BACKGROUND: Secondary bacterial infections of the respiratory system are one of the biggest medical concerns in patients undergoing hospitalization with a diagnosis of COVID-19. Opportunistic upper respiratory tract bacterial colonization or carriage typically precedes the majority of lower respiratory tract infections and pneumonia. Few studies have examined the relationship between the SARS-CoV-2 virus and bacterial colonization in COVID-19 patients. AIM: This study looked into the link between COVID-19 patients who have SARS-CoV-2 illness and respiratory system bacterial colonization and how this colonization could impact on COVID-19 clinical presentation. METHODS: This research thus examines this relationship by conducting an analytical, cross-sectional study with 210 COVID-19 patients. The patients are categorized into mild and moderate-to-severe cases, which will be compared with 50 non-COVID-19 controls. All participants provided sputum samples that were subjected to microbiological culture analysis. To identify specific microbes, a VITEK Compact automatic microbiology analyzer was employed. RESULT: The findings of the research highlighted that, as the severity of COVID-19 infection increased, significant changes in bacterial colonization patterns emerged. A normal oral flora was found to be present in the control group, while a notable increase in pathogenic bacteria was evident in those with moderate-severe COVID-19. Furthermore, severe cases presented with Gram-positive bacteria, particularly Staphylococcus aureus. Additionally, Gram-negative bacteria (i.e., Klebsiella pneumoniae, Pseudomonas aeruginosa, and Haemophilus influenzae) were commonly identified in moderate-severe cases, indicating more extensive bacterial colonization. CONCLUSION: The need to develop more comprehensive approaches to diagnosing COVID-19 and creating targeted treatment plans is highlighted through the increasing presence of Gram-negative bacteria and polymicrobial colonization in COVID-19 cases at admission. Thus, this research highlights the importance of monitoring bacterial colonization in the upper respiratory tracts of individuals diagnosed with COVID-19. CLINICAL TRIAL NUMBER: Not applicable

Introduction: In the phase 3 DREAMM-7 trial (NCT04246047), belantamab mafodotin (belamaf) plus bortezomib and dexamethasone (BVd) demonstrated significant progression-free survival (PFS) and overall survival (OS) benefits vs daratumumab plus bortezomib and dexamethasone (DVd) in patients with relapsed/refractory multiple myeloma (RRMM) who had received ≥1 prior line of therapy (LOT). Minimal residual disease (MRD) negativity has been shown to be a predictor of PFS and OS in multiple myeloma. The first interim analysis of the DREAMM-7 trial (data cutoff: October 2, 2023) showed that patients in the BVd arm had a significantly higher rate of complete response (CR)–based MRD negativity vs those in the DVd arm. MRD was declared statistically significant at the second interim analysis (data cutoff: October 7, 2024) due to the prespecified testing hierarchy. The purpose of the current analysis was to evaluate the number of patients who achieved sustained MRD negativity for ≥12 months in the DREAMM-7 trial and to describe their demographics and baseline disease characteristics. Methods: As previously reported, patients treated with ≥1 prior LOT were randomized (1:1) to BVd or DVd in DREAMM-7. The primary endpoint was independent review committee–assessed PFS. OS and MRD negativity at achievement of ≥ CR were key secondary endpoints. Patients achieving ≥ CR were tested for MRD negativity by next-generation sequencing with 10−5 sensitivity and 10−6 sensitivity (exploratory analysis). Results: At data cutoff (October 7, 2024), CR–based MRD negativity rates in pts with ≥ CR were 70% (61/87) vs 59% (26/44) in the BVd vs DVd arms, respectively, at the 10−5 sensitivity threshold; rates in the intention-to-treat (ITT) population were 25% (95% CI, 19.8%-31.0%) vs 10% (95% CI, 6.9%-14.8%). At the 10−6 sensitivity threshold, rates in patients with ≥ CR were 45% (39/87) vs 23% (10/44) in the BVd vs DVd arms, respectively; rates in the ITT population were 16% (95% CI, 11.7%-21.3%) vs 4% (95% CI, 1.9%-7.2%). Median time to first CR–based MRD negativity was 11.14 months in the BVd arm vs 17.02 months in the DVd arm. Sustained ≥ CR MRD negativity was observed for ≥12 months in 57% (35/61) of patients who reached MRD negative status in the BVd arm vs 42% (11/26) of patients in the DVd arm. In patients who had sustained MRD negativity for ≥12 months, age was balanced between treatment arms. All patients had Revised International Staging System stages of I or II at screening. The DVd arm had a greater proportion of patients with 1 prior LOT (91%) vs the BVd arm (63%); the remaining patients in both arms received ≥2 prior LOTs. The proportion of patients with high-risk cytogenetics was greater in the BVd arm (40%) vs the DVd arm (27%). Conclusions: BVd demonstrated greater overall MRD negativity rates at 10−5 and 10−6 thresholds compared with DVd. In addition, for those patients achieving MRD negativity, more patients had sustained MRD-negative status for ≥12 months in BVd arm compared with DVd arm, further demonstrating the link between achieving deep and durable treatment responses. Funding: GSK (study ID, 207503). Drug-linker technology licensed from Seagen Inc; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa.

ABSTRACT:Belantamab mafodotin (belamaf) combined with standard therapies demonstrated significant progression-free survival (PFS) and overall survival benefits in DREAMM-7 and PFS benefit in DREAMM-8 in relapsed/refractory multiple myeloma. Belamaf dose modifications managed adverse events, including belamaf-related ocular events. Ocular events included ocular adverse reactions (eg, dry eyes, photophobia, eye irritation) and protocol-mandated ophthalmic examination findings. Protocol-recommended dose modifications for ocular events were driven by ophthalmic examination findings and included belamaf dose delays until resolution and reductions. We used descriptive analyses to evaluate the impact of dose modifications on managing ocular events and treatment efficacy. In patients with normal baseline vision who were receiving treatment, dose modifications extended belamaf dosing intervals to a median of 8 to 12 weeks by 9 months; the prevalences of reduced vision to bilateral 20/50 or worse and ocular adverse reactions were highest in the first 3 months and remained low at later time points. The median time to resolution after grade ≥2 ophthalmic examination findings was 12 weeks. Rates of belamaf discontinuations due to ocular events were low. Almost all responders (partial response or better) required dose modifications. Most patients achieved a response before an extended (>2 cycles) dose delay; most who had not, subsequently achieved or deepened their response. In DREAMM-7 and DREAMM-8, the median PFS in patients with ≥1 dose delay of ≥12 weeks was 36.6 months and not reached, respectively. Ocular events were common but effectively managed with dose modifications, allowing for patients to remain on treatment and derive robust efficacy benefit. The trials were registered at www.clinicaltrials.gov as #NCT04246047 (DREAMM-7) and #NCT04484623 (DREAMM-8).

Background: There is a significant need for effective and well-tolerated therapies for patients (pts) with functional high-risk (FHR) MM. In DREAMM-7 (D7; NCT04246047), belamaf, bortezomib, and dexamethasone (BVd) demonstrated significant PFS and OS benefit vs daratumumab-Vd (DVd) in pts with RRMM with ≥1 prior line of therapy (LOT). In DREAMM-8 (D8; NCT04484623), belamaf, pomalidomide, and dexamethasone (BPd) demonstrated a significant PFS benefit vs PVd in pts with RRMM who received ≥1 prior LOT, including lenalidomide. Here, we present a subgroup analysis in pts with FHR MM treated with 1 prior LOT. Methods: Pts treated with ≥1 prior LOT were randomized (1:1) to BVd or DVd in D7 and BPd or PVd in D8. The primary endpoint of both trials was independent review committee–assessed PFS. Key secondary endpoints for both trials were OS, MRD, and DOR. In the D7 and D8 trials, FHR was defined as RRMM that progressed ≤18 mo after the start of ASCT or start of first-line therapy. Descriptive statistics were used for response rates, MRD negativity (10−5) rates, and adverse events (AEs). Hazard ratios (HRs) for PFS, OS, and DOR were estimated with the Cox model. The Kaplan-Meier method estimated median survival times. Results: Baseline disease characteristics were generally balanced between treatment arms in pts with 1 prior LOT, regardless of FHR status. In D7, 125 pts per arm who received 1 prior LOT were treated with BVd or DVd, with 43 pts in each arm having FHR MM. In D8, 82 and 77 pts who received 1 prior LOT were treated with BPd and PVd, respectively, with 28 (BPd) and 31 pts (PVd) having FHR MM. In D7, median follow-up was 28.2 mo for pts who received 1 prior LOT and 39.4 mo for pts with FHR MM. In D8, median follow-up was 21.8 mo for all pts. In D7, median PFS was longer in the BVd vs DVd arm, both in pts with 1 prior LOT (36.6 mo vs 19.1 mo; HR, 0.52; 95% CI, 0.36-0.76), and in those with FHR MM (28.4 mo vs 13.4 mo; HR, 0.65; 95% CI, 0.37-1.14). Similarly, in D8, median PFS favored the BPd vs PVd arm, both in pts with 1 prior LOT (not reached [NR] vs 18.5 mo; HR, 0.50; 95% CI, 0.30-0.85) and in those with FHR MM (NR vs 14.8 mo; HR, 0.66; 95% CI, 0.28-1.54). In pts treated with 1 prior LOT in D7, ORR was similar between BVd and DVd arms (83% vs 82%), with greater depth of response in the BVd arm (≥ CR: 39% vs 24%). In pts treated with 1 prior LOT in D7, ≥ CR MRD negativity rates were 28% (35/125) with BVd vs 14% (18/125) with DVd. In D7 pts with FHR MM, both ORR (86% vs 74%) and depth of response (≥ CR: 33% vs 21%) were higher with BVd vs DVd, respectively. In D7 pts with FHR MM, ≥ CR MRD negativity rates were 21% (9/43) with BVd vs 9% (4/43) with DVd. In pts treated with 1 prior LOT in D8, ORR was higher with PVd (88%) vs BPd (79%); however, response was deeper with BPd (≥ CR: 46% vs 23%). In pts treated with 1 prior LOT in D8, ≥ CR MRD negativity rates were 33% (27/82) with BPd vs 5% (4/77) with PVd. In D8 pts with FHR MM, ORR was comparable between pts in the BPd and PVd arms (82% vs 87%, respectively), with greater depth of response seen with BPd (≥ CR: 50% vs 23%). In pts with FHR MM in D8, ≥ CR MRD negativity rates were higher with BPd (36% [10/28]) than with PVd (7% [2/31]). In both the D7 and D8 trials, mOS was NR in pts with 1 prior LOT, regardless of FHR status. Among D7 pts with FHR MM, 70% in the BVd arm and 58% in the DVd arm were alive. Among pts with FHR MM in D8, 79% in the BPd arm vs 77% in the PVd arm were alive. In D7 pts treated with 1 prior LOT and FHR MM, grade 3/4 treatment-related AEs (TRAEs) related to any study treatment occurred in 91% with BVd and 60% with DVd. In D8 pts treated with 1 prior LOT and FHR MM, grade 3/4 TRAEs related to any study treatment occurred in 78% with BPd and 71% with PVd. Conclusions: In both D7 and D8, BVd and BPd were associated with extended PFS vs standard-of-care (SOC) regimens DVd and PVd, respectively, in patients with FHR MM. Deeper responses with higher rates of ≥ CR MRD negativity were also observed vs SOC regimens in both studies. mOS was NR in both trials at the time of this analysis.Funding:GSK (study numbers: 207503; 207499). Drug linker technology licensed from Seagen Inc; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa

The respiratory tract possesses a highly regulated innate defense system that includes cilia-mediated mucociliary clearance (MCC). Efficient MCC relies on appropriate hydration of airway surfaces, which is controlled by a blend of transepithelial sodium and liquid absorption, as well as anion and liquid secretion. The latter is mediated primarily by the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel. Succinate is derived from parasites, microorganisms, and inflammatory cells, and its concentration increases in the airway surface liquid during infections, activating the G protein-coupled succinate receptor (SUCNR1), which acts as a succinate sensor. Because MCC is tightly regulated by second messengers, we tested the hypothesis that succinate signaling was linked to CFTR activity. We observed that SUCNR1 activation stimulated anion secretion, increased mucus transport, and induced tracheal constriction in mouse airways. In the CftrΔF508/ΔF508 mouse, increased mucus transport and tracheal constriction were not observed, whereas succinate-induced electrogenic anion secretion remained unaffected. Stimulation of normal human bronchial epithelial cells with succinate activated CFTR-dependent anion secretion and increased airway surface liquid height. Moreover, human bronchial epithelial cells derived from ΔF508-CF individuals that lacked succinate-induced anion secretion, unless incubated with elexacaftor-tezacaftor-ivacaftor, which restored succinate-induced anion secretion, confirmed the tight relationship between SUCNR1 signaling and CFTR function. We have identified a novel mechanism for regulating CFTR/MCC activation that is defective in cystic fibrosis airways. We propose that succinate acts as a danger molecule that alerts the airways to the presence of pathogens leading to a flushing out of the airways.

SARS-CoV-2 is the viral pathogen responsible for COVID-19. Although morbidity and mortality frequently occur as a result of lung disease, the gastrointestinal (GI) tract is recognized as a primary location for SARS-CoV-2. Connections and interactions between the microbiome of the gut and respiratory system have been linked with viral infections via what has been referred to as the ‘gut-lung axis’ with potential aerodigestive communication in health and disease. This research explored the relationship between the microbiomes of the upper respiratory and GI tracts in patients with COVID-19 and examined Extraesophageal reflux (EOR), a mechanism which could contribute to dysregulated communication between the GI and respiratory tract (as identified in COVID-19). 97 patients with a laboratory diagnosis of COVID-19 infection, and 50 age-matched controls were recruited and stool, saliva and sputum were obtained from each participant. ELISA Pepsin tests and Reflux Symptom Index scores (RSI) were conducted for EOR assessment. DNA sequencing of the V4 region of the 16 S rRNA gene was performed for microbiome analysis. No differences were observed between the fecal microbiome’s alpha and Shannon diversity indices; however, a distinct microbial composition was observed in COVID-19 patients (when compared to the controls). The respiratory microbiota from individuals with COVID-19 demonstrated a statistically significant reduction in Shannon diversity and bacterial richness alongside an overall reduction in the prevalence of organisms from a typical healthy respiratory microbiome. Furthermore, the bacterial richness of the stool and sputum samples was significantly lower among COVID-19 patients admitted to ICU. A significantly higher RSI score and salivary pepsin level were detected among those with COVID-19. The data indicates that COVID-19 is associated with a dysregulation of both the gut and lung microbiome with a more marked perturbation in the lung, particularly among COVID-19 patients who had been admitted to the ICU. The presence of increased RSI scores, combined with elevated levels of Pepsin, suggests that increased micro-aspiration may occur, which is consistent with of under-recognized interactions between the GI and lung microbiomes in COVID-19 patients and requires additional study. Such studies would benefit from the insights provided by biological samples which reflect the continuum of the aerodigestive tract.

BACKGROUND:Belantamab mafodotin, bortezomib, and dexamethasone showed significant progression-free survival benefit compared with daratumumab, bortezomib, and dexamethasone in relapsed or refractory multiple myeloma in the phase 3 DREAMM-7 study. We aimed to evaluate the effect of belantamab mafodotin, bortezomib, and dexamethasone compared with daratumumab, bortezomib, and dexamethasone on health-related quality of life (HRQOL) using various patient-reported outcomes in patients who participated in DREAMM-7. METHODS:This phase 3, open-label, randomised controlled trial, done at 142 hospitals in 20 countries included adult patients aged 18 years or older with relapsed or refractory multiple myeloma who received at least one previous line of therapy and progressed during or after their most recent treatment and had an Eastern Cooperative Oncology Group performance status of 0 to 2. Eligible patients were randomly assigned (1:1) by a central interactive response technology system to receive intravenous belantamab mafodotin (2·5 mg/kg once on day 1 of each 21-day cycle) or intravenous daratumumab (16 mg/kg once a week in cycles 1-3, every 3 weeks in cycles 4-8, and every 4 weeks in cycle 9 and beyond). Patients in both treatment groups also received subcutaneous bortezomib (1·3 mg/m2 on days 1, 4, 8, and 11 of 21-day cycles) and oral or intravenous dexamethasone (20 mg on the day of and day after bortezomib administration) for the first 8 cycles. Treatment continued until progressive disease, unacceptable toxic effects, withdrawal of consent, or death (whichever occurred first). Patient-reported outcomes were secondary and exploratory objectives. Secondary patient-reported outcome endpoints were change from baseline in HRQOL, as measured by the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and EORTC QLQ-MY20, and maximum postbaseline score for each item attribute on the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). Exploratory patient-reported outcome endpoints included changes from baseline in symptoms and related effects as measured by Ocular Surface Disease Index (OSDI), change from baseline in FACT-GP5 score, and change from baseline in the EQ-5D VAS. EORTC QLQ-C30, EORTC QLQ-MY20, and FACT-GP5 scores were analysed in the intention-to-treat population, and PRO-CTCAE and OSDI vision-related functioning scores were analysed in the safety population (patients who received at least one dose of treatment). Results were summarised using descriptive statistics. Least-squares mean changes from baseline were estimated using a restricted maximum likelihood-based mixed model. This study was registered with ClinicalTrials.gov, NCT04246047, and is ongoing. FINDINGS:Between May 7, 2020, and June 28, 2021, 494 patients were included in the intention-to-treat population of the DREAMM-7 study (median follow-up 28·2 months, IQR 14·6-31·4) and were randomly assigned to either belantamab mafodotin, bortezomib, and dexamethasone (n=243) or daratumumab, bortezomib, and dexamethasone (n=251). 222 (45%) of 494 patients were female and 272 (55%) were male. The mean age in the total study population was 64·0 years (SD 9·80). Most patients were White (409 [83%] of 494), Asian (61 [12%]), or Black or African American (20 [4%]). Patients in both groups had stable mean EORTC QLQ-C30 and QLQ-MY20 scores over time. At each timepoint, most patients reported stable or improved scores in the global health status/quality of life (64 [56%] of 115 patients to 85 [75%] of 114 patients in the belantamab mafodotin group and 105 [51%] of 207 patients to 156 [65%] of 240 patients in the daratumumab group), role functioning (103 [53%] of 196 patients to 77 [68%] of 114 patients in the belantamab mafodotin group and 99 [50%] of 197 patients to 92 [69%] of 134 patients in the daratumumab group), and physical functioning domains (132 [66%] of 201 patients to 101 [77%] of 131 patients in the belantamab mafodotin group and 115 [58%] of 197 patients to 102 [76%] of 134 patients in the daratumumab group) of the EORTC QLQ-C30 and of the disease symptom domain scores of the EORTC QLQ-MY20 (79 [72%] of 109 patients to 95 [83%] of 115 patients in the belantamab mafodotin group and 126 [66%] of 190 patients to 164 [74%] of 221 patients in the daratumumab group). Most patients in the belantamab mafodotin group (155 [77%] of 202 to 79 [96%] of 82) and the daratumumab group (155 [86%] of 181 to 60 [100%] of 60) reported being "not at all," "a little," or "somewhat" bothered by treatment side-effects at each visit, as determined by the FACT-GP5. INTERPRETATION:HRQOL was generally maintained or improved over time with belantamab mafodotin, bortezomib, and dexamethasone treatment. Our findings, in conjunction with previously reported clinical benefits, support the use of belantamab mafodotin as a potential new standard of care in relapsed or refractory multiple myeloma. FUNDING:GSK. TRANSLATIONS:For the Polish and Spanish translations of the abstract see Supplementary Materials section.

7546 Background: In DREAMM-7 (NCT04246047), BVd exhibited a significant improvement in the risk of progression or death vs DVd in pts with RRMM who had ≥1 prior line of treatment. In a post hoc analysis (Mateos et al; ASCO 2024) of pts with ≥1 HRC abnormality (HRCA), including t(4;14), t(14;16), and 17p13del, more pts had deep responses (defined as complete response [CR] or better) with BVd (45%; 95% CI, 32.6%-57.4%) than with DVd (13%; 95% CI, 6.1%-23.3%). Up to 70% of pts at early relapse have amp1q, which confers an increased risk of disease progression. Here we present an updated post hoc efficacy analysis in pts with HRCA, including amp1q. Methods: Pts were randomized 1:1 to BVd or DVd as previously reported. For this analysis, pts with HRC were defined as those having ≥1 HRCA, including t(4;14), t(14;16), t(14;20), 17p13del, and amp1q (defined as ≥4 copies of chromosome 1q21). Descriptive statistics were used to summarize results, with 95% exact CI. Hazard ratios (HRs) for progression-free survival (PFS) were estimated using the Cox model, with 95% CI based on the Brookmeyer-Crowley method. Results: The ITT population included 494 pts: BVd, n=243; DVd, n=251. In the BVd arm, 122/243 pts (50%) had HRC, of which 41 (17%) had t(4;14), 8 (3%) had t(14;16), 1 (0.4%) had t(14;20), 30 (12%) had 17p13del, and 94 (39%) had amp1q. In the DVd arm, 115/251 (46%) had HRC, of which 42 (17%) had t(4;14), 6 (2%) had t(14;16), 1 (0.4%) had t(14;20), 35 (14%) had 17p13del, and 79 (31%) had amp1q. Median PFS in pts with ≥1 HRCA was 33.2 mo (95% CI, 20.1 mo-not reached) with BVd vs 11.1 mo (95% CI, 9.0-15.1 mo) with DVd (HR, 0.40; 95% CI, 0.27-0.59), and 18-mo PFS rates were 61% and 38%, respectively. PFS benefit favored BVd across subgroups (HR [95% CI]): t(4;14), 0.36 [0.19-0.67]; 17p13del, 0.25 [0.11-0.61]; amp1q, 0.48 [0.31-0.73]; t (14;16) and t(14;20) were not analyzed due to low numbers. In pts with ≥1 HRCA, overall response rate was 81% (n=99; 95% CI, 73.1%-87.7%) with BVd and 69% (n=79; 95% CI, 59.4%-77.0%) with DVd; more pts achieved ≥CR with BVd than with DVd (Table). The benefit was maintained across subgroups. Conclusions: In pts with RRMM and ≥1 HRCA, PFS benefit favored BVd vs DVd, and BVd demonstrated a higher rate of deep response. Current outcomes in pts with HRC features are suboptimal, and these data support BVd as a potential standard-of-care regimen in these pts with high unmet need. Clinical trial information: NCT04246047 . Patients achieving ≥CR in HRC Groups n/N (%); 95% CI BVd DVd t (4;14) 20/41 (49); 32.9-64.9 6/42 (14); 5.4-28.5 t (14;16) 1/8 (13); 0.3-52.7 0/6; 0-45.9 17p13del 11/30 (37); 19.9-56.1 4/35 (11); 3.2-26.7 amp1q 31/94 (33); 23.6-43.4 16/79 (20); 12.0-30.8 ≥1 HRCA 48/122 (39); 30.6-48.6 20/115 (17); 11.0-25.6

Background: In DREAMM-7 (NCT04246047), belantamab mafodotin (belamaf) plus bortezomib and dexamethasone (BVd) demonstrated a statistically significant and clinically meaningful progression-free survival (PFS) benefit vs the standard-of-care triplet daratumumab, bortezomib, and dexamethasone (DVd) in patients with relapsed or refractory multiple myeloma who had received ≥1 prior line of treatment. MRD negativity has been shown to be a predictor of PFS and overall survival (OS) in multiple myeloma. Here, we aimed to understand if MRD negativity translated to improvements in PFS and OS in the DREAMM-7 trial. Methods: In DREAMM-7,patients with ≥1 prior line of treatment were randomized (1:1) to BVd or DVd. The primary endpoint was independent review committee (IRC)-assessed PFS. OS and aMRD negative status by next-generation sequencing with 10-5 sensitivity; follow-up testing was performed every 6 months thereafter until progressive disease. An exploratory MRD analysis was also performed in patients who achieved a very good partial response or better (≥VGPR). Post hoc subgroup analyses of PFS (IRC assessed) and OS were performed based on IRC-assessed response (≥CR or ≥ VGPR) and MRD- negative status and evaluated using the Kaplan-Meier method; CIs were estimated using the Brookmeyer-Crowley method. Results: In total, 494 patients (BVd, n=243; DVd, n=251) were randomized in the intention-to-treat population. As previously reported, at the first interim analysis (data cutoff: October 2, 2023; median follow-up, 28.2 months), a higher proportion of patients in the BVd arm had CR-based MRD-negative status vs the DVd arm (60 of 243 [25%] vs 24 of 251 [10%] patients). A higher proportion of patients achieved sustained MRD negativity for ≥12 months (≥CR) with BVd (10%) vs DVd (2%) by the data cutoff. Rates of CR-based MRD negativity favored BVd vs DVd in prespecified subgroups of patients with disease refractory to lenalidomide (25% vs 6%) and patients with ≥1 high-risk cytogenetic abnormality (31% vs 7%); this is consistent with findings from the intention-to-treat analysis. A similar trend was observed in an exploratory analysis of patients with ≥VGPR, with 94 of 243 (39%) patients achieving VGPR-based MRD negativity in the BVd arm vs 43 of 251 (17%) patients in the DVd arm. Inability to achieve MRD-negative status was associated with lower PFS and OS outcomes compared with the intention-to-treat population. Among patients who did not achieve CR-based MRD negativity, median PFS was 15.3 months (95% CI, 12.7-18.0 months; BVd, 25.0 months; DVd, 11.8 months), with an 18-month PFS rate of 45% (95% CI, 40%-50%; BVd, 57%; DVd, 36%); median OS was not reached at the data cutoff, and the 18-month OS rate was 74% (95% CI, 69%-78%; BVd, 79%; DVd, 70%). In patients who achieved CR-based MRD-negative status, median PFS and OS were not reached; by the data cutoff, 13% (BVd, 10%; DVd, 21%) of patients had PFS events, and 5% (BVd, 5%; DVd, 4%) had OS events. Conclusions: In the DREAMM-7 trial, patients in the BVd arm achieved MRD-negative status at more than double the rate observed in the DVd arm, and more patients achieved sustained MRD-negative status for ≥12 months with BVd. MRD negativity was associated with durable PFS and OS benefits, which is consistent with previous reports; this highlights the importance of the greater response depth that is achieved with BVd. Funding statement: GSK (Study # 207503) Drug linker technology licensed from Seagen Inc.; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa.

Introduction Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrotic lung disease frequently complicated by gastro-oesophageal reflux disease. Although several observational studies and a pilot study have investigated the role of proton pump inhibitors (PPIs) in IPF, their efficacy is unknown and there is much debate in international IPF guidelines on their use. We aim to undertake an adequately powered double-blind placebo-controlled randomised multicentre clinical trial to assess the change in forced vital capacity (FVC), cough and other important patient-reported outcomes, following 12-month therapy with PPIs in people with IPF.Methods and analysis A total of 298 patients with IPF diagnosed by a multidisciplinary team according to international guidelines who are not receiving PPIs will be enrolled. Patients are randomised equally to receive two capsules of lansoprazole or two placebo capsules, two times per day for 12 months. The primary outcome for the trial is change in FVC, measured at home, between the first week and last week of the study period. Secondary assessments include cough frequency (in a subgroup) measured using the VitaloJAK cough monitor, the King’s Brief Interstitial Lung Disease questionnaire, the Raghu Scale for Pulmonary Fibrosis, Medical Research Council dyspnoea score, EQ-5D-5L, Leicester Cough Questionnaire, modified DeMeester reflux symptoms questionnaire and opportunistically captured routine lung function measurements. High-resolution CT scoring will be undertaken in a subgroup. The trial is designed to determine whether treating people with IPF with lansoprazole will reduce the reduction in FVC over a year. The COVID-19 pandemic required the study to be undertaken as a remote trial.Ethics and dissemination This study received ethical approval from the East of England Cambridgeshire and Hertfordshire Research Ethics Committee (reference 20/EE/0043; integrated research application system number 269050). Trial results will be published in a peer-reviewed journal upon completion.Trial registration number ISRCTN13526307; ClinicalTrials.gov NCT04965298.

BACKGROUND:In the primary (first interim) analysis of the DREAMM-7 trial (median follow-up 28·2 months), belantamab mafodotin, bortezomib, and dexamethasone (BVd) showed a statistically significant and clinically meaningful progression-free survival benefit versus daratumumab, bortezomib, and dexamethasone (DVd) in patients with relapsed or refractory multiple myeloma (RRMM) after at least one line of therapy. The aim of this study is to report overall survival from the second interim analysis, with extended follow-up. METHODS:In the ongoing global, open-label, randomised, phase 3 DREAMM-7 trial done at 142 study centres (research facilities, hospitals, and institutions) in 20 countries across North America, South America, Europe, and the Asia-Pacific region, eligible patients were aged at least 18 years and had confirmed multiple myeloma (according to International Myeloma Working Group criteria), an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and progression on or after at least one previous line of therapy. Patients were randomly assigned (1:1) by use of a central interactive response technology system to receive BVd, which comprised belantamab mafodotin 2·5 mg/kg intravenously every 3 weeks plus bortezomib 1·3 mg/m2 subcutaneously (twice weekly in 21-day cycles, for up to eight cycles) plus dexamethasone 20 mg orally or intravenously (on the day of, and after, bortezomib; for up to eight cycles), or DVd, which comprised daratumumab 16 mg/kg intravenously (21-day cycles; once weekly in cycles 1-3, every 3 weeks in cycles 4-8, and every 4 weeks in cycle 9 and beyond) plus bortezomib and dexamethasone; bortezomib and dexamethasone doses and schedules were the same as those in the BVd group. Randomisation was stratified by number of previous lines of therapy, previous bortezomib, and Revised International Staging System stage. Treatment assignments were unmasked for study personnel and patients; however, they were masked to the independent review committee. Patients received treatment until progressive disease, death, unacceptable toxicity, withdrawal of consent, or loss to follow-up, whichever occurred first. The primary endpoint was progression-free survival; key secondary endpoints were overall survival, minimal residual disease negativity in patients with a complete response or better, duration of response to treatment, and safety. Analysis of efficacy endpoints was based on assessments in all patients who were randomly assigned (ie, the intention-to-treat population). The safety population included all randomly assigned patients who received one or more doses of study treatment. This trial is registered with ClinicalTrials.gov, NCT04246047, and is ongoing. FINDINGS:From May 7, 2020, to June 28, 2021, of 623 patients assessed for eligibility, 494 were randomly assigned to receive BVd (n=243) or DVd (n=251); 272 (55%) were male, and 409 (83%) were White. The median age of the patients was 64·5 years (IQR 57·0-71·0). At the updated data cutoff (Oct 7, 2024) and median follow-up (39·4 months [IQR 14·6-42·9]), early, sustained, and significant overall survival benefit was observed with BVd versus DVd. Median overall survival was not reached (NR; 95% CI NR-NR) with BVd and NR (41·0 months-NR) with DVd (hazard ratio [HR] 0·58; 95% CI 0·43-0·79; p=0·0002). BVd versus DVd led to greater than double the minimal residual disease-negativity rates in patients with a complete response or better (25% [95% CI 19·8%-31·0%] vs 10% [6·9%-14·8%]) and median duration of response (40·8 months [95% CI 30·5 months-NR] vs 17·8 months [13·8-23·6]). Analysis of progression-free survival 2 showed that the treatment benefit favouring BVd versus DVd was maintained following subsequent antimyeloma therapy; median progression-free survival 2 was NR with BVd (95% CI 45·6-NR) versus 33·4 months (95% CI 26·7-44·9) with DVd (HR, 0·59; 95% CI, 0·45-0·77). The most common grade 3 or 4 adverse event was thrombocytopenia (135 [56%] of 242 with BVd vs 87 [35%] of 246 with DVd). Serious adverse events occurred in 129 (53%) of 242 patients receiving BVd and 94 (38%) of 246 patients receiving DVd; the most common events were pneumonia (29 [12%] vs 11 [4%]), pyrexia (12 [5%] vs 10 [4%]), and COVID-19 (11 [5%] vs 10 [4%]). Treatment-related serious adverse events that led to death occurred in seven (3%) of 242 patients receiving BVd (pneumonia [n=4], gastrointestinal haemorrhage [n=1], subdural haemorrhage [n=1], or mesenteric vessel thrombosis [n=1]) and two (1%) of 246 receiving DVd (COVID-19 [n=2]). INTERPRETATION:DREAMM-7 showed significant and clinically meaningful overall survival, progression-free survival, minimal residual disease negativity, and duration of response benefits with BVd versus DVd. BVd could be a new standard of care for RRMM. FUNDING:GSK.