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The management of myeloma in the elderly is shifting its focus towards reducing the risk of under-treating fit patients and the risk of over-treating frail patients. Frailty assessment is required in this patient group in order to individualise treatment decisions. In addition to the proven prognostic values of the International Myeloma Working Group (IMWG) frailty score and the revised Myeloma Co-morbidity Index (R-MCI), a new easy-to-use frailty-based risk profile score (high-risk (i.e. frail), medium risk (i.e. intermediate-fitness) and low-risk (i.e. fit)) named Myeloma Risk Profile (MRP) was shown to be predictive of survival in the clinical trial setting. In this retrospective real-world study, we set out to evaluate the frailty characteristics and clinical outcomes according to the different MRP scoring algorithm categories (frail vs. intermediate vs fit), in a high risk cohort of elderly newly diagnosed myeloma patients treated with the fixed-duration triplet therapy VCD (bortezomib with cyclophosphamide and dexamethasone). Clinical outcomes included: reason for treatment discontinuation, overall response rate (ORR), overall survival (OS), progression-free survival (PFS), and adverse events (AEs). Out of 100 patients, 62 were frail, 27 were intermediate and 11 were fit, according to MRP scores. To enable meaningful comparisons between comparable numbers, subgroups analyses for ORR, OS, PFS, and AEs focused on frail (n = 62) versus intermediate or fit (n = 38) patients. The proportion of patients in each subgroup who were able to complete the planned course of treatment was (frail: 43.5% vs. intermediate or fit: 55.3%). A higher proportion in the frail subgroup discontinued therapy due to progressive disease (19.4% vs. 2.6%). Discontinuation due to toxicity was comparable across subgroups (14.5% vs. 15.8%), ORR in the total cohort was 75%, and this was comparable between subgroups (frail: 74.2% vs. intermediate or fit: 76.3%). There was a trend for a shorter median OS in the frail subgroup but without a statistical significance: (frail vs. intermediate or fit): (46 months vs. not reached, HR: 1.94, 95% CI 0.89–4.2, p = 0.094). There was no difference in median PFS between subgroups: (frail vs. intermediate or fit): (11.8 vs. 9.9 months, HR: 0.99, 95% CI: 0.61–1.61, P = 0.982). This cohort demonstrated a higher incidence rate of AEs in frail patients compared to those in the intermediate or fit group: patients with at least one any grade toxicity (85.5% vs. 71.1%), patients with at least one ≥G3 AE (37.1% vs. 21.1%). In conclusion, our study is to the first to evaluate clinical outcomes according to MRP in a high risk real-world cohort of patients treated exclusively with the proteasome inhibitor-based VCD therapy. Our study demonstrated a trend for worse OS in addition to worse AE outcomes in the frail group, but no difference in PFS with this fixed-duration therapy. MRP is an easy-to-use tool in clinical practice; its prognostic value was validated in the real-world in a large cohort of patients from the Danish Registry. Further evaluation of MRP in the real-world when continuous therapies are used, can further support the generalisability of its prognostic value in elderly myeloma patients. [ABSTRACT FROM AUTHOR]

Keywords: Castleman disease; interleukins; POEMS; KSHV/HHV8; HIV; TAFRO EN Castleman disease interleukins POEMS KSHV/HHV8 HIV TAFRO 328 337 10 11/01/21 20211101 NES 211101 Methodology This "Good Practice Paper" was compiled according to the British Society for Haematology (BSH) process at (http://www.b-s-h.org.uk/guidelines). Despite the success of IL-6-signalling blockade, there remains a significant unmet clinical need not only for patients who are intolerant of anti-IL-6 therapy, but also for a reliable disease-modifying therapy.50 Tocilizumab is a monoclonal antibody that antagonises the IL-6 receptor (IL-6R) to block signal transduction.57 Tocilizumab is licensed in Japan, but not in the UK, for the treatment of iMCD-TAFRO. Survival rates for MCD are not clear given changes in in diagnostic criteria, reporting and therapy.7 Nevertheless, the 5-year OS rate for MCD have been estimated at ˜65%.4 Human herpesvirus 8-associated MCD (HHV8-MCD) A proportion of cases of MCD have been attributed to infection with HHV8. The choice of therapy in MCD depends on the presentation of the patient as well as identification of drivers of disease: HHV8-MCD, POEMS-MCD, iMCD (NOS and TAFRO). [Extracted from the article]

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. [ABSTRACT FROM AUTHOR]

There are limited real world data on ixazomib, lenalidomide, and dexamethasone (IRd) in multiply relapsed myeloma. We analyzed outcomes of 116 patients who received IRd predominantly at second and subsequent relapse including those refractory to proteasome inhibitors (PIs). With a median follow up 16.3 months, the overall response rate was 66.9%; median progression-free survival (PFS) was 17.7 months with median overall survival (OS) not reached (NR). PFS and OS were significantly shorter in advanced disease (PFS; 12.6 vs. 21.2 months (p =.01), OS; 15.9 months vs. NR (p =.01) for ISS3 vs. ISS 1&2, respectively). PFS and OS were significantly shorter in clinical high risk (CHR) compared to standard risk (SR) patients (PFS; 9.3 months vs. NR (p =.001), OS; 11.5 months vs. NR (p <.001), respectively). There was a trend toward shorter PFS in PI-refractory patients 13.7 vs. 19.6 months for non-PI refractory (p =.2). The triplet combination was generally well tolerated. [ABSTRACT FROM AUTHOR]

Summary: Proteasome inhibitors have been associated with thrombotic microangiopathy (TMA) — a group of disorders characterised by occlusive microvascular thrombosis causing microangiopathic haemolytic anaemia, thrombocytopenia and end‐organ damage. To date, carfilzomib‐associated TMA has predominantly been described in relapsed/refractory myeloma patients. We report eight patients with newly diagnosed myeloma who experienced TMA events while receiving carfilzomib on the phase II CARDAMON trial. The first three occurred during maintenance single‐agent carfilzomib, two occurred at induction with carfilzomib given with cyclophosphamide and dexamethasone (KCd) and three occurred during KCd consolidation. At TMA presentation 6/8 were hypertensive; 7/8 had acute kidney injury and in three, renal impairment persisted after resolution of TMA in other respects. The mechanism of carfilzomib‐associated TMA remains unclear, though patients with known hypertension seem particularly susceptible. Given the first three cases occurred during maintenance after a longer than five‐week treatment break, a protocol amendment was instituted with: aggressive hypertension management, carfilzomib step‐up dosing (20 mg/m2 on day 1) at start of maintenance before dose escalation to 56 mg/m2 maximum, and adding 10 mg dexamethasone as premedication to maintenance carfilzomib infusions. No further TMA events occurred during maintenance following this amendment and the TMA incidence reduced from 4·2 to 1·6 per 1 000 patient cycles. [ABSTRACT FROM AUTHOR]

Objective: There are limited data on the efficacy and tolerability of VCD chemotherapy in transplant‐non‐eligible (TNE) newly diagnosed myeloma (NDMM) patients. In this retrospective study, we set out to evaluate this triplet combination in this setting across Thames Valley Cancer Network (UK). Methods: The primary end point was overall response rate (ORR). Secondary outcomes included event‐free survival (EFS), overall survival (OS) and adverse events (AEs). Results: In a total cohort of 158 patients, ORR for total cohort was 72.1%. Median EFS was 10.5 months, and for subgroups by age (<75:11.7 vs ≥75:10.3 months, P =.124), by Charlson Co‐morbidity Index (CCI) (<5:11.1 vs ≥5:8.2 months, P =.345). The 4‐month landmark analysis showed the following median EFS results: by cumulative bortezomib dose (≥26 mg/m2: 9.0 months vs <26 mg/m2: 6.4, P =.13), by cumulative cyclophosphamide dose (≥7000 mg: 9.2 vs <7000 mg: 7.0 months, P =.02) and by cumulative dexamethasone dose (>600 mg: 7.8 vs ≤600 mg: 8.3 months, P =.665). Median OS was 46.9 months. The incidence rate of AE was as follows: any grade (76.8%), ≥G3 (27.1%), ≥G3 haematological AEs (7.9%), any grade infections (31.1%) and ≥G3 infections (11.9%). Conclusion: This study demonstrated a good ORR achieved from fixed duration VCD, which was reasonably well tolerated. This was followed by modest median EFS. We envisage that the latter may be improved in this patient group with the use of a higher cumulative bortezomib dose (≥26 mg/m2) which showed a trend for improved EFS although without statistical significance (P =.13), and with the use of a higher cumulative cyclophosphamide doses (≥7000 mg, P =.02), subject to tolerability and close monitoring. [ABSTRACT FROM AUTHOR]

In the 15 patients who died, nine remained on therapy, ( I n i = 9/18, 50%), five ( I n i = 5/18, 27-8%) had their treatment paused for up to eight weeks, one patient had his treatment stopped altogether ( I n i = 1/18, 5-6%) and the exact modification was missing in the remaining three cases ( I n i = 3/18 = 16-7%). Baseline characteristics of patients who continued myeloma treatment (as per pre-COVID-19 plan) and those who had their myeloma disease management modified as a result of the COVID-19 pandemic (including stopping therapy), and their haematological response at the time and treatment regimen. Keywords: infection; myeloma; myeloma treatment EN infection myeloma myeloma treatment e136 e139 4 03/19/21 20210315 NES 210315 Concern for higher mortality in myeloma patients was reflected in the response to the first wave of the novel coronavirus SARS-CoV-2 (COVID-19) pandemic. In conclusion, this descriptive study of 219 MM patients illustrates how a systematic approach to a patient's risk of infection and individualised treatment modifications are possible and may have contributed to a low incidence rate of COVID-19 infection. [Extracted from the article]

Bioregenerative life-support systems (BLSS) involving plants will be required to realize self-sustaining human settlements beyond Earth. To improve plant productivity in BLSS, the quality of the solar spectrum can be modified by lightweight, luminescent films. CuInS2/ZnS quantum dot (QD) films were used to down-convert ultraviolet/blue photons to red emissions centered at 600 and 660 nm, resulting in increased biomass accumulation in red romaine lettuce. All plant growth parameters, except for spectral quality, were uniform across three production environments. Lettuce grown under the 600 and 660 nm-emitting QD films respectively increased edible dry mass (13 and 9%), edible fresh mass (11% each), and total leaf area (8 and 13%) compared with under a control film containing no QDs. Spectral modifications by the luminescent QD films improved photosynthetic efficiency in lettuce and could enhance productivity in greenhouses on Earth, or in space where, further conversion is expected from greater availability of ultraviolet photons. Parrish et al. demonstrate the modification of an incoming solar spectrum through downconversion of high energy UV/blue photons into orange/red photons using luminescent quantum dot films, leading to improved growth of leaf vegetables. Such technology can improve greenhouse productivity while reducing energy costs and can be useful to realize self-sustaining human settlements beyond Earth. [ABSTRACT FROM AUTHOR]

Objectives: The treatment paradigm in newly diagnosed multiple myeloma (NDMM) is evolving toward individualized, risk‐directed, and longer duration of therapy (DOT). The objective of this study was to describe treatment patterns and outcomes in non‐transplant NDMM in four European countries. Methods: This retrospective chart review included adults with NDMM diagnosed between January 1, 2012, and December 31, 2013 (early cohort), or April 1, 2016, and March 31, 2017 (recent cohort). Results: Among 836 patients, molecular testing was performed in 21% and 35% patients of early vs recent cohorts; proteasome inhibitor (PI)/alkylator combinations were the principal first‐line (1 L) therapy (39% vs 43%). Use of immunomodulatory drug (IMID)/alkylator combinations declined from early to recent cohort (26% vs 13%) but IMID (7% vs 16%) use increased. Few patients (5%) received 1 L maintenance therapy. Two‐thirds of patients were treated with a fixed duration intent, with a median 7‐month 1 L DOT and progression‐free survival (PFS) of 32.8 months in the early cohort. Both 1 L DOT and PFS were longer with oral compared to injectable regimens. Conclusions: Although frontline treatment patterns changed significantly, 1 L DOT is short. The uptake of molecular testing and 1 L maintenance is low. These results highlight areas of unmet need in NDMM. [ABSTRACT FROM AUTHOR]

Real-world assessment of the clinical impact of symptomatic infection with severe acute respiratory syndrome coronavirus (COVID-19 disease) in patients with multiple myeloma receiving systemic anti-cancer therapy Keywords: COVID-19; multiple myeloma; systemic antic-cancer therapy EN COVID-19 multiple myeloma systemic antic-cancer therapy e83 e86 4 07/20/20 20200715 NES 200715 Infection with the novel coronavirus SARS-CoV-2, resulting in an acute respiratory disease (COVID-19), is the cause of the current pneumonia pandemic, with a rapid rise in cases being reported in the European Union and UK.1,2 The UK index case was identified on January 31, 2020 and, given the rapid spread and high mortality rate of COVID-19, it is imperative to define the impact on patients with co-existing medical conditions.3 Multiple myeloma (MM), the second-most common haematological malignancy, is a cancer of the mature B-cell lineage, and is associated with both cellular and humoral immune dysfunction that renders patients susceptible to infections, especially of the respiratory tract.4-7 This, coupled with a median age at presentation of 70 years in a population with frequent co-existing medical conditions, means the outcomes of MM patients infected with COVID-19 warrants particular attention. Six patients had clinical/laboratory features of cytokine release syndrome.8,9 One patient was treated with ruxolitinib, but did not survive; one patient received tocilizimab (recovered); and four patients received supportive care only, none of whom survived. [Extracted from the article]

Similarly, median PFS (Figure 1(B)) and TTNT (Figure 1(C)) were significantly shorter in the FDT cohort (9.0 vs. 25.7 months; I p i < 0.0001 and 16.7 vs. 42.2 months; I p i < 0.0001, respectively); after 5 years, more patients in the FDT cohort had progressed to second-line treatment (94% vs. 61%). Conversely, a study that evaluated patient preferences for multiple myeloma (MM) treatment attributes reported that achieving TFI after frontline therapy can sometimes drive patient preference for FDT [[11]]. The median frontline treatment duration of 4.6 months for patients in our real-world FDT cohort was substantially shorter than the 15.4 months for patients treated with MPT in the MM-020 trial [[3]]. [Extracted from the article]

Background: The measurement of monoclonal free light chains is being increasingly utilized since the introduction of serum-based assays. It is important for laboratories to determine their own reference ranges in order to reflect the local population. The aim of this study was to determine if age-adjusted reference ranges for serum free light chains would have implications for demand management of further laboratory investigations including immunofixation. Methods: After certain exclusions, 4293 samples from individuals seen in primary care across Oxfordshire between 2014 and 2016 were identified for analysis of patient characteristics, serum free light chain results and estimated glomerular filtration rate. Results: We found age to be an independent variable when considering serum free light chain concentrations, ratio and estimated glomerular filtration rate. The reference ranges derived from our data differ markedly from the original Binding Site ranges. When the age-specific ranges are retrospectively applied to our population, there is a 38% decrease in follow-up testing with no loss of specificity. Conclusion: We feel confident implementing new age-specific serum free light chain reference ranges in our laboratory. We have developed a simple algorithm for evaluating serum free light chains based on age and estimated glomerular filtration rate. We encourage laboratories to establish their own local reference ranges using large cohorts and their chosen serum free light chain assay platform. [ABSTRACT FROM AUTHOR]

Treatment of transplant-ineligible (TNE) newly diagnosed multiple myeloma (NDMM) requires a balance between disease control and maintaining quality of life (QoL). Patients value treatment-free remission periods in this incurable condition, as they are associated with better QoL. We set out to study clinical outcomes of consecutive TNE NDMM patients in routine care treated in Thames Valley Cancer Network between 2009 and 2017. The primary outcome was the evaluation of the treatment-free interval (TFI) after 1st and subsequent lines of therapy in the total cohort and in individual subgroups, according to age (≤75 vs. >75 years), and co-morbidities using Charlson Co-morbidity Index (CCI): mild: 0–2 vs. moderate: 3–4 vs. severe: ≥5). Secondary outcomes include response rates, overall survival (OS) and progression-free survival (PFS) between subgroups: according to age and according to co-morbidities. In a total cohort of 292 patients, median TFI (IQR) was longest after first-line therapy 6.9 months (1.4–16.9), reducing after second line therapy to 1.8 months (.7–6.9), and after third line therapy to 0.6 months (0.2–1.5). Median TFI followed the same trend across the different subgroups, by age (≤75, >75 years) and by CCI (0–2, 3–4, ≥5). Overall response rate (ORR) to first line therapy for total cohort was 67%, with responses categorised as complete response (CR): 21%, very good partial response: 16%, partial response: 30%, stable disease: 18%, and progressive disease: 8%. ORR in individual subgroups by age were (≤75: 70% vs. >75: 63%), and by CCI (0–2: 65% vs. 3–4: 71% vs. ≥5: 77%). Median OS and PFS for the total cohort were (30.2 months, 95% CI: 23.8–36.9), and (9 months, 95% CI: 7.9–9.8), respectively. Patients aged >75 years showed a significant reduction in OS and PFS compared to those ≤75 years of age: OS (49.0 vs. 22.4 months, p<0.0001, HR: 2.08, 95% CI: 1.5–2.8), PFS (9.7 vs. 8.0 months, p<0.01, HR: 1.47, 95% CI: 1.1–1.9). Median OS was significantly reduced with worsening co-morbidities: (CCI 0–2: 52.4 months vs. CCI 3–4: 33.0 months vs. CCI ≥5: 24.0 months, p = 0.01, HR: 1.43, 95% CI: 1.1–1.9). Median PFS was significantly reduced in the severely co-morbid subgroup (CCI 0–2: 9.4 months vs. CCI 3–4: 9.6 months vs. CCI ≥5: 7.1 months, p = 0.025, HR: 1.3, 95% CI: 1.0–1.6). This study demonstrated that first line therapy in the TNE NDMM setting resulted in the longest TFI which was modest at a median of 6.9 months, and decreased significantly following subsequent lines of therapy and across the different subgroups by age and by co-morbidities. Therapy objective should be to maximise the benefit of first line treatment. We envisage that the recent shift towards a continuous therapeutic approach will benefit TNE patients in view of improved survival data demonstrated by a number phase 3 trials. When continuous therapy is not appropriate due to patient choice or toxicities, an efficacious (not limited to thalidomide and bortezomib) but tolerable first line FDT strategy, which can maximise TFI and maintain a good QoL, remains a reasonable alternative approach. [ABSTRACT FROM AUTHOR]

Twenty-nine patients (97%) received at least two cycles of therapy and one patient discontinued carfilzomib after one cycle. Carfilzomib therapy is ongoing in 17 patients and was discontinued in 13 patients. Five patients received full twice-weekly dosing throughout therapy, and six patients were dose-reduced to weekly upfront (i.e. from cycle 1). Depending on the severity of hypertension, management consisted of introducing an antihypertensive (e.g., amlodipine) in two patients, an antihypertensive dose increase in two patients, carfilzomib dose reduction in two patients, and an antihypertensive plus carfilzomib dose reduction in one patient. [Extracted from the article]

Background: Bortezomib is a cornerstone in the management of multiple myeloma. It remains an attractive treatment option because it is efficacious, reasonably well tolerated and easy to administer. However, data on resource implications in the UK for both patients and healthcare providers are limited. Methods: We conducted a retrospective study of 127 patients to assess implications of bortezomib therapy on patients and healthcare resources. A patient-episode was defined as a patient attending the chemotherapy day treatment unit solely for bortezomib administration. Data were collected for the duration of therapy as follows: cost of drug calculated using the UK's bortezomib indicative price as per British National Formulary, cost of drug administration in the chemotherapy day treatment unit calculated using the National Health Service's schedule of service cost, time from check-in to drug administration, patient travel time and distance calculated using Google maps, and cost of travel. Results: Median drug cost and administration cost per patient were £8336 (£2084–£108,368) and £4640 (£290–£15,080), respectively. Median time from check-in to administration was 63 min (range 5–433), median travel time was 90 min (range 8–270) and 80 min (range 8–280) during peak and off-peak periods, respectively. Median return travel distance was 33.4 miles (range 1.2–224) for travel cost per patient per trip was £8.35–£13.20. Conclusions: Our real-world resource analysis demonstrated that delivering bortezomib therapy can be associated with significant cost and time implications for patients and healthcare providers. Our study method sets a basis for evaluating resource implications of other novel approaches to myeloma therapy. [ABSTRACT FROM AUTHOR]

Summary: Unlike AL amyloid and cast nephropathy, the long‐term outcomes of monoclonal gammopathy of renal significance (MGRS) patients with other renal histopathologies remain unclear. It is uncertain if early intervention improves renal outcomes, because of a lack of evidence from prospective studies. In this retrospective study, we examined outcomes of 41 MGRS patients treated between 2004 and 2017 across five centres: four in the UK and one in the Republic of Ireland. The primary outcome measure was renal survival estimated by Kaplan–Meier product‐limit method. Thirty‐three patients (80·5%) were kappa light chain (LC) restricted. Twenty‐seven patients (65·9%) presented with LC deposition disease on renal histology. At 24 months follow‐up, estimated renal survival was 81·6% for the whole cohort. The estimated overall survival was 80·3% at 48 months. At 24 months, patients who had chronic kidney disease (CKD) stage 2–3b at diagnosis showed an estimated renal survival of 100% compared to 80·7% in those with CKD stage 4–5 at diagnosis (P = 0·04). Poorer outcomes in MGRS patients were historically attributed to delayed diagnosis due to small plasma cell clones, as well as the need for renal biopsy. [ABSTRACT FROM AUTHOR]

The article presents a study that investigated a serological surrogate for bone marrow assessment to optimise patient management and the patient experience. It discussed the findings to demonstrate a potential use for performed serological tests as surrogate markers for bone marrow minimal residual disease (MRD) negativity. It mentions the Isotype and International Staging System (ISS) distribution, median marrow plasma cell involvement, and median lactate dehydrogenase levels.

Bortezomib, a first generation proteasome inhibitor, is used in both newly diagnosed and relapsed myeloma settings. Considerable differences exist in the usage of bortezomib therapy in the clinical practice setting in comparison to clinical trial setting as well manufacturer’s recommendations. These differences include route of administration (intravenous (iv) vs. subcutaneous (sc)), frequency from twice to once weekly, choice of alkylating agent used in combination with bortezomib (melphalan or cyclophosphamide), and choice of glucocorticoids (dexamethasone or prednisolone). We reviewed data from 272 consecutive bortezomib-treated myeloma patients, who received therapy within the regional Thames Valley Cancer Network for both newly diagnosed myeloma (NDMM, n = 120) and relapsed MM (RMM, n = 152). We investigated the influence of age, sex, transplant, bortezomib combinations (doublet vs. triplet), cumulative bortezomib dose per treatment line (<50mg vs. ≥50mg), and route of administration (iv vs. sc) on time to next treatment (TTNT) and on overall survival (OS). Route of bortezomib administration (iv vs. sc) influenced neither OS (41 vs 35 months, p = 0.5), nor TTNT (14 vs. 19 months, p = 0.052). Our study showed a statistically significant improvement in median OS in patients receiving a cumulative dose ≥50mg compared to <50mg (42 vs. 33months, p = 0.003), although presence of confounders need to be taken into account, such as disease stage, performance status, genetic changes and prior therapies. Median OS was longer using triplet therapies compared to a doublet in the RMM cohort (37 vs. 29 months, p = 0.06), although this did not reach statistical significance. Multivariate Cox Regression analysis showed that cumulative bortezomib dose ≥50mg (p = 0.002, HR = 1.83, 95% CI 1.25–2.67) and autologous transplant (p = 0.002, HR = 2.6, 95% CI 1.41–3.98) were both significant factors associated with improved OS. Our data argues in favour of continuing bortezomib for the recommended duration as per Summary of Product Characteristics (SPC), subject to good tolerability, in order to deepen response or extend the duration of best response. [ABSTRACT FROM AUTHOR]

Keywords: myeloma; COVID-19; clinical trials EN myeloma COVID-19 clinical trials e14 e16 3 12/21/20 20210101 NES 210101 COVID-19 - caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) - has spread to over 213 countries and territories, with 24,021,218 cases, including 821,462 deaths, reported to WHO by 28 August 2020.1 In the UK alone, there were 328,846 laboratory-confirmed cases and 41,465 COVID-19-associated deaths.2 Self-isolation and physical distancing measures were implemented in most jurisdictions to limit the spread of the virus. PIs may be potentially biased to alter treatment based on local COVID-19 clusters and patients' favourable MM response. Therefore, sensitivity analyses will be performed with and without the inclusion of affected patients to assess the significance of the measures taken on patient outcomes. [Extracted from the article]

Keywords: DPACE; DTPACE; efficacy; myeloma; survival; VRDPACE; VTDPACE EN DPACE DTPACE efficacy myeloma survival VRDPACE VTDPACE 231 233 3 07/24/20 20200801 NES 200801 The use of dexamethasone plus thalidomide in combination with a continuous infusion of cisplatin, doxorubicin, cyclophosphamide and etoposide (DTPACE) was first described in relapsed myeloma (MM) and showed effectiveness as induction therapy before autologous stem cell transplant (ASCT).1 The addition of bortezomib to DTPACE (VTDPACE) led to improved outcomes.2,3 Historical indications for DPACE-based therapies include salvage treatment of aggressive MM, plasma cell leukaemia and initial presentation with extra-medullary disease. Baseline patient, disease and treatment characteristics were collected from the local chemotherapy database and patient records between 2009 and 2017. The majority of patients who received >2 lines of therapy had received a prior ASCT (15/17:88.2%) and only a small group (3/17:17.6%) consolidated DPACE with a further ASCT (2 SP nd sp ASCT in all 3 patients). [Extracted from the article]

Multiple myeloma (MM) is a progressive plasma cell malignancy, with a range of clinical features including bone lesions, renal insufficiency, anaemia, and hypercalcaemia. Novel agents have significantly improved patient survival, however most patients will suffer multiple relapses. Although clinical challenges and economic costs of relapse are recognised, the psychological impact of relapse is not fully appreciated. Additionally, there is little information on how physicians perceive the impact of relapse on their patients’ emotional state and how this might affect patient management. Through face-to-face interviews with 50 relapsed and/or refractory MM patients and 30 haematologists across ten countries, we have used real-world evidence to explore and characterise the burden of living with MM, particularly the impact of relapsed disease. This exploratory study illustrates the impact of the disease on friends and family, and the physical and emotional burden experienced by the patient resulting from both MM and its treatment. Haematologists feel poorly equipped to deal with the emotional aspects of patient relapse, lacking the time and resources to adequately deal with these issues. Focused educational and support tools/resources targeted at both physicians and patients are required to facilitate physician–patient communication to help reduce the emotional burden of living with MM. [ABSTRACT FROM AUTHOR]

Myeloma patients who become refractory to immunomodulatory agents ( IMiDs) and bortezomib have poor survival, with limited therapeutic options. Pomalidomide has shown improved survival and good tolerability in this patient cohort in clinical trials, but real world data are scarce. We retrospectively analysed all patients treated with pomalidomide at five UK centres between 2013 and 2016. Of 85 patients identified, 70 had sufficient information for response assessments. Median age was 66 years [40-89], 96·5% were refractory to IMiDs, 72·9% were refractory to both an IMiD and bortezomib and 92·9% were refractory to their last treatment. Of 45 patients with fluorescence in situ hybridization results 64% had adverse risk, 19 patients (22·4%) had an estimated glomerular filtration rate <45 ml/min. Grade ≥3 non-haematological toxicities occurred in 42·4%, and grade ≥3 neutropenia and thrombocytopenia in 38% and 24% respectively, but only 18·8% had dose reductions. The overall response rate was 52·9%. At a median follow-up of 13·2 months, median progression-free survival was 5·2 months [95% confidence interval ( CI) 4·150-6·238], and median overall survival was 13·7 months (95% CI 11·775-15·707). No significant difference was seen in response, survival or tolerability by renal function, age or cytogenetic risk. This real-world data support the results seen in published clinical trials. [ABSTRACT FROM AUTHOR]

Consolidation with high-dose chemotherapy and autologous stem cell transplantation (ASCT) is the standard of care for transplantation-eligible patients with multiple myeloma, based on randomized trials showing improved progression-free survival with autologous transplantation after combination chemotherapy induction. These trials were performed before novel agents were introduced; subsequently, combinations of immunomodulatory drugs and proteasome inhibitors as induction therapy have significantly improved rates and depth of response. Ongoing randomized trials are testing whether conventional autologous transplantation continues to improve responses after novel agent induction. Although these results are awaited, it is important to review strategies for improving outcomes after ASCT. Conditioning before ASCT with higher doses of melphalan and combinations of melphalan with other agents, including radiopharmaceuticals, has been explored. Tandem ASCT, consolidation, and maintenance therapy after ASCT have been investigated in phase III trials. Experimental cellular therapies using ex vivo–primed dendritic cells, ex vivo–expanded autologous lymphocytes, Killer Immunoglobulin Receptor (KIR)-mismatched allogeneic natural killer cells, and genetically modified T cells to augment ASCT are also in phase I trials. This review summarizes these strategies and highlights the importance of exploring strategies to augment ASCT, even in the era of novel agent induction. [ABSTRACT FROM AUTHOR]

The article presents a study that uses polyethylene glycol (PEG) in modifying thin film deposition by Chemical Bath Deposition (CBD) to synthesize zinc oxide (ZnO) hexagonal single crystal slices with 0001 and 0001 facets. It focuses on the controlled growth of crystals such as those of ZnO and notes that the use of PEG as reagent in CBD yielded product with flatter lamellar morphologies. It establishes a pathway for developing active ZnO catalysts and other functional materials.

A new family of quaternary semiconductors Cu2ZnAS4−x and CuZn2AS4 (A = Al, Ga, In) has been synthesized in the form of wurtzite phase nanocrystals for the first time. The nanocrystals can be converted to the stannite phase via thermal annealing under a N2 atmosphere. A direct band gap in the visible wavelength region combined with a high absorption cross-section makes these materials promising for solar energy conversion applications. [ABSTRACT FROM AUTHOR]

Myeloma is one of the most common malignancies that results in osteolytic lesions of the spine. Complications, including pathological fractures of the vertebrae and spinal cord compression, may cause severe pain, deformity and neurological sequelae. They may also have significant consequences for quality of life and prognosis for patients. For patients with known or newly diagnosed myeloma presenting with persistent back or radicular pain/weakness, early diagnosis of spinal myeloma disease is therefore essential to treat and prevent further deterioration. Magnetic resonance imaging is the initial imaging modality of choice for the evaluation of spinal disease. Treatment of the underlying malignancy with systemic chemotherapy together with supportive bisphosphonate treatment reduces further vertebral damage. Additional interventions such as cement augmentation, radiotherapy, or surgery are often necessary to prevent, treat and control spinal complications. However, optimal management is dependent on the individual nature of the spinal involvement and requires careful assessment and appropriate intervention throughout. This article reviews the treatment and management options for spinal myeloma disease and highlights the value of defined pathways to enable the proper management of patients affected by it. [ABSTRACT FROM AUTHOR]

In November 2014 the International Myeloma Working Group ( IMWG) revised the definition of multiple myeloma, such that asymptomatic patients with newly diagnosed multiple myeloma without any of the traditional ' CRAB' (hyper calcaemia, renal impairment, anaemia, bone disease) end organ damage criteria but with one of three new criteria would be recommended to start treatment. Previously, the standard of care for such patients was expectant management. These three new criteria are: greater than 60% clonal plasma cells on bone marrow biopsy, a serum free light chain ( sFLC) ratio of >100 (the involved sFLC must be >100 mg/l) and greater than one unequivocal focal lesion on advanced imaging (low dose whole body computerized tomography, magnetic resonance imaging, 18F fluorodeoxyglucose positron emission tomography). Although this would appear to affect a small number of patients, the impact of these changes are broad, leading to an increased use of advanced imaging, a debate around the management of patients previously diagnosed with smouldering myeloma, changed terminology and clinical trial design and an extension of the use of biomarkers. For the first time the philosophy of treatment in myeloma will change from treatment initiation only being triggered by overt end organ damage to an era where sub clinical risk factors will also be taken into account. [ABSTRACT FROM AUTHOR]

Double relapsed and/or refractory multiple myeloma (DRMM), MM that is relapsed and/or refractory to bortezomib and lenalidomide, carries a poor prognosis. The healthcare costs of DRMM have not previously been reported. We analyzed detailed medical resource utilization (MRU) costs, drug costs and outcomes for 39 UK patients receiving standard DRMM therapy. Median OS in this cohort was 5.6 months. The mean cost of DRMM treatment plus MRU until death was £23,472 [range: £1,411–£90,262], split between drug costs £11,191 and other resource use costs £12,281. The cost per assumed quality-adjusted life year (QALY) during DRMM was £66,983. These data provide a standard of care comparison when evaluating the cost-effectiveness of new drugs in DRMM. [ABSTRACT FROM AUTHOR]

Treatment options are limited in myeloma relapsed or refractory to both bortezomib and lenalidomide (double-relapsed/refractory multiple myeloma; DRMM). Bendamustine is an antitumour agent that has efficacy in relapsed myeloma. We retrospectively analysed data from 30 DRMM patients who received a combination of bendamustine, thalidomide and dexamethasone (BTD) in 28-day treatment cycles. Bendamustine was administered with a cumulative dose of up to 200 mg/m. Thalidomide (50-150 mg) was given daily as tolerated, and dexamethasone was given at an equivalent dose of up to 160 mg per cycle. A median of 5 (2-9) treatment cycles were administered per patient. Twenty-six patients (87 %) achieved stable disease or better. At a median follow-up time of 12.1 (2.3-21.5) months, median (95 % CI) progression-free survival and overall survival were 4.0 (2.6-5.3) months and 7.2 (5.2-9.2) months, respectively. The most common grade 3-4 adverse events were haematological: anaemia ( n = 8, 34.8 %), neutropenia ( n = 16, 69.6 %) and thrombocytopenia ( n = 10, 43.5 %). Non-haematological toxicities included pain ( n = 3, 13.0 %), infection ( n = 7, 30.4 %) and sensory neuropathy ( n = 1, 4.3 %). We propose that BTD is a viable salvage treatment option for DRMM patients. [ABSTRACT FROM AUTHOR]

The ultimate goal of supercapacitor research industries is to develop devices which could be used as flexible, portable, ultrathin and highly-efficient power sources. However, the bulk NiCo2O4 materials prevent the achievement of high energy density as well as immense rate performance due to the limited electroactive surface area. In this work, we proposed a new breakthrough strategy to develop highly porous hierarchical flexible nanosheets of NiCo2O4–graphene oxide (NiCo2O4–GO) on nickel foam by a facile electrochemical deposition method. The morphogenesis of the NiCo2O4–GO hybrid nanostructure-based electrode exhibits hierarchical porous flexible nanosheet-like structures. The electrochemical properties of these electrodes were investigated by cyclic voltammetry and galvanostatic charge–discharge measurements in 3 M KOH electrolyte. The obtained results exhibit that this new hybrid nanostructure has a specific capacitance of 1078 F g−1 at a discharge current of 1 mA with great cyclic stability. These excellent capacitive performances of NiCo2O4–GO can be attributed to its hierarchical porous nanosheet-like unique structure. This unique structure provides efficient ion transport that is highly desirable for superior rate capability and excellent cycling stability. Hence, our method provides a promising facile and binder-free nanostructure electrode for next generation high-performance supercapacitor applications. [ABSTRACT FROM AUTHOR]

A facile method has been developed for the synthesis of nearly mono-dispersed iron oxide nanocrystals. The structural analysis of the synthesized iron oxide nanocrystals reveals the magnetite phase of Fe3O4. The average particle size of the iron oxide was estimated to be 8 ± 2 nm. The observed particle size is in good correlation with the particle size estimated by magnetic measurements. Furthermore, these nanocrystals showed bi-functional ferromagnetic and superparamagnetic behavior below and above the blocking temperature, respectively. The potential use of these nanocrystals as an electrode for supercapacitors was examined by investigating the electrochemical behavior of iron oxide using cyclic voltammetry (CV) and galvanostatic charge–discharge tests. The CV characteristics of the iron oxide electrode showed a typical pseudocapacitive behavior in 3 M KOH solution. Moreover, the specific capacitance of 185 F g−1 at the current of 1 mA was observed with excellent cyclic stability, which is much higher than the reported value for iron oxide. The higher specific capacitance is due to the uniform nano-size of iron oxide. This work provides an ultimate facile method to synthesize nanostructured iron oxide for application in next generation energy storage materials. [ABSTRACT FROM AUTHOR]

Cu2FeSnS4 nanocrystals with the wurtzite structure are synthesized by quick injection of a mixture of 1-dodecanethiol and tert-dodecanethiol into a mixture of Cu(acac)2, Fe(acac)3, SnCl4, and oleylamine (210 °C, 30 min). [ABSTRACT FROM AUTHOR]

Free circulating DNA is present in the plasma of healthy subjects, and is elevated in conditions characterized by increased cell death, such as cancer and physical trauma. Analysis of circulating DNA in plasma could provide a useful biomarker in sickle cell disease (SCD) in view of the increased cell turnover through chronic ongoing haemolysis, recurrent vaso-occlusion and inflammation. Plasma DNA was determined by real-time quantitative polymerase chain reaction (PCR) amplification of the β-globin gene ( HBB) in 154 patients with SCD [105 haemoglobin (Hb)SS, 46 HbSC and three HbS/ β0 thalassaemia] and 53 ethnically matched controls. Blood samples were obtained from all patients in steady state; 21 of the 154 patients were also sampled during admission to hospital for acute pain. Median concentration of circulating plasma DNA in acute pain was more than 10-fold that in steady state and in controls – 10070 vs. 841 and 10070 vs. 933 genome equivalents/ml respectively ( P < 0·0001, in both cases). During steady state, patients had plasma DNA levels similar to controls. Plasma DNA levels in SCD correlated with C-reactive protein levels ( P < 0·005) and total white cell counts ( P < 0·05) in steady state. The study shows that plasma DNA concentration may have potential as a biomarker in sickle cell patients. [ABSTRACT FROM AUTHOR]

Interactions between multiple myeloma (MM) and bone marrow (BM) are well documented to support tumour growth, yet the cellular mechanisms underlying pain in MM are poorly understood. We have used in vivo murine models of MM to show significant induction of nerve growth factor (NGF) by the tumour-bearing bone microenvironment, alongside other known pain-related characteristics such as spinal glial cell activation and reduced locomotion. NGF was not expressed by MM cells, yet bone stromal cells such as osteoblasts expressed and upregulated NGF when cultured with MM cells, or MM-related factors such as TNF-α. Adiponectin is a known MM-suppressive BM-derived factor, and we show that TNF-α-mediated NGF induction is suppressed by adiponectin-directed therapeutics such as AdipoRON and L-4F, as well as NF-κB signalling inhibitor BMS-345541. Our study reveals a further mechanism by which cellular interactions within the tumour-bone microenvironment contribute to disease, by promoting pain-related properties, and suggests a novel direction for analgesic development. [ABSTRACT FROM AUTHOR]

Cu2ZnMS4-x (M: Al, Ga, In) nanocrystals are prepared by the colloidal hot-injection method starting with thermal decomposition of a 2:1:1 molar mixture of Cu(acac)2, Zn(acac)2, and M(acac)3 in oleylamine under N2 (Schlenk line, 150 °C) followed by quickly injecting a mixture of n-dodecanethiol and tert-dodecanethiol and subsequent heating (250 °C, 1 h), with the latter leading to a structural transition from the wurtzite to the stannite phase. [ABSTRACT FROM AUTHOR]