Secondary Plasma Research Articles

Energy budget of the bifurcated component in the radio pulsar profile of PSR J1012+5307

The bifurcated emission component (BEC) in the radio profile of the millisecond pulsar J1012+5307 can be interpreted as the signature of the curvature radiation beam polarised orthogonally to the plane of electron trajectory. Since the beam is intrinsically narrow (~1 deg), the associated emission region must be small for the observed BEC to avoid smearing out by spatial convolution. We estimate whether the energy available in the stream is sufficient to produce such a bright feature in the averaged profile. The energy considerations become complicated by the angular constraints imposed by the width of the microbeam, and by the specific spectrum of the BEC which is found to have the spectral index xi ~ -0.9 in comparison to the index of xi ~ -2 for the total profile. For typical parameters, the luminosity of the BEC is determined to be 4 10^{25} erg/s, whereas the maximum-possible beam-size-limited power of the stream is L_max ~ 2 10^{29} erg/s. This implies the minimum energy-conversion efficiency of eta ~ 2 10^{-4}. The BEC's luminosity does not exceed any absolute limits of energetics, in particular, it is smaller than the power of primary electron and/or secondary plasma stream. However, the implied efficiency of energy transfer into the radio band is extreme if the coherently emitting charge-separated plasma density is limited to the Goldreich-Julian value. This suggests that the bifurcated shape of the BEC has macroscopic origin, however, several uncertainties (eg. the dipole inclination and spectral shape) make this conclusion not firm.

Effects of the insecticide fipronil on reproductive endocrinology in the fathead minnow

Gamma-aminobutyric acid (GABA) and GABA receptors play an important role in neuroendocrine regulation in fish. Disruption of the GABAergic system by environmental contaminants could interfere with normal regulation of the hypothalamic-pituitary-gonadal axis, leading to impaired fish reproduction. The present study used a 21-d fathead minnow (Pimephales promelas) reproduction assay to investigate the reproductive toxicity of fipronil (FIP), a broad-spectrum phenylpyrazole insecticide that acts as a noncompetitive blocker of GABA receptor-gated chloride channels. Continuous exposure up to 5 µg FIP/L had no significant effect on most of the endpoints measured, including fecundity, secondary sexual characteristics, plasma steroid and vitellogenin concentrations, ex vivo steroid production, and targeted gene expression in gonads or brain. The gonad mass, gonadosomatic index, and histological stage of the gonad were all significantly different in females exposed to 0.5 µg FIP/L compared with those exposed to 5.0 µg FIP/L; however, there were no other significant effects on these measurements in the controls or any of the other treatments in either males and females. Overall, the results do not support a hypothesized adverse outcome pathway linking FIP antagonism of the GABA receptor(s) to reproductive impairment in fish.

Structural control of carbon nickel nano-composite thin films without substrate heating

A variety of characterization techniques have been employed to study the growth and structure of carbon nickel thin films fabricated by ionised magnetron sputter deposition. A two target magnetron system is used along with an RF powered coil to create a secondary plasma, with a DC bias applied at the substrate. By varying the substrate bias it is possible to control the flux and energy of the depositing species and therefore the resulting film microstructure. Films typically consist of nickel-based nano-particles within a carbon matrix. It has been observed that a change between the metastable hexagonal structure of nickel and the stable face centred cubic phase can be induced. This change in metal crystallinity is accompanied by a change in carbon ordering. The ability to control the film structure and morphology without the need for post-deposition heat treatments opens up the possibility of depositing a range of structures onto temperature sensitive substrates such as polymers.

Phase I, double-blind, placebo-controlled, ascending single subcutaneous dose, safety, tolerability, and pharmacokinetic study of sustained release granisetron (APF530).

e20587 Background: Although several 5-HT3antagonists are approved for chemotherapy-induced nausea and vomiting, agents with longer duration of therapeutic benefit are needed. APF530 incorporates a polymer that allows for controlled and sustained release of granisetron. Methods: Adult males were randomized to receive subcutaneous (SC) APF530 125 mg, 250 mg, 500 mg, or 1 g (groups A-D, respectively) and simultaneous placebo. Groups B-D subsequently received intravenous (IV) granisetron ≥ 7 days after APF530 dosing. Safety, tolerability, pharmacokinetics (PK), and absolute bioavailability of granisetron from APF530 were examined. Results: 26 subjects were randomized. All APF530 doses were well tolerated; most adverse events (AEs) were mild injection site reactions (pain on palpation, erythema); all resolved. Other AEs included headache (IV, SC), upper abdominal pain (SC), and constipation (SC). PK parameters were generally dose proportional (Table). APF530 elicited slow sustained absorption of granisetron; tmax was 8-10 h, and some subjects had secondary plasma peaks at 24-96 h. Systemic levels were reached within 30 min. Based on AUCall, granisetron was shown to be completely bioavailable from the SC dose formulation of APF530. Conclusions: APF530 safety profile was similar to that of granisetron, with the addition of mild injection site reactions. Granisetron was completely bioavailable at all APF530 doses. PK parameters were generally dose proportional. Absorption of granisetron from APF530 was prolonged compared with that from IV granisetron. Clinical trial information: NCT01416259. [Table: see text]

Gas discharge source of metal vapor and fast gas atoms

A source of metal atom flow coinciding in time and space with a flow of fast gas atoms has been studied and the study results are presented. The fast particles are produced due to charge exchange collisions of ions accelerated by potential difference between a plasma emitter inside the source and secondary plasma inside a process vacuum chamber. The emitter is the glow discharge plasma, whose electrons are confined in an electrostatic trap formed by a cold hollow cathode and an emissive grid the latter being negative both to the cathode and the chamber. The metal atoms are produced due to sputtering a target placed at the hollow cathode bottom by ions from the plasma emitter with energy up to 3 keV. Sputtered atoms cross the emitter, together with accelerated ions enter the chamber through the emissive grid and deposit on pieces placed therein. When a mixture of argon and nitrogen is used, the metal nitride coatings are being synthesized and interruptedly bombarded during the synthesis by atoms and molecules with energy variable from ∼10 to ∼300 eV.

A study on the temporally and spatially resolved OH radical distribution of a room-temperature atmospheric-pressure plasma jet by laser-induced fluorescence imaging

In this paper, the time and spatially resolved OH distribution of a room-temperature atmospheric-pressure plasma jet is investigated using a laser-induced fluorescence (LIF) method. The plasma jet is generated in room air by applying a nanosecond pulsed high voltage onto a ceramic tube with helium gas flow. It is found that, before the plasma ‘bullet’ propagates through the region detected by the laser, there are low OH LIF signals, which are from the OH left from previous discharge pulses. After the propagation of the primary plasma ‘bullet’ (generated by the primary discharge at the rising edge of the voltage pulse) through the detected region, the OH LIF signals are more than doubled. Furthermore, after the propagation of the secondary plasma ‘bullet’ (generated by the secondary discharge at the falling edge of the voltage pulse) through the detected region, the OH LIF signals are doubled again. Then, after the voltage pulse, the OH LIF signals decay slowly until about 120 µs. Starting from about 120 µs after the voltage pulse, the OH LIF signals have a third increase; its peak value is more than doubled. Detailed investigations find that this is due to the gas flow, which blows the OH generated inside the discharge tube to the detected region. In addition, spatially resolved OH LIF signals show that the signal intensity is stronger on both edges, which gives rise to the donut shape of the OH distribution. Further studies reveal that this might be due to the interaction of the plasma plume with the surrounding water vapor in the air.

Electron-ion hybrid instability experiment upgrades to the Auburn Linear Experiment for Instability Studies

The Auburn Linear EXperiment for Instability Studies (ALEXIS) is a laboratory plasma physics experiment used to study spatially inhomogeneous flows in a magnetized cylindrical plasma column that are driven by crossed electric (E) and magnetic (B) fields. ALEXIS was recently upgraded to include a small, secondary plasma source for a new dual source, interpenetrating plasma experiment. Using two plasma sources allows for highly localized electric fields to be made at the boundary of the two plasmas, inducing strong E × B velocity shear in the plasma, which can give rise to a regime of instabilities that have not previously been studied in ALEXIS. The dual plasma configuration makes it possible to have independent control over the velocity shear and the density gradient. This paper discusses the recent addition of the secondary plasma source to ALEXIS, as well as the plasma diagnostics used to measure electric fields and electron densities.

Source of metal atoms and fast gas molecules for coating deposition on complex shaped dielectric products

Beam-assisted deposition of wear-resistant coatings on complex shaped dielectric products is used as a source of slow metal atoms and fast gas molecules with coinciding trajectories of their movement from a common emissive grid to the products. This allows keeping the ratio of metal atom flow density to that of fast molecules constant as well as uniformity of deposited coating properties at the whole surface of the planetary rotating inside vacuum chamber products, including their cavities. The fast molecules are produced due to charge-exchange collisions of ions accelerated by potential difference between a plasma emitter inside the source and secondary plasma inside the chamber. The plasma emitter is produced by glow discharge with confinement of electrons in an electrostatic trap formed by a cold hollow cathode and an emissive grid the latter being negative to both the cathode and the chamber. Metal vapor is produced due to sputtering of a target placed at the bottom of the hollow cathode by ions from the plasma emitter accelerated by a negative bias voltage 2kV.

Perioperative Therapeutic Plasmapheresis

Perioperative Therapeutic Plasmapheresis

Insights in the laser-induced breakdown spectroscopy signal generation underwater using dual pulse excitation — Part I: Vapor bubble, shockwaves and plasma

Plasma and vapor bubble formation and evolution after a nanosecond laser pulse delivered to aluminum targets inside water were studied by fast photography. This technique was also applied to monitor the plasma produced by a second laser pulse and for different interpulse delays. The bubble growth was evident only after 3μs from the first laser pulse and the bubble shape changed during expansion and collapse cycles. The evolution and propagation of the initial shockwave and its reflections both from the back sample surface and cell walls were detected by Schlieren photography. The primary plasma develops in two phases: violent particle expulsion and ionization during the first μs, followed by slow plasma growth from the ablation crater into the evolving vapor bubble. The shape of the secondary plasma strongly depends on the inner bubble pressure whereas the particle expulsion into the expanded bubble is much less evident. Both the primary and secondary plasma have similar duration of about 30μs. Detection efficiency of the secondary plasma is much reduced by light refraction at the curved bubble–water interface, which behaves as a negative lens; this leads to an apparent reduction of the plasma dimensions. Defocusing power of the bubble lens increases with its expansion due to the lowering of the vapor's refraction index with respect to that of the surrounding liquid (Lazic et al., 2012 [1]). Smell's reflections of secondary plasma radiation at the expanded bubble wall redistribute the detected intensity on a wavelength-dependent way and allow gathering of the emission also from the external plasma layer that otherwise, would not enter into the optical system.

Insights in the laser induced breakdown spectroscopy signal generation underwater using dual pulse excitation — Part II: Plasma emission intensity as a function of interpulse delay

Influence of time delay between two laser pulses on the LIBS (laser induced breakdown spectroscopy) signal inside liquids was investigated and the results are compared with data from literature. Plasma was produced by laser ablation (LA) of aluminum inside water and its emission after the second laser pulse was characterized by spectrally and time resolved detection. Light propagation through the vapor bubble formed by the first laser pulse was studied by measurements of beam scattering and transmission. Optical absorption by the evolving bubble is not significant, but its growth is accompanied by lowering of its refraction index nb with respect to surrounding liquid; this effect increases defocusing both of the incident beam and of the out-coming plasma radiation. Collection efficiency of the secondary plasma emission rapidly degrades with the cavity growth, but close to its full expansion the LIBS signal partially recovers through Snell's reflections at the liquid–vapor interface, which produce a bright spot close to the bubble center. Such a light redistribution allows detecting of the emission from external plasma volume, otherwise deflected out of the collection system. Except for strong line transitions from the main sample constituents, self-absorbed inside the high-pressure cavity, we observed the highest LIBS signal when sending the second pulse well before the bubble is fully expanded. Transitions of the pressure wave through the focal volume, formed by the first laser pulse and reflected from the cell's walls and sample back-plane, enhances the LIBS signal importantly. The measured lifetime of the secondary plasma rapidly decreases with the bubble expansion. Here, we also discuss the optimization of the optical collection system and some analytical aspects of double-pulse (DP) LIBS inside liquids.

A double-plasma source of continuous bipolar ion-ion beam

A double-plasma source capable of the generation of a continuous bipolar ion-ion beam is described. The quasi-neutral ion-ion flow to an extraction electrode is formed in the system containing primary inductively coupled plasma separated from a secondary plasma by an electrostatic grid-type filter. The total current of each ion species to the 250 mm diameter extraction electrode is about 80 mA; the electron current does not exceed 30% of the ion current. Method of positive/negative ion current ratio control is proposed, allowing the ion currents ratio variation in wide range.

Long time evolution of collisionless shocks in laser produced counterstreaming plasmas

Long time evolution of collisionless shocks in laser-produced plasmas is discussed. By irradiating a double plane target a high Mach number collisionless shock has been observed in laser produced counterstreaming plasmas [Kuramitsu et al., Phys. Rev. Lett., 106, 175002 (2011)]. While in early time we observe the shock in front of one plane, which is irradiated with the laser, we observe another shock in front of the other plane in much later time than the first shock formation. These two shocks coexist and collide or merge with each other as time passes. This means that the upstream plasmas for the first and second shocks have to be provided from the second and first shock sides, respectively, i.e., both the first and second shock have to be collisionless. There are two major candidates to account for the long time evolution of the collisionless shocks. One is that the secondary plasmas at the planes can be continuously created by the plasmas from the other planes. Another is that the actual shock thickness is much thiner than the detection limit, as indicated by numerical simulations.

Structure modification of titanium oxide thin films by rf-plasma assistance in Ti–O2 reactive dc and pulsed dc sputtering

Titanium oxide films have been deposited by Ti–O2 reactive direct current (dc) and pulsed dc sputtering under the presence of the secondary radio-frequency (rf)-plasma to the primary cathode discharge at various discharge pressures in order to reveal effects of rf-plasma assistance on film structure and properties. At low discharge pressures, film structure changes from anatase to rutile by rf-plasma assistance to dc and pulsed dc discharge. At high discharge pressures, films changes from the mixtures of weakly ordered anatase to amorphous by rf-assistance. Refractive index of films deposited increases by rf-plasma assistance in either of dc and pulsed dc sputtering, showing a highest index of 2.57 at a discharge pressure of 3.0Pa. The enhancement of refractive index becomes remarkable at high discharge pressures. Furthermore, the surface of films becomes smoother by the presence of the secondary rf plasma. Being similar to the tendency of the refractive index change, the smoothening of film surface by the presence of the secondary rf plasma is remarkable at high discharge pressures. It is concluded that film structure changes from rutile to amorphous and is simultaneously densified by rf-plasma assistance to dc and pulsed dc discharge at a high discharge pressure, yielding films with a high refractive index and smooth surface.

Physical processes of the interaction of ion and plasma streams with a target surface in a dense plasma focus device

Dynamics of the interaction of powerful streams of high-temperature plasma and fast ions generated in a device of the “Dense Plasma Focus” (DPF) type has been studied for a special case. In these experiments solid conductive targets with the shape of a plate and a tube, respectively, were placed normally and axially with respect to the Z axis of the DPF chamber on its cathode side. The secondary plasma spread out from the target surface has been examined. The shock-wave action upon the flat targets produced by the ion beam has been revealed.

Patterns of CNS Involvement in Relapsed and/or Refractory Multiple Myeloma.

AbstractAbstract 2925 Background:Multiple myeloma (MM) patients can present with neurologic manifestation either as part of the disease process or as a therapeutic complication, such as due to metabolic disorders such as hypercalcemia, uremia and hyperviscosity; due to peripheral neuropathy, spinal cord compression and cranial nerve infiltration. Invasion of the central nervous system (CNS) in MM disease is an extremely rare occurrence and is associated with advanced disease with poor prognosis. Herein, we are presenting the UARK experience of CNS involvement in MM. Patients and Methods:The UARK MM database was used to conduct a retrospective analysis identifying CNS MM cases presenting between January 1996 and March 2012. Cases were identified from a review of the cytology laboratory archive material; data were also retrieved from the cytogenetic laboratory database, and magnetic resonance imaging (MRI). Descriptive analyses were performed on available data on patient characteristics, disease course and outcomes. Results:35 patients were identified with mean age at diagnosis being 55.4 years (range: 32–80 years) presenting with neurologic symptoms enlisted in Table 1. All patients had received prior systemic chemotherapy (SC) alone (n=11), or combination of SC and autologous stem cell transplant (ASCT, n=21), or combination of ASCT and allogeneic stem cell transplant (n=3). Eight (23.5%) patients had elevated B2M >5.5 mg/L, twenty four (71%) patients had elevated LDH (> 2 times upper limit of normal) and 5 (14%) had secondary plasma cell leukemia. The mean interval from diagnosis of MM to diagnosis of CNS MM was 23.5 months (range: 3–121 months). At the time of diagnosis of CNS MM, 3 (8.6%) patients were in complete remission (CR) by standard criteria and 15 (42.9%) patients were in progressive disease (PD). Magnetic resonance imaging (MRI) was performed in 34 patients, showing diffuse or localized leptomeningeal disease in 20 (58.8%) patients, 3 (8.8%) patients had a combination of both leptomeningeal disease with adjacent breakout MM focal lesion, and 2 (6%) patients had MM focal lesions adjacent to the meninges and sinuses without leptomeningeal disease. All 35 patients had malignant plasma cells in CSF analysis. 31 patients received chemotherapy to include intrathecal chemotherapy (IT) as a part of their treatment. IT consisted of cytarabine, methotrexate and hydrocortisone +/− thiotepa. 28 patients were treated with both IT and SC together: alone (n=8), or in combination of ASCT (n=13), or combination of ASCT and cranial irradiation (CI) (n=4), or combination with CI (n=1), or combination with both CI and Allogeneic SCT (n=1), or with Allogeneic SCT (n=1). Conclusion:In our experience, CNS MM is an aggressive terminal disease feature associated with other poor prognostic disease features such as high B2M, LDH and secondary plasma cell leukemia. The present review suggests that the patterns for CNS involvement are variable, such as hematogenous spread of plasma cells seen in PCL, or direct continuous spread from the eroded lytic lesions of the skull. The available novel agents do not provide therapeutic concentrations of drug in the CSF as they do not cross the blood-brain barrier. The study highlights an unmet need in this subset of high risk, relapsed/refractory MM patients. Adequate CNS penetration needs to be considered in MM novel drug development.Table 1Neurological symptoms and signs with CNS-MMLimb Weakness37%Confusion29%Headache26%Seizure17%Visual disturbances17%Cranial nerve palsies17%Paraesthesia14%Nausea/Vomiting11%Speech disturbances6%Paraparesis6%Urinary incontinence2%Gait disturbances2% Disclosures:No relevant conflicts of interest to declare.

Phase II Study of Pomalidomide (Pom) in Genomically Defined High Risk Relapsed and Refractory Multiple Myeloma (RRMM)

AbstractAbstract 4083 Background:Pom is a third generation immunomodulatory drug (IMiD) which has demonstrated safety and efficacy in RRMM with prior exposure/resistant to other IMiDs and bortezomib. This is the first report on a phase II clinical trial employing Pomalidomide (Pom) in genomically defined high risk RRMM. Methods:First cycle Pom was given at 4mg orally Days 1–21 every 28 days; dexamethasone (DEX) or bortezomib (BOZ) could be given in absence of PR or better from Cycle #3. In the absence of at least PR, Pom dose was escalated to 5mg. Cox regression modeling was employed for univariate and multivariate analyses, whereas Kaplan-Meier curves were used for overall survival (OS) and progression free survival (PFS). Results:30 patients with RRMM were enrolled. Baseline characteristics included age >=65yr in 47%, ISS stage >=II was seen in 74% of patients, cytogenetic abnormalities (CA) within 6 months in 79%, and GEP-defined high risk in 66% by GEP70-gene model, 97% by GEP80-gene model, 13% had extramedullary disease (EMD), and 7% had secondary plasma cell leukemia (SPCL). 26/30 patients (87%) had prior autologous stem cell transplant, 23/30 patients (77%) had had at least 2 transplants. 22 patients (73%) had disease progression while on lenalidomide, bortezomib or both within 60 days of enrollment. At least 2 cycle of treatment were administered to 28 (93%) patients enrolled, 20 (67%) patients received >4 cycle of treatment and 16 (53%) received > 6 cycles. 15 patients (50%) discontinued therapy primarily due to progression or death. 5 (17%) patients achieved PR or better as best response. PFS benefit was observed in older patients (HR=0.29, p=0.008), with high LDH presenting an increased risk for OS (HR=14.64, p=0.013.) Most common toxicities, counting all toxicities (>=grade 3) were: thrombocytopenia (63%), leukopenia (63%), anemia (40%), hypophosphatemia (20%) and hypocalcemia (23%). Overall and progression- free survival at 12 months were 64% and 20%, respectively. Conclusions:The present trial is the first investigation evaluating Pom's clinical activity in high risk RRMM and demonstrates good anti-myeloma activity in this heavily pre-treated patient population. Given the activity in poor prognostic clinical features such as EMD and SPCL, there is precedence to evaluate Pom as an IMiD of choice in combination with other novel agents for this subset of RRMM. [Display omitted] Table 1Drugs Administered by Cycle. Number of patients receiving given drug combinations in given cycle. (Note: the denominator used for calculating percentages is number of patients who started the cycle. In some columns, percentages do not add up to 100% because data was missing for some patients.)Cycle 1 (n=30)Cycle 2 (n=28)Cycle 3 (n=23)Cycle 4 (n=20)Cycle 5 (n=17)Cycle 6 (n=16)Pom alone29 (100%)28 (100%)12 (52%)7 (35%)5 (29%)4 (25%)Pom + Dex0 (0%)0 (0%)9 (39%)5 (25%)5 (29%)4 (25%)Pom + Vel0 (0%)0 (0%)0 (0%)1 (5%)2 (12%)2 (13%)Pom + Dex + Vel0 (0%)0 (0%)1 (4%)6 (30%)4 (24%)3 (19%) Disclosures:No relevant conflicts of interest to declare.

Bendamustine As Salvage Therapy in Multiple Myeloma: A Retrospective, Multicenter Study From the Italian Compassionate Use Program in 78 Heavily Pre-Treated Patients.

AbstractAbstract 2971 Introduction:Bendamustine is a bifunctional alkylating agent approved for the treatment of several lymphoproliferative disorders. Studies have evidenced its efficacy in multiple myeloma (MM), but data so far available in this setting are scarce. We performed a retrospective analysis of Italian patients with relapsed/refractory MM, who had received bendamustine as salvage therapy within a national compassionate use program. Patients and methods:Seventy-eight patients (42 males, 36 females) were collected in 19 hematological centers. Mean age was 64.2 years (range 38–84). ISS was equally distributed, with about one third of patents being represented in single stages. Twenty-three of 43 analyzed patients had cytogenetic abnormalities, the most frequent being del13q (14 patients); t(4;14) and t(11;14) were observed in 4 and 2 patients, respectively, while t(6;14), del17p or complex karyotype occurred in single patients. The median number of prior lines of therapy was 4 (range 1–10). Ninety-seven percent of patients had previously received bortezomib, 94% IMIDs, 85% melphalan, 74% cyclophosphamide, 45% anthracyclines, 26% other drugs, 33% radiotherapy. Sixty percent of patients had undergone autologous and 4% allogeneic stem cell transplantation. The last treatment before bendamustine was a bortezomib-based regimen in 31%, an IMIDs-based regimen in 42%, a combined bortezomib/IMIDs-based regimen in 9%, while 18% of patients had received other therapies. Seventy-three percent of patients were resistant to last therapy received, while 27% had relapsed. Median duration of response to last treatment received before bendamustine was 9 months (range 2–46). Median Hb value was 10.1 g/dl (range 7.6–14.9), WBC count 2.700/μl (range 550–15.200), PLT count 130.000/μl (range 6.000–410.000). Serum creatinine, calcium, beta2-microglobulin and LDH levels were increased in 12 (15%), 4 (5%), and 44 (56%) patients, respectively, while albumin levels were decreased in 27 patients (35%). The median percentage of marrow plasma cells (as evaluated in 57 cases) was 60% (range 1–100). Seventy-six percent of patients had osteolytic bone involvement and 78% extramedullary localizations, with 13% showing secondary plasma cell leukemia and 7% documented amyloidosis or proteinuria. Finally, 45% of patients presented with at least one severe comorbidity, mainly cardio-vascular, liver or pulmonary dysfunction, and diabetes. Results:A total of 236 cycles was administered (median 3, range 1–9). In 47% of patients bendamustine was variously associated to bortezomib (23%), or IMIDs (21%), or to a combination of both (3%). In 80% of patients receiving bendamustine +/− steroids, a median dose of 90 mg/sqm for two consecutive days every 28 days was employed; the median dose was 80 mg/sqm when bendamustine was combined with bortezomib, 60 mg/sqm with IMIDs (total range: 40–140 mg/sqm). The remaining patients received single, monthly doses ranging from 60 to 150 mg/sqm. According to IMWG uniform response criteria, 21 out of 73 evaluable patients achieved a response after a median time of 3 months. In particular, there were 16 PR, 1 VGPR, 1 sCR, and 3 CR; overall response rate (ORR) was, therefore, 29%. Response rate was 10% (4/39) in bendamustine single agent +/− steroids, 38% (5/13) in bendamustine + bortezomib and 62% (10/16) in bendamustine + IMIDs subgroups, respectively. Responders had received a lower number of previous treatments than non responders (median 3 vs 4). Response rate was higher in relapsed (12/21, 57%) than in resistant patients (10/57, 17%). The time to best response ranged from 1 to 8 months. After a median follow-up of 8 months, median PFS duration was 6 months, with 13 out of 21 responding patients not yet progressed. Median OS of the entire cohort was 6.2 months (7 months in responders and 4 months in non responders, range 0–27). Grade 3–4 hematological and non-hematological toxicities occurred in 56% and 15% of patients, respectively, causing three interruptions of the treatment. Conclusions:Though with the clear limits due to the high heterogeneity of treatments applied and of population analyzed, our data indicate that bendamustine may be a therapeutic option in heavily pretreated MM, suggesting a possible non cross-resistance with other agents. Its earlier use with appropriate doses and combinations might further improve the results obtained in this study. Disclosures:Musto:Mundipharma: Honoraria. Off Label Use: Bendamustine in relapsed/refractory myeloma. Fragasso:Mundipharma: Honoraria. Baldini:Mundipharma: Honoraria. Storti:Mundipharma: Honoraria.

Very Low to Low Doses of Continuous Azacitidine in Combination with Standard Doses of Lenalidomide and Low-Dose Dexamethasone (Rd) in Patients with Relapsed or Refractory Multiple Myeloma (RRMM): Interim Results of a Phase I/II Study

AbstractAbstract 5031 Background:Myeloma inevitably becomes refractory to available agents primarily due to accumulation of genetic and epigenetic mutations in the aberrant clone. The s-phase dependent DNA methylation inhibitor azacitidine may help overcome epigenetically mediated resistance in myeloma cells that cycle despite treatment and reactivate alternate growth control programs in cells with genetic apoptosis resistance. Here we present interim results of an ongoing phase I/II study that explores the safety, antimyeloma activity, and epigenetic effects of continuous azacitidine at predicted non-cytotoxic doses in combination with Rd in RRMM Methods:Entry criteria included measurable disease, relapsed or refractory state, and glomerular filtration rate ≥ 60ml/min (Cockroft-Gault). Lenalidomide 25mg d1–21 every 28d and dexamethasone 40mg weekly were fixed. In phase I (3×3 design) azacitidine was escalated from 30 to 40mg/m2 SC weekly (DL 1 and 2) to 30, 40, and maximally 50mg/m2 SC twice a week (DL 3–5). Dose limiting toxicity (DLT) was assessed during cycle 1 and response every 28 days according to IMWG uniform response criteria (partial response, PR, or better) and adapted EBMT criteria (minor response, MR). Plasma activity of cytidine deaminase (CDA) was measured in dose levels 3–5, using HPLC to quantify deamination of added cytidine (Wilcoxon exact test). Phase II enrolls 10 additional patients at the highest tolerated dose and includes global gene expression and DNA methylation arrays before and after cycle 1 in CD138+, CD34+, and remaining bone marrow cells. Results:Twenty patients with relapsed (n=1) or refractory (n=19) MM were enrolled after they had received a median of 4 prior regimens (range 1–10). Their disease was refractory to lenalidomide (n=17), bortezomib and/or carfilzomib (n=16), or both lenalidomide and proteasome inhibitors (n=14). 18 patients had received alkylators, 8 high dose chemotherapy, and 6 anthracyclines. One DLT was observed in 1 out of 6 patients treated at DL 4; neutropenic fever without other evidence for infection. No DLT occurred in 4 patients treated so far at DL 5. Grade 3 and 4 toxicities were seen in 11 patients, neutropenia in 9 (lowest ANC 0. 24K/mm3), thrombocytopenia in 4 (lowest 16K/mm3, transfusions used in 1 to avoid treatment delay), neutropenic fever in 2 (1 after cycle 1), and diarrhea, depression, deep venous thrombosis, and a possibly related pleural effusion with hypoxemia in 1 patient each. DL 1 and 2 (n=6) yielded only one MR, but as azacitidine was increased to twice a week (DL 3–5, n=14) the clinical benefit response rate (CBRR, ≥MR) and response rate (RR, ≥PR) increased to 35. 7% and 28. 6%, respectively with 1 very good partial response (VGPR), 3 PR and 1 MR. The patient with MR had secondary plasma cell leukemia (sPCL) after 7 prior regimens and had to be taken off trial due to cytopenias but was continued on reduced azacitidine (20mg/m2), lenalidomide (5–10mg), and prednisone (50mg TIW) reaching PR off trial and achieving a 10 month time to progression (TTP). Of all other responding patients, only the one treated with weekly azacitidine progressed while receiving azacitidine (TTP 3 months), one patient with sPCL progressed during azacitidine interruption for neutropenic fever, another patient was taken off trial due to pleural effusion with hypoxemia, 2 are still on study, currently for 8 and 3 months. The median time to response was 1 cycle (range 1–7). Responders in DL 3–5 had similar treatment histories as the entire cohort, refractory to last Rx: 80%, median previous regimens: 4 (range 1–7), refractory to lenalidomide: 60%, to proteasome inhibitors: 80%, and to both: 60%; but their plasma CDA activity was lower than in non-responders (Figure 1). Women treated at DL 3–5 (n=6) responded better than men (n=8), likely related to lower plasma CDA activity (Figure 2). Conclusions:Azacitidine was generally well tolerated up to the target maximal dose of 50mg/m2SC twice a week (BIW) in combination with Rd given to 4 out of 6 patients required for establishing the phase 2 dose. Encouraging response rates in refractory MM correlated with low plasma activity of the azacitidine inactivating enzyme CDA found predominantly in women. Results support development of azacitidine in RRMM and argue for testing combination with the competitive inhibitor of CDA, tetrahydrouridine. Until then, dose escalation in non-responding but tolerating patients will be explored. [Display omitted] [Display omitted] Disclosures:Reu:Celgene: Research Funding. Off Label Use: Azacitidine in multiple myeloma. Kindwall-Keller:Celgene: Speakers Bureau; TEVA: Speakers Bureau. Duong:Celgene: Research Funding.

The Expression Pattern of Small Nucleolar and Small Cajal Body-Specific RNAs Characterizes Distinct Molecular Subtypes of Multiple Myeloma

AbstractAbstract 3955Small nucleolar RNAs (snoRNAs) and small Cajal body-specific RNAs (scaRNAs) are non-coding RNAs involved in the maturation of other RNA molecules and generally located in the introns of host genes. It is an emerging evidence that altered sno/scaRNAs expression may play a pathological role in cancer. Impaired sno/scaRNAs expression has recently been reported both in acute leukemia and smoldering myeloma that rapidly progressed to symptomatic disease. In addition, as regards multiple myeloma (MM), very recent data suggested an oncogenic role for SCARNA22 in those MM patients over-expressing SCARNA22/MMSET as a result of t(4;14) translocation. However, comprehensive information concerning the expression behavior of sno/scaRNAs in MM is still lacking.This study elucidates the patterns of sno/scaRNAs expression in MM by profiling purified malignant plasma cells from 55 MMs, 8 secondary plasma cell leukemias (sPCL) and 4 normal controls using Human Gene 1.0 ST arrays.Overall, a global sno/scaRNAs down-regulation was found in MMs and at more extent in sPCLs compared to normal plasma cells. Whereas SCARNA22 resulted the only sno/scaRNA characterizing the TC4 MM, TC2 group displayed a distinct sno/scaRNA signature overexpressing members of SNORD115 and SNORD116 families located in a region finely regulated by an imprinting center at 15q11 which, however, resulted overall hypomethylated in MMs independently of the SNORD115 and SNORD116 expression levels. In addition, impaired expression of sno/scaRNAs raised from the comparison between MM and sPCL, suggested a role in tumor progression. Furthermore, to uncover possible mechanisms at the basis of sno/scaRNAs deregulation, we investigated the correlation between sno/scaRNAs and the corresponding host-genes expression levels, outlining the coordinated expression of up to 50% of sno/scaRNAs/host-genes pairs. Finally, we investigated whether the sno/scaRNAs transcriptional pattern may be influenced by allelic imbalances involving their genomic location, as already demonstrated concerning mRNA expression, and revealed a dosage effect involving several chromosomal regions.Our data extend the current view of sno/scaRNAs deregulation in cancer and add novel information into the bio-molecular complexity of plasma cell dyscrasias. Furthermore, our findings may contribute to develop functional approaches to examine the activity of deregulated sno/scaRNAs in MM, as well as to further enlighten their possible role as targets of novel therapeutic agents. Disclosures:No relevant conflicts of interest to declare.