Monoclonal gammopathy of undetermined significance: a consensus statement.

On February 25, 2009, a panel of international experts on plasma cell dyscrasia and skeletal disease met to discuss monoclonal gammopathy of undetermined significance (MGUS). This non-malignant B-cell disorder is the most common plasma cell dyscrasia and is associated with an increased risk of developing serious B-cell disorders. Individuals with MGUS also have an increased risk of osteoporosis and osteopenia associated with an increased likelihood of developing fractures especially in the vertebral column, peripheral neuropathy and thromboembolic events.

Risk stratification in the era of novel therapies.

Multiple myeloma (MM) is an heterogeneous disease and this concept, together with the recent discovery of new drugs with novel mechanisms of action, will lead to the design of individualized treatments. The term "high-risk MM" includes those patients with at least one of the following features: deletion of 17p or t(4;14) or t(14;16), detected by fluorescence in situ hybridization analysis; deletion of 13q detected by conventional cytogenetics; or hypodiploidy or complex karyotype. In addition, patients with high proliferative activity of plasma cells (> or = 3%) measured by the PC labeling index or S-phase by flow cytometry as well as those with a poor response to induction therapy are also high risk.

How to treat a newly diagnosed young patient with multiple myeloma.

Survival rates of young patients with myeloma have increased markedly in the last decade, mainly due to the use of autologous stem cell transplantation (ASCT) and new, highly efficient rescue treatments. In order to improve the survival of newly diagnosed young patients further, the next steps need to focus on increasing the activity of upfront or debulking regimens, improving the efficacy of ASCT, mainly through the conditioning regimen, and increasing the duration of responses through more effective maintenance or consolidation therapies. Nevertheless, this approach is being challenged by the favorable results obtained with long-term treatment with novel agents and the possibility of reserving the ASCT until relapse.

In vitro and in vivo rationale for the triple combination of panobinostat (LBH589) and dexamethasone with either bortezomib or lenalidomide in multiple myeloma.

Background: Combinations of drug treatments based on bortezomib or lenalidomide plus steroids have resulted in very high response rates in multiple myeloma. However, most patients still relapse, indicating the need for novel combination partners to increase duration of response or to treat relapsed disease. We explored the antimyeloma activity of triple combinations of these well-established schemes with panobinostat, a novel deacetylase inhibitor with a multi-targeted profile.

The pleiotropic effects of natural AAV infections on liver-directed gene transfer in macaques.

Adeno-associated viral (AAV) vectors hold great potential for liver-directed gene therapy. Stable and high levels of transgene expression have been achieved in many murine models. Systemic delivery of AAV vectors in nonhuman primates (NHPs) that are natural hosts of AAVs appear to be challenging due to the high prevalence of pre-existing neutralizing antibodies (NAbs).

How I treat multiple myeloma in younger patients.

Therapeutic options for multiple myeloma (MM) patients have changed quickly in recent years and uncertainty has arisen about optimal approaches to therapy. A reasonable goal of MM treatment in younger "transplant eligible" patients is to initiate therapy with a target goal of durable complete remission, and the anticipated consequence of long-term disease control. [corrected] To achieve this goal we recommend induction therapy with multi-agent combination chemotherapies (usually selected from bortezomib, lenalidomide, thalidomide, cyclophosphamide, and corticosteriods) which when employed together elicit frequent, rapid, and deep responses.

The synergy of panobinostat plus doxorubicin in acute myeloid leukemia suggests a role for HDAC inhibitors in the control of DNA repair.

Acute myeloid leukemia (AML) is a clonal disorder characterized by the accumulation of myeloid blasts in the bone marrow. Here, we report the effects of the novel histone deacetylase inhibitor panobinostat (LBH589) in combination with doxorubicin on AML cells. Panobinostat exhibited potent anti-AML activity in all AML cell lines tested and in primary AML cells from patients (IC(50)<20 nM).

The persistence of immunophenotypically normal residual bone marrow plasma cells at diagnosis identifies a good prognostic subgroup of symptomatic multiple myeloma patients.

Multiparameter flow cytometry immunophenotyping allows discrimination between normal (N-) and myelomatous (MM-) plasma cells (PCs) within the bone marrow plasma cell compartment (BMPCs). Here we report on the prognostic relevance of detecting more than 5% residual normal plasma cells from all bone marrow plasma cells (N-PCs/BMPCs) by multiparameter flow cytometry in a series of 594 newly diagnosed symptomatic MM patients, uniformly treated according to the Grupo Español de MM 2000 (GEM2000) protocol. Our results show that symptomatic MM patients with more than 5% N-PCs/BMPCs (n = 80 of 594; 14%) have a favorable baseline clinical prospect, together with a significantly lower frequency of high-risk cytogenetic abnormalities and higher response rates.

Adeno-associated virus-mediated gene transfer to nonhuman primate liver can elicit destructive transgene-specific T cell responses.

Gene transfer to murine liver with vectors based on novel adeno-associated virus (AAV) serotypes is efficient, stable, and safe even in the setting of antigenic transgene products. We undertook a study in cynomolgus macaques to evaluate the relevance of these findings to primates. The vectors were based on AAV serotype 7 and expressed green fluorescence protein (GFP) from the cytomegalovirus enhanced beta-actin promoter in both single-stranded and self-complementary genomes.

Interleukin-1 regulates keratinocyte expression of T cell targeting chemokines through interleukin-1 receptor associated kinase-1 (IRAK1) dependent and independent pathways.

IL-1 is a potent pro-inflammatory cytokine that activates intracellular signaling cascades some of which may involve IL-1 receptor associated kinase-1 (IRAK1). Psoriasis is a T cell dependent chronic inflammatory condition of the skin of unknown cause. IL-1 has been implicated in psoriasis pathology, but the mechanism has not been elucidated.

Both expanded and uncultured mesenchymal stem cells from MDS patients are genomically abnormal, showing a specific genetic profile for the 5q- syndrome.

The presence of cytogenetic aberrations on mesenchymal stem cells (MSC) from myelodysplastic syndrome (MDS) patients is controversial. The aim of the study is to characterize bone marrow (BM) derived MSC from patients with MDS using: kinetic studies, immunophenotyping, fluorescent in situ hybridization (FISH) and genetic changes by array-based comparative genomic hybridization (array-CGH). In all 36 cases of untreated MDS were studied.

Percutaneous Transendocardial Delivery of Self-complementary Adeno-associated Virus 6 Achieves Global Cardiac Gene Transfer in Canines.

Achieving efficient cardiac gene transfer in a large animal model has proven to be technically challenging. Previous strategies have used cardiopulmonary bypass or dual catheterization with the aid of vasodilators to deliver vectors, such as adenovirus, adeno-associated virus (AAV), or plasmid DNA. Although single-stranded AAV (ssAAV) vectors have shown the greatest promise, they suffer from delayed expression, which might be circumvented using self-complementary vectors.

New drugs in multiple myeloma: mechanisms of action and phase I/II clinical findings.

The outcome of multiple myeloma has substantially improved over the past decade, mainly due to recently approved drugs, such as thalidomide, lenalidomide, and bortezomib. Nevertheless, most patients still relapse and, therefore, drugs with new mechanisms of action are urgently needed to overcome this resistance. In this Review, we discuss some of the new targeted therapeutic strategies under assessment in preclinical and clinical studies in multiple myeloma.

Zalypsis: a novel marine-derived compound with potent antimyeloma activity that reveals high sensitivity of malignant plasma cells to DNA double-strand breaks.

Multiple myeloma (MM) remains incurable, and new drugs with novel mechanisms of action are still needed. In this report, we have analyzed the action of Zalypsis, an alkaloid analogous to certain natural marine compounds, in MM. Zalypsis turned out to be the most potent antimyeloma agent we have tested so far, with IC(50) values from picomolar to low nanomolar ranges.

Percutaneous transendocardial delivery of self-complementary adeno-associated virus 6 achieves global cardiac gene transfer in canines.

Achieving efficient cardiac gene transfer in a large animal model has proven to be technically challenging. Previous strategies have used cardiopulmonary bypass or dual catheterization with the aid of vasodilators to deliver vectors, such as adenovirus, adeno-associated virus (AAV), or plasmid DNA. Although single-stranded AAV (ssAAV) vectors have shown the greatest promise, they suffer from delayed expression, which might be circumvented using self-complementary vectors.

Adeno-associated virus (AAV) serotype 9 provides global cardiac gene transfer superior to AAV1, AAV6, AAV7, and AAV8 in the mouse and rat.

Heart disease is the leading cause of morbidity and mortality. Cardiac gene transfer may serve as a novel therapeutic approach. This investigation was undertaken to compare cardiac tropisms of adeno-associated virus (AAV) serotypes 1, 6, 7, 8, and 9.

Aplidin, a marine organism-derived compound with potent antimyeloma activity in vitro and in vivo.

Despite recent progress in its treatment, multiple myeloma (MM) remains incurable, thus necessitating identification of novel anti-MM agents. We report that the marine-derived cyclodepsipeptide Aplidin exhibits, at clinically achievable concentrations, potent in vitro activity against primary MM tumor cells and a broad spectrum of human MM cell lines, including cells resistant to conventional (e.g.

Individualizing treatment of patients with myeloma in the era of novel agents.

Progress in the understanding of multiple myeloma (MM) cell biology has led to the identification of new relevant prognostic factors and subsequently different risk groups. This concept, together with the recent discovery of new drugs with novel mechanisms of action, will probably lead to individualized treatment according to the different patients' characteristics. In this review, we focus on current available agents already approved for MM, and discuss individualized treatment approaches for both transplantation candidates (subdivided into standard and high-risk patients) and elderly patients.

Efficacy and safety of bortezomib in patients with renal impairment: results from the APEX phase 3 study.

Renal impairment is associated with poor prognosis in multiple myeloma (MM). This subgroup analysis of the phase 3 Assessment of Proteasome Inhibition for Extending Remissions (APEX) study of bortezomib vs high-dose dexamethasone assessed efficacy and safety in patients with relapsed MM with varying degrees of renal impairment (creatinine clearance (CrCl) <30, 30-50, 51-80 and >80 ml min(-1)). Time to progression (TTP), overall survival (OS) and safety were compared between subgroups with CrCl < or =50 ml min(-1) (severe-to-moderate) and >50 ml min(-1) (no/mild impairment).

Should prophylactic granulocyte-colony stimulating factor be used in multiple myeloma patients developing neutropenia under lenalidomide-based therapy?

Lenalidomide combined with dexamethasone has significant clinical activity in the treatment of multiple myeloma (MM). In previous clinical trials lenalidomide-induced neutropenia was a frequent side-effect, often leading to treatment delays and dose reductions. We describe three MM patients treated with lenalidomide plus dexamethasone, which developed grade 3/4 neutropenia during the initial cycles, but without serious infection.

Adenovirus-based vaccine prevents pneumonia in ferrets challenged with the SARS coronavirus and stimulates robust immune responses in macaques.

A ferret model of severe acute respiratory syndrome (SARS)-CoV infection was used to evaluate the efficacy of an adenovirus vaccine. Animals were subjected to heterologous prime-boost using vectors from human serotype 5 and chimpanzee derived adenoviruses (human AdHu5 and chimpanzee AdC7) expressing spike protein followed by intranasal challenge with SARS-CoV. Vaccination led to a substantial reduction in viral load and prevented the severe pneumonia seen in unvaccinated animals.

Gene transfer of wild-type apoA-I and apoA-I Milano reduce atherosclerosis to a similar extent.

Background: The atheroprotective effects of systemic delivery of either apolipoprotein A-I (wtApoA-I) or the naturally occurring mutant ApoA-I Milano (ApoA-IM) have been established in animal and human trials, but direct comparison studies evaluating the phenotype of ApoA-I or ApoAI-Milano knock-in mice or bone marrow transplantated animals with selectively ApoA-I or ApoAI-Milano transduced macrophages give conflicting results regarding the superior performance of either one. We therefore sought to compare the two forms of apoA-I using liver-directed somatic gene transfer in hypercholesterinemic mice--a model which is most adequately mimicking the clinical setting.

Methods And Results: Vectors based on AAV serotype 8 (AAV2.

Heparin binding directs activation of T cells against adeno-associated virus serotype 2 capsid.

Activation of T cells to the capsid of adeno-associated virus (AAV) serotype 2 vectors has been implicated in liver toxicity in a recent human gene therapy trial of hemophilia B. To further investigate this kind of toxicity, we evaluated T-cell responses to AAV capsids after intramuscular injection of vectors into mice and nonhuman primates. High levels of T cells specific to capsids of vectors based on AAV2 and a phylogenetically related AAV variant were detected.