dexamethasone (D) on overall survival (OS), event-free survival (EFS), time to next therapy, and post-relapse survival in Total Therapy 3 were examined, using time-dependent methodology, relevant to induction, peritransplantation, consolidation, and maintenance phases. Univariately, OS and EFS were longer in case higher doses were used of all agents during induction, consolidation (except T), and maintenance (except V and T). The favorable OS and EFS impact of D induction dosing provided the rationale for examining the expression of glucocorticoid receptor NR3C1, top-tertile levels of which significantly prolonged OS and EFS and rendered outcomes independent of D and T dosing, whereas T and D, but not V, dosing was critical to outcome improvement in the bottom-tertile NR3C1 setting.

High-risk myeloma is associated with global elevation of miRNAs and overexpression of EIF2C2/AGO2.

MicroRNAs (miRNAs) are noncoding RNAs that regulate global gene expression. miRNAs often act synergistically to repress target genes, and their dysregulation can contribute to the initiation and progression of a variety of cancers. The clinical relationship between global expression of miRNA and mRNA in cancer has not been studied in detail.