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Castleman disease (CD) includes a group of rare and heterogeneous disorders with characteristic lymph node histopathological abnormalities. CD can occur in a single lymph node station, which is referred to as unicentric CD (UCD). CD can also involve multicentric lymphadenopathy and inflammatory symptoms (multicentric CD [MCD]). MCD includes human herpesvirus-8 (HHV-8)–associated MCD, POEMS-associated MCD, and HHV-8−/idiopathic MCD (iMCD). The first-ever diagnostic and treatment guidelines were recently developed for iMCD by an international expert consortium convened by the Castleman Disease Collaborative Network (CDCN). The focus of this report is to establish similar guidelines for the management of UCD. To this purpose, an international working group of 42 experts from 10 countries was convened to establish consensus recommendations based on review of treatment in published cases of UCD, the CDCN ACCELERATE registry, and expert opinion. Complete surgical resection is often curative and is therefore the preferred first-line therapy, if possible. The management of unresectable UCD is more challenging. Existing evidence supports that asymptomatic unresectable UCD may be observed. The anti–interleukin-6 monoclonal antibody siltuximab should be considered for unresectable UCD patients with an inflammatory syndrome. Unresectable UCD that is symptomatic as a result of compression of vital neighboring structures may be rendered amenable to resection by medical therapy (eg, rituximab, steroids), radiotherapy, or embolization. Further research is needed in UCD patients with persisting constitutional symptoms despite complete excision and normal laboratory markers. We hope that these guidelines will improve outcomes in UCD and help treating physicians decide the best therapeutic approach for their patients.

Background: Patients with multiple myeloma, an incurable haematological cancer, often receive palliative care only late in their trajectory. Criteria for early referral are lacking. Aim: To identify which patients might benefit from early integration, by identifying trajectories of health-related quality of life and the determinants for declining or poor Health related quality of life . Design: Prospective, longitudinal cohort study. Participants: Multiple myeloma patients at all stages (newly diagnosed, first-line or second-line treatment, early or later treatment-free interval, refractory disease) from in- and outpatient units at 14 hospitals in England were recruited. In addition to clinical information and standardised Health related quality of life and psychological aspects, the Myeloma Patient Outcome Scale (MyPOS) measured palliative care concerns. Results: A total of 238 patients were recruited, on average 3.5 years ( SD: 3.4) post-diagnosis. Latent mixture growth models identified four Health related quality of life trajectories. Classes 3 and 4 represent trajectories of stable poor Health related quality of life or declining Health related quality of life over an 8-month period. The strongest predictors of poor outcome at the end of follow-up were general symptom level (odds ratio (OR): 1.3, 95% CI: 1.0–1.6, p = 0.028), presence of clinically relevant anxiety (OR: 1.2, 95% confidence interval (CI): 1.0–1.4, p = 0.019), and presence of pain (OR: 1.02, 95% CI: 1.0–1.1, p = 0.018), all being more predictive than demographic or clinical characteristics. Conclusion: General symptom level, pain and presence of anxiety predict declining Health related quality of life in multiple myeloma. Identification of patients with palliative care needs should focus on assessing patient-reported symptoms and psychosocial well-being for identifying those at risk of deterioration.

Background Renal impairment is a life threatening complication of myeloma with up to 20-25% of patients presenting with renal dysfunction. Around 28% of newly diagnosed myeloma patients with renal failure do not survive beyond 100 days compared with 10% overall. In addition to poor survival, there are no quality of life (QoL) data from published renal failure myeloma studies to guide management. OPTIMAL trial utilizes the EuroQoL (EQ-5D-3L) heath questionnaire, a validated instrument for health outcomes, to measure QoL in these patients. It is a 3 level, 5 dimensional questionnaire, assessing mobility, self-care, usual activity, pain/discomfort and anxiety/depression with either no problems, some problems or extreme problems. Participants also rate their current health on a visual analogue scale (VAS) of 0-100. We hypothesize that reported QoL in typical myeloma trials are better than the QoL for patients with renal impairment such as those recruited into the OPTIMAL trial. Methods OPTIMAL is a randomised, multi-centre phase II trial of newly diagnosed myeloma patients with renal impairment (ClinicalTrials.gov Identifier: NCT02424851). Participants were randomised to receive four 12 week cycles of Bortezomib, Bendamustine and Dexamethasone (BBD) or Thalidomide, Bendamustine and Dexamethasone (BTD); all participants received bendamustine and dexamethasone in 3 week cycles. Participants not considered suitable for autologous stem cell transplant (ASCT) could be given a further 2 cycles of treatment in their respective arms. Patient reported outcomes were measured using the validated EQ-5D-3L. Participants were asked to complete a questionnaire at baseline and on day 1 of each treatment cycle and at 1 month and 12 month follow up visits. Differences in changes of EQ-5D-3L and the VAS scores between baseline and 1 month follow up were assessed by 2 sample t-tests. To compare the EQ-5D-3L data from the OPTIMAL trial to others, a literature search was conducted to see if any data were available that provided further insight into the QoL in patient's diagnosed with myeloma and renal failure. PUBMED and MEDLINE were explored and authors emailed if EQ-5D-3L data was not identified. Results OPTIMAL recruited 31 patients between March 2015 and March 2019 from 7 centres within the UK. Of these, 17 patients completed EQ-5D-3L at baseline and at 1 month follow up; 8 on BBD and 9 on BTD. Sixty five per cent of patients were ≤70 years old, 76% male, 35% were CKD stage 4 and 65% were CKD stage 5, 59% had planned ASCT, 88% had ECOG performance status 0 or 1, 35% were on dialysis and 94% were ISS stage III. At baseline a mean of 35.2% of patients reported some or extreme problems across the 5 QoL domains compared with 36.6% at 1 month follow up (Table 1). No significant changes were detected in mean EQ-5D-3L (p=0.33) or VAS scores (p=0.72) between baseline and 1 month follow up by treatment arm (Table 2). Additionally, no differences in EQ-5D-3L scores were found between age group or dialysis status (p>0.1; Table 3). However, some improvement in anxiety and depression levels were observed overall with 59% of patients reporting none at baseline increasing to 76% at follow up. No changes were reported in self-care or the ability to perform usual activities. Mobility decreased from 71% experiencing no problems to 59%. In order to compare QoL reported by OPTIMAL with QoL reported in published myeloma trials, a literature search was undertaken and identified 48 articles of which only 11 studies reported QoL and only 4 of these reported the EQ-5D-5L. No studies assessed QoL in patients similar to the OPTIMAL trial patient population with renal impairment. However a couple of studies demonstrated improved QoL at 3 months compared to baseline across treatment arms. Conclusion It is well known that treatments used within clinical trials can significantly improve the outcomes for patients but it is important to also measure the impact on patient's QoL. The OPTIMAL trial demonstrated that this poor prognostic set of patients with renal impairment had significant reduction in anxiety and depression at 1 month follow up. It was disappointing that a literature search demonstrated a paucity of QoL data routinely collected and reported within clinical trials. Patients need to know the impact of treatments on outcomes such as survival but also need to know the impact on their QoL. Funding: NAPP Pharmaceuticals, JANSSEN-Cilag Ltd and Blood Cancers UK. Disclosures Ramasamy: Takeda: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Bristol Myers Squibb: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Bristol Myers squibb: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria; Janssen: Research Funding; Amgen: Honoraria; Sanofi: Honoraria; Abbvie: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Janssen: Honoraria; Amgen: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Takeda: Speakers Bureau. Lindsay:Amgen: Other: Travel Expenses; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Takeda: Honoraria, Other: Travel Expenses.

Castleman disease (CD) describes a group of heterogeneous hematologic disorders with characteristic histopathological features. CD can present with unicentric or multicentric (MCD) regions of lymph node enlargement. Some cases of MCD are caused by human herpesvirus-8 (HHV-8), whereas others are HHV-8–negative/idiopathic (iMCD). Treatment of iMCD is challenging, and outcomes can be poor because no uniform treatment guidelines exist, few systematic studies have been conducted, and no agreed upon response criteria have been described. The purpose of this paper is to establish consensus, evidence-based treatment guidelines based on the severity of iMCD to improve outcomes. An international Working Group of 42 experts from 10 countries was convened by the Castleman Disease Collaborative Network to establish consensus guidelines for the management of iMCD based on published literature, review of treatment effectiveness for 344 cases, and expert opinion. The anti–interleukin-6 monoclonal antibody siltuximab (or tocilizumab, if siltuximab is not available) with or without corticosteroids is the preferred first-line therapy for iMCD. In the most severe cases, adjuvant combination chemotherapy is recommended. Additional agents are recommended, tailored by disease severity, as second- and third-line therapies for treatment failures. Response criteria were formulated to facilitate the evaluation of treatment failure or success. These guidelines should help treating physicians to stratify patients based on disease severity in order to select the best available therapeutic option. An international registry for patients with CD (ACCELERATE, #NCT02817997) was established in October 2016 to collect patient outcomes to increase the evidence base for selection of therapies in the future.

Improving outcomes in multiple myeloma will involve not only development of new therapies but also better use of existing treatments. We performed RNA sequencing on samples from newly diagnosed patients enrolled in the phase 2 PADIMAC (Bortezomib, Adriamycin, and Dexamethasone Therapy for Previously Untreated Patients with Multiple Myeloma: Impact of Minimal Residual Disease in Patients with Deferred ASCT) study. Using synthetic annealing and the large margin nearest neighbor algorithm, we developed and trained a 7-gene signature to predict treatment outcome. We tested the signature in independent cohorts treated with bortezomib- and lenalidomide-based therapies. The signature was capable of distinguishing which patients would respond better to which regimen. In the CoMMpass data set, patients who were treated correctly according to the signature had a better progression-free survival (median, 20.1 months vs not reached; hazard ratio [HR], 0.40; confidence interval [CI], 0.23-0.72; P = .0012) and overall survival (median, 30.7 months vs not reached; HR, 0.41; CI, 0.21-0.80; P = .0049) than those who were not. Indeed, the outcome for these correctly treated patients was noninferior to that for those treated with combined bortezomib, lenalidomide, and dexamethasone, arguably the standard of care in the United States but not widely available elsewhere. The small size of the signature will facilitate clinical translation, thus enabling more targeted drug regimens to be delivered in myeloma.

Background Renal impairment is a life threatening complication of myeloma with up to 20-25% of patients presenting with renal dysfunction. Outcome is poor as a result of a high early mortality. Around 28% of newly diagnosed myeloma patients with renal failure do not survive beyond 100 days compared with 10% overall. Studies have shown that within weeks of diagnosing myeloma with renal failure, treatment with dexamethasone alone or combined with bortezomib lowers serum free light chain (sFLC) levels by more than 50% in half of patients; achieving lower sFLC levels in this early period is associated with a greater chance of being alive and dialysis free at 100 days. Methods OPTIMAL is a randomised, multi-centre phase II trial of newly diagnosed myeloma patients with renal impairment. Renal impairment defined as 18 years old, chronic kidney disease (CKD) stage 4 or 5, not pregnant or risk of pregnancy for child bearing women, or partner of male participants, free of malignancies for >2 years, able to comply with all trial requirements and give fully informed consent. Patients were randomised to receive 4 cycles of either Bortezomib, Bendamustine and Dexamethasone (BBD) or Thalidomide, Bendamustine and Dexamethasone (BTD); all participants received bendamustine and dexamethasone in three week cycles. Treatment period for participants receiving 4 cycles of therapy was 12 weeks. Participants not considered suitable for autologous stem cell transplant (ASCT) could be given a further two cycles of treatment (up to 6 cycles in total) in their respective arms. The trial was powered to detect 23% differences in the percentage of patients achieving >50% reduction in sFLC between treatment arms, e.g. from 60% to 83%, with 80% power and a 5% 2-sided significance level, recruiting 60 patients in each arm. At the pre-planned interim analysis, the data and safety monitoring committee endorsed the closure of the trial as a 60% difference in sFLC was detected and there was no obvious benefit for the BTD arm. This was also endorsed by the trial steering committee and trial management group. Co-primary endpoints were sFLC response from baseline to week 6 (after receiving two cycles of trial treatment) and renal response according to the modified International Myeloma Working Group (IMWG) criteria after receiving four cycles of trial treatment. Secondary endpoints included haematological responses, toxicity and overall survival. Results OPTIMAL recruited 31 patients between March 2015 and March 2019 from seven centres within the UK; 16 on BBD and 15 on BTD. Fifty two per cent of patients were ≤70 years old, 55% male, 35% were CKD stage 4 and 65% were CKD stage 5, 48% had planned autologous-stem cell transplantation, 75% had ECOG performance status 0 or 1, 29% were on dialysis and 90% were ISS stage III. Serum free light chain response was assessed in 29 patients where samples were available at screening and at the end of two cycles of treatment. 81% of patients on BBD achieved vGPR compared to 23% on BTD, Fisher's p=0.006, table 1. Nine patients were on dialysis at the time of screening (6 on BBD and 3 on BTD). Complete or partial renal response was achieved by 2 (50%) of patients on BBD compared to 1 (11%) on BTD, Fisher's p=0.05, table 2. Two patients on BBD arm reported reversibility of dialysis dependency after four cycles of treatment. Two patients not previously on dialysis required dialysis after 4 cycles of BTD. Seven deaths were reported from the total 31 patients (5 (31%) on BBD arm and 2 (13%) on BTD arm). There were 33 reported serious adverse events (SAEs) 14 on BBD and 19 on BTD. Conclusion OPTIMAL demonstrated a significant increase in the number of sFLC responders after the first 2 cycles for those patients allocated BBD compared to BTD; this trend continued when assessing renal response after 4 cycles with more patients being dialysis independent after receiving BBD. Funding: Project funded by NAPP Pharmaceuticals, JANSSEN-Cilag Ltd and Bloodwise (formerly named Leukaemia and Lymphoma Research). Disclosures Ramasamy: Oncopeptides and Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; NAPP Pharmaceuticals Ltd.: Research Funding; Janssen-Cilag Ltd.: Research Funding. Drayson:Abingdon Health: Consultancy, Equity Ownership.

Objectives Multiple myeloma (MM) is an incurable haematological disease. Due to novel agents, overall survival has improved in this group, yet there are no systematic reviews to understand the symptom profiles resulting from disease and treatment-related toxicities. We aimed to synthesise data on prevalence of symptoms in patients with MM. Methods A systematic database and grey literature search was conducted in 6 databases. Random effects meta-analysis with inverse variance weighting to pool prevalence data was performed. Results 36 studies were included of which 34 studies (N = 3,023) provided data for meta-analysis. 27 distinct symptoms were reported, with the majority of studies focusing on pain (n=27), fatigue (n=19) and problems with functioning (n=15). The most prevalent symptoms were fatigue (98.8%, 95% CI 98.1 – 99.2%), pain (73%, 39.9 – 91.7), constipation (65.2%, 22.9-92.2) and tingling in the hands/feet with 53.4% (0.4-99.7). The most common problems were decreased physical functioning (98.9%, 98.2 – 99.3), decreased cognitive functioning (80.2%, 40 – 96.1) and financial difficulties (78.4%, 39.1 – 95.4). These problems were present in newly diagnosed to advanced disease stage. Conclusions Optimal quality of life and good symptom management in this incurable disease can only be achieved by routinely assessing symptoms throughout the disease trajectory. This article is protected by copyright. All rights reserved.

The NF-κB transcription factor pathway is aberrantly activated in multiple myeloma (MM) and many other cancers, where it promotes malignancy by upregulating survival genes, thus providing a compelling rationale for therapeutically targeting this pathway in MM. However, despite aggressive efforts to develop a specific NF-κB or IκB kinase (IKK)β inhibitor, no such inhibitor has been approved, due to the preclusive toxicities associated with the general suppression of NF-κB. As a key pathogenetic activity of NF-κB in MM is to block apoptosis through the induction of target genes, an attractive alternative to globally inhibiting NF-κB would be to therapeutically target the non-redundant, cancer-specific downstream effectors of the NF-κB survival pathway. Recently, we identified the interaction between the NF-κB-regulated antiapoptotic factor, GADD45β, and the JNK kinase, MKK7, as a pathogenically critical and cancer cell-restricted survival module downstream of NF-κB and novel therapeutic target in MM. Further, we developed a D-tripeptide inhibitor of the GADD45β/MKK7 complex, DTP3, which effectively kills MM cells by inducing MKK7/JNK-dependent apoptosis and, importantly, is not toxic to normal tissues. Due to this cancer-cell specificity, DTP3 has similar anti-cancer efficacy to bortezomib, but more than 100-fold higher cancer-cell specificity in patient MM cells, ex vivo. DTP3 also displays potent and cancer-selective activity against MM in preclinical animal models, with no apparent side-effects, and far greater therapeutic index than existing treatments. DTP3 further displays synergistic activity with conventional MM therapies, such as bortezomib, suggesting a clinical utility as frontline combination therapy. Additionally, it retains therapeutic efficacy in MM cells that are resistant to most common MM treatments, suggesting further clinical utility. We currently aim to conduct a phase I/IIa clinical trial of DTP3 in MM to deliver clinical Proof of Concept for a cancer-selective NF-κB-targeting strategy as a highly effective novel therapy. This first-in-man study will commence in late 2015. We report here the results from the regulatory pharmacodynamics (PD), safety pharmacology, pharmacokinetic (PK), and toxicology studies. 28-day intravenous (i.v.) repeat dose toxicology studies in rat and dog demonstrate that DTP3 is well tolerated, with no significant target organs of toxicity at up to 17 times the optimal exposure in mouse efficacy models. Toxicokinetic (TK) analyses indicate that DTP3 does not accumulate on repeat dosing. Safety pharmacology studies indicate no adverse effect on the central nervous, cardiovascular or respiratory systems. In an Ames assay, DTP3 was not mutagenic. In the rat, i.v. DTP3 rapidly and extensively distributes to tissues, does not pass the blood-brain barrier, and is readily eliminated in urine (30%) and faeces (60%). No major metabolites have been identified. In vitro, DTP3 did not inhibit or induce major human cytochrome P450 isoforms, suggesting no potential for drug interactions via P450. In vitro, DTP3 is neither a substrate for nor inhibitor of P-gp or BCRP, nor is it a substrate or inhibitor of most transporters evaluated. However, DTP3 is a substrate for the uptake transporters, MATE1, MATE2-K and OATP1B3, with some inhibitory potential for MATE1 and MATE2-K at high concentrations. PD studies in a mouse xenograft model show that i.v. bolus injection of at least 10 mg/kg of DTP3 over 2 weeks, daily, every other day, or every 3 days, is highly effective in causing complete tumour regression. The PK and TK evaluation of DTP3 in rat and dog identified long plasma half-lives, modelled into a half-life of 20-24 hr in man. On these bases, we have proposed an initial clinical dosing regimen of DTP3 of three times per week i.v., testing doses from 0.5 to 20 mg/kg. The data also support a subcutaneous route of administration, and an i.v. bolus regimen of twice per week. Collectively, the preclinical package demonstrates the outstanding selective pharmacology and efficacy of DTP3, combined with excellent i.v. tolerability, wide therapeutic window, and favourable PK profile, and supports progression into clinical development. A companion biomarker programme has also been developed in order to inform patient stratification, demonstrate pathway-specific PD activity and proof of mechanism, and so maximise the chance of a positive clinical response. Disclosures Tornatore: Kesios Therapeutics Ltd.: Consultancy, Equity Ownership, Honoraria, Patents & Royalties. Adams:Kesios Therapeutics Ltd.: Consultancy. Kelly:Kesios Therapeutics Ltd.: Consultancy. Ruvo:Kesios Therapeutics Ltd.: Equity Ownership, Patents & Royalties. Oakervee:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Schey:Celgene Corporation: Honoraria. Apperley:Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ARIAD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Franzoso:Kesios Therapeutics Ltd.: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.

Battelle Energy Alliance, LLC, managing and operating contractor for the U.S. Department of Energy’s Idaho National Laboratory, is the lead laboratory for the U.S. Department of Energy’s advanced vehicle testing. Battelle Energy Alliance, LLC contracted with Intertek Testing Services, North America to conduct several U.S. Department of Defense-based micro-climate studies to identify potential U.S. Department of Defense transportation systems that are strong candidates for introduction or expansion of plug-in electric vehicles (PEVs). The study included Joint Base Lewis McChord, located in Washington State; Naval Air Station Whidbey Island, located in Washington State; and United States Marine Corp Base Camp Lejeune, located in North Carolina. The project was divided into four tasks for each of the three bases studied. Task 1 consisted of surveying the non-tactical fleet of vehicles to begin review of vehicle mission assignments and types of vehicles in service. In Task 2, the daily operational characteristics of the vehicles were identified to select vehicles for further monitoring and attachment of data loggers. Task 3 recorded vehicle movements in order to characterize the vehicles’ missions. Results of the data analysis and observations were provided. Individual observations of these selected vehicles provided the basis for recommendations related to PEV adoptionmore » (i.e., whether a battery electric vehicle or plug-in hybrid electric vehicle [collectively referred to as PEVs] can fulfill the mission requirements). It also provided the basis for recommendations related to placement of PEV charging infrastructure. In Task 4, an implementation approach was provided for near-term adoption of PEVs into the respective fleets. Each facility was provided detailed reports on each of these tasks. This paper summarizes and provides observations on the project and completes Intertek’s required actions.« less

The Office of National Statistics (London, UK) has reported 4040 new patients in the year 2007, with an annual age standardized incidence rate of 4.8 per 100,000 population (range 4.7 - 5.0). Overall survival (OS) in the last decade has improved from 2 - 3 years to 7 - 8 years in the UK. The introduction of IMids for the treatment of myeloma has had a significant impact on outcomes in this life-threatening disease.Pomalidomide, a thalidomide analogue, is a promising anti-myeloma agent with encouraging responses in relapsed/refractory myeloma patients. Pomalidomide has a potent anti-myeloma activity in vitro and in vivo, acting both directly on myeloma cells and on the cells in the bone marrow microenvironment. We have reviewed the chemistry and mechanisms of action of pomalidomide and the literature on pre-clinical and early Phase I and II clinical trials that demonstrates significant clinical efficacy in the relapsed setting and in lenalidomide refractory myeloma patients.Pomalidomide has shown significant activity in relapsed/refractory disease and is now being taken into Phase III trials in combination with dexamethasone. The exact place of pomalidomide in the management of myeloma, however, is evolving as more clinical experience is gained with this agent and further data published from clinical trials.

We report the results of a Phase I/II dose escalation study to determine the maximum tolerated dose (MTD) of cyclophosphamide when combined with lenalidomide and dexamethasone in relapsed/refractory myeloma. Thirty-one patients were enrolled in cohorts of 3, at five dose levels of cyclophosphamide to a maximum of 700 mg on days 1 and 8 of a 28-d cycle. Patients received lenalidomide 25 mg days 1-21 and dexamethasone 20 mg orally days 1-4 and 8-11. The MTD was 600 mg cyclophosphamide, days 1 and 8. Grade 3/4 haematological complications occurred in 26% of patients, grade 3/4 infection in 3% (both at 700 mg cyclophosphamide), with thromboembolic complications in 6% of patients. Overall complete response (CR) rate was 29%, very good partial response rate 7% and partial response rate 45% giving an overall response rate of 81%. After 21 months median follow-up, projected 2-year progression-free survival was 56%, with 80% overall survival at 30 months. Ten further patients were treated at MTD with a 40% CR rate. No dose reductions for any study drugs or deaths occurred during cycles 1-9. Lenalidomide, cyclophosphamide and dexamethasone is a safe, effective combination in relapsed myeloma inducing a high response rate, warranting further investigation in phase III trials.

The HDACis (histone deacetylation inhibitors) are an active class of drugs that have been used to treat a wide variety of tumours including breast cancer, prostate cancer, multiple myeloma, thyroid cancer and Hodgkin's and non-Hodgkin's lymphoma. One HDAC, vorinostat, has been licensed by the FDA, but more work is needed to identify and delineate the histone and nonhistone targets of these agents. In this article, Dr Steve Schey considers the place of HDACis in future cancer therapy. Copyright © 2010 John Wiley & Sons, Ltd.

We previously reported that daily dose pomalidomide (CC-4047), a thalidomide analogue, has excellent anti-myeloma activity but is associated with myelosuppression and deep vein thrombosis. We report here a phase 1 study to determine the maximum tolerated dose (MTD) of pomalidomide at 1 mg, 2 mg, 5 mg and 10 mg on alternate days (ad). Twenty patients with relapsed myeloma were treated. Grade 4 neutropenia occurred in all patients receiving 10 mg and the MTD was defined as 5 mg ad. No thrombotic events were observed. Pomalidomide was continued following the 4-week MTD study in 17/20 patients for a median of 14 months. 10% of patients had a complete response and >50% reduction in paraprotein was achieved in 50% of subjects. Progression-free survival was 10.5 months and median overall survival was 33 months. A significant rise was observed in the proportion of CD8(+) cells. Alternate day pomalidomide was associated with a marked reduction in the incidence of thrombosis whilst maintaining excellent anti-myeloma activity. This trial provides further in vivo evidence that pomalidomide modulates the immune system in myeloma patients. Phase 2 studies to further assess the optimal schedule of administration and anti-myeloma activity of this agent are planned.

Peripheral T-cell lymphomas (PTCL) are a rare and heterogeneous subset of lymphomas with a poorer prognosis compared with B-cell lymphomas. We conducted a retrospective study of 82 patients who received high-dose therapy for PTCL (autologous SCT (ASCT) N=64; allogeneic SCT (Allo-SCT) N=18). With a median follow-up from ASCT of 37 months from transplant, 33 patients were alive; 20 died of progressive disease, 10 died from non-relapse mortality (NRM) with 1 unknown cause. Three-year overall survival (OS) and progression-free survival (PFS) were 53% (95% confidence interval (CI) 42, 67) and 50% (95% CI 39, 64), respectively. Factors significantly affecting OS and PFS on univariate analysis were histological subtype and chemotherapy sensitivity. In a multivariate analysis, the only factor with significant impact was chemotherapy sensitivity. After a median follow-up from Allo-SCT of 57 months, five patients were alive; five died of progressive disease and eight died from NRM. The 3-year OS and PFS were 39% (95% CI 22, 69) and 33% (95% CI 17, 64), respectively, and the 3-year relapse rate was 28% (95% CI 6, 50). These results demonstrate that high-dose chemotherapy with autologous stem cell rescue has a substantial role in the management of T-cell lymphoma. The use of full-intensity allogeneic transplantation is limited by high transplant-related mortality, and exploration of reduced intensity regimens is warranted.

Background Multiple myeloma, the second most common haematological cancer, remains incurable. Its incidence is rising due to population ageing. Despite the impact of the disease and its treatment, not much is known on who is most in need of supportive and palliative care. This study aimed to (a) assess symptom severity, palliative care concerns and health-related quality of life (HRQOL) in patients with multiple myeloma, and (b) to determine which factors are associated with a lower quality of life. We further wanted to know (c) whether general symptom level has a stronger influence on HRQOL than disease characteristics. Methods This multi-centre cross-sectional study sampled two cohorts of patients with multiple myeloma from 18 haematological cancer centres in the UK. The Myeloma Patient Outcome Scale (MyPOS) was used to measure symptoms and concerns. Measures of quality of life included the EORTC QLQ-C30, its myeloma module and the EuroQoL EQ-5D. Data were collected on socio-demographic, disease and treatment characteristics and phase of illness. Point prevalence of symptoms and concerns was determined. Multiple regression models quantified relationships between independent factors and the MyPOS, EORTC global quality of life item and EQ5D Index. Results Five-hundred-fifty-seven patients, on average 3.5 years (SD: 3.4) post-diagnosis, were recruited. 18.2 % had newly diagnosed disease, 47.9 % were in a treatment-free interval and 32.7 % had relapsed/progressive disease phase. Patients reported a mean of 7.2 symptoms (SD: 3.3) out of 15 potential symptoms. The most common symptoms were pain (72 %), fatigue (88 %) and breathlessness (61 %). Those with relapsed/progressive disease reported the highest mean number of symptoms and the highest overall palliative care concerns (F = 9.56, p

Battelle Energy Alliance, LLC, managing and operating contractor for the U.S. Department of Energy’s (DOE) Idaho National Laboratory (INL), is the lead laboratory for U.S. Department of Energy’s Advanced Vehicle Testing Activity (AVTA). INL’s conduct of the AVTA resulted in a significant base of knowledge and experience in the area of testing light-duty vehicles that reduced transportation-related petroleum consumption. Due to this experience, INL was tasked by DOE to develop agreements with companies that were the recipients of The American Recovery and Reinvestment Act of 2009 (ARRA) grants, that would allow INL to collect raw data from light-duty vehicles and charging infrastructure. INL developed non-disclosure agreements (NDAs) with several companies and their partners that resulted in INL being able to receive raw data via server-to-server connections from the partner companies. This raw data allowed INL to independently conduct data quality checks, perform analysis, and report publicly to DOE, partners, and stakeholders, how drivers used both new vehicle technologies and the deployed charging infrastructure. The ultimate goal was not the deployment of vehicles and charging infrastructure, cut rather to create real-world laboratories of vehicles, charging infrastructure and drivers that would aid in the design of future electric drive transportation systems. Themore » five projects that INL collected data from and their partners are: • ChargePoint America - Plug-in Electric Vehicle Charging Infrastructure Demonstration • Chrysler Ram PHEV Pickup - Vehicle Demonstration • General Motors Chevrolet Volt - Vehicle Demonstration • The EV Project - Plug-in Electric Vehicle Charging Infrastructure Demonstration • EPRI / Via Motors PHEVs – Vehicle Demonstration The document serves to benchmark the performance science involved the execution, analysis and reporting for the five above projects that provided lessons learned based on driver’s use of the vehicles and recharging decisions made. Data is reported for the use of more than 25,000 vehicles and charging units.« less

Task 1includes a survey of the inventory of non-tactical fleet vehicles at Naval Air Station Whidbey Island (NASWI) to characterize the fleet. This information and characterization are used to select vehicles for monitoring that takes place during Task 2. This monitoring involves data logging of vehicle operation in order to identify the vehicle’s mission and travel requirements. Individual observations of these selected vehicles provide the basis for recommendations related to PEV adoption. It also identifies whether a battery electric vehicle or plug-in hybrid electric vehicle (collectively referred to as PEVs) can fulfill the mission requirements and provide observations related to placement of PEV charging infrastructure. This report provides the results of the assessments and observations of the current non-tactical fleet, fulfilling the Task 1 requirements.

Background Multiple myeloma is an incurable cancer with a rising incidence globally. Less toxic treatments are increasingly available, so patients are living longer and treatment decisions are increasingly guided by QOL concerns. There is no QOL assessment tool designed specifically for use in the clinical care of people with myeloma. This study aimed to develop and test the psychometric properties of a new myeloma-specific QOL questionnaire designed specifically for use in the clinical setting – the MyPOS. Methods The MyPOS was developed using findings from a previously reported literature review and qualitative study. The prototype MyPOS was pretested using cognitive interviews in a purposive sample of myeloma patients and refined prior to field testing. The psychometric properties of the MyPOS were evaluated in a multi-centre, cross sectional survey of myeloma patients recruited from 14 hospital trusts across England. Results The prototype MyPOS contained 33 structured and open questions. These were refined using cognitive interviews with 12 patients, and the final MyPOS contained 30 items taken forward for field-testing. The cross-sectional survey recruited 380 patients for the MyPOS validation. Mean time to complete was 7 minutes 19 seconds with 0.58% missing MyPOS items overall. Internal consistency was high (α = 0.89). Factor analysis confirmed three subscales: Symptoms & Function; Emotional Response and Healthcare Support. MyPOS total scores were higher (worse QOL) in those with active disease compared to those in the stable or plateau phase (F = 11.89, p

Advances in treatments for multiple myeloma (MM) have resulted in improved survival. However, patients who have become refractory to novel agents have a poor prognosis, with a median overall survival (OS) of nine months, or as low as three months in the absence of further treatment after failure of

In Task 1, a survey was completed of the inventory of non-tactical fleet vehicles at the Marine Corps Base Camp Lejeune (MCBCL) to characterize the fleet. This information and characterization was used to select vehicles for further monitoring, which involves data logging of vehicle movements in order to identify the vehicle’s mission and travel requirements. Individual observations of these selected vehicles provide the basis for recommendations related to PEV adoption. It also identifies whether a battery electric vehicle or plug-in hybrid electric vehicle (collectively referred to as PEVs) can fulfill the mission requirements and provides observations related to placement of PEV charging infrastructure. This report provides the list of vehicles selected by MCBCL and Intertek for further monitoring and fulfills the Task 2 requirements.

Background Health-related quality of life (HRQoL) is an important element for consideration in treatment decisions in patients with relapsed/refractory multiple myeloma (RRMM). The pivotal MM-003 (A Phase 3, Multicenter, Randomized, Open-Label Study to Compare the Efficacy and Safety of Pomalidomide in Combination With Low-Dose Dexamethasone vs. High-Dose Dexamethasone in Patients With Refractory Multiple Myeloma or Relapsed and Refractory Multiple Myeloma and Companion Study [NIMBUS]) randomized, open-label, multicenter, phase III trial demonstrated improved progression-free survival (PFS) and prolonged overall survival (OS) with pomalidomide (POM) plus low-dose dexamethasone (POM + LoDEX) versus high-dose dexamethasone (HiDEX) in patients with RRMM in whom lenalidomide (LEN) and bortezomib (BORT) had failed. MM-003 also investigated HRQoL as a predefined secondary end point. Patients and Methods Recruited patients (n = 455) were refractory to their last treatment and had failed LEN and BORT after ≥ 2 consecutive cycles of each (alone or in combination). Eight clinically relevant and validated HRQoL domains from the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30, EORTC QLQ-MY20, and EQ-5D questionnaires were selected for analysis. Time to symptom worsening based on minimally important differences (MIDs) was calculated. Results Clinically meaningful improvements in HRQoL as determined by MIDs, regression analyses, and best response analyses were observed more frequently in patients receiving POM + LoDEX than in those receiving HiDEX. POM + LoDEX significantly extended median time to clinically meaningful worsening in HRQoL versus HiDEX in 4 HRQoL domains and demonstrated a trend in an additional 3 domains. Patients in the HiDEX arm experienced earlier HRQoL deterioration compared with those in the POM + LoDEX arm in each domain analyzed. Conclusion POM + LoDEX offer good clinical outcomes that lead to improved and prolonged HRQoL compared with HiDEX in patients with RRMM and end-stage disease.

Several U.S. Department of Defense-based studies were conducted to identify potential U.S. Department of Defense transportation systems that are strong candidates for introduction or expansion of plug-in electric vehicles (PEVs). Task 1 included a survey of the inventory of non-tactical fleet vehicles at the Marine Corps Base Camp Lejeune (MCBCL) to characterize the fleet. This information and characterization will be used to select vehicles for monitoring that takes place during Task 2. This monitoring involves data logging of vehicle operation in order to identify the vehicle’s mission and travel requirements. Individual observations of these selected vehicles provide the basis for recommendations related to PEV adoption. It also identifies whether a battery electric vehicle or plug-in hybrid electric vehicle (collectively referred to as PEVs) can fulfill the mission requirements and provides observations related to placement of PEV charging infrastructure.

A major limitation to the treatment of multiple myeloma by the thalidomide analogue CC-4047 (Actimid) is the development of a severe neutropenia. We investigated the hypothesis that this effect may have been due to CC-4047 enhancing the removal of neutrophils from the circulation by altering the expression of surface adhesion molecules required for endothelial binding, by binding to platelets, or by enhancing apoptosis. Flow cytometric analysis was used to examine the expression of neutrophil surface molecules, platelet binding and apoptosis in whole blood samples from 19 patients with multiple myeloma who were assigned to receive either 1, 2, 5 or 10 mg of CC-4047 every other day (e.o.d.) for 28 days. CC-4047 induced dose-related decreases in neutrophil numbers and increases in the percentage of CD64-positive neutrophils, but had little, or no effect on the expression of CD11b, CD62L or CD162, neutrophil-platelet binding, or apoptosis. Relative decreases in the neutrophil count were inversely associated with relative increases in the intensity of CD64 expression on neutrophils (r=- 0.307; p=0.028). Although seven patients developed severe neutropenia, none suffered severe or recurrent bacterial infections. The percentage of CD64-positive neutrophils was still increased in eight patients who continued receiving 1-5 mg CC-4047 e.o.d. for several months afterwards, but neutrophil counts were similar to pre-treatment values.

iv EXECUTIVE SUMMARY v ACRONYMS xii 1. INTRODUCTION 13 2. NON-TACTICAL VEHICLES 14 2.1 Fleet Vehicle Survey 14 2.2 Vehicle Missions 15 2.3 General Services Administration Vehicle Replacement Requirements 16 2.4 Plug-In Electric Vehicle Availability 17 2.5 Plug-In Electric Vehicle Charging 19 3. VEHICLE MISSION REPLACEMENT GUIDANCE 20 3.1 Background and Methods 20 3.2 Pool Mission Guidance 20 3.3 Support Mission Guidance 21 3.4 Transport Mission Guidance 22 3.5 Enforcement Mission Guidance 23 4. JOINT BASE LEWIS McCHORD REPLACEMENT APPROACH 23 4.1 Joint Base Lewis McChord Summary Replacement Approach 24 4.1.1 Replacement Approach for Sedans 26 4.1.2 Replacement Approach for Non-Sedan Vehicles 27 4.2 Analysis Results – 6th MP Group 27 4.2.1 Replacement Approach for 6th MP Group Sedans 28 4.2.2 Replacement Approach for 6th MP Group Non-Sedan Vehicles 28 4.3 Analysis Results – Directorate of Community Activities Support Group 28 4.3.1 Replacement Approach for the Directorate of Community Activities Support Group Sedans 29 4.3.2 Replacement Approach for the Directorate of Community Activities Support Group Non-Sedan Vehicles 30

Epidemiology data on multiple myeloma (MM) occurrence and outcome is inconsistent whilst a major limitation of randomized controlled trials is selection bias. We present a population-based analysis of patients diagnosed with MM in the South Thames area, which comprises 5.4 million adult inhabitants. A total of 855 cases of MM were ascertained between 1999 and 2000 in a collaborative project involving haematologists and the Thames Cancer Registry. The age-standardized rate was 3.29 per 100 000 and 4.82 cases per 100 000 (World Standard and European Population respectively). The median age was 73 years. The median survival for the whole group was 24 months whist it was 42 and 18 months in those aged less than 65 years and greater than 65 years respectively (P < 0.001). This population study has shown a higher incidence than previously reported in the UK and Europe and provides a benchmark for future studies. If survival is to be improved, future clinical trials and health care planning should consider patients over 65 years of age.

Phase II study of ISIS 3521, an antisense oligodeoxynucleotide to protein kinase C alpha, in patients with previously treated low-grade non-Hodgkin's lymphoma Background: The purpose of this study was to assess the efficacy and safety of ISIS 3521, an antisense phosphorothioate oligonucleotide to protein kinase C a in patients with relapsed low-grade non-Hodgkin's lymphoma (NHL). Patients and methods: Twenty-six patients received ISIS 3521 (2 mg/kg/day) as a continuous infusion over 21 days of each 28-day cycle. Results: The median age of the patients was 53 years (range 37-77). Histological subtypes were low-grade follicular lymphoma (n = 22) and B-cell small lymphocytic lymphoma (n = 4). Twenty-one (81%) had stage IH/IV disease. The median number of previous lines of chemotherapy was two (range one to six). A total of 87 cycles of ISIS 3521 were administered. Twenty-three patients were assessable for response. Three patients achieved a partial response. No complete responses were observed. Ten patients had stable disease. Grade 3-4 toxicity was as follows: neutropenia (3.8%) and thrombocytopenia (26.9%). Conclusions: ISIS 3521 has demonstrated anti-tumour activity in patients with relapsed low-grade NHL. There may be a potential role for this agent in combination with conventional chemotherapy for advanced low- grade lymphoma, and further trials are warranted.

The prognosis for patients with non-Hodgkin's lymphoma (NHL) and advanced Hodgkin's disease (HD) who relapse following autologous transplant is poor. We report on a pilot study designed to evaluate the feasibility of using Cyclosporin A and interferon alpha to induce autologous GVHD following a second autologous transplant for relapsed lymphoma. In all, 10 patients entered the study with median age 46.5 years. Diagnosis was NHL (n=7) or Hodgkin's lymphoma (n=3). All had relapsed from a prior autologous transplant. The second transplant was well tolerated by all patients. Histological changes consistent with cutaneous GVHD developed in 30% of patients at a median of 22.5 days from transplant and settled spontaneously in all cases. Five patients have died (four from progressive disease) at a median 7 months from second transplant. Five patients are still alive and in complete remission at a median of 20 months from transplant. Median overall survival for the group is 13.5 months and median relapse-free survival has not been reached at 42 months. This is a well-tolerated regimen for use in this poor-risk group of patients with lymphoma. The overall survival and event-free survival are encouraging, however further studies are necessary.

Myeloma remains incurable with conventional treatment in the vast majority of patients. The introduction of thalidomide in 1999 for the treatment of relapsed disease offers the opportunity to treat patients who have developed myelotoxicity or who are refractory to conventional chemotherapy. The optimal schedule remains unresolved and only two studies have reported long term follow-up data. We report a phase II low dose escalation study of thalidomide with long term follow-up showing overall survival (OS) of 19 months and progression free survival (PFS) of 14 months. In addition we report on the side effects and toxicity and give recommendations for the use of thalidomide in the relapsed setting based upon these findings.

Although nonmyeloablative conditioning regimen transplantations (NMTs) induce engraftment of allogeneic stem cells with a low spectrum of toxicity, graft-versus-host disease (GVHD) remains a significant cause of morbidity and mortality. In vivo T-cell depletion, using alemtuzumab, has been shown to reduce the incidence of GVHD. However, this type of maneuver, although reducing GVHD, may have an adverse impact on disease response, because NMTs exhibit their antitumor activity by relying on a graft-versus-malignancy effect. To explore the efficacy of alemtuzumab compared with methotrexate (MTX) for GVHD prophylaxis, we have compared the results in 129 recipients of a sibling NMT enrolled in 2 prospective studies for chronic lymphoproliferative disorders. Both NMTs were based on the same combination of fludarabine and melphalan, but the United Kingdom regimen (group A) used cyclosporin A plus alemtuzumab, whereas the Spanish regimen (group B) used cyclosporin A plus MTX for GVHD prophylaxis. Patients receiving alemtuzumab had a higher incidence of cytomegalovirus (CMV) reactivation (85% versus 24%,P

We describe the toxicity and efficacy of donor lymphocyte infusions (DLIs) given to 81 patients (median age, 50 years) after reduced-intensity conditioning (RIC) transplantations performed at 16 centers in the United Kingdom. The diseases treated included non-Hodgkin lymphoma (NHL; n = 29), chronic myeloid leukemia (CML; n = 12), myeloma (n = 11), acute myeloid leukemia (AML; n = 10), and chronic lymphocytic leukemia (CLL; n = 9). Eighty-eight percent received stem cells from sibling donors. The patients received 130 infusions (median, 1; range, 1-4). Indications for DLI were unsatisfactory response/disease progression in 51 patients, mixed chimerism in 18, preemptive in 10, and other in 2. Graft hypoplasia was uncommon (11%). Grade II to IV graft-versus-host disease (GVHD) occurred in 23 of 81 patients (28%) and limited and extensive chronic GVHD in 5 of 69 and 18 of 69 evaluable patients (total incidence 33%). Conversion from mixed to full donor chimerism occurred in 19 of 55 evaluable patients (35%) at a median of 48 days after the DLI; partial responses occurred in 6 patients (total response rate 45%). Eighteen of 51 (35%) patients with measurable disease after stem cell transplantation had a complete response (2 molecular), and 5 a partial response (total response rate 45%). Eleven of 17 evaluable complete responders had full donor chimerism. Eight of 13 patients with follicular NHL had complete responses as did 4 of 12 patients with CML. Clinical and chimeric responses correlated strongly with acute and chronic GVHD. Forty-seven patients (58%) survive at a median of 508 days after transplantation (range, 155-1171 days) with a median Karnofsky score of 90. Thirty-four patients (42%) died at a median of 211 days after transplantation with the major causes being progressive disease (26%) and GVHD (9%). Further systematic studies are required to determine the efficacy and optimum use of DLI for patients with each disease treated by nonmyeloablative stem cell transplantation.

The discovery that multiple myeloma is associated with new vessel formation and is correlated with survival and proliferation led initially to the use of thalidomide for patients with relapsed or refractory disease. The outcome with conventional chemotherapy in this setting has historically been very poor. New insights into the biology of the disease suggests that thalidomide may work via a number of other mechanisms and the advent of the thalidomide analogues with their differential effects on survival and proliferation pathways has opened up a new era in the understanding and treatment of the disease. The encouraging results from phase I/II trials of these agents has meant that for the first time in 50 years there is the opportunity to improve outcome. Further work is in progress to define how best to use these drugs and their role in treatment at different stages of the disease.

This report focuses on the Sleeping Bear Dunes National Lakeshore (SLBE) fleet to identify daily operational characteristics of select vehicles and report findings on vehicle and mission characterizations to support the successful introduction of plug-in electric vehicles (PEVs) into the agencies’ fleets. Individual observations of these selected vehicles provide the basis for recommendations related to electric vehicle adoption and whether a battery electric vehicle (BEV) or plug-in hybrid electric vehicle (PHEV) (collectively plug-in electric vehicles, or PEVs) can fulfill the mission requirements.

This report focuses on the National Institute of Health (NIH) fleet to identify daily operational characteristics of select vehicles and report findings on vehicle and mission characterizations to support the successful introduction of plug-in electric vehicles (PEVs) into the agencies’ fleets. Individual observations of these selected vehicles provide the basis for recommendations related to electric vehicle adoption and whether a battery electric vehicle (BEV) or plug-in hybrid electric vehicle (PHEV) (collectively plug-in electric vehicles, or PEVs) can fulfill the mission requirements.

This report focuses on the Department of Veterans Affairs, VA Manhattan Campus (VA- Manhattan) fleet to identify the daily operational characteristics of select vehicles and report findings on vehicle and mission characterizations to support successful introduction of plug-in electric vehicles (PEVs) into the agency’s fleet. Individual observations of these selected vehicles provide the basis for recommendations related to electric vehicle adoption and whether a battery electric vehicle or plug-in hybrid electric vehicle (collectively called PEVs) can fulfill the mission requirements.

This report focuses on the NASA White Sands Test Facility (WSTF) fleet to identify daily operational characteristics of select vehicles and report findings on vehicle and mission characterizations to support the successful introduction of plug-in electric vehicles (PEVs) into the agencies’ fleets. Individual observations of these selected vehicles provide the basis for recommendations related to electric vehicle adoption and whether a battery electric vehicle (BEV) or plug-in hybrid electric vehicle (PHEV) (collectively plug-in electric vehicles, or PEVs) can fulfill the mission requirements.