Cost-effectiveness of screening tools for identifying depression in early pregnancy: a decision tree model.

BACKGROUND: Although the effectiveness of screening tools for detecting depression in pregnancy has been investigated, there is limited evidence on the cost-effectiveness. This is vital in providing full information to decision makers. This study aimed to explore the cost-effectiveness of different screening tools to identify depression in early pregnancy compared to no screening. METHODS: A decision tree was developed to model the identification and treatment pathways of depression from the first antenatal appointment to 3-months postpartum using the Whooley questions, the Edinburgh Postnatal Depression Scale (EPDS) and the Whooley questions followed by the EPDS, compared to no screening. The economic evaluation took an NHS and Personal Social Services perspective. Model parameters were taken from a combination of sources including a cross-sectional survey investigating the diagnostic accuracy of screening tools, and other published literature. Cost-effectiveness was assessed in terms of the incremental cost per quality adjusted life years (QALYs). Cost-effectiveness planes and cost-effectiveness acceptability curves were produced using a net-benefit approach based on Monte Carlo simulations of cost-outcome data. RESULTS: In a 4-way comparison, the Whooley, EPDS and Whooley followed by the EPDS each had a similar probability of being cost-effective at around 30% for willingness to pay values from £20,000-30,000 per QALY compared to around 20% for the no screen option. CONCLUSIONS: All three screening approaches tested had a higher probability of being cost-effective than the no-screen option. In the absence of a clear cost-effectiveness advantage for any one of the three screening options, the choice between the screening approaches could be made on other grounds, such as clinical burden of the screening options. Limitations include data availability and short time horizon, thus further research is needed. CLINICAL TRIALS REGISTRATION: N/A.

CCND2 and CCND3 hijack immunoglobulin light-chain enhancers in cyclin D1- mantle cell lymphoma.

Mantle cell lymphoma (MCL) is characterized by the t(11;14)(q13;q32) translocation resulting in overexpression of cyclin D1. However, a small subset of cyclin D1- MCL has been recognized, and approximately one-half of them harbor CCND2 translocations while the primary event in cyclin D1-/D2- MCL remains elusive. To identify other potential mechanisms driving MCL pathogenesis, we investigated 56 cyclin D1-/SOX11+ MCL by fluorescence in situ hybridization (FISH), whole-genome/exome sequencing, and gene-expression and copy-number arrays. FISH with break-apart probes identified CCND2 rearrangements in 39 cases (70%) but not CCND3 rearrangements. We analyzed 3 of these negative cases by whole-genome/exome sequencing and identified IGK (n = 2) and IGL (n = 1) enhancer hijackings near CCND3 that were associated with cyclin D3 overexpression. By specific FISH probes, including the IGK enhancer region, we detected 10 additional cryptic IGK juxtapositions to CCND3 (6 cases) and CCND2 (4 cases) in MCL that overexpressed, respectively, these cyclins. A minor subset of 4 cyclin D1- MCL cases lacked cyclin D rearrangements and showed upregulation of CCNE1 and CCNE2. These cases had blastoid morphology, high genomic complexity, and CDKN2A and RB1 deletions. Both genomic and gene-expression profiles of cyclin D1- MCL cases were indistinguishable from cyclin D1+ MCL. In conclusion, virtually all cyclin D1- MCLs carry CCND2/CCND3 rearrangements with immunoglobulin genes, including a novel IGK/L enhancer hijacking mechanism. A subset of cyclin D1-/D2-/D3- MCL with aggressive features has cyclin E dysregulation. Specific FISH probes may allow the molecular identification and diagnosis of cyclin D1- MCL.

Multiple myeloma with central nervous system relapse.

Central nervous system involvement in multiple myeloma is a rare complication but carries a very poor prognosis. We provide a review of current literature, including presentation, treatment and survival data, and describe our experience in a regional hematologic malignancy diagnosis center where, over a 15-year period, ten cases were identified. Although the median age of onset, frequently between 50-60 years, is comparatively young, those diagnosed usually have a preceding diagnosis of multiple myeloma and often have had several lines of treatment. We discuss putative underlying factors such as prior treatment and associations including possible risk factors and features suggestive of a distinct biology. Central nervous system involvement may be challenging to diagnose in myeloma, displaying heterogeneous symptoms that can be confounded by neurological symptoms caused by the typical features of myeloma or treatment side-effects. We discuss the clinical features, imaging and laboratory methods used in diagnosis, and highlight the importance of considering this rare complication when neurological symptoms occur at presentation or, more commonly, during the disease pathway. In the absence of clinical trial data to inform an evidence-based approach to treatment, we discuss current and novel treatment options. Finally, we propose the establishment of an International Registry of such cases as the best way to collect and subsequently disseminate presentation, diagnostic and treatment outcome data on this rare complication of multiple myeloma.

The impact of cytogenetics on duration of response and overall survival in patients with relapsed multiple myeloma (long-term follow-up results from BSBMT/UKMF Myeloma X Relapse [Intensive]): a randomised, open-label, phase 3 trial.

The Myeloma X trial (ISCRTN60123120) registered patients with relapsed multiple myeloma. Participants were randomised between salvage autologous stem cell transplantation (ASCT) or weekly cyclophosphamide following re-induction therapy. Cytogenetic analysis performed at trial registration defined t(4;14), t(14;16) and del(17p) as high-risk. The effect of cytogenetics on time to progression (TTP) and overall survival was investigated. At 76 months median follow-up, ASCT improved TTP compared to cyclophosphamide (19 months (95% confidence interval [95% CI] 16-26) vs. 11 months (9-12), hazard ratio [HR]: 0·40, 95% CI: 0·29-0·56, P < 0·001), on which the presence of any single high-risk lesion had a detrimental impact [likelihood ratio test (LRT): P = 0·011]. ASCT also improved OS [67 months (95% CI 59-not reached) vs. 55 months (44-67), HR: 0·64, 95% CI: 0·42-0·99, P = 0·0435], with evidence of a detrimental impact with MYC rearrangement (LRT: P = 0·021). Twenty-one (24·7%) cyclophosphamide patients received an ASCT post-trial, median OS was not reached (95% CI: 39-not reached) for these participants compared to 31 months (22-39), in those who did not receive a post-trial ASCT. The analysis further supports the benefit of salvage ASCT, which may still be beneficial after second relapse in surviving patients. There is evidence that this benefit reduces in cytogenetic high-risk patients, highlighting the need for targeted study in this patient group.

Minimal residual disease is an independent predictor for 10-year survival in CLL.

Minimal residual disease (MRD) negativity, defined as <1 chronic lymphocytic leukemia (CLL) cell detectable per 10 000 leukocytes, has been shown to independently predict for clinical outcome in patients receiving combination chemoimmunotherapy in the frontline setting. However, the long-term prognostic value of MRD status in other therapeutic settings remains unclear. Here, we retrospectively analyzed, with up to 18 years follow-up, all patients at our institution who achieved at least a partial response (PR) with various therapies between 1996 and 2007, and received a bone marrow MRD assessment at the end of treatment according to the international harmonized approach. MRD negativity correlated with both progression-free survival (PFS) and overall survival (OS) independent of the type and line of treatment, as well as known prognostic factors including adverse cytogenetics. The greatest impact of achieving MRD negativity was seen in patients receiving frontline treatment, with 10-year PFS of 65% vs 10% and 10-year OS of 70% vs 30% for MRD-negative vs MRD-positive patients, respectively. Our results demonstrate the long-term benefit of achieving MRD negativity, regardless of the therapeutic setting and treatment modality, and support its use as a prognostic marker for long-term PFS and as a potential therapeutic goal in CLL.

Accuracy of the Whooley questions and the Edinburgh Postnatal Depression Scale in identifying depression and other mental disorders in early pregnancy.

BACKGROUND: There is limited evidence on the prevalence and identification of antenatal mental disorders. Aims To investigate the prevalence of mental disorders in early pregnancy and the diagnostic accuracy of depression-screening (Whooley) questions compared with the Edinburgh Postnatal Depression Scale (EPDS), against the Structured Clinical Interview DSM-IV-TR. METHOD: Cross-sectional survey of women responding to Whooley questions asked at their first antenatal appointment. Women responding positively and a random sample of women responding negatively were invited to participate. RESULTS: Population prevalence was 27% (95% CI 22-32): 11% (95% CI 8-14) depression; 15% (95% CI 11-19) anxiety disorders; 2% (95% CI 1-4) obsessive-compulsive disorder; 0.8% (95% CI 0-1) post-traumatic stress disorder; 2% (95% CI 0.4-3) eating disorders; 0.3% (95% CI 0.1-1) bipolar disorder I, 0.3% (95% CI 0.1-1%) bipolar disorder II; 0.7% (95% CI 0-1) borderline personality disorder. For identification of depression, likelihood ratios were 8.2 (Whooley) and 9.8 (EPDS). Diagnostic accuracy was similar in identifying any disorder (likelihood ratios 5.8 and 6). CONCLUSIONS: Endorsement of Whooley questions in pregnancy indicates the need for a clinical assessment of diagnosis and could be implemented when maternity professionals have been appropriately trained on how to ask the questions sensitively, in settings where a clear referral and care pathway is available. Declaration of interest L.M.H. chaired the National Institute for Health and Care Excellence CG192 guidelines development group on antenatal and postnatal mental health in 2012-2014.

High-dose chemotherapy plus autologous stem-cell transplantation as consolidation therapy in patients with relapsed multiple myeloma after previous autologous stem-cell transplantation (NCRI Myeloma X Relapse [Intensive trial]): a randomised, open-label, phase 3 trial.

BACKGROUND: Relapsed multiple myeloma has no standard treatment, and the role of autologous stem-cell transplantation (ASCT) has not been fully defined. We aimed to compare high-dose melphalan plus salvage ASCT with cyclophosphamide in patients with relapsed multiple myeloma who had previously undergone ASCT. METHODS: This multicentre, randomised, open-label, phase 3 study recruited patients aged at least 18 years with multiple myeloma who needed treatment for first progressive or relapsed disease at least 18 months after a previous ASCT from 51 centres across the UK. Before randomisation, eligible patients received bortezomib, doxorubicin, and dexamethasone (PAD) induction therapy and then underwent peripheral blood stem-cell mobilisation and harvesting if applicable. Eligible patients (with adequate stem-cell harvest) were randomly assigned (1:1), using an automated telephone randomisation line, to either high-dose melphalan 200 mg/m(2) plus salvage ASCT or oral cyclophosphamide (400mg/m(2) per week for 12 weeks). Randomisation was stratified by length of first remission or plateau and response to PAD re-induction therapy. The primary endpoint was time to disease progression, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00747877, and EudraCT, number 2006-005890-24. FINDINGS: Between April 16, 2008, and Nov 19, 2012, 297 patients were registered, of whom 293 received PAD re-induction therapy. Between Aug 26, 2008, and Nov 16, 2012, 174 patients with sufficient PBSCs were randomised to salvage ASCT (n=89) or cyclophosphamide (n=85). After a median follow-up of 31 months (IQR 19-42), median time to progression was significantly longer in the salvage ASCT than in the cyclophosphamide group (19 months [95% CI 16-25] vs 11 months [9-12]; hazard ratio 0·36 [95% CI 0·25-0·53]; p<0·0001). Frequently reported (in >10% of patients) grade 3-4 adverse events with PAD induction, salvage ASCT, and cyclophosphamide were: neutropenia (125 [43%] of 293 patients after PAD, and 63 [76%] of 83 patients in the salvage ASCT group vs 11 [13%] of 84 patients in the cyclophosphamide group), thrombocytopenia (150 [51%] after PAD, and 60 [72%] vs four [5%], respectively), and peripheral neuropathy (35 [12%] after PAD, and none vs none, respectively). INTERPRETATION: This study provides evidence for the improved efficacy of high-dose melphalan plus salvage ASCT when compared with cyclophosphamide in patients with relapsed multiple myeloma eligible for intensive therapy, which might help to guide clinical decisions regarding the management of such patients. FUNDING: Cancer Research UK.

Report from the European Myeloma Network on interphase FISH in multiple myeloma and related disorders.

The European Myeloma Network has organized two workshops on fluorescence in situ hybridization in multiple myeloma. The first aimed to identify specific indications and consensus technical approaches of current practice. A second workshop followed a quality control exercise in which 21 laboratories analyzed diagnostic cases of purified plasma cells for recurrent abnormalities. The summary report was discussed at the EHA Myeloma Scientific Working Group Meeting 2010. During the quality control exercise, there was acceptable agreement on more than 1,000 tests. The conclusions from the exercise were that the primary clinical applications for FISH analysis were for newly diagnosed cases of MM or frank relapse cases. A range of technical recommendations included: 1) material should be part of the first draw of the aspirate; 2) samples should be sent at suitable times to allow for the lengthy processing procedure; 3) most importantly, PCs must be purified or specifically identified; 4) positive cut-off levels should be relatively conservative: 10% for fusion or break-apart probes, 20% for numerical abnormalities; 5) informative probes should be combined to best effect; 6) in specialist laboratories, a single experienced analyst is considered adequate; 7) at least 100 PC should be scored; 8) essential abnormalities to test for are t(4;14), t(14;16) and 17p13 deletions; 9) suitable commercial probes should be available for clinically relevant abnormalities; 10) the clinical report should be expressed clearly and must state the percentage of PC involved and the method used for identification; 11) a retrospective European based FISH data bank linked to clinical data should be generated; and 12) prospective analysis should be centralized for upcoming trials based on the recommendations made. The European Myeloma Network aims to build on these recommendations to establish standards for a common European data base to define subgroups with prognostic significance.

Ethics Update. Revisions strengthen AHIMA's code of ethics.

A new update to AHIMA's Code of Ethics addresses recent changes in technology, healthcare, and association management-and the accompanying complexity of competing interests and obligations they can bring.

IgD multiple myeloma: biology, diagnosis, and treatment.

IgD multiple myeloma is uncommon. Patients generally present at a younger age and have shorter progression free and overall survivals (OSs). Its rarity has inhibited development of a specific risk stratification system or informed best treatment protocols. We present interphase fluorescence in situ hybridization results from a group of 29 cases. These showed evidence of a decreased male to female ratio, decreased OS in patients aged 70 and over, better outcomes in those with kappa light chain restriction, and CD56 positive patients had longer survivals than those lacking CD56. We discuss the biology of IgD multiple myeloma, the need for prospective studies, and challenges for improvements in diagnosis and treatment. We suggest an International Register to accelerate development of best practice guidelines for diagnosis, risk stratification, and treatment.

Monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia.

BACKGROUND: A diagnosis of chronic lymphocytic leukemia (CLL) requires a count of over 5000 circulating CLL-phenotype cells per cubic millimeter. Asymptomatic persons with fewer CLL-phenotype cells have monoclonal B-cell lymphocytosis (MBL). The goal of this study was to investigate the relation between MBL and CLL. METHODS: We investigated 1520 subjects who were 62 to 80 years of age with a normal blood count and 2228 subjects with lymphocytosis (>4000 lymphocytes per cubic millimeter) for the presence of MBL, using flow cytometry. Monoclonal B cells were further characterized by means of cytogenetic and molecular analyses. A representative cohort of 185 subjects with CLL-phenotype MBL and lymphocytosis were monitored for a median of 6.7 years (range, 0.2 to 11.8). RESULTS: Monoclonal CLL-phenotype B cells were detected in 5.1% of subjects (78 of 1520) with a normal blood count and 13.9% (309 of 2228) with lymphocytosis. CLL-phenotype MBL had a frequency of 13q14 deletion and trisomy 12 similar to that of CLL and showed a skewed repertoire of the immunoglobulin heavy variable group (IGHV) genes. Among 185 subjects presenting with lymphocytosis, progressive lymphocytosis occurred in 51 (28%), progressive CLL developed in 28 (15%), and chemotherapy was required in 13 (7%). The absolute B-cell count was the only independent prognostic factor associated with progressive lymphocytosis. During follow-up over a median of 6.7 years, 34% of subjects (62 of 185) died, but only 4 of these deaths were due to CLL. Age above 68 years and hemoglobin level below 12.5 g per deciliter were the only independent prognostic factors for death. CONCLUSIONS: The CLL-phenotype cells found in the general population and in subjects with lymphocytosis have features in common with CLL cells. CLL requiring treatment develops in subjects with CLL-phenotype MBL and with lymphocytosis at the rate of 1.1% per year.

Practical Application of Fluorescent In Situ Hybridization Techniques in Clinical Diagnostic Laboratories.

Fluorescent in situ hybridization (FISH) techniques can be used to identify a range of chromosome abnormalities that are clinically significant in many cancers. Multicolor FISH can be used to identify multiple targets, which can be simultaneously detected in individual cells using digital imaging microscopy. In an era of precision medicine there is a requirement to make a precise diagnosis and to have a molecular classification of the tumor that can guide therapy. Cancer genomics is now regarded as a sub-specialism in pathology and genomic testing needs to be robustly integrated into the routine diagnostic practice.The FISH techniques described in this chapter have been developed over many years in a busy hematopathology diagnostic laboratory. We describe robust in-house methods for both liquid samples (blood and bone marrow mainly) and formalin-fixed paraffin-embedded (FFPE) tissue biopsies that allow for large numbers of slides to be set up in batches. The techniques described are for interphase cells in tissues where metaphase chromosome techniques are generally not applicable. Some of the FISH tests need to be carried out as an "out-of-hours" emergency test to make a critical diagnosis while others provide prognostic information and are used to guide downstream patient management.

Postoperative hyperglycaemia of diabetic patients undergoing cardiac surgery - a clinical audit.

BACKGROUND: Previous studies have shown that hyperglycaemia is associated with postoperative complications in cardiac surgical patients. Conversely, well-controlled glucose levels are said to reduce major infectious complications in diabetic patients. AIM/OBJECTIVES: The purpose of this clinical audit was to evaluate the blood glucose levels of diabetic patients undergoing cardiac surgery and to determine the effectiveness of postoperative glycaemic control. METHODS: A group of 150 patients from a large Irish cardiac surgery centre was selected by convenience sampling. An audit tool was designed to capture the patients' blood glucose levels, treatment regimes and postoperative complications. FINDINGS: The findings showed major variations between 'high', 'good' and 'borderline' blood glucose levels in the pre- and postoperative phase. Although blood glucose testing practices seemed inconsistent, mean levels measured 'borderline'. Furthermore, the treatment regimes varied greatly and suggest a lack of consensus regarding the management of postoperative hyperglycaemia. A total of 52% (n = 78) patients developed 114 complications with a level of 21.4% (n = 32) postoperative wound infections. CONCLUSION: The findings from this audit highlight the importance of regular blood glucose testing to enable early detection of hyperglycaemia and timely initiation of appropriate treatments regimes for diabetic patients undergoing cardiac surgery. Findings also show that hyperglycaemia derangement may make a difference in the recovery phase. While patients will benefit from lesser wound infections, hospitals might save costs involved with treating postoperative complications. RELEVANCE TO PRACTICE: More consistent blood glucose testing might be achieved through the use of evidence-based protocols. However, the education of staff is as important as it develops knowledge on the complex metabolic interactions of diabetic patients undergoing cardiac surgery. While this means investing in staff education and policy development, costs for daily care and expensive treatments for complications will be saved as patient recovery will be speedier and less eventful.

Protocol for a two-arm feasibility RCT to support postnatal maternal weight management and positive lifestyle behaviour in women from an ethnically diverse inner city population: the SWAN feasibility trial.

INTRODUCTION: A high BMI during and after pregnancy is linked to poor pregnancy outcomes and contributes to long-term maternal obesity, hypertension, and diabetes. Evidence of feasible, effective postnatal interventions is lacking. This randomised controlled trial will assess the feasibility of conducting a future definitive trial to determine effectiveness and cost-effectiveness of lifestyle information and access to Slimming World® (Alfreton, UK) groups for 12 weeks commencing from 8 to 16 weeks postnatally, in relation to supporting longer-term postnatal weight management in women in an ethnically diverse inner city population. METHODS/ANALYSIS: Women will be recruited from one maternity unit in London. To be eligible, women will be overweight (BMI 25-29.9 kg/m2) or obese (BMI ≥ 30 kg/m2) as identified at their first antenatal contact, or have a normal BMI (18.5-24.9 kg/m2) at booking but gain excessive gestational weight as assessed at 36 weeks gestation. Women will be aged 18 and over, can speak and read English, expecting a single baby, and will not have accessed weight management groups in this pregnancy. Women will be randomly allocated to standard care plus lifestyle information and access to Slimming World® (Alfreton, UK) groups or standard care only. A sample of 130 women is required.Feasibility trial objectives reflect those considered most important inform a decision about undertaking a definitive future trial. These include estimation of impact of lifestyle information and postnatal access to Slimming World® (Alfreton, UK) on maternal weight change between antenatal booking weight and weight at 12 months postbirth, recruitment rate and time to recruitment, retention rate, influence of lifestyle information and Slimming World® (Alfreton, UK) groups on weight management, diet, physical activity, breastfeeding, smoking cessation, alcohol intake, physical and mental health, infant health, and health-related quality of life 6 and 12 months postnatally. An embedded process evaluation will assess acceptability of study processes and procedures to women. ETHICS/DISSEMINATION: London-Camberwell St Giles Research Ethics Committee, reference: 16/LO/1422. Outcomes will be disseminated in peer-reviewed journals and presentations at national and international conferences. TRIAL REGISTRATION: Trial registration number: ISRCTN 39186148. Protocol version number: v7, 13 August 17. Trial sponsor: King's College London.

IgM myeloma: a rare entity characterized by a CD20-CD56-CD117- immunophenotype and the t(11;14).

IgM myeloma is a very rare and poorly defined entity. In a detailed assessment of 10 cases, it was demonstrated that 70% had an aberrant phenotype based on the expression of CD19, CD45, CD27 and Cyclin D1 but all cases lacked CD56 and CD117. Interphase fluorescence in situ hybridization demonstrated deletion 13 in 50% while 5/8 cases assessed had a t(11;14). Despite the high incidence of the t(11;14), CD20 was only expressed in one of nine cases. We conclude that IgM myeloma is a distinctive subset characterized by a CD20-CD56-CD117- phenotype and the t(11;14).

A standard lexicon for biodiversity conservation: unified classifications of threats and actions.

An essential foundation of any science is a standard lexicon. Any given conservation project can be described in terms of the biodiversity targets, direct threats, contributing factors at the project site, and the conservation actions that the project team is employing to change the situation. These common elements can be linked in a causal chain, which represents a theory of change about how the conservation actions are intended to bring about desired project outcomes. If project teams want to describe and share their work and learn from one another, they need a standard and precise lexicon to specifically describe each node along this chain. To date, there have been several independent efforts to develop standard classifications for the direct threats that affect biodiversity and the conservation actions required to counteract these threats. Recognizing that it is far more effective to have only one accepted global scheme, we merged these separate efforts into unified classifications of threats and actions, which we present here. Each classification is a hierarchical listing of terms and associated definitions. The classifications are comprehensive and exclusive at the upper levels of the hierarchy, expandable at the lower levels, and simple, consistent, and scalable at all levels. We tested these classifications by applying them post hoc to 1191 threatened bird species and 737 conservation projects. Almost all threats and actions could be assigned to the new classification systems, save for some cases lacking detailed information. Furthermore, the new classification systems provided an improved way of analyzing and comparing information across projects when compared with earlier systems. We believe that widespread adoption of these classifications will help practitioners more systematically identify threats and appropriate actions, managers to more efficiently set priorities and allocate resources, and most important, facilitate cross-project learning and the development of a systematic science of conservation.

Intravascular large B-cell lymphoma associated with a near-tetraploid karyotype, rearrangement of BCL6, and a t(11;14)(q13;q32).

Chromosome analysis of a patient with intravascular large B-cell lymphoma (IVL) revealed a complex, near-tetraploid karyotype with 83 chromosomes. Abnormalities included a t(11;14)(q13;q32), which was confirmed with both interphase fluorescence in situ hybridization (FISH) using an IGH/cyclin D1 dual-color, dual-fusion probe set and cyclin D1 immunohistochemical analysis. Abnormality of 3q was also evident. Interphase FISH analysis with a dual-color, break-apart probe set confirmed rearrangement of BCL6. To our knowledge, this is the first report of these abnormalities in IVL.

The effect of salvage autologous stem-cell transplantation on overall survival in patients with relapsed multiple myeloma (final results from BSBMT/UKMF Myeloma X Relapse [Intensive]): a randomised, open-label, phase 3 trial.

BACKGROUND: The Myeloma X trial previously reported improved durability of response (time to disease progression) in patients with relapsed multiple myeloma with salvage autologous stem-cell transplantation (ASCT) compared with oral cyclophosphamide in patients with multiple myeloma relapsing after a first ASCT. We report the final overall survival results of the trial. METHODS: BSBMT/UKMF Myeloma X was a multicentre, randomised, open-label, phase 3 trial done at 51 centres in the UK. Eligible patients with multiple myeloma relapsing after a previous ASCT were re-induced with intravenous bortezomib (1·3 mg/m(2) on days 1, 4, 8, 11), intravenous doxorubicin (9 mg/m(2) per day on days 1-4), and oral dexamethasone (40 mg/day on days 1-4, 8-11, and 15-18 during cycle 1 and days 1-4 during cycles 2-4), with supportive care as per local institutional protocols before randomisation in a 1:1 ratio to either high-dose melphalan (200 mg/m(2)) and salvage ASCT or weekly oral cyclophosphamide (400 mg/m(2) per week for 12 weeks). Randomisation was by permuted blocks stratified by length of first remission and response to re-induction treatment. The primary endpoint was time to disease progression; the study was also powered to detect a difference in the secondary endpoint, overall survival. Further secondary endpoints were the proportion of patients achieving an objective response, progression-free survival, overall survival, toxic effects and safety, pain, and quality of life. Prespecified exploratory endpoints included time to second objective disease progression (PFS2). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00747877, and the European Clinical Trials Database, number 2006-005890-24, and is now in long-term follow-up. FINDINGS: Between April 16, 2008, and Nov 19, 2012, 297 patients were registered into the study and 174 were randomly assigned to receive either high-dose melphalan and salvage ASCT (n=89) or oral weekly cyclophosphamide (n=85). 173 (58%) of 297 patients relapsed after more than 24 months from first ASCT. 75 (43%) of 174 randomised patients had died at follow-up: salvage ASCT (n=31 [35%]) versus oral weekly cyclophosphamide (n=44 [52%]). Updated time to disease progression shows continued advantage in the salvage ASCT group compared with the weekly cyclophosphamide group (19 months [95% CI 16-26] vs 11 months [9-12]; hazard ratio [HR] 0·45 [95% CI 0·31-0·64] log-rank p<0·0001). Median overall survival was superior in the salvage ASCT group compared with weekly cyclophosphamide group (67 months [95% CI 55-not estimable] vs 52 months [42-60]; log-rank p=0·022; HR 0·56 [0·35-0·90], p=0·0169). Time to second objective disease progression was superior in the salvage ASCT group compared with the weekly cyclophosphamide group (67 months [52-not estimable] vs 35 months [31-43]; HR 0·37 [0·24-0·57], log-rank p<0·0001). During extended follow-up, no further treatment-related or treatment-unrelated adverse events were reported. 15 second primary malignancies were reported in 12 patients (salvage ASCT [n=7] vs oral weekly cyclophosphamide [n=5]). The cumulative incidence of second primary malignancies at 60 months after trial entry was 5·2% (2·1-8·2). INTERPRETATION: Salvage ASCT increases overall survival during consolidation of re-induction treatment in patients with multiple myeloma at first relapse after a first ASCT. The delay of salvage ASCT to third-line treatment or later might not confer the same degree of advantage as seen with salvage ASCT at first relapse. FUNDING: Cancer Research UK, Janssen-Cilag, and Chugai Pharma UK.