Daratumumab, lenalidomide, and dexamethasone in relapsed/refractory myeloma: a cytogenetic subgroup analysis of POLLUX

High cytogenetic risk abnormalities confer poor outcomes in multiple myeloma patients. In POLLUX, daratumumab/lenalidomide/dexamethasone (D-Rd) demonstrated significant clinical benefit versus lenalidomide/dexamethasone (Rd) in relapsed/refractory multiple myeloma (RRMM) patients. We report an updated subgroup analysis of POLLUX based on cytogenetic risk. The cytogenetic risk was determined using fluorescence in situ hybridization/karyotyping; patients with high cytogenetic risk had t(4;14), t(14;16), or del17p abnormalities. Minimal residual disease (MRD; 10–5) was assessed via the clonoSEQ® assay V2.0. 569 patients were randomized (D-Rd, n = 286; Rd, n = 283); 35 (12%) patients per group had high cytogenetic risk. After a median follow-up of 44.3 months, D-Rd prolonged progression-free survival (PFS) versus Rd in standard cytogenetic risk (median: not estimable vs 18.6 months; hazard ratio [HR], 0.43; P < 0.0001) and high cytogenetic risk (median: 26.8 vs 8.3 months; HR, 0.34; P = 0.0035) patients. Responses with D-Rd were deep, including higher MRD negativity and sustained MRD-negativity rates versus Rd, regardless of cytogenetic risk. PFS on subsequent line of therapy was improved with D-Rd versus Rd in both cytogenetic risk subgroups. The safety profile of D-Rd by cytogenetic risk was consistent with the overall population. These findings demonstrate the improved efficacy of daratumumab plus standard of care versus standard of care in RRMM, regardless of cytogenetic risk

Retrospective matched-pairs analysis of bortezomib plus dexamethasone versus bortezomib monotherapy in relapsed multiple myeloma

Bortezomib-dexamethasone is widely used for relapsed myeloma in routine clinical practice, but comparative data versus single-agent bortezomib are lacking. This retrospective analysis compared second-line treatment with bortezomib- dexamethasone and bortezomib using 109 propensity score-matched pairs of patients treated in three clinical trials: MMY-2045, APEX, and DOXIL-MMY-3001. Propensity scores were estimated using logistic regression analyses incorporating 13 clinical variables related to drug exposure or clinical outcome. Patients received intravenous bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11, in 21-day cycles, alone or with oral dexamethasone 20 mg on the days of/after bortezomib dosing. Median bortezomib cumulative dose (27.02 and 28.60 mg/m2) and treatment duration (19.6 and 17.6 weeks) were similar with bortezomib-dexamethasone and bortezomib, respectively. The overall response rate was higher (75% vs. 41%; odds ratio=3.467; P<0.001), and median time-to-progression (13.6 vs. 7.0 months; hazard ratio [HR]=0.394; P=0.003) and progression-free survival (11.9 vs. 6.4 months; HR=0.595; P=0.051) were longer with bortezomib-dexamethasone versus bortezomib, respectively. Rates of anygrade adverse events, most common grade 3 or higher adverse events, and discontinuations due to adverse events appeared similar between the groups. Two patients per group died of treatment-related adverse events. These data indicate the potential benefit of bortezomib-dexamethasone compared with single-agent bortezomib at first relapse in myeloma. The MMY-2045, APEX, and DOXIL-MMY-3001 clinical trials were registered at, respectively, clinicaltrials.gov identifier: 00908232, 00048230, and 00103506

Daratumumab, lenalidomide, and dexamethasone in relapsed/refractory myeloma: a cytogenetic subgroup analysis of POLLUX

High cytogenetic risk abnormalities confer poor outcomes in multiple myeloma patients. In POLLUX, daratumumab/lenalidomide/dexamethasone (D-Rd) demonstrated significant clinical benefit versus lenalidomide/dexamethasone (Rd) in relapsed/refractory multiple myeloma (RRMM) patients. We report an updated subgroup analysis of POLLUX based on cytogenetic risk. The cytogenetic risk was determined using fluorescence in situ hybridization/karyotyping; patients with high cytogenetic risk had t(4;14), t(14;16), or del17p abnormalities. Minimal residual disease (MRD; 10–5) was assessed via the clonoSEQ® assay V2.0. 569 patients were randomized (D-Rd, n = 286; Rd, n = 283); 35 (12%) patients per group had high cytogenetic risk. After a median follow-up of 44.3 months, D-Rd prolonged progression-free survival (PFS) versus Rd in standard cytogenetic risk (median: not estimable vs 18.6 months; hazard ratio [HR], 0.43; P < 0.0001) and high cytogenetic risk (median: 26.8 vs 8.3 months; HR, 0.34; P = 0.0035) patients. Responses with D-Rd were deep, including higher MRD negativity and sustained MRD-negativity rates versus Rd, regardless of cytogenetic risk. PFS on subsequent line of therapy was improved with D-Rd versus Rd in both cytogenetic risk subgroups. The safety profile of D-Rd by cytogenetic risk was consistent with the overall population. These findings demonstrate the improved efficacy of daratumumab plus standard of care versus standard of care in RRMM, regardless of cytogenetic risk

Daratumumab Plus Lenalidomide And Dexamethasone Versus Lenalidomide And Dexamethasone In Relapsed Or Refractory Multiple Myeloma: Updated Analysis Of POLLUX

In the POLLUX study, daratumumab plus lenalidomide/dexamethasone significantly reduced risk of progression/death versus lenalidomide/dexamethasone alone in relapsed/refractory multiple myeloma. We provide one additional year of follow up and include the effect on minimal residual disease and in clinically relevant subgroups. After 25.4 months of follow up, daratumumab plus lenalidomide/dexamethasone prolonged progression-free survival versus lenalidomide/dexamethasone alone (median not reached vs. 17.5 months; hazard ratio, 0.41; 95% confidence interval, 0.31-0.53; P12 and ≤12 months and >6 and ≤6 months. No new safety signals were observed. In relapsed/refractory multiple myeloma patients, daratumumab plus lenalidomide/dexamethasone continued to improve progression-free survival and deepen responses versus lenalidomide/dexamethasone. Trial Registration: clinicaltrials.gov identifier: 02076009

Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: Patients with multiple myeloma treated with lenalidomide maintenance therapy have improved progression-free survival, primarily following autologous stem-cell transplantation. A beneficial effect of lenalidomide maintenance therapy on overall survival in this setting has been inconsistent between individual studies. Minimal data are available on the effect of maintenance lenalidomide in more aggressive disease states, such as patients with cytogenetic high-risk disease or patients ineligible for transplantation. We aimed to assess lenalidomide maintenance versus observation in patients with newly diagnosed multiple myeloma, including cytogenetic risk and transplantation status subgroup analyses. METHODS: The Myeloma XI trial was an open-label, randomised, phase 3, adaptive design trial with three randomisation stages done at 110 National Health Service hospitals in England, Wales, and Scotland. There were three potential randomisations in the study: induction treatment (allocation by transplantation eligibility status); intensification treatment (allocation by response to induction therapy); and maintenance treatment. Here, we report the results of the randomisation to maintenance treatment. Eligible patients for maintenance randomisation were aged 18 years or older and had symptomatic or non-secretory multiple myeloma, had completed their assigned induction therapy as per protocol and had achieved at least a minimal response to protocol treatment, including lenalidomide. Patients were randomly assigned (1:1 from Jan 13, 2011, to Jun 27, 2013, and 2:1 from Jun 28, 2013, to Aug 11, 2017) to lenalidomide maintenance (10 mg orally on days 1-21 of a 28-day cycle) or observation, and stratified by allocated induction and intensification treatment, and centre. The co-primary endpoints were progression-free survival and overall survival, analysed by intention to treat. Safety analysis was per protocol. This study is registered with the ISRCTN registry, number ISRCTN49407852, and clinicaltrialsregister.eu, number 2009-010956-93, and has completed recruitment. FINDINGS: Between Jan 13, 2011, and Aug 11, 2017, 1917 patients were accrued to the maintenance treatment randomisation of the trial. 1137 patients were assigned to lenalidomide maintenance and 834 patients to observation. After a median follow-up of 31 months (IQR 18-50), median progression-free survival was 39 months (95% CI 36-42) with lenalidomide and 20 months (18-22) with observation (hazard ratio [HR] 0·46 [95% CI 0·41-0·53]; p<0·0001), and 3-year overall survival was 78·6% (95% Cl 75·6-81·6) in the lenalidomide group and 75·8% (72·4-79·2) in the observation group (HR 0·87 [95% CI 0·73-1·05]; p=0·15). Progression-free survival was improved with lenalidomide compared with observation across all prespecified subgroups. On prespecified subgroup analyses by transplantation status, 3-year overall survival in transplantation-eligible patients was 87·5% (95% Cl 84·3-90·7) in the lenalidomide group and 80·2% (76·0-84·4) in the observation group (HR 0·69 [95% CI 0·52-0·93]; p=0·014), and in transplantation-ineligible patients it was 66·8% (61·6-72·1) in the lenalidomide group and 69·8% (64·4-75·2) in the observation group (1·02 [0·80-1·29]; p=0·88). By cytogenetic risk group, in standard-risk patients, 3-year overall survival was 86·4% (95% CI 80·0-90·9) in the lenalidomide group compared with 81·3% (74·2-86·7) in the observation group, and in high-risk patients, it was 74.9% (65·8-81·9) in the lenalidomide group compared with 63·7% (52·8-72·7) in the observation group; and in ultra-high-risk patients it was 62·9% (46·0-75·8) compared with 43·5% (22·2-63·1). Since these subgroup analyses results were not powered they should be interpreted with caution. The most common grade 3 or 4 adverse events for patients taking lenalidomide were haematological, including neutropenia (362 [33%] patients), thrombocytopenia (72 [7%] patients), and anaemia (42 [4%] patients). Serious adverse events were reported in 494 (45%) of 1097 patients receiving lenalidomide compared with 150 (17%) of 874 patients on observation. The most common serious adverse events were infections in both the lenalidomide group and the observation group. 460 deaths occurred during maintenance treatment, 234 (21%) in the lenalidomide group and 226 (27%) in the observation group, and no deaths in the lenalidomide group were deemed treatment related. INTERPRETATION: Maintenance therapy with lenalidomide significantly improved progression-free survival in patients with newly diagnosed multiple myeloma compared with observation, but did not improve overall survival in the intention-to-treat analysis of the whole trial population. The manageable safety profile of this drug and the encouraging results in subgroup analyses of patients across all cytogenetic risk groups support further investigation of maintenance lenalidomide in this setting. FUNDING:Cancer Research UK, Celgene, Amgen, Merck, and Myeloma UK

It is time to define an organizational model for the prevention and management of infections along the surgical pathway : a worldwide cross-sectional survey

Background The objectives of the study were to investigate the organizational characteristics of acute care facilities worldwide in preventing and managing infections in surgery; assess participants' perception regarding infection prevention and control (IPC) measures, antibiotic prescribing practices, and source control; describe awareness about the global burden of antimicrobial resistance (AMR) and IPC measures; and determine the role of the Coronavirus Disease 2019 pandemic on said awareness. Methods A cross-sectional web-based survey was conducted contacting 1432 health care workers (HCWs) belonging to a mailing list provided by the Global Alliance for Infections in Surgery. The self-administered questionnaire was developed by a multidisciplinary team. The survey was open from May 22, 2021, and June 22, 2021. Three reminders were sent, after 7, 14, and 21 days. Results Three hundred four respondents from 72 countries returned a questionnaire, with an overall response rate of 21.2%. Respectively, 90.4% and 68.8% of participants stated their hospital had a multidisciplinary IPC team or a multidisciplinary antimicrobial stewardship team. Local protocols for antimicrobial therapy of surgical infections and protocols for surgical antibiotic prophylaxis were present in 76.6% and 90.8% of hospitals, respectively. In 23.4% and 24.0% of hospitals no surveillance systems for surgical site infections and no monitoring systems of used antimicrobials were implemented. Patient and family involvement in IPC management was considered to be slightly or not important in their hospital by the majority of respondents (65.1%). Awareness of the global burden of AMR among HCWs was considered very important or important by 54.6% of participants. The COVID-19 pandemic was considered by 80.3% of respondents as a very important or important factor in raising HCWs awareness of the IPC programs in their hospital. Based on the survey results, the authors developed 15 statements for several questions regarding the prevention and management of infections in surgery. The statements may be the starting point for designing future evidence-based recommendations. Conclusion Adequacy of prevention and management of infections in acute care facilities depends on HCWs behaviours and on the organizational characteristics of acute health care facilities to support best practices and promote behavioural change. Patient involvement in the implementation of IPC is still little considered. A debate on how operationalising a fundamental change to IPC, from being solely the HCWs responsibility to one that involves a collaborative relationship between HCWs and patients, should be opened.Peer reviewe

It is time to define an organizational model for the prevention and management of infections along the surgical pathway: a worldwide cross-sectional survey

Background The objectives of the study were to investigate the organizational characteristics of acute care facilities worldwide in preventing and managing infections in surgery; assess participants' perception regarding infection prevention and control (IPC) measures, antibiotic prescribing practices, and source control; describe awareness about the global burden of antimicrobial resistance (AMR) and IPC measures; and determine the role of the Coronavirus Disease 2019 pandemic on said awareness. Methods A cross-sectional web-based survey was conducted contacting 1432 health care workers (HCWs) belonging to a mailing list provided by the Global Alliance for Infections in Surgery. The self-administered questionnaire was developed by a multidisciplinary team. The survey was open from May 22, 2021, and June 22, 2021. Three reminders were sent, after 7, 14, and 21 days. Results Three hundred four respondents from 72 countries returned a questionnaire, with an overall response rate of 21.2%. Respectively, 90.4% and 68.8% of participants stated their hospital had a multidisciplinary IPC team or a multidisciplinary antimicrobial stewardship team. Local protocols for antimicrobial therapy of surgical infections and protocols for surgical antibiotic prophylaxis were present in 76.6% and 90.8% of hospitals, respectively. In 23.4% and 24.0% of hospitals no surveillance systems for surgical site infections and no monitoring systems of used antimicrobials were implemented. Patient and family involvement in IPC management was considered to be slightly or not important in their hospital by the majority of respondents (65.1%). Awareness of the global burden of AMR among HCWs was considered very important or important by 54.6% of participants. The COVID-19 pandemic was considered by 80.3% of respondents as a very important or important factor in raising HCWs awareness of the IPC programs in their hospital. Based on the survey results, the authors developed 15 statements for several questions regarding the prevention and management of infections in surgery. The statements may be the starting point for designing future evidence-based recommendations. Conclusion Adequacy of prevention and management of infections in acute care facilities depends on HCWs behaviours and on the organizational characteristics of acute health care facilities to support best practices and promote behavioural change. Patient involvement in the implementation of IPC is still little considered. A debate on how operationalising a fundamental change to IPC, from being solely the HCWs responsibility to one that involves a collaborative relationship between HCWs and patients, should be opened

Prevention and management of adverse events of novel agents in multiple myeloma: a consensus of the European Myeloma Network

During the last few years, several new drugs have been introduced for treatment of patients with multiple myeloma, which have significantly improved the treatment outcome. All of these novel substances differ at least in part in their mode of action from similar drugs of the same drug class, or are representatives of new drug classes, and as such present with very specific side effect profiles. In this review, we summarize these adverse events, provide information on their prevention, and give practical guidance for monitoring of patients and for management of adverse events