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Pemanfaatan teknologi informasi dalam membuat perencanaan proses produksi dan pelaporan yang cepat akurat dan terintegrasi sangat dibutuhkan oleh suatu organisasi dalam perusahaan, seperti halnya yang ada dalam penelitian di PT.X dimana perusahaan melakukan kegiatan operasional perusahaan yaitu dalam pembuatan jadwal untuk semua operator serta laporan-laporan harian. Namun pada prakteknya dalam melakukan kegiatan perusahaan diatas banyak kendala-kendala yang muncul yaitu sering terjadinya ketidaksesuaian data-data di lapangan dengan data-data di laporan. Adapun tujuan dari penelitian ini yaitu dirancangnya suatu sistem aplikasi penjadwalan dan pelaporan kegiatan produksi menggunakan sistem database MySQL dan dalam pengembangan sistem menggunakan metode Waterfall. Setelah dilakukan perancangan, implementasi & pengujian pada aplikasi penjadwalan dalam pelaporan produksi menghasilkan performance yang baik. Sistem ini selanjutnya bisa dimanfaatkan oleh perusahaan guna memperlancar proses kegiatan produksi.

Treatment of myeloma has benefited from the introduction of more effective and better tolerated agents, improvements in supportive care, better understanding of disease biology, revision of diagnostic criteria, and new sensitive and specific tools for disease prognostication and management. Assessment of minimal residual disease (MRD) in response to therapy is one of these tools, as longer progression-free survival (PFS) is seen consistently among patients who have achieved MRD negativity. Current therapies lead to unprecedented frequency and depth of response, and next-generation flow and sequencing methods to measure MRD in bone marrow are in use and being developed with sensitivities in the range of 10−5 to 10−6 cells. These technologies may be combined with functional imaging to detect MRD outside of bone marrow. Moreover, immune profiling methods are being developed to better understand the immune environment in myeloma and response to immunomodulatory agents while methods for molecular profiling of myeloma cells and circulating DNA in blood are also emerging. With the continued development and standardization of these methodologies, MRD has high potential for use in gaining new drug approvals in myeloma. The FDA has outlined two pathways by which MRD could be qualified as a surrogate endpoint for clinical studies directed at obtaining accelerated approval for new myeloma drugs. Most importantly, better understanding of MRD should also contribute to better treatment monitoring. Potentially, MRD status could be used as a prognostic factor for making treatment decisions and for informing timing of therapeutic interventions. Clin Cancer Res; 23(15); 3980–93. ©2017 AACR.

1) Munshi Figures, 2) MRD Negativity Associated With Longer Progression-free Survival And Overall Survival In Newly Diagnosed Multiple Myeloma Patients

Active Clinical Trials in Myeloma Using Minimal Residual Disease Assessment as Exploratory or Secondary Endpoints

Context: Guillain-Barré syndrome is a polyradiculoneuropathy of heterogeneous manifestations, necessarily presenting progressive appendicular weakness of variable intensity associated with reduction or abolition of deep reflexes. One of its variants is known as Miller Fisher Syndrome (MFS), characterized by ophthalmoparesis, ataxy and areflexia. It usually has, by etiology, immunomediated reactions induced by acute infections, including HIV. Objectives: This report aims to describe a case of MFS with concomitants HIV infection, attended in a tertiary hospital in northern Paraná and compared it with the literature. [1,7] Case report: A 27-year-old white male patient who presented binocular diplopia, dysarthria, dysphagia, generalized hypotonia, myasfasciculations, sensory ataxia and arreflexia, with a score on the Medical Research Council (MRC) muscle strength scale of 54 points. Treatment with empirical intravenous human immunoglobulina ( IVIG ) was performed pending the result of serologies for etiological screening. He was discharged after eleven days of hospitalization with partial symptomatic improvement and results indicative of acute HIV infection. We compared this case with those described in the published literature Discussion: We compared this case with those described in the published literature and given the low incidence found in the literature of patients with the stage of HIV viremia and the opening of the picture of SMF, the concrete pathophysiology itself is still unknown. The mechanism, however, in which the literature proposes in two theories: (1) an autoimmune action against myelin due to abnormal immunoregulation by HIV; (2) direct action of neurotropic strains of HIV-1. [2.3] Our literature review shows that since 1995, cases of associated guillain barré syndrome have already been reported in the course of HIV viremia. Treatment with immunoglobulin at a dose of 400mg / kg / day for 5 days was done and the symptoms improved. [1,4,6,7] Conclusion: It is exposed, then, a case of HIV-induced MFS whose relationship has consistency, temporality, biological plausibility, coherence and analogy compatible with current literature.

This research studied the effect of sodium bicarbonate content on the properties of epoxy. Sodium bicarbonate (SB) was used as foaming agent to improve the properties of thermosetting epoxy resin. The samples of epoxy foam were produced using mixing method. Sodium bicarbonate was selected as blowing agent by reason of the environmental friendly and low cost concern. Mechanical, physical and morphology properties were done. Sodium bicarbonate content was varied at 5, 10, 15, 20 and 25 part per hundred (phr), respectively. It can be highlighted that the optimum content of the SB was selected at 15 phr and it gave the moderate porosity percentage (%), and moderate value in mechanical and density properties, higher SB content exhibited lower flexural properties.

Introdução Migrânea tem alta prevalência, incapacitante, periódica e acomete várias gerações em uma mesma família. Além das dores de cabeça, são prevalentes dores no pescoço e os pontos-gatilho associados. Objetivo Tratar os indivíduos com migrânea crônica e cervicalgia, através da técnica de liberação miofascial Fascial Manipulation (FM). Verificar a possibilidade em diminuir a frequência, duração e intensidade de dores de cabeça após a realização da terapia manual e a quantidade de consumo de analgésico após o tratamento. Método Estudo natural em ensaio clínico experimental, analítico - projeto piloto (n-36) em abordagem terapêutica no tratamento intervencionista da (FM) em voluntários. Randomizado, com três grupos (grupo tratamento com a técnica mais medicação preventiva, grupo massagem placebo mais medicação preventiva e grupo controle somente medicação preventiva). Optou-se pela padronização dos medicamentos, o fármaco succinato de sumatriptana (50 mg) mais naproxeno sódico (500 mg) e o topiramato com dose de ascensão, única e diária de 25mg, elevando-se para 100mg em duas doses dia, ou maior dose tolerável. Longitudinal com avaliação independente e reavaliações com algometria. A inclusão é através do diagnóstico dado pelo neurologista, que selecionam voluntários conforme a classificação internacional das cefaleias da IHS 2018. Os desfechos primários serão reduzir as dores de cabeça através da diminuição da percepção da intensidade, frequência e duração da dor pelo diário de cefaleia, ficha (VAS) e ficha de controle de fármacos. Redução das dores cervicais miofasciais, pelo questionário Brasil-nbq e algometria de músculos e nervos por algômetro digital sueco Somedic Sales AB. Melhora na qualidade de vida pelo questionário Whoqol-bref, melhora do impacto na incapacidade pela migrânea pelo questionário MIDAS. Melhora do apertamento dentário (noturno e diurno) por inventário. Melhora das amplitudes de movimentos das articulações altas da coluna cervical pela avaliação de fleximetria (flexion rotation test). Resultados e Conclusões Estudo em andamento até o momento.

This thesis discusses the problem of the large area consumption required to perform fast Fourier transform (FFT) operations. Fast Fourier transform architectures require a large amount of processing elements to perform its operation. The larger the required FFT size, the more processing elements needed and, therefore, a larger implementation area needed. The main sources for the area consumption are the large number of multiplications FFT computations. In this thesis, a study has been made about most common FFT architectures like memory based FFT architectures and pipelined FFT architectures. Moreover, some studies have been made about the previously implemented FFT butterfly architectures, and some ideas about how to optimize area in the entire FFT system and inside FFT butterflies. The objective of the thesis is to optimize the area usage inside a single FFT butterfly. Area optimization is achieved by developing a unified FFT butterfly architecture that contains multiradix FFT architectures. That concept enables the usage of fewer amount of FFT butterflies inside the system to achieve larger FFT operations. In addition, by using shift-add concept instead of multipliers, the area can be optimized significantly. Memory organization has been put into consideration when implementing the proposed FFT architectures, which implied the need of sequential version of the FFT butterflies. All these concepts were mixed together to result in a final version that is the best area-optimized in this thesis. After implementing the various versions of FFT architectures using sharing resources, sequential processing, and shift-add concepts, their results were compared into the previously implemented traditional version. The final proposed architectures, which are sequential and multiplierless radix-2, 3, 4, 5, and multi-radix FFT architectures. From the comparison results, the proposed implementations achieved thesis objectives, resulting in about 60% of area reduction compared to the previously implemented FFT butterflies’ architectures.

Objectives In 2018, a nationwide mandatory switch from originator to biosimilar adalimumab was conducted in Denmark. The available biosimilar was GP2017 (Hyrimoz) in Eastern regions and SB5 (Imraldi) in Western regions. We aimed to assess the comparative effectiveness of GP2017 versus SB5 in patients with rheumatoid arthritis (RA)/psoriatic arthritis (PsA)/axial spondyloarthritis (AxSpA). Methods Observational cohort study based on the DANBIO registry with geographical cluster pseudo-randomisation, analysed by emulating a randomised clinical trial. Main outcome was adjusted 1-year treatment retention (Cox regression). Furthermore, 6 months’ remission rates (logistic regression), reasons for withdrawal and back-switching to originator were investigated (overall and stratified by indication). Results Overall, of 1570 eligible patients, 1318 switched and were included (467 RA/321 PsA/530 AxSpA); 623 (47%) switched to GP2017, 695 (53%) to SB5. Baseline characteristics of the two clusters were largely similar, but some differences in registration practice were observed. The combined 1-year retention rate for the two biosimilars was 89.5%. Compared with SB5, estimated risk of withdrawal for GP2017 was lower (HR 0.60; 95% CI 0.42 to 0.86) and 6 months’ remission rate was higher (OR 1.72; 95% CI 1.25 to 2.37). Stratified analyses gave similar results (statistically significant for RA). During 1 year, 8.5% and 12.9% withdrew GP2017 and SB5, respectively (primarily lack of effect and adverse events), of whom 48 patients (3.6%) back-switched. Conclusion This head-to-head comparison of GP2017 versus SB5 following a mandatory switch from the originator indicated differences in effectiveness in routine care. This may reflect a true difference, but other explanations, for example, differences in excipients, differences between clusters and residual confounding cannot be ruled out.

Multiple myeloma (MM) is an incurable hematologic malignancy with disparities in outcomes noted among racial-ethnic subgroups, likely due to disparities in access to effective treatment modalities. Clinical trials can provide access to evidence-based medicine but representation of minorities on therapeutic clinical trials has been dismal. We evaluated the impact of patient race-ethnicity in pooled data from nine large national cooperative group clinical trials in newly diagnosed MM. Among 2896 patients enrolled over more than two decades, only 18% were non-White and enrollment of minorities actually decreased in most recent years (2002–2011). African-Americans were younger and had more frequent poor-risk markers, including anemia and increased lactate dehydrogenase. Hispanics had the smallest proportion of patients on trials utilizing novel therapeutic agents. While adverse demographic (increased age) and clinical (performance status, stage, anemia, kidney dysfunction) factors were associated with inferior survival, patient race-ethnicity did not have an effect on objective response rates, progression-free, or overall survival. While there are significant disparities in MM incidence and outcomes among patients of different racial-ethnic groups, this disparity seems to be mitigated by access to appropriate therapeutic options, for example, as offered by clinical trials. Improved minority accrual in therapeutic clinical trials needs to be a priority.

Few studies have addressed the cost patterns of patients with multiple myeloma (MM) before and after first relapse. This US claims analysis evaluated, from a US health plan perspective, patterns of total direct costs of care from treatment initiation to progression for patients with MM treated with novel agents, using time to next therapy (TTNT) as a proxy measure for progression.A retrospective study was conducted using a large US claims database, evaluating patients with claims for MM between 2006 and 2013. Patients with claims for stem cell transplant (SCT) were excluded. The analysis focused on patients receiving lenalidomide (LEN) or bortezomib (BORT) based treatment, for whom complete claim history was available through initiation of subsequent treatment. Average patient monthly direct costs were determined, including medical and pharmacy costs, and total cost patterns over quarterly time periods were calculated.The study population comprised 2843 patients with newly diagnosed MM (NDMM) and 1361 with relapsed MM. Total monthly cost for patients with NDMM declined steadily, from $15,734 initially to $5082 at 18+ months after therapy. Upon initiation of second-line therapy, total monthly costs rose to $13,876 and declined to $6446 18 months later. Although NDMM cost levels for individual ordinal months were similar between the LEN and BORT groups, TTNT was longer for LEN-based treatments (37 months). The BORT-treated cohort had higher average monthly total costs for NDMM and for the common time period through 37 months after initiation of therapy ($7534 vs $10,763 for LEN and BORT, respectively). Key limitations of this study, in addition to the lack of mortality and staging information available from claims data, include the definition of TTNT based on change in treatment or a defined gap in therapy prior to retreatment, which may differ from actual time of progression in some patients.For patients with NDMM receiving either LEN- or BORT-based treatment without SCT, followed until TTNT, total direct monthly costs (drug + medical) declined steadily over time. Monthly costs returned to near initial levels when patients began second-line therapy and then followed a similar pattern of decline. Due to the longer TTNT for patients initiated on LEN and the associated longer period of below-average costs, patients initiated with LEN-based treatments had mean monthly total costs$3200 lower than total costs for patients initiated on BORT during the first 3 years after starting treatment, cumulating to nearly $120,000 in lower costs for patients initiated on LEN.

Fludarabine (F) and cyclophosphamide (C) remain backbones of up-front chemotherapy regimens for chronic lymphocytic leukemia (CLL). We report long-term follow-up of a randomized F versus FC trial in untreated, symptomatic CLL (NCT00003764, clinicaltrials.gov). With median follow-up of 88 months, estimated median progression-free survival (PFS) was 19.3 versus 48.1 months for F (N=109) and FC (N=118) respectively (p

The authors assessed the overall response rate, including confirmed complete response (CR) and partial response, in patients with relapsed/refractory multiple myeloma treated with sorafenib. Qualitative and quantitative toxicities associated with this regimen were evaluated. Patients were eligible if they had a confirmed diagnosis of refractory or relapsed (RR) multiple myeloma (MM) with measurable monoclonal protein. Patients had to have adequate renal, hepatic, hematologic, and cardiac function with a Zubrod performance status of 0–2. Patients were given 400 mg sorafenib by mouth twice daily for 28-day treatment cycles. These patients were followed up for a maximum of 3 years to assess responses and adverse events. Twenty-three patients were enrolled. Of these, five were found to be ineligible for the following reasons: four had insufficient documentation of the baseline disease and one patient did not have measurable disease. All eighteen eligible patients were evaluable for toxicities. Three patients experienced grade 4 toxicities: one with thrombocytopenia, one with anemia, and one with renal failure. Four of the eighteen eligible patients were not assessable for response due to removal from protocol treatment prior to adequate disease assessment. Specifically, three were removed for either grade 4 toxicity or progression of disease and one was removed per patient choice (due to reasons unrelated to treatment). Of the 18 patients who were assessed for toxicities, 5 (27.8%) received at least one fully dosed cycle, 2 (11.1%) of whom had all cycles fully dosed. No responses were observed on this study of the 14 patients who were assessable for response. All patients have discontinued protocol treatment as of August 2008. Overall survival at 12 months was 50% (95% CI 27–73%) and median progression-free survival was 1.2 months (95% CI 1.0–5.4). The trial did not exhibit activity by the International Uniform Response Criteria for MM. Further research should focus on combination therapy of sorafenib with standard treatments in selected patients with RR MM.

Background: PNK-007 is an allogeneic, off the shelf cell therapy product enriched for CD56+/CD3- NK cells expanded from placental CD34+ cells. PNK-007 cells exhibit cytotoxicity against various cancer cell types, including multiple myeloma (MM), and secrete cytokines during co-culture with cancer cells. This is a Phase I study of single infusion PNK-007 after autologous stem cell transplant (ASCT) in MM. Methods: Placental CD34+ cells were cultivated in the presence of cytokines for 35 days to generate PNK-007 under cGMP standards followed by release testing. HLA matching and KIR mismatching were not used. Four treatment arms were evaluated on patients (pts) following ASCT: 10 million (M) cells/kg Day (D) 14 with or without recombinant human IL-2 (rhIL-2), 30M cells/kg D14 with rhIL-2, or 30M cells/kg D7 with rhIL-2. rhIL-2 was administered subcutaneously at 6M units every other day for up to 6 doses to facilitate PNK-007 expansion. Pts received variable pre-ASCT induction therapy. Maintenance therapy was permitted after the Day 90-100 visit (D90). Subjects were followed for up to 1-year. Results: 15 pts who received PNK-007 (12 of whom received rhIL-2) were followed on this study. Pts aged 44-69 yrs included 12 newly diagnosed (ND)MM and 3 relapsed/refractory (RR)MM. The 3 RRMM pts had received 1, 2 or 5 prior lines of therapy, with 2 pts having previous ASCT. All pts had been exposed to immunomodulatory drug (IMiDs) and proteasome inhibitors (PIs). No serious adverse events (AEs) were attributable to PNK-007 and no dose-limiting toxicity, GvHD, graft failure or graft rejection were observed. 12/15 pts started maintenance therapy following the transplant while participating in this study, at the physician's discretion. Based on physician assessed responses by International Myeloma Working Group pre-ASCT, of the NDMM pts 10/12 achieved VGPR or better (1 CR and 9 VGPR), 1/12 achieved PR and 1/12 was not assessed during pre-ASCT induction. By D90 10/12 pts achieved VGPR or better (5 CR or sCR and 5 VGPR), 1/12 maintained PR and 1/12 stable disease. At 1-year 9/11 achieved VGPR or better (4 CR or sCR and 5 VGPR), 2/11 were not assessed and 1 was removed from the study prior to 1 year due to failure to respond to ASCT. Of the RRMM pts 2/3 achieved PR and 1/3 was not assessed during pre-ASCT induction, by D90 2/3 achieved VGPR and the pt that had not been assessed pre-ASCT achieved PR. At 1-year, 1 pt maintained VGPR, 1 pt was not assessed and 1 pt did not continue to the 1-year visit. Using a validated Euro-flow minimal residual disease (MRD) assay of bone marrow aspirate (BMA) samples, of the NDMM pts 4/12 were MRD negative (MRD-) pre-ASCT; by D90 9/12 were MRD-. At 1-year 6/12 were MRD-, 2/12 had insufficient BMA to perform testing, 2/12 refused BMA procedure, 1/12 did not convert to MRD-, and 1 was removed from the study prior to 1-year due to failure to respond to ASCT. Of the RRMM pts 0/3 were MRD- pre-ASCT with 1/3 having insufficient BMA to perform testing; by D90 1/3 were MRD-. At 1-year 1/3 was MRD-, 1/3 did not convert to MRD- and 1 pt did not continue to the 1-year visit. PNK-007 infusion did not interfere with immune reconstitution kinetics. Platelet, neutrophil, and absolute lymphocyte counts recovered by day 28 post-ASCT in 12/15 patients. All pts' sera tested negative for the presence of anti-HLA antibodies at all timepoints indicating the absence of humoral immunity and alloantibodies to PNK-007. Conclusion: PNK-007 is the first fully allogeneic, off the shelf CD34+ derived NK cell product in MM clinical trials. A single infusion of PNK-007 up to 30M cells/kg with and without rhIL-2 was well tolerated in the post-ASCT setting. We established the feasibility of infusing PNK-007 as early as 7 days post-ASCT without negative impact on blood count recovery or successful engraftment. BMA MRD- status was observed in 7/9 MRD evaluable pts at 1-year post ASCT. These clinical data are encouraging and warrant further evaluation. Disclosures Holstein: Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees; Sorrento: Consultancy; GSK: Consultancy; Genentech: Membership on an entity's Board of Directors or advisory committees. Cooley:Fate Therapeutics, Inc: Employment, Equity Ownership. Hari:Cell Vault: Equity Ownership; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Amgen: Research Funding; Spectrum: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria. Jagannath:BMS: Consultancy; Merck: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Medicom: Speakers Bureau; Multiple Myeloma Research Foundation: Speakers Bureau. Balint:Celgene: Equity Ownership; Celularity, Inc: Employment. Van Der Touw:Celularity, Inc: Employment. Zhang:Celularity Inc: Employment. Hariri:Celularity Inc: Employment. Vij:Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Genentech: Honoraria; Janssen: Honoraria; Karyopharm: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Research Funding.

Celularity has developed a GMP platform for generating Placenta-derived intermediate Natural Killer cells (PNK-007): an allogeneic cytotoxic NK cell product culture-expanded and differentiated from placental CD34+ progenitor cells. In a 10 patient relapsed/refractory AML phase I study, PNK-007 infusion was evaluated following Cyclophosphamide-Fludarabine (Cy-Flu) conditioning treatment. Patients received a single PNK-007 infusion of 1 million (M) cells/kg, 3M cells/kg, or 10M cells/kg followed by rhIL-2 administered subcutaneously at 6M units every other day for up to 6 doses to facilitate PNK-007 persistence and expansion. Here, we report PNK-007 cell persistence, AML monitoring, and broader immune profiling from Phase I translational studies. PNK-007 persistence in the blood was observed between 7 and 28 days post infusion in patients dosed ≥ 3M cells/kg. Functional analysis of PNK-007 isolated from the blood of one patient indicated post-infusion NK cell effector activity. This included sustained expression of NKp30, NKp46, and DNAM-1 NK cell activating receptors. CD94, CD11a, and CD16 expression were increased relative to the pre-infusion cell product. CD57 and KIRs were absent at infusion, but were found on a subset of PNK-007 post-infusion indicating further NK maturation in vivo. Negligible expression of immunoinhibitory checkpoint receptors was observed on PNK-007 14 days post-infusion including PD-1, TIM3, and LAG3. Post-infusion PNK-007 cells stained positive for granzyme B, perforin, and secreted IFNγ, but not TNFα in response to acute activation. In the month following Cy-Flu conditioning, we observed limited reconstitution of myeloid and lymphoid cells, consistent with other reports investigating this patient population. T cells at day 7 were 35-65% CD4+Foxp3+ and sustained T cell expansion in two patients beyond day 14 was associated with elevated PD-1 expression. Patients were B and NK cell deficient and showed negligible monocyte reconstitution alongside neutropenia. Elevated monocyte and neutrophil counts in two patients occurred in the context of significantly increased AML burden in the blood. In those patients, between 25-50% of monocytes did not express MHC-II consistent with myeloid-derived suppressor cells. Our translational studies allow us to monitor PNK-007 cell persistence and maturation in addition to characterizing broader immune reconstitution from clinical samples. PNK-007 maturation data from this study are consistent with our preclinical models. We further show in this patient population that immune reconstitution appears compromised following Cy-Flu conditioning. Our data identify kinetics of PNK-007 persistence alongside hematopoietic recovery and AML disease. Citation Format: William van der Touw, Lin Kang, Julie M. Curtsinger, Vanessa Voskinarian-Berse, Bhavani Stout, Mohamad Hussein, Sarah A. Cooley, Jeffrey S. Miller, Robert Hariri, Xiaokui Zhang. Immune monitoring of PNK-007, an allogeneic, off the shelf NK cell in a Phase I study of acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-070.

Background: PNK-007 is an allogeneic, off the shelf cell therapy enriched for CD56+/CD3- NK cells expanded from placental CD34+ cells. PNK-007 exhibits cytotoxicity against various cancer cell types, including acute myeloid leukemia (AML), and secretes cytokines during co-culture with cancer cells. Reported here are results of a Phase I first-in-man study in relapsed/refractory (r/r) AML patients (pts). Methods: Placental CD34+ cells were cultivated in the presence of cytokines for 35 days to generate PNK-007 under the cGMP standards with release testing. HLA matching/KIR mismatching were not used. Eligible pts received a single PNK-007 infusion of 1, 3, or 10 million (M) cells/kg followed by rhIL-2 administered subcutaneously at 6M units every other day for up to 6 doses to facilitate PNK-007 expansion. Eligible pts with r/r AML received Lymphodepletion with Cy-Flu (60mg/kg Cy Days -5 to -4; 25mg/m2 Flu Days -6 to -2). Results: Ten pts, age range 30-70 years (median 66), KPS >70%, and WHO Classifications of recurrent genetic abnormalities (n=4), MDS-related changes (n=4), not otherwise specified (n=2), were treated with a single PNK-007 infusion followed by 5 to 6 rhIL-2 injections. These pts received 1 to 5 (median 3) prior lines of AML therapy and included 5 pts with a history of MDS and 5 pts received prior allogeneic SCT. Flow cytometric analysis of pt blood showed in vivo PNK-007 persistence, proliferation (Ki67) and maturation at dose levels 3M and 10M cells/kg between 7 to 28 days post-infusion. Functional analysis of PNK-007 isolated from 1 pt showed NK cell effector activity. One pt treated with 10M cells/kg PNK-007 developed Cytokine Release Syndrome (CRS) 14 days after infusion and was effectively managed with tocilizumab. This CRS event was deemed a dose-limiting toxicity. The other 9 pts did not experience CRS symptoms and PNK-007 was well tolerated with no infusion reactions or GvHD. No deaths were attributed to PNK-007. Efficacy was defined as complete remission rate (CR or CRp) at Day 42 and overall survival (OS) at 24 months. Although 2 of 8 efficacy evaluable patients had evidence of clinical benefit, Day 42 bone marrow biopsy could not be performed in either pt. On Day 21, a complete response with incomplete platelet recovery (CRp) was observed in the pt who experienced CRS. On Day 14, another patient treated at 10M cells/kg was observed to achieve MLFS. All pts died during the follow-up period of the study; 80% due to progressive AML and 20% due to AML-related complications. Median OS was 2.4 months. Conclusion: PNK-007 is a fully allogeneic, off the shelf CD34+ derived NK cell product. A single infusion of PNK-007 up to 10M cells/kg with rhIL-2 following Cy-Flu conditioning was safe and well tolerated, with one treatable CRS event observed. Two of 10 pts treated achieved clinical response, assessed by the investigators as CRp and MLFS. Observed clinical data warrant further evaluation of PNK-007 treatment in AML. Citation Format: Sarah Cooley, Parameswaran Hari, James McCloskey, Michael Byrne, Eunice Wang, Mohamad Hussein, Erica Giarritta, Xiaokui Zhang, Robert Hariri, Jeffrey S. Miller. A Phase I study of PNK-007, allogeneic, off the shelf NK cell in relapsed/refractory AML (NCT02781467) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT079.

Background: PNK-007 is an allogeneic, off the shelf cell therapy enriched for CD56+/CD3- NK cells expanded from placental CD34+ cells. PNK-007 exhibit cytotoxicity against various cancer cell types, including multiple myeloma (MM), and secrete cytokines during co-culture with cancer cells. This is a Phase I study of single infusion PNK-007 after autologous stem cell transplant (ASCT) in MM. Methods: Placental CD34+ cells were cultivated in the presence of cytokines for 35 days to generate PNK-007 under cGMP standards followed by release testing. HLA matching and KIR mismatching were not used. Four treatment arms were evaluated on eligible patients (pts) following ASCT: 10 million (M) cells/kg Day (D) 14 with or without rhIL-2, 30M cells/kg D14 with rhIL-2 or 30M cells/kg D7 with rhIL-2. rhIL-2 was administered subcutaneously at 6M units every other day for up to 6 doses to facilitate PNK-007 expansion. Pts received variable pre-ASCT induction therapy. Maintenance therapy was permitted after the Day 90-100 visit (D90). Enrollment is complete, and all pts have completed the D90 visit as of the cutoff date Oct 26, 2018. Results: 15 pts who received PNK-007 (12 of whom received rhIL-2) were evaluated for clinical response at D90. Pts aged 44-69 yrs included 12 newly diagnosed (ND)MM and 3 relapsed/refractory (RR)MM. The 3 RRMM received 1, 2 or 5 prior lines of therapy, with 2 pts having previous ASCT. All pts had been exposed to IMiDs and PIs. No dose-limiting toxicity, GvHD, graft failure or graft rejection were observed. No serious adverse events (AEs) were attributable to PNK-007 and the reported AEs were consistent with AEs related to ASCT. Based on physician assessed responses by International Myeloma Working Group pre-ASCT, 10/15 pts achieved VGPR or better (1 CR and 9 VGPR), and by D90, 12/15 pts achieved VGPR or better (5 CR or sCR and 7 VGPR). Using a validated Euro-flow minimal residual disease (MRD) assay by bone marrow aspirate (BMA), pre-ASCT, 4/15 pts were MRD negative (MRD-), and by D90, 10/15 pts were MRD-. At one-year post-ASCT, 4/6 pts were MRD-, with 1 converting to MRD-, 1 inadequate sample, and 1 remaining MRD+. PNK-007 did not interfere with immune reconstitution kinetics. Administration of rhIL-2 coincided with a transient increase in circulating regulatory T cell levels. Host NK cells reached a maximum level between 21-28 days post-ASCT followed by contraction independent of rhIL-2 administration. Conclusion: PNK-007 is the first fully allogeneic, off the shelf CD34+ derived NK cell product in MM clinical trials. A single infusion of PNK-007 up to 30M cells/kg with and without rhIL-2 was well tolerated in the post-ASCT setting. We established the feasibility of infusing PNK-007 as early as 7 days post-ASCT without negative impact on blood count recovery. Attainment of BMA MRD- status was observed in 10/15 pts at D90. These clinical data are encouraging and warrant further evaluation. Citation Format: Sarah A. Holstein, Sarah A. Cooley, Parameswaran Hari, Sundar Jagannath, Catherine R. Balint, William van der Touw, Michele L. Donato, Philip L. McCarthy, Paul K. Wallace, Xiaokui Zhang, Robert J. Hariri, Mohamad A. Hussein, Ravi Vij. A Phase I study of PNK-007, allogeneic, off the shelf NK cell, post autologous transplant in multiple myeloma (NCT02955550) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT108.

A previous interim report of MM-011, the first study that combined lenalidomide with anthracycline-based chemotherapy followed by lenalidomide maintenance for relapsed and/or refractory multiple myeloma (RRMM), showed promising safety and activity. We report the long-term outcomes of all 76 treated patients with follow-up ≥ 5 years. This single-center phase I/II study administered lenalidomide (10 mg on days 1-21 of every 28-day cycle), intravenous liposomal doxorubicin (40 mg/m(2) on day 1), dexamethasone (40 mg on days 1-4), and intravenous vincristine (2 mg on day 1). After 4-6 planned induction cycles, lenalidomide maintenance therapy was given at the last tolerated dose until progression, with or without 50 mg prednisone every other day. The median number of previous therapies was 3 (range, 1-7); 49 (64.5%) patients had refractory disease. Forty-three (56.6%) patients received maintenance therapy. Grade 3/4 adverse events occurred during induction and maintenance therapy in 48.7% and 25.6% of patients, respectively. Four (5.3%) treatment-related deaths occurred during induction. Responses were seen in 53.0% (at least partial response) and 71.2% (at least minor response) of patients. Overall, median progression-free survival and overall survival were 10.5 and 19.0 months, respectively; in patients with refractory disease these values were 7.5 and 11.3 months, respectively. Lenalidomide with anthracycline-based chemotherapy followed by maintenance lenalidomide provided durable control in patients with RRMM (ClinicalTrials.gov number, NCT00091624).

Advances in survival in multiple myeloma have focused payer attention on the cost of care. An assessment was conducted to compare the costs of two recent treatments for relapsed/refractory multiple myeloma (rrMM), from the perspective of a US payer.An economic model estimated the total costs of care for two guideline-recommended therapies in rrMM patients: bortezomib (BORT) and lenalidomide plus dexamethasone (LEN/DEX). To evaluate total treatment costs, the costs associated with drug treatment, medical resource utilization, and adverse event (AE) management were determined for each regimen over a common 1-year period. Medical costs and grade 3/4 AE costs were based on rates from published literature, package inserts, and fee schedules (US dollars). To evaluate cost per outcome, assessments determined the monthly costs without disease progression based on pivotal clinical trials (APEX [BORT] and MM-009/MM-010 [LEN/DEX]). Univariate sensitivity analyses and alternative scenarios were also conducted.Drug costs for the treatments were very similar, differing by under $10 per day. Medical and AE management costs for BORT were higher by more than $40 per day. Treatment with BORT had annual excess total costs of$17,000 compared with LEN/DEX. A cost advantage for LEN/DEX was maintained across a variety of sensitivity analyses. Total cost per month without progression was 11% lower with LEN/DEX.This analysis relied on separate studies having similar comparators, populations, and end-points. Actual treatment patterns and costs pre- and post-relapse may vary from the base scenario and sensitivities modeled. The 12-month time frame captures the preponderance of costs for a relapse line of therapy, yet may not reflect the entirety of costs. There is insufficient evidence to determine whether, or how, a difference in the lifetime costs of the two regimens would vary from the 1-year cost difference.While rrMM treatment with BORT and LEN/DEX had comparable drug costs, total treatment costs for BORT were higher due to ongoing direct medical and AE management costs. Total costs per outcome (a month without disease progression) were lower for LEN/DEX.

Treatment of myeloma has benefited from the introduction of more effective and better tolerated agents, improvements in supportive care, better understanding of disease biology, revision of diagnostic criteria, and new sensitive and specific tools for disease prognostication and management. Assessment of minimal residual disease (MRD) in response to therapy is one of these tools, as longer progression-free survival (PFS) is seen consistently among patients who have achieved MRD negativity. Current therapies lead to unprecedented frequency and depth of response, and next-generation flow and sequencing methods to measure MRD in bone marrow are in use and being developed with sensitivities in the range of 10−5 to 10−6 cells. These technologies may be combined with functional imaging to detect MRD outside of bone marrow. Moreover, immune profiling methods are being developed to better understand the immune environment in myeloma and response to immunomodulatory agents while methods for molecular profiling of myeloma cells and circulating DNA in blood are also emerging. With the continued development and standardization of these methodologies, MRD has high potential for use in gaining new drug approvals in myeloma. The FDA has outlined two pathways by which MRD could be qualified as a surrogate endpoint for clinical studies directed at obtaining accelerated approval for new myeloma drugs. Most importantly, better understanding of MRD should also contribute to better treatment monitoring. Potentially, MRD status could be used as a prognostic factor for making treatment decisions and for informing timing of therapeutic interventions. Clin Cancer Res; 23(15); 3980–93. ©2017 AACR.

Despite increased levels of automation in manufacturing occupations in recent years, many activities are still performed through human intervention and involve Manual Material Handling (MMH), thus exposing workers to stress due to over-exertion and potential Work-Related Musculoskeletal Disorders (WRMSDs). An early ergonomic and physical demand assessment of work activities is critical to reducing exposure to risk and to maintaining desired levels of productivity. Biomechanics consists of applying concepts of static and dynamic equilibrium to different parts of the human musculoskeletal system using free-body diagrams to estimate muscle force and loads generated across the joints and tissues. System dynamics is a powerful tool applied in resolving complex problems with different influencing variables. This technique can help designers and managers to understand, evaluate and simulate the factors causing problems in the system. This paper presents the application of System Dynamics modeling to assess the biomechanical risks associated with manual material handling tasks. The case study presents predicted cumulative biomechanical compressive loads from material handling task and can assist project managers to understand and reduce exposure to ergonomic risks in the workplace.

Preclinical studies have shown that targeted combination therapy consisting of vorinostat and bortezomib has antitumor activity in multiple myeloma (MM). We examined this drug combination in advanced relapsing and/or refractory MM patients (n = 34). Although the maximum tolerated dose was not reached, the study found this combination regimen generally well tolerated and clinically active in relapsed and/or refractory MM patients.Development of targeted therapies for MM has improved response rates and increased patient survival, but ultimately the disease becomes refractory and progresses. Vorinostat combined with bortezomib has demonstrated synergistic antiproliferative and proapoptotic activity in preclinical models of MM. The objectives of this study were to determine the maximum tolerated dose for vorinostat with bortezomib in patients with advanced MM and to evaluate the clinical benefit of this new drug combination.Patients ≥ 18 years old with relapsed and/or refractory MM were enrolled into escalating dose cohorts of vorinostat and bortezomib combination therapy. Thirty-four patients were enrolled and were evaluable for safety and efficacy analyses.All patients reported adverse events, 89% of which were mild to moderate in severity. Thirteen patients experienced 29 serious adverse events, 12 (41%) of which were considered drug-related. The maximum tolerated dose was not reached. Partial responses were observed in 9 (27%) patients. Minimal responses were observed in 2 additional patients (6%), and another 20 patients (59%) experienced disease stabilization.Vorinostat with bortezomib is generally well-tolerated and has clinical activity in patients with relapsed and/or refractory MM. Response rates were similar in patients previously exposed to bortezomib and patients who were naive to bortezomib therapy.

Lenalidomide (REVLIMID), an immunomodulatory compound targeting both cancer cells and their microenvironment, has substantial activity in several difficult-to-manage hematological malignancies. In previously treated multiple myeloma, lenalidomide produces high-quality responses combined with sustained disease control. Recently, several randomized studies have demonstrated a clinical benefit of continuous lenalidomide treatment in newly diagnosed multiple myeloma. In many patients with refractory anemia associated with lower risk myelodysplastic syndromes and a 5q chromosome deletion, lenalidomide leads to transfusion independence, considerably improving quality of life. It has a manageable safety profile, and its oral formulation reduces the burden on patients. Several phase III trials are ongoing in other indications currently underserved by conventional therapy, such as chronic lymphocytic leukemia, non-Hodgkin's lymphoma, and prostate cancer. Several early-stage studies are exploring lenalidomide alone and in combination across different hematological malignancies, solid tumors, and immune-related disorders.

This first-in-human, phase I study evaluated the safety, maximum-tolerated dose, pharmacokinetics, and antitumor activity of dacetuzumab in 44 patients with advanced multiple myeloma. Patients received intravenous dacetuzumab, either in 4 uniform weekly doses (first 4 cohorts) or using a 5-week intrapatient dose escalation schedule (7 subsequent cohorts; the last 3 cohorts received steroid pre-medication). An initial dose of 4 mg/kg dacetuzumab exceeded the maximum-tolerated dose for uniform weekly dosing. Intrapatient dose escalation with steroid pre-medication appeared effective in reducing symptoms of cytokine release syndrome and the maximum-tolerated dose with this dosing schema was 12 mg/kg/week. Adverse events potentially related to dacetuzumab included cytokine release syndrome symptoms, non-infectious ocular inflammation, and elevated hepatic enzymes. Peak dacetuzumab blood levels increased with dose. Nine patients (20%) had a best clinical response of stable disease. The observed safety profile suggested that dacetuzumab may be combined with other multiple myeloma therapies. Two combination trials are ongoing. Clinical trials gov identifier: NCT00079716.

The design of innovative, more effective, less toxic therapy of multiple myeloma (MM) is emerging in parallel to a better understanding of the underlying pathophysiology of this common hematologic malignancy. Thalidomide has changed the treatment paradigm of patients with MM. Its efficacy, however, has been compromised by significant side effects. IMiDs® (immunodulatory compounds) are structural and functional analogs of thalidomide that were specifically designed to create new agents with enhanced immunomodulatory and anticancer properties and better tolerability profiles. In this article, we review the clinical trial development of the second-generation IMiDs®, lenalidomide and pomalidomide. Both agents demonstrate potent activity and are highly effective and well tolerated treatment options for patients with MM.

Purpose Thalidomide-dexamethasone (THAL-DEX) is standard induction therapy for multiple myeloma (MM). Tandem melphalan-based transplantations have yielded superior results to single transplantations. Phase II trial S0204 was designed to improve survival results reported for the predecessor, phase III trial S9321 by 50%. Patients and Methods Newly diagnosed patients with MM were eligible for S0204 with THAL-DEX induction, tandem melphalan-based tandem transplantation, and THAL-prednisone maintenance. Results Of 143 eligible patients, 142 started induction, 73% completed first transplantation, 58% completed second transplantation, and 56% started maintenance. The quantity of stem cells required for two transplantations was reached in 88% of 111 patients undergoing collection, 74% of whom completed both transplantations. Partial response, very good partial remission, and complete response were documented after 12 months of maintenance therapy in 87%, 72%, and 22% of patients, respectively. During a median follow-up time of 37 months, 4-year estimates of event-free and overall survival were 50% and 64%, respectively. Survival outcomes were superior for International Staging System (ISS) stage 1 disease, when lactate dehydrogenase (LDH) levels were normal and a second transplantation was applied in a timely fashion. Conclusion Both overall survival (P = .0002) and event-free survival (P < .0001) were significantly improved with S0204 compared with S9321 when 121 and 363 patients, respectively, were matched on ISS stage and LDH.

Prior studies of myeloma treated with conventional chemotherapy or autologous stem cell transplantation have shown immunohistochemistry for cyclin D1, fibroblast growth factor receptor 3, and p53 to be prognostically significant. The clinical significance of these phenotypic abnormalities in thalidomide-based regimens is currently unknown. We examined the clinical significance of immunohistochemistry for cyclin D1, fibroblast growth factor receptor 3, p53, and cyclin D3 in 94 patients treated with pegylated doxorubicin, vincristine, dexamethasone, and thalidomide, including 49 newly diagnosed and 45 relapsed/refractory patients. The incidence of positivity for cyclin D1, fibroblast growth factor receptor 3, p53, and cyclin D3 was similar in newly diagnosed versus relapsed/refractory groups (37%, 8%, 4%, and 2% versus 42%, 7%, 11%, and 2%, respectively). In contrast to prior studies of other therapeutic regimens, cyclin D1 negativity or fibroblast growth factor receptor 3 positivity did not convey an adverse progression-free or overall survival. p53 positivity, although uncommon, was associated with shorter progression-free and overall survival in newly diagnosed cases. The findings suggest that a thalidomide-based regimen may overcome the poor prognosis associated with a cyclin D1-negative or fibroblast growth factor receptor 3-positive phenotype.

Recent studies have shown a clinical benefit of lenalidomide, an oral immunomodulatory drug, plus dexamethasone in patients with relapsed/refractory multiple myeloma (MM). The most common grade 3-4 adverse events were cytopenias, fatigue, muscle cramps, rash, infection, insomnia, and venous thromboembolism. Lenalidomide in combination with dexamethasone has been approved by the United States Food and Drug Administration and the European Medicines Agency for the treatment of patients with MM who have received at least one prior therapy. An expert panel reviewed the efficacy and toxicity of lenalidomide plus dexamethasone, and provided recommendations on the management of patients receiving this treatment. Patient selection is straightforward, as prognostic factors do not appear to heavily influence efficacy. In addition, the panel agreed on strategies for the management of side effects. The recommendations presented here will aid the safe administration of lenalidomide, and avoid unnecessary dose reduction and discontinuation, thus assuring the best efficacy of treatment. (c) 2008 Elsevier Ltd. All rights reserved.

Cancer impacts each patient and family differently. Our current understanding of the disease is primarily limited to clinical hallmarks of cancer, but many specific molecular mechanisms remain elusive. Genetic markers can be used to determine predisposition to tumor development, but molecularly targeted treatment strategies that improve patient prognosis are not widely available for most cancers. Individualized care plans, also described as personalized medicine, still must be developed by understanding and implementing basic science research into clinical treatment. Proteomics holds great promise in contributing to the prevention and cure of cancer because it provides unique tools for discovery of biomarkers and therapeutic targets. As such, proteomics can help translate basic science discoveries into the clinical practice of personalized medicine. Here we describe how biological mass spectrometry and proteome analysis interact with other major patient care and research initiatives and present vignettes illustrating efforts in discovery of diagnostic biomarkers for ovarian cancer, development of treatment strategies in lung cancer, and monitoring prognosis and relapse in multiple myeloma patients.

Purpose: We generated a humanized antibody, HuLuc63, which specifically targets CS1 (CCND3 subset 1, CRACC, and SLAMF7), a cell surface glycoprotein not previously associated with multiple myeloma. To explore the therapeutic potential of HuLuc63 in multiple myeloma, we examined in detail the expression profile of CS1, the binding properties of HuLuc63 to normal and malignant cells, and the antimyeloma activity of HuLuc63 in preclinical models.Experimental Design: CS1 was analyzed by gene expression profiling and immunohistochemistry of multiple myeloma samples and numerous normal tissues. HuLuc63-mediated antimyeloma activity was tested in vitro in antibody-dependent cellular cytotoxicity (ADCC) assays and in vivo using the human OPM2 xenograft model in mice.Results: CS1 mRNA was expressed in >90% of 532 multiple myeloma cases, regardless of cytogenetic abnormalities. Anti-CS1 antibody staining of tissues showed strong staining of myeloma cells in all plasmacytomas and bone marrow biopsies. Flow cytometric analysis of patient samples using HuLuc63 showed specific staining of CD138+ myeloma cells, natural killer (NK), NK-like T cells, and CD8+ T cells, with no binding detected on hematopoietic CD34+ stem cells. HuLuc63 exhibited significant in vitro ADCC using primary myeloma cells as targets and both allogeneic and autologous NK cells as effectors. HuLuc63 exerted significant in vivo antitumor activity, which depended on efficient Fc-CD16 interaction as well as the presence of NK cells in the mice.Conclusions: These results suggest that HuLuc63 eliminates myeloma cells, at least in part, via NK-mediated ADCC and shows the therapeutic potential of targeting CS1 with HuLuc63 for the treatment of multiple myeloma.

Purpose The long-term impact of thalidomide plus dexamethasone (thal/dex) as primary therapy for newly diagnosed multiple myeloma (MM) is unknown. The goal of this study was to compare thalidomide plus dexamethasone versus placebo plus dexamethasone (placebo/dex)as primary therapy for newly diagnosed MM. Patients and Methods In this double-blind, placebo-controlled trial, patients with untreated symptomatic MM were randomized to thal/dex (arm A) or to placebo plus dexamethasone (dex) (arm B). Patients in arm A received oral thalidomide 50 mg daily, escalated to 100 mg on day 15, and to 200 mg from day 1 of cycle 2 (28-day cycles). Oral dex 40 mg was administered on days 1 through 4, 9 through 12, and 17 through 20 during cycles 1 through 4 and on days 1 through 4 only from cycle 5 onwards. Patients in arm B received placebo and dex, administered as in arm A. The primary end point of the study was time to progression. This study is registered at http://ClinicalTrials.gov ( NCT00057564 ). Results A total of 470 patients were enrolled (235 randomly assigned to thal/dex and 235 to placebo/dex). The overall response rate was significantly higher with thal/dex compared with placebo/dex (63% v 46%), P < .001. Time to progression (TTP) was significantly longer with thal/dex compared with placebo/dex (median, 22.6 v 6.5 months, P < .001). Grade 4 adverse events were more frequent with thal/dex than with placebo/dex (30.3% v 22.8%). Conclusion Thal/dex results in significantly higher response rates and significantly prolongs TTP compared with dexamethasone alone in patients with newly diagnosed MM.

OBJECTIVE To describe an association between renal cell carcinoma (RCC) and multiple myeloma (MM) in patients with both disorders, and suggest possible explanations for the association. PATIENTS AND METHODS We retrospectively reviewed the records of patients with MM and RCC at the Cleveland Clinic between 1990 and 2005, and identified 1100 with MM, 2704 with RCC and eight with concomitant MM and RCC. The medical records of these eight patients were reviewed. RESULTS In four of the eight patients, RCC was diagnosed after the MM at 3, 8, 23 and 46 months, respectively; in the remaining four, the RCC was diagnosed before MM by 108, 35, 13 and 1 months, respectively. The number of cases of RCC expected in the present 1100 patients with MM over 15 years was lower than the four recorded (P

Recognition of cancer-specific antigens resulted in development of monoclonal antibodies as treatments for various neoplasms including chronic lymphocytic leukemia (CLL). Two monoclonal antibodies, alemtuzumab and rituximab, have been extensively studied, as monotherapy or in combination, in patients with various clinical stages of CLL. Alemtuzumab, particularly when combined with fludarabine-based chemotherapy, sequentially or concomitantly, represents a promising therapeutic approach that results in improved efficacy by further reducing levels of residual disease in previously untreated or relapsed/refractory CLL. On the other hand, single-agent rituximab has limited activity by itself, even at very high doses, and seldom induces complete remissions. However, rituximab is feasible to combine with conventional chemotherapies such as purine analogs, alkylating chemotherapy and/or alemtuzumab. Newer monoclonal antibodies are already showing activity in relapsed/refractory CLL and will eventually be evaluated in combinations with conventional chemotherapy, or with already established antibodies. Modern definitions for assessment of responses such as minimal residual disease negativity (MRD negativity) are emerging and, consequently, development of assays capable of measuring such responses. MRD negativity should become the primary objective of clinical trials when evaluating treatment interventions in patients with CLL. The future of monoclonal antibodies for treatment of CLL is bright.

The effectiveness of IFN-alpha2b for human multiple myeloma has been variable. TRAIL has been proposed to mediate IFN-alpha2b apoptosis in myeloma. In this study we assessed the effects of IFN-alpha2b signaling on the apoptotic activity of TRAIL and human myeloma cell survival. While TRAIL was one of the most potently induced proapoptotic genes in myeloma cells following IFN-alpha2b treatment, less than 20% of myeloma cells underwent apoptosis. Thus, we hypothesized that an IFN-stimulated gene (ISG) with prosurvival activity might suppress TRAIL-mediated apoptosis. Consistent with this, IFN-alpha2b stabilized mitochondria and inhibited caspase-3 activation, which antagonized TRAIL-mediated apoptosis and cytotoxicity after 24 hours of cotreatment in cell lines and in fresh myeloma cells, an effect not evident after 72 hours. Induced expression of G1P3, an ISG with largely unknown function, was correlated with the antiapoptotic activity of IFN-alpha2b. Ectopically expressed G1P3 localized to mitochondria and antagonized TRAIL-mediated mitochondrial potential loss, cytochrome c release, and apoptosis, suggesting specificity of G1P3 for the intrinsic apoptosis pathway. Furthermore, RNAi-mediated downregulation of G1P3 restored IFN-alpha2b-induced apoptosis. Our data identify the direct role of a mitochondria-localized prosurvival ISG in antagonizing the effect of TRAIL. Curtailing G1P3-mediated antiapoptotic signals could improve therapies for myeloma or other malignancies.

Although interactions with bone marrow stromal cells are essential for multiple myeloma (MM) cell survival, the specific molecular and cellular elements involved are largely unknown, due in large part to the complexity of the bone marrow microenvironment itself. The T-cell costimulatory receptor CD28 is also expressed on normal and malignant plasma cells, and CD28 expression in MM correlates significantly with poor prognosis and disease progression. In contrast to T cells, activation and function of CD28 in myeloma cells is largely undefined. We have found that direct activation of myeloma cell CD28 by anti-CD28 mAb alone induces activation of PI3K and NFκB, suppresses MM cell proliferation, and protects against serum starvation and dexamethasone (dex)–induced cell death. Coculture with dendritic cells (DCs) expressing the CD28 ligands CD80 and CD86 also elicits CD28-mediated effects on MM survival and proliferation, and DCs appear to preferentially localize within myeloma infiltrates in primary patient samples. Our findings suggest a previously undescribed myeloma/DC cell-cell interaction involving CD28 that may play an important role in myeloma cell survival within the bone marrow stroma. These data also point to CD28 as a potential therapeutic target in the treatment of MM.

Multiple myeloma is an incurable disease for which there are 2 clinical research strategies. One strategy is to focus on managing the disease as a chronic process aiming to minimize the negative impact on survival with minimal or no compromise of the quality of life. The other strategy is to pursue total eradication of the malignant clone, thus achieving cure for the disease. Over the past decade, the myeloma communities have seen several new agents approved for the therapy of multiple myeloma. Although these agents do not result in cure, they target the disease microenvironment, allowing for a better overall response rate and improved quality of response. The latter appears to be influencing the disease outcome in improved progression-free survival, translating into a longer overall survival. Despite the advances in the discovery of immune modulator compounds, chemotherapy continues to be an important part of the myeloma therapeutic armamentarium. Recently, several investigators have explored combining traditional chemotherapeutic agents with proteasome inhibitors and immune modulators.

Purpose The combination of fludarabine and cyclophosphamide is an effective regimen for patients with chronic lymphocytic leukemia (CLL). However, it may be accompanied by increased toxicity compared with fludarabine alone. E2997 is a phase III randomized Intergroup trial comparing fludarabine and cyclophosphamide (FC arm) versus fludarabine (F arm) alone in patients receiving their first chemotherapy regimen for CLL. Patients and Methods Symptomatic, previously untreated patients with CLL were randomly assigned to receive either fludarabine 25 mg/m2 intravenously (IV) days 1 through 5 or cyclophosphamide 600 mg/m2 IV day 1 and fludarabine 20 mg/m2 IV days 1 through 5. These cycles were repeated every 28 days for a maximum of six cycles. Results A total of 278 patients were randomly assigned in this Intergroup study. Treatment with fludarabine and cyclophosphamide was associated with a significantly higher complete response (CR) rate (23.4% v 4.6%; P < .001) and a higher overall response (OR) rate (74.3% v 59.5%, P = .013) than treatment with fludarabine as a single agent. Progression-free survival (PFS) was also superior in patients treated with fludarabine and cyclophosphamide than those treated with fludarabine (31.6 v 19.2 months, P < .0001). Fludarabine and cyclophosphamide caused additional hematologic toxicity, including more severe thrombocytopenia (P = .046), but it did not increase the number of severe infections (P = .812). Conclusion Fludarabine and cyclophosphamide produced an increase in OR and CR, and it improved PFS in patients with previously untreated CLL compared with fludarabine alone and was not associated with an increase in infectious toxicity.

Clonotypic B lymphocytes may underlie relapse of patients with multiple myeloma. Rituximab, a CD20 monoclonal antibody, may result in eradication of the monoclonal B cells. We conducted a phase II study of rituximab in combination with melphalan and prednisone therapy (MP) followed by rituximab maintenance in newly diagnosed multiple myeloma patients. Sixteen patients (35%) had CD20 positive bone marrow plasma cells, while 9 patients (20%) had unknown CD20 status. No patient had a complete remission, 26 patients (58%) had a partial response, 6 patients (13%) had a minimal response, and 8 patients (18%) had stable disease. The median event-free survival was 14 months, and the 7-year overall survival was 30%. The toxicity of the combination was overall manageable and consistent with what is generally noted with MP chemotherapy. The combination of rituximab to MP therapy did not result in improved response rate or event-free survival.

The majority of intracellular proteins undergo degradation through the ubiquitin-proteasome pathway. The proteasome pathway has a role in regulating cell proliferation, differentiation, survival and apoptosis. The naturally occurring proteasome inhibitor lactacystin was the first proteasome inhibitor noted to induce apoptosis in vitro. Compared with first-generation proteasome inhibitors, bortezomib (PS-341), a dipeptide boronic acid, has exhibited higher potency and specificity, and has been approved for the treatment of relapsed or refractory myeloma. However, there are some patients who do not respond to therapy or who respond briefly and then relapse. It is becoming increasingly clear that myeloma cells respond to the stress caused by proteasome inhibitors (bortezomib) via rapidly up-regulating pathways that suppress apoptosis, thus attenuating its antitumour activity. The delineation of these molecular pathways and mechanisms to circumvent them are needed to allow this important class of agents to remain vital in the armamentarium of the management of multiple myeloma and other malignancies.

BACKGROUND Pegylated liposomal doxorubicin has pharmacologic and safety advantages over conventional doxorubicin. METHODS For this noninferiority trial, 192 patients with newly diagnosed, active multiple myeloma were randomized to receive either combined pegylated liposomal doxorubicin (40 mg/m2) and vincristine (1.4 mg/m2; maximum, 2.0 mg) as an intravenous infusion on Day 1 plus reduced-dose dexamethasone (40 mg) orally on Days 1–4 (DVd) (n = 97 patients) or combined vincristine (0.4 mg per day) and conventional doxorubicin (9 mg/m2 per day) as a continuous intravenous infusion on Days 1–4 plus reduced-dose dexamethasone (VAd) (n = 95 patients) for at least 4 cycles. Treatment was repeated every 4 weeks until patients either achieved maximal response, disease progression, or unacceptable toxicity or underwent transplantation. The primary endpoints were response and toxicity. RESULTS Objective response rates (DVd, 44%; VAd, 41%), progression-free survival (hazard ratio, 1.11; P = 0.69), and overall survival (hazard ratio, 0.88; P = 0.67) were similar between the treatment groups. However, DVd was associated with significantly less Grade 3/4 neutropenia or neutropenic fever (10% vs. 24%; P = 0.01), a lower incidence of sepsis, and less antibiotic use. Compared with VAd, DVd also significantly decreased the need for central venous access (P < 0.0001) and growth-factor support (P = 0.03) and resulted in less alopecia (20% vs. 44%; P < 0.001) but more hand–foot syndrome (25% vs. 1%; P < 0.001), mainly Grade 1/2. CONCLUSIONS The DVd regimen demonstrated similar efficacy with less toxicity and supportive care compared with VAd, which should improve clinical utility and optimize the opportunity for transplantation. Cancer 2006. © 2006 American Cancer Society.

Multiple myeloma is a clonal disorder of plasma cells which is considered incurable with currently available therapies. Substantial advances have been achieved in the past decade with the identification of cellular mechanisms that confer drug resistance. This has resulted in newer agents such as arsenic trioxide (Trisenox™), lenalidomide (Revlimid™) and bortezomib (Velcade™) with promising activity in this disease. In this review article we will outline the history, mechanisms of action, pharmacology, and clinical trials of arsenic trioxide in multiple myeloma.

The design of innovative, more effective, less toxic therapy for multiple myeloma (MM) is emerging in parallel to a better understanding of the underlying pathophysiology of this common hematologic malignancy. Thalidomide has changed the treatment paradigm for patients with myeloma. Its efficacy, however, has been compromised to some degree by its side effects. Immunomodulatory drugs (IMiDs) are structural and functional analogues of thalidomide that were specifically designed to produce new agents with enhanced immunomodulating and anticancer properties but with less toxicity. In this article, we review the clinical trial development of second-generation IMiDs lenalidomide and CC-4047. Both agents demonstrate potent activity with manageable toxicities and provide another treatment opportunity for patients with MM.

Osteonecrosis of the jaw has been linked with bisphosphonate use in breast cancer and multiple myeloma patients. We report 17 cases of patients with plasma cell dyscrasia being treated with bisphosphonate who developed osteonecrosis/osteomyelitis of the jaw. Seventeen patients evaluated at our institution between 1998 and 2005 are reported. All were being treated with bisphosphonates for a median of 5 mo prior to the onset of jaw symptoms. Sixteen of the 17 patients are 51 yr or older. None of the patients had been irradiated in the jaw nor had obvious osseous manifestation of multiple myeloma in the jaw. Thirteen patients were receiving zoledronic acid and four patients were receiving pamidronate at the onset of jaw symptoms. Six of the 17 did receive both agents at some time and all of these individuals were receiving zoledronic acid at diagnosis. Microorganisms were isolated in 7/17 patients with the most common organism being actinomycosis. We have initiated the following guidelines in an effort to ameliorate the incidence of this complication. Patients should have a full dental examination at the time of diagnosis of the plasma cell dyscrasia especially if bisphosphonates are to be considered as part of the therapy. In addition, bisphosphonates are held for a period of 3 mo prior to invasive dental procedures to allow for the osteoclastic recovery, therefore enhanced debris removal and lessening the chance of creating a fertile bacterial medium. Following the dental procedure we would re-introduce bisphosphonates only after the healing process is complete. Finally, multiple myeloma patients diagnosed with jaw osteonecrosis probably have a concurrent infection and should be aggressively treated with antibiotics.