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Background: The emergence of highly active novel agents has led some to question the role of autologous haematopoietic stem-cell transplantation (HSCT) and subsequent consolidation therapy in newly diagnosed multiple myeloma. We therefore compared autologous HSCT with bortezomib–melphalan–prednisone (VMP) as intensification therapy, and bortezomib–lenalidomide–dexamethasone (VRD) consolidation therapy with no consolidation. Methods: In this randomised, open-label, phase 3 study we recruited previously untreated patients with multiple myeloma at 172 academic and community practice centres of the European Myeloma Network. Eligible patients were aged 18–65 years, had symptomatic multiple myeloma stage 1–3 according to the International Staging System (ISS), measurable disease (serum M protein >10 g/L or urine M protein >200 mg in 24 h or abnormal free light chain [FLC] ratio with involved FLC >100 mg/L, or proven plasmacytoma by biopsy), and WHO performance status grade 0–2 (grade 3 was allowed if secondary to myeloma). Patients were first randomly assigned (1:1) to receive either four 42-day cycles of bortezomib (1·3 mg/m2 administered intravenously or subcutaneously on days 1, 4, 8, 11, 22, 25, 29, and 32) combined with melphalan (9 mg/m2 administered orally on days 1–4) and prednisone (60 mg/m2 administered orally on days 1–4) or autologous HSCT after high-dose melphalan (200 mg/m2), stratified by site and ISS disease stage. In centres with a double HSCT policy, the first randomisation (1:1:1) was to VMP or single or double HSCT. Afterwards, a second randomisation assigned patients to receive two 28-day cycles of consolidation therapy with bortezomib (1·3 mg/m2 either intravenously or subcutaneously on days 1, 4, 8, and 11), lenalidomide (25 mg orally on days 1–21), and dexamethasone (20 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12) or no consolidation; both groups received lenalidomide maintenance therapy (10 mg orally on days 1–21 of a 28-day cycle). The primary outcomes were progression-free survival from the first and second randomisations, analysed in the intention-to-treat population, which included all patients who underwent each randomisation. All patients who received at least one dose of study drugs were included in the safety analyses. This study is registered with the EU Clinical Trials Register (EudraCT 2009-017903-28) and ClinicalTrials.gov (NCT01208766), and has completed recruitment. Findings: Between Feb 25, 2011, and April 3, 2014, 1503 patients were enrolled. 1197 patients were eligible for the first randomisation, of whom 702 were assigned to autologous HSCT and 495 to VMP; 877 patients who were eligible for the first randomisation underwent the second randomisation to VRD consolidation (n=449) or no consolidation (n=428). The data cutoff date for the current analysis was Nov 26, 2018. At a median follow-up of 60·3 months (IQR 52·2–67·6), median progression-free survival was significantly improved with autologous HSCT compared with VMP (56·7 months [95% CI 49·3–64·5] vs 41·9 months [37·5–46·9]; hazard ratio [HR] 0·73, 0·62–0·85; p=0·0001). For the second randomisation, the number of events of progression or death at data cutoff was lower than that preplanned for the final analysis; therefore, the results from the second protocol-specified interim analysis, when 66% of events were reached, are reported (data cutoff Jan 18, 2018). At a median follow-up of 42·1 months (IQR 32·3–49·2), consolidation therapy with VRD significantly improved median progression-free survival compared with no consolidation (58·9 months [54·0–not estimable] vs 45·5 months [39·5–58·4]; HR 0·77, 0·63–0·95; p=0·014). The most common grade ≥3 adverse events in the autologous HSCT group compared to the VMP group included neutropenia (513 [79%] of 652 patients vs 137 [29%] of 472 patients), thrombocytopenia (541 [83%] vs 74 [16%]), gastrointestinal disorders (80 [12%] vs 25 [5%]), and infections (192 [30%] vs 18 [4%]). 239 (34%) of 702 patients in the autologous HSCT group and 135 (27%) of 495 in the VMP group had at least one serious adverse event. Infection was the most common serious adverse event in each of the treatment groups (206 [56%] of 368 and 70 [37%] of 189). 38 (12%) of 311 deaths from first randomisation were likely to be treatment related: 26 (68%) in the autologous HSCT group and 12 (32%) in the VMP group, most frequently due to infections (eight [21%]), cardiac events (six [16%]), and second primary malignancies (20 [53%]). Interpretation: This study supports the use of autologous HSCT as intensification therapy and the use of consolidation therapy in patients with newly diagnosed multiple myeloma, even in the era of novel agents. The role of high-dose chemotherapy needs to be reassessed in future studies, in particular in patients with undetectable minimal residual disease after four-drug induction regimens including a monoclonal antiboby combined with an immunomodulatory agent and a proteasome inhibitor plus dexamethasone. Funding: Janssen and Celgene. © 2020 Elsevier Ltd

Introduction We previously reported the results of the phase III randomized HOVON-87/NMSG-18 study for Newly Diagnosed Multiple Myeloma patients not eligible for stem cell transplantation (nte-NDMM). The efficacy of melphalan, prednisolone and either thalidomide followed by thalidomide maintenance (MPT-T) versus lenalidomide followed by lenalidomide maintenance (MPR-R) was found to be comparable, being consistent across subgroups defined by age, cytogenetic risk and ISS [1]. As frailty is known to affect clinical outcome, we investigated the impact of frailty on outcome. Methods Frailty was assessed by a modification of the IMWG frailty score based on age, the Charlson Comorbidity Index (retrospectively retrieved from the list of comorbidities that were present at entry) and the WHO performance as a proxy for (instrumental) Activities of Daily Living ((i)ADL). To assess the effect of frailty on progression free survival (PFS) and OS, the logrank test was used, while the chi-squared test was used to evaluate the association of frailty with discontinuation rate and toxicity. Results All 637 eligible patients from the HOVON-87/NMSG-18 trial were included in the analysis. Median age was 73 years; 66% of patients were 80 years. A CCI of 0, 1, 2 and >=3 was found in 61, 20, 7 and 4% of patients respectively (8% unknown). The most common comorbidities were diabetes mellitus without end organ complications (12%) and myocardial infarction (6%). A WHO performance of 0, 1 and >= 2 was observed in 35, 47 and 16% respectively (3% unknown). Univariate analyses showed that older age (>80 years: HR 1.59 [95% CI 1.12-2.25]), a higher CCI (CCI >=2: HR 1.41 [95% CI 1.01-1.95]); and a poor WHO performance (WHO >=2: HR 2.05 [1.49-2.82]) were associated with an inferior OS. HR's were 1.07 [95% CI 0.82-1.40] and 1.27 [95% CI 0.98- 1.65] for age 76-80 years and WHO performance respectively. For age and the CCI the IMWG frailty score classification was used. For the WHO, scores were assigned based on the HR: WHO 0; 0 points, WHO 1; 1 point and WHO >=2; 2 points. Fit patients were defined as a proxy frailty score of 0, unfit as a score of 1 and frail as a score of >=2, comparable to the IMWG frailty score. Using this modified IMWG frailty score, 135 patients were fit (21%), 199 were unfit (31%) and 259 were frail (41%) (7% unknown). The median OS was found to be significantly different in fit versus unfit versus frail patients; 58, 55 and 46 months respectively (p=0.004). In contrast no significant difference in median PFS was found; 26, 20 and 21 months respectively (p=0.30). The inferior OS for the frail might be partly explained by higher discontinuation rate of induction therapy; 50%, versus 43% in unfit, and 34% in fit patients (p=0.011), being mainly due to excessive toxicity (25, 23 and 16% respectively). The cumulative incidence of treatment discontinuation on protocol (induction plus maintenance), corrected for death and progressive disease which were considered as competing risks, is depicted in figure 1B. Discontinuation rate at 2 years for fit, unfit, and frail patients were 48%, 48%, and 59% respectively (p=0.06). There were significantly more grade >=3 adverse events on protocol in frail and unfit patients (both 86%) as compared to fit patients (77%, p=0.039). Especially more grade >=3 infections were found in frail (28% versus 18% in unfit and 13% in fit). In contrast, frailty was not associated with hematological toxicity. Conclusion We here present a modified frailty score, using the WHO performance instead of the (i)ADL, combined with age and the CCI, that enables the identification of frail MM patients with an inferior OS, a higher discontinuation rate and a higher rate of grade >= 3 toxicity. This non-laborious modified frailty score can be easily implemented in clinical trials and allows to compare the outcome of frail patients in nte-NDMM trials, which will hopefully result in frailty-adapted therapy in clinical daily practice. (Figure Presented).

To directly compare the performance of four clinical decision rules (CDRs) (Wells rule, revised Geneva score, simplified Wells rule and simplified revised Geneva score) in combination with D-dimer testing in excluding acute pulmonary embolism (PE). Prospective cohort study. In patients with suspected PE, the clinical probability of PE was assessed on the basis of the results of the CDRs and D-dimer test results using a computer program which calculated all CDRs and indicated the next diagnostic step. The CDRs results were compared using the outcome measure 'PE' assessed by CT-scanning or by the occurrence of venous thromboembolism or PE during a 3-month follow-up period after excluding PE. A total of 807 consecutive patients with suspected PE were included. PE prevalence was 23%. The number of patients categorised as 'PE unlikely' ranged from 62% (simplified Wells rule) to 72% (Wells rule). This CDR result combined with a normal D-dimer level excluded PE, which was the case in 22-24% of patients. There was no difference between the CDRs in the number of missed PEs (1 missed (0.5-0.6%); upper 95% CI: 2.9-3.1%). Although 30% of the patients had discordant CDR outcomes, PE was missed in none of the patients with discordant CDRs and a normal D-dimer result. All four CDRs show similar performance for exclusion of acute PE in combination with a normal D-dimer level. In addition this prospective study indicates that also the simplified scores can be used in clinical practice

Background: Four different clinical decision rules (CDRs) (Wells score, Revised Geneva score (RGS), simplified Wells score and simplified RGS) safely exclude pulmonary embolism (PE), when combined with a normal D-dimer test. Recently, an age adjusted cut-off of the D-dimer (patient's age x 10 ig/L) greatly increased the number of patients in whom PE could safely be excluded. We validated the age-adjusted D-dimer test and assessed its performance in combination with the four CDRs in patients with suspected PE. Methods: Eight hundred and thirty-four consecutive patients with suspected PE were included of whom 414 were > 50 years (50%). The proportion of patients in whom PE could be excluded with an unlikely CDR combined with a normal age-adjusted D-dimer test was calculated and compared with the conventional D-dimer cut-off. We assessed VTE failure rates during 3-months follow-up. Results: Compared to the conventional D-dimer cut-off level, a normal age-adjusted D-dimer level substantially increased the number of patients in whom PE could be safely excluded. All CDRs performed equally well. This difference was nearly fourfold in patients > 70 years, where the Wells rule excluded more patients than the other CDRs. Conclusion: The age-adjusted D-dimer increases the number of older patients in whom PE can be safely excluded, irrespective of the Wells score or RGS, thereby avoiding unnecessary imaging tests.

Background: Several clinical decision rules (CDRs) are available for the exclusion of acute pulmonary embolism (PE) but not directly compared. This prospective multicenter study directly compared the performance of four CDRs (Wells rule, revised Geneva score, simplified Wells rule and simplified revised Geneva score) in excluding PE in combination with D-dimer testing. Methods: The clinical probability of PE was assessed using a computer program, which calculated all CDRs and indicated the next diagnostic step. Clinical care was guided by the results of the CDRs and D-dimer results. A 'PE unlikely' result according to all CDRs in combination with a normal D-dimer result excluded PE, while patients with 'PE likely' according to at least one of the CDRs or an abnormal D-dimer result underwent CT-scanning. CDRs results were compared with PE prevalence indentified by CT-scanning or venous thromboembolism during 3-month follow-up. Results: Eight hundred and seven consecutive patients with suspected acute PE were included and PE prevalence was 23%. The number of patients categorized as 'PE unlikely' ranged from 62% (simplified Wells rule) to 72% (Wells rule). Combined with a normal D-dimer level, the CDRs excluded PE in 22-24% of patients. The total failure rates of the CDR-D-dimer combinations were similar (one failure, 0.5-0.6%, upper 95% CI 2.9-3.1%). Despite 30% of the patients had discordant CDR outcomes, PE was missed in none of the patients with discordant CDRs and a normal D-dimer result. Conclusions: All four CDRs show similar performance for exclusion of acute PE in combination with a normal D-dimer level. This prospective validation indicates that the simplified scores may be used in clinical practice.

Background: Diagnostic strategies in patients with suspected pulmonary embolism (PE) are well defined but their value in patients presenting with clinically suspected recurrent PE has not been established. The aim of this study was to determine the performance of a simple diagnostic strategy using the Wells clinical decision rule (CDR), quantitative D-dimer testing and computed tomography pulmonary angiography (CTPA) in patients with clinically suspected recurrent PE. Methods: Five hundred and sixteen patients with suspected recurrent PE were included in this multicenter clinical outcome study. An unlikely clinical probability (Wells rule four points or less) in combination with a normal D-dimer (cut-off 500 ng/mL) test result excluded PE and all other patients underwent multislice CTPA. Anticoagulant treatment was started if PE was demonstrated and treatment was withheld in all other patients. Primary outcome was the 3-month venous thromboembolism (VTE) recurrence rate in patients with normal tests, who had not been treated with anticoagulation. Results: An unlikely probability was found in 176 of 516 patients (34%), and the combination of an unlikely CDR-score and normal D-dimer excluded PE in 88 (17%) patients, without recurrent VTE during follow-up (0%; 95% CI 0-3.3%). CTPA excluded PE in 253 patients. During follow-up eight patients had a recurrent VTE (3.2%; 95% CI 1.5-5.9%). All patients had recurrent PE, of which two were fatal. Conclusion: In patients with suspected recurrent PE, the combination of an unlikely Wells CDR score and normal D-dimer safely excludes pulmonary embolism. In patients with a high risk probability or abnormal D-dimer, a CTPA excluding PE, however, is associated with a high rate of recurrent PE. Additional studies using alternative diagnostic algorithms - including performing ultrasonography after normal CT - are urgently needed.

Background The emergence of highly active novel agents has led some to question the role of autologous haematopoietic stem-cell transplantation (HSCT) and subsequent consolidation therapy in newly diagnosed multiple myeloma. We therefore compared autologous HSCT with bortezomib-melphalan-prednisone (VMP) as intensification therapy, and bortezomib-lenalidomide-dexamethasone (VRD) consolidation therapy with no consolidation.Methods In this randomised, open-label, phase 3 study we recruited previously untreated patients with multiple myeloma at 172 academic and community practice centres of the European Myeloma Network. Eligible patients were aged 18-65 years, had symptomatic multiple myeloma stage 1-3 according to the International Staging System (I S S), measurable disease (serum M protein >10 g/L or urine M protein >200 mg in 24 h or abnormal free light chain [FLC] ratio with involved FLC >100 mg/L, or proven plasmacytoma by biopsy), and WHO performance status grade 0-2 (grade 3 was allowed if secondary to myeloma). Patients were first randomly assigned (1:1) to receive either four 42-day cycles of bortezomib (1.3 mg/m 2 administered intravenously or subcutaneously on days 1, 4, 8, 11, 22, 25, 29, and 32) combined with melphalan (9 mg/m(2) administered orally on days 1-4) and prednisone (60 mg/m(2) administered orally on days 1-4) or autologous HSCT after high-dose melphalan (200 mg/m(2)), stratified by site and ISS disease stage. In centres with a double HS CT policy, the first randomisation (1:1:1) was to VMP or single or double HSCT. Afterwards, a second randomisation assigned patients to receive two 28-day cycles of consolidation therapy with bortezomib (1.3 mg/m(2)either intravenously or subcutaneously on days 1, 4, 8, and 11), lenalidomide (25 mg orally on days 1-21), and dexamethasone (20 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12) or no consolidation; both groups received lenalidomide maintenance therapy (10 mg orally on days 1-21 of a 28-day cycle). The primary outcomes were progression-free survival from the first and second randomisations, analysed in the intention-to-treat population, which included all patients who underwent each randomisation. All patients who received at least one dose of study drugs were included in the safety analyses. This study is registered with the EU Clinical Trials Register (EudraCT 2009-017903-28) and ClinicalTrials.gov (NCT01208766), and has completed recruitment.Findings Between Feb 25, 2011, and April 3, 2014, 1503 patients were enrolled. 1197 patients were eligible for the first randomisation, of whom 702 were assigned to autologous HSCT and 495 to VMP; 877 patients who were eligible for the first randomisation underwent the second randomisation to VRD consolidation (n=449) or no consolidation (n=428). The data cutoff date for the current analysis was Nov 26, 2018. At a median follow-up of 60.3 months (IQR 52. 2-67. 6), median progression-free survival was significantly improved with autologous HSCT compared with VMP (56.7 months [95% CI 49.3-64.5] vs 41.9 months [37.5-46.9]; hazard ratio [HR] 0.73, 0.62-0.85; p=0.0001). For the second randomisation, the number of events of progression or death at data cutoff was lower than that preplanned for the final analysis; therefore, the results from the second protocol-specified interim analysis, when 66% of events were reached, are reported (data cutoff Jan 18, 2018). At a median follow-up of 42.1 months (IQR 32.3-49.2), consolidation therapy with VRD significantly improved median progression-free survival compared with no consolidation (58.9 months [54.0-not estimable] vs 45.5 months [39.5-58.4]; HR 0.77, 0.63-0.95; p=0.014). The most common grade >= 3 adverse events in the autologous HSCT group compared to the VMP group included neutropenia (513 [79%] of 652 patients vs 137 [29%] of 472 patients), thrombocytopenia (541 [83%] vs 74 [16%]), gastrointestinal disorders (80 [12%] vs 25 [5%]), and infections (192 [30%] vs 18 [4%]). 239 (34%) of 702 patients in the autologous HSCT group and 135 (27%) of 495 in the VMP group had at least one serious adverse event. Infection was the most common serious adverse event in each of the treatment groups (206 [56%] of 368 and 70 [37%] of 189). 38 (12%) of 311 deaths from first randomisation were likely to be treatment related: 26 (68%) in the autologous HSCT group and 12 (32%) in the VMP group, most frequently due to infections (eight [21%]), cardiac events (six [16%]), and second primary malignancies (20 [53%]).Interpretation This study supports the use of autologous HSCT as intensification therapy and the use of consolidation therapy in patients with newly diagnosed multiple myeloma, even in the era of novel agents. The role of high-dose chemotherapy needs to be reassessed in future studies, in particular in patients with undetectable minimal residual disease after four-drug induction regimens including a monoclonal antiboby combined with an immunomodulatory agent and a proteasome inhibitor plus dexamethasone. Copyright (C) 2020 Elsevier Ltd. All rights reserved.