Realist analysis of whether emergency departments with primary care services generate 'provider-induced demand'.

BACKGROUND: It is not known whether emergency departments (EDs) with primary care services influence demand for non-urgent care ('provider-induced demand'). We proposed that distinct primary care services in EDs encourages primary care demand, whereas primary care integrated within EDs may be less likely to cause additional demand. We aimed to explore this and explain contexts (C), mechanisms (M) and outcomes (O) influencing demand. METHODS: We used realist evaluation methodology and observed ED service delivery. Twenty-four patients and 106 staff members (including Clinical Directors and General Practitioners) were interviewed at 13 EDs in England and Wales (240 hours of observations across 30 days). Field notes from observations and interviews were analysed by creating 'CMO' configurations to develop and refine theories relating to drivers of demand. RESULTS: EDs with distinct primary care services were perceived to attract demand for primary care because services were visible, known or enabled direct access to health care services. Other influencing factors included patients' experiences of accessing primary care, community care capacity, service design and population characteristics. CONCLUSIONS: Patient, local-system and wider-system factors can contribute to additional demand at EDs that include primary care services. Our findings can inform service providers and policymakers in developing strategies to limit the effect of potential influences on additional demand when demand exceeds capacity.

Adverse childhood experiences among early care and education teachers: Prevalence and associations with observed quality of classroom social and emotional climate.

This study examines the prevalence of self-reported adverse childhood experiences (ACEs) among a sample of 349 early care and education teachers. Seventy-three percent of the sample reported experiencing at least one ACE and 22% reported experiencing 4 or more ACEs. Live observational assessments of the quality of the social and emotional climate in teacher's classrooms were conducted for a subsample of 58 teachers. Within this subsample, reporting a higher number of ACEs was associated with facilitating a lower quality social and emotional classroom climate. Individual ACEs were also examined. Teachers who reported experiencing incarceration of a family member, physical abuse, or emotional abuse were observed to facilitate a lower quality social and emotional classroom climate. This study provides preliminary insight into the prevalence of ACEs among members of the early care and education workforce. Further, it extends previous work examining the multi-generational impacts of ACEs within families by showing that ACEs may influence the care that is provided to children in childcare settings.

Streptococcal superantigen-induced expansion of human tonsil T cells leads to altered T follicular helper cell phenotype, B cell death and reduced immunoglobulin release.

Streptococcal pyrogenic exotoxin (Spe) A expression is epidemiologically linked to streptococcal tonsillo-pharyngitis and outbreaks of scarlet fever, although the mechanisms by which superantigens confer advantage to Streptococcus pyogenes are unclear. S. pyogenes is an exclusively human pathogen. As the leucocyte profile of tonsil is unique, the impact of SpeA production on human tonsil cell function was investigated. Human tonsil cells from routine tonsillectomy were co-incubated with purified streptococcal superantigens or culture supernatants from isogenic streptococcal isolates, differing only in superantigen production. Tonsil cell proliferation was quantified by tritiated thymidine incorporation, and cell surface characteristics assessed by flow cytometry. Soluble mediators including immunoglobulin were measured using enzyme-linked immunosorbent assay. Tonsil T cells proliferated in response to SpeA and demonstrated typical release of proinflammatory cytokines. When cultured in the absence of superantigen, tonsil preparations released large quantities of immunoglobulin over 7 days. In contrast, marked B cell apoptosis and abrogation of total immunoglobulin (Ig)A, IgM, and IgG production occurred in the presence of SpeA and other superantigens. In SpeA-stimulated cultures, T follicular helper (Tfh) cells showed a reduction in C-X-C chemokine receptor (CXCR)5 (CD185) expression, but up-regulation of OX40 (CD134) and inducible T cell co-stimulator (ICOS) (CD278) expression. The phenotypical change in the Tfh population was associated with impaired chemotactic response to CXCL13. SpeA and other superantigens cause dysregulated tonsil immune function, driving T cells from Tfh to a proliferating phenotype, with resultant loss of B cells and immunoglobulin production, providing superantigen-producing bacteria with a probable survival advantage.

A phase I/II study of KW-2478, an Hsp90 inhibitor, in combination with bortezomib in patients with relapsed/refractory multiple myeloma.

BACKGROUND: KW-2478 is a novel non-ansamycin Hsp90 inhibitor with modest single-agent activity in relapsed/refractory myeloma but which shows synergistic antimyeloma activity with bortezomib (BTZ) in preclinical studies. This study determined the safety, preliminary clinical activity, and pharmacokinetics of KW-2478, an Hsp90 inhibitor, in combination with BTZ in patients with relapsed/refractory multiple myeloma (MM). METHODS: Phase I dose escalation determined the recommended phase II dose (RP2D) of KW-2478 plus BTZ, which was then used during phase II. RESULTS: The maximum tolerated dose was not reached during phase I and the RP2D was KW-2478 175 mg m-2 plus BTZ 1.3 mg m-2 on days 1, 4, 8, and 11 every 3 weeks. In the efficacy evaluable phase I/II population treated at the RP2D (n=79), the objective response rate was 39.2% (95% confidence interval: 28.4-50.9%), clinical benefit rate 51.9% (40.4-63.3%), median progression-free survival 6.7 (5.9-not reached (NR)) months, and median duration of response 5.5 (4.9-NR) months. In the phase I/II safety population (n=95), the most frequently observed treatment-related grade 3/4 adverse events were diarrhoea, fatigue, and neutropenia (each in 7.4% of patients), and nausea and thrombocytopenia (each in 5.3%). CONCLUSIONS: KW-2478 plus BTZ was well tolerated with no apparent overlapping toxicity in patients with relapsed/refractory MM. The antimyeloma activity of KW-2478 in combination with BTZ as scheduled in this trial appeared relatively modest; however, the good tolerability of the combination would support further exploration of alternate dosing schedules and combinations.

Assessing myeloma bone disease with whole-body diffusion-weighted imaging: comparison with x-ray skeletal survey by region and relationship with laboratory estimates of disease burden.

AIM: To estimate and compare the extent of myeloma bone disease by skeletal region using whole-body diffusion-weighted imaging (WB-DWI) and skeletal survey (SS) and record interobserver agreement, and to investigate differences in imaging assessments of disease extent and apparent diffusion coefficient (ADC) between patients with pathological high versus low disease burden. MATERIALS AND METHODS: Twenty patients with relapsed myeloma underwent WB-DWI and SS. Lesions were scored by number and size for each skeletal region by two independent observers using WB-DWI and SS. Observer scores, ADC, and ADC-defined volume of tumour-infiltrated marrow were compared between patients with high and low disease burden (assessed by serum paraproteins and marrow biopsy). RESULTS: Observer scores were higher on WB-DWI than SS in every region (p<0.05) except the skull, with greater interobserver reliability in rating the whole skeleton (WB-DWI: ICC = 0.74, 95% CI: 0.443-0.886; SS: ICC = 0.44, 95% CI: 0.002-0.730) and individual body regions. WB-DWI scores were not significantly higher in patients with high versus low disease burden (observer 1: mean ± SD: 48.8 ± 7, 38.6 ± 14.5, observer 2: mean ± SD: 37.3 ± 13.5, 30.4 ± 15.5; p = 0.06, p = 0.35). CONCLUSION: WB-DWI demonstrated more lesions than SS in all regions except the skull with greater interobserver agreement. Sensitivity is not a limiting factor when considering WB-DWI in the management pathway of patients with myeloma.

Progression free survival of myeloma patients who become IFE-negative correlates with the detection of residual monoclonal free light chain (FLC) by mass spectrometry.

Deeper responses are associated with improved survival in patients being treated for myeloma. However, the sensitivity of the current blood-based assays is limited. Historical studies suggested that normalisation of the serum free light chain (FLC) ratio in patients who were negative by immunofixation electrophoresis (IFE) was associated with improved outcomes. However, recently this has been called into question. Mass spectrometry (MS)-based FLC assessments may offer a superior methodology for the detection of monoclonal FLC due to greater sensitivity. To test this hypothesis, all available samples from patients who were IFE negative after treatment with carfilzomib and lenalidomide-based induction and autologous stem cell transplantation (ASCT) in the Myeloma XI trial underwent FLC-MS testing. FLC-MS response assessments from post-induction, day+100 post-ASCT and six months post-maintenance randomisation were compared to serum FLC assay results. Almost 40% of patients had discordant results and 28.7% of patients with a normal FLC ratio had residual monoclonal FLC detectable by FLC-MS. FLC-MS positivity was associated with reduced progression-free survival (PFS) but an abnormal FLC ratio was not. This study demonstrates that FLC-MS provides a superior methodology for the detection of residual monoclonal FLC with FLC-MS positivity identifying IFE-negative patients who are at higher risk of early progression.

Mycophenolic acid trough level monitoring: relevance in acute and chronic graft versus host disease and its relation with albumin.

Mycophenolate mofetil (MMF) is used to treat acute and chronic graft versus host disease (GvHD). There is scant evidence in the literature about mycophenolic acid (MPA) trough level monitoring in GvHD. We therefore reviewed 32 patients treated with MMF for acute (n = 19) or chronic GvHD (n = 13). Twelve (63%) of 19 patients with acute GvHD and nine (69%) of 13 with chronic GvHD showed a good response. In all 21 patients who responded to MMF, their mean total MPA levels were therapeutic (1-3.5 mg/L), whereas five of 11 patients who did not respond had sub-therapeutic mean MPA levels (p = 0.002). Sixteen (66%) of 24 steroid refractory or dependent patients responded to MMF. Associations between the mean total MPA level for each patient and the corresponding mean serum albumin concentration showed therapeutic mean total MPA levels for all 23 patients with mean albumin ≥ 31 g/L but sub-therapeutic mean total MPA levels in five of nine patients with mean albumin <31 g/L (p = 0.0006). In conclusion, MMF is efficacious in steroid refractory and dependent acute or chronic GvHD with statistically significant correlation between therapeutic plasma total MPA trough levels and clinical response. Serum albumin levels should be taken into account when considering MMF dose adjustments.

Consensus guidelines for the optimal management of adverse events in newly diagnosed, transplant-ineligible patients receiving melphalan and prednisone in combination with thalidomide (MPT) for the treatment of multiple myeloma.

Thalidomide has received approval from the European Agency for the Evaluation of Medicinal Products for the treatment of newly diagnosed multiple myeloma (MM) patients older than 65 years or ineligible for transplant. The results of five phase III trials assessing thalidomide in combination with melphalan and prednisone (MPT) have demonstrated significantly improved response rates compared with melphalan and prednisone (MP) alone. Additionally, two of these studies showed that survival was extended by approximately 18 months in patients treated with MPT compared with MP alone. Thalidomide, in combination with MP, is associated with adverse events (AEs) including peripheral neuropathy and venous thromboembolism. In order to optimize the efficacy of MPT, a good awareness of these AEs is imperative. This manuscript outlines both evidence- and consensus-based recommendations discussed by a panel of experts, to provide a practical guide for physicians addressing the effective management of newly diagnosed, transplant-ineligible MM patients receiving thalidomide therapy.

Mokken scaling and principal components analyses of the CORE-OM in a large clinical sample.

In a sample of 543 adult National Health Service (NHS) patients referred to a Psychological Therapies Service, the responses to the Clinical Outcomes in Routine Evaluation-Outcome Measure (CORE-OM) self-report questionnaire were examined using conventional principal components analysis (PCA) and a unique application of Mokken Scaling Procedure (MSP). Following the theoretical views of G. A. Foulds, it was suggested that some items more properly belong to the universe of attitudes and traits rather than that of symptoms and states. Accordingly, the analyses were carried out both with and without the CORE-OM Risk domain items. Both PCAs produced a very large first component of Psychological distress, while the small second component differs. With all items included, the second component was of Risk. With the risk items excluded, the second component was now Functioning. The MSP results, respectively, were of a five-item scale of Functioning (impaired by depression) and on the second analysis, a five-item Functioning scale (impaired by anxiety). There was discussion on the criteria for item selection, the time scale specified in questionnaire instructions and the optimum number of items required for a symptom scale. It was concluded that the CORE-OM item pool did not conform to its purported face validity domains and subdomains, but predominantly constitutes a large Psychological distress scale with considerable item redundancy.

Detection of Rift Valley fever viral activity in Kenya by satellite remote sensing imagery.

Data from the advanced very high resolution radiometer on board the National Oceanic and Atmospheric Administration's polar-orbiting meteorological satellites have been used to infer ecological parameters associated with Rift Valley fever (RVF) viral activity in Kenya. An indicator of potential viral activity was produced from satellite data for two different ecological regions in Kenya, where RVF is enzootic. The correlation between the satellite-derived green vegetation index and the ecological parameters associated with RVF virus suggested that satellite data may become a forecasting tool for RVF in Kenya and, perhaps, in other areas of sub-Saharan Africa.

Planning to halve Gram-negative bloodstream infection: getting to grips with healthcare-associated Escherichia coli bloodstream infection sources.

BACKGROUND: A thorough understanding of the local sources, risks, and antibiotic resistance for Escherichia coli bloodstream infection (BSI) is required to focus prevention initiatives and therapy. AIM: To review the sources and antibiotic resistance of healthcare-associated E. coli BSI. METHODS: Sources and antibiotic resistance profiles of all 250 healthcare-associated (post 48 h) E. coli BSIs that occurred within our secondary and tertiary care hospital group from April 2014 to March 2017 were reviewed. Epidemiological associations with urinary source, gastrointestinal source, and febrile neutropenia-related BSIs were analysed using univariable and multivariable binary logistic regression models. FINDINGS: E. coli BSIs increased 9% from 4.0 to 4.4 per 10,000 admissions comparing the 2014/15 and 2016/17 financial years. Eighty-nine cases (36%) had a urinary source; 30 (34%) of these were classified as urinary catheter-associated urinary tract infections (UTIs). Forty-five (18%) were related to febrile neutropenia, and 38 (15%) had a gastrointestinal source. Cases were rarely associated with surgical procedures (11, 4%) or indwelling vascular devices (seven, 3%). Female gender (odds ratio: 2.3; 95% confidence interval: 1.2-4.6) and older age (1.02; 1.00-1.05) were significantly associated with a urinary source. No significant associations were identified for gastrointestinal source or febrile neutropenia-related BSIs. Forty-seven percent of the isolates were resistant to ciprofloxacin, 37% to third-generation cephalosporins, and 22% to gentamicin. CONCLUSION: The gastrointestinal tract and febrile neutropenia together accounted for one-third of E. coli BSI locally but were rare associations nationally. These sources need to be targeted locally to reduce an increasing trend of E. coli BSIs.

Combination of flow cytometry and functional imaging for monitoring of residual disease in myeloma.

The iliac crest is the sampling site for minimal residual disease (MRD) monitoring in multiple myeloma (MM). However, the disease distribution is often heterogeneous, and imaging can be used to complement MRD detection at a single site. We have investigated patients in complete remission (CR) during first-line or salvage therapy for whom MRD flow cytometry and the two imaging modalities positron emission tomography (PET) and diffusion-weighted magnetic resonance imaging (DW-MRI) were performed at the onset of CR. Residual focal lesions (FLs), detectable in 24% of first-line patients, were associated with short progression-free survival (PFS), with DW-MRI detecting disease in more patients. In some patients, FLs were only PET positive, indicating that the two approaches are complementary. Combining MRD and imaging improved prediction of outcome, with double-negative and double-positive features defining groups with excellent and dismal PFS, respectively. FLs were a rare event (12%) in first-line MRD-negative CR patients. In contrast, patients achieving an MRD-negative CR during salvage therapy frequently had FLs (50%). Multi-region sequencing and imaging in an MRD-negative patient showed persistence of spatially separated clones. In conclusion, we show that DW-MRI is a promising tool for monitoring residual disease that complements PET and should be combined with MRD.

Vector competence of selected African mosquito (Diptera: Culicidae) species for Rift Valley fever virus.

Outbreaks of Rift Valley fever (RVF) in Egypt, Yemen, and Saudi Arabia have indicated the potential for this disease to spread from its enzootic areas in sub-Saharan Africa. Because little is known about the potential for most African mosquito species to transmit RVF virus (family Bunyaviridae, genus Phlebovirus, RVFV), we conducted studies to determine the vector competence of selected African species of mosquitoes for this virus. All eight species tested [Aedes palpalis (Newstead), Aedes mcintoshi Huang, Aedes circumluteolus (Theobald), Aedes calceatus Edwards, Aedes aegypti (L.), Culex antennatus (Becker), Culex pipiens (L.), and Culex quinquefasciatus Say], were susceptible to infection, and all except Ae. calceatus, Ae. aegypti and Cx. quinquefasciatus transmitted RVFV by bite after oral exposure. Estimated transmission rates for mosquitoes that successfully transmitted RVFV by bite ranged from 5% for Ae. mcintoshi to 39% for Ae. palpalis for mosquitoes that fed on a hamster with a viremia > or = 10(8) plaque-forming units of virus/ml. We did not recover RVFV from any of 3,138 progeny of infected female mosquitoes. RVFV is unusual among arboviruses in that it has been isolated in nature from a large number of species and that numerous mosquitoes and other arthropods are able to transmit this virus in the laboratory. The recent introduction and spread of West Nile virus into the Americas and the spread of RVFV to the Arabian Peninsula illustrates the potential for viruses, once enzootic in Africa, to spread to other parts of the world.

Evaluating serial screening cultures to detect carbapenemase-producing Enterobacteriaceae following hospital admission.

BACKGROUND: Carbapenem-producing Enterobacteriaceae (CPE) are on the rise worldwide. National guidelines for the prevention and control of CPE recommend screening for the detection of asymptomatic carriers on admission. AIM: To evaluate the benefit of serial screens for detecting the carriage of CPE and other antibiotic-resistant Gram-negative bacteria following hospital admission. METHODS: All CPE screens, which were cultured on chromogenic media and the presence of a carbapenemase confirmed by polymerase chain reaction, were analysed for a six-month period. National guidelines in England recommend three serial screens for CPE separated by 48 h for admission screening for 'at-risk' patients, during which the patient is isolated. Two screening scenarios were tested. In scenario A, patients received three screens at the specified timepoints, in line with English national guidelines; in scenario B, patients received three consecutive screens, but not necessarily within the specified timepoints, during one admission. General linear models or conditional logistic regression were used to detect any significant change in the rate of carriage. FINDINGS: There was no significant increase in the detected carriage rate of CPE across any of the three timepoints in the scenarios tested. However, there was a significant increase in the detected rate of carriage of Gram-negative bacteria, Enterobacteriaceae, and resistant Enterobacteriaceae (excluding CPE) in scenario B. CONCLUSION: Three serial screens were not useful for the detection of CPE carriage on admission. The increase in the carriage rate of other Gram-negative bacteria may be explained by 'unmasking' of pre-existing carriage, or acquisition. This argues for regular screening of long-stay patients.

Prediction of outcome in newly diagnosed myeloma: a meta-analysis of the molecular profiles of 1905 trial patients.

Robust establishment of survival in multiple myeloma (MM) and its relationship to recurrent genetic aberrations is required as outcomes are variable despite apparent similar staging. We assayed copy number alterations (CNA) and translocations in 1036 patients from the NCRI Myeloma XI trial and linked these to overall survival (OS) and progression-free survival. Through a meta-anlysis of these data with data from MRC Myeloma IX trial, totalling 1905 newly diagnosed MM patients (NDMM), we confirm the association of t(4;14), t(14;16), t(14;20), del(17p) and gain(1q21) with poor prognosis with hazard ratios (HRs) for OS of 1.60 (P=4.77 × 10-7), 1.74 (P=0.0005), 1.90 (P=0.0089), 2.10 (P=8.86 × 10-14) and 1.68 (P=2.18 × 10-14), respectively. Patients with 'double-hit' defined by co-occurrence of at least two adverse lesions have an especially poor prognosis with HRs for OS of 2.67 (P=8.13 × 10-27) for all patients and 3.19 (P=1.23 × 10-18) for intensively treated patients. Using comprehensive CNA and translocation profiling in Myeloma XI we also demonstrate a strong association between t(4;14) and BIRC2/BIRC3 deletion (P=8.7 × 10-15), including homozygous deletion. Finally, we define distinct sub-groups of hyperdiploid MM, with either gain(1q21) and CCND2 overexpression (P<0.0001) or gain(11q25) and CCND1 overexpression (P<0.0001). Profiling multiple genetic lesions can identify MM patients likely to relapse early allowing stratification of treatment.

Counting the cost of an outbreak of carbapenemase-producing Enterobacteriaceae: an economic evaluation from a hospital perspective.

OBJECTIVE: To perform an economic evaluation on the cost associated with an outbreak of carbapenemase-producing Enterobacteriaceae (CPE). METHODS: We performed an observational economic evaluation of an outbreak of CPE (NDM-producing Klebsiella pneumoniae) affecting 40 patients in a group of five hospitals across three sites in West London. Costs were split into actual expenditure (including anti-infective costs, enhanced CPE screening, contact precautions, temporary ward-based monitors of hand and environmental practice, and environmental decontamination), and 'opportunity cost' (staff time, bed closures and elective surgical missed revenue). Costs are estimated from the hospital perspective over the 10-month duration of the outbreak. RESULTS: The outbreak cost €1.1m over 10 months (range €0.9-1.4m), comprising €312 000 actual expenditure, and €822 000 (range €631 000-€1.1m) in opportunity cost. An additional €153 000 was spent on Estates renovations prompted by the outbreak. Actual expenditure comprised: €54 000 on anti-infectives for 18 patients treated, €94 000 on laboratory costs for screening, €73 000 on contact precautions for 1831 contact precautions patient-days, €42 000 for hydrogen peroxide vapour decontamination of 24 single rooms, €43 000 on 2592 hours of ward-based monitors, and €6000 of expenditure related to ward and bay closures. Opportunity costs comprised: €244 000 related to 1206 lost bed-days (range 366-2562 bed-days, €77 000-€512 000), €349 000 in missed revenue from 72 elective surgical procedures, and €228 000 in staff time (range €205 000-€251 000). Reduced capacity to perform elective surgical procedures related to bed closures (€349 000) represented the greatest cost. CONCLUSIONS: The cost estimates that we present suggest that CPE outbreaks are highly costly.

Hyperhaploidy is a novel high-risk cytogenetic subgroup in multiple myeloma.

Hyperhaploid clones (24-34 chromosomes) were identified in 33 patients with multiple myeloma (MM), demonstrating a novel numerical cytogenetic subgroup. Strikingly, all hyperhaploid karyotypes were found to harbor monosomy 17p, the single most important risk stratification lesion in MM. A catastrophic loss of nearly a haploid set of chromosomes results in disomies of chromosomes 3, 5, 7, 9, 11, 15, 18, 19 and 21, the same basic set of odd-numbered chromosomes found in trisomy in hyperdiploid myeloma. All other autosomes are found in monosomy, resulting in additional clinically relevant monosomies of 1p, 6q, 13q and 16q. Hypotriploid subclones (58-68 chromosomes) were also identified in 11 of the 33 patients and represent a duplication of the hyperhaploid clone. Analysis of clones utilizing interphase fluorescence in situ hybridization (iFISH), metaphase FISH and spectral karyotyping identified either monosomy 17 or del17p in all patients. Amplification of 1q21 was identified in eight patients, demonstrating an additional high-risk marker. Importantly, our findings indicate that current iFISH strategies may be uninformative or ambiguous in the detection of these clones, suggesting this patient subgroup maybe underreported. Overall survival for patients with hyperhaploid clones was poor, with a 5-year survival rate of 23.1%. These findings identify a distinct numerical subgroup with cytogenetically defined high-risk disease.

Overexpression of EZH2 in multiple myeloma is associated with poor prognosis and dysregulation of cell cycle control.

Myeloma is heterogeneous at the molecular level with subgroups of patients characterised by features of epigenetic dysregulation. Outcomes for myeloma patients have improved over the past few decades except for molecularly defined high-risk patients who continue to do badly. Novel therapeutic approaches are, therefore, required. A growing number of epigenetic inhibitors are now available including EZH2 inhibitors that are in early-stage clinical trials for treatment of haematological and other cancers with EZH2 mutations or in which overexpression has been correlated with poor outcomes. For the first time, we have identified and validated a robust and independent deleterious effect of high EZH2 expression on outcomes in myeloma patients. Using two chemically distinct small-molecule inhibitors, we demonstrate a reduction in myeloma cell proliferation with EZH2 inhibition, which leads to cell cycle arrest followed by apoptosis. This is mediated via upregulation of cyclin-dependent kinase inhibitors associated with removal of the inhibitory H3K27me3 mark at their gene loci. Our results suggest that EZH2 inhibition may be a potential therapeutic strategy for the treatment of myeloma and should be investigated in clinical studies.

Spatial genomic heterogeneity in multiple myeloma revealed by multi-region sequencing.

In multiple myeloma malignant plasma cells expand within the bone marrow. Since this site is well-perfused, a rapid dissemination of "fitter" clones may be anticipated. However, an imbalanced distribution of multiple myeloma is frequently observed in medical imaging. Here, we perform multi-region sequencing, including iliac crest and radiology-guided focal lesion specimens from 51 patients to gain insight into the spatial clonal architecture. We demonstrate spatial genomic heterogeneity in more than 75% of patients, including inactivation of CDKN2C and TP53, and mutations affecting mitogen-activated protein kinase genes. We show that the extent of spatial heterogeneity is positively associated with the size of biopsied focal lesions consistent with regional outgrowth of advanced clones. The results support a model for multiple myeloma progression with clonal sweeps in the early phase and regional evolution in advanced disease. We suggest that multi-region investigations are critical to understanding intra-patient heterogeneity and the evolutionary processes in multiple myeloma.In multiple myeloma, malignant cells expand within bone marrow. Here, the authors use multi-region sequencing in patient samples to analyse spatial clonal architecture and heterogeneity, providing novel insight into multiple myeloma progression and evolution.