PURPOSE Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly and selectively releases alkylating agents into tumor cells. The phase II HORIZON trial evaluated the efficacy of melflufen plus dexamethasone in relapsed and refractory multiple myeloma (RRMM), a population with an important unmet medical need. PATIENTS AND METHODS Patients with RRMM refractory to pomalidomide and/or an anti-CD38 monoclonal antibody received melflufen 40 mg intravenously on day 1 of each 28-day cycle plus once weekly oral dexamethasone at a dose of 40 mg (20 mg in patients older than 75 years). The primary end point was overall response rate (partial response or better) assessed by the investigator and confirmed by independent review. Secondary end points included duration of response, progression-free survival, overall survival, and safety. The primary analysis is complete with long-term follow-up ongoing. RESULTS Of 157 patients (median age 65 years; median five prior lines of therapy) enrolled and treated, 119 patients (76%) had triple-class–refractory disease, 55 (35%) had extramedullary disease, and 92 (59%) were refractory to previous alkylator therapy. The overall response rate was 29% in the all-treated population, with 26% in the triple-class–refractory population. In the all-treated population, median duration of response was 5.5 months, median progression-free survival was 4.2 months, and median overall survival was 11.6 months at a median follow-up of 14 months. Grade ≥ 3 treatment-emergent adverse events occurred in 96% of patients, most commonly neutropenia (79%), thrombocytopenia (76%), and anemia (43%). Pneumonia (10%) was the most common grade 3/4 nonhematologic event. Thrombocytopenia and bleeding (both grade 3/4 but fully reversible) occurred concomitantly in four patients. GI events, reported in 97 patients (62%), were predominantly grade 1/2 (93%); none were grade 4. CONCLUSION Melflufen plus dexamethasone showed clinically meaningful efficacy and a manageable safety profile in patients with heavily pretreated RRMM, including those with triple-class–refractory and extramedullary disease.

Background Transmission of covid-19 can occur through inhalation of fine droplets or aerosols containing infectious virus. The objective of this study was to identify situations, patient characteristics, environmental parameters and aerosol-generating procedures (AGPs) associated with airborne SARS-CoV-2 virus. Methods Air samples were collected near hospitalised covid-19 patients and analysed by RT-qPCR. Results were related to distance to the patient, most recent patient diagnostic PCR Ct-value, room ventilation and ongoing potential AGP. Results In total 310 air samples were collected, and of these 26 (8%) were positive. Of the 231 samples from patient rooms, 22 (10%) were positive for SARS-CoV-2. Positive air samples were associated with a low patient Ct-value (OR 5.0 for a Ct-value <25 vs >25, p=0.01, 95% confidence interval 1.18 to 29.5) and a shorter physical distance to the patient (OR 2.0 for every meter closer to the patient, p=0.05, CI 1.0 to 3.8). A mobile HEPA-filtration unit in the room decreased the proportion of positive samples (OR 0.3, p=0.02, CI 0.12 to 0.98). No association was observed between SARS-CoV-2 positive air samples and mechanical ventilation, high flow nasal cannula, nebulizer treatment or non-invasive ventilation. An association was found with positive expiratory pressure (PEP) training (p<0.01) and a trend towards association for airway manipulation, including bronchoscopies and in- and extubations. Conclusions Our results show that major risk factors for airborne SARS-CoV-2 include short physical distance, high patient viral load and poor room ventilation. AGPs, as traditionally defined, seem to be of secondary importance.

Background Covid-19 transmission via exhaled aerosol particles has been considered an important route for the spread of infection, especially during super-spreading events involving loud talking or singing. However, no study has previously linked measurements of viral aerosol emissions to transmission rates. Methods During Feb-Mar 2021, covid-19 cases that were close to symptom onset were visited with a mobile laboratory for collection of exhaled aerosol particles during breathing, talking and singing, respectively, and of nasopharyngeal and saliva samples. Aerosol samples were collected using a BioSpot-VIVAS and a NIOSH bc-251 two-stage cyclone, and all samples were analyzed by RT-qPCR for SARS-CoV-2 RNA detection. We compared transmission rates between households with aerosol-positive and aerosol-negative index cases. Results SARS-CoV-2 RNA was detected in at least one aerosol sample from 19 of 38 (50%) included cases. The odds ratio of finding positive aerosol samples decreased with each day from symptom onset (OR 0.55, 95CI 0.30-1.0, p=0.049). The highest number of positive aerosol samples were from singing, 16 (42%), followed by talking, 11 (30%), and the least from breathing, 3 (8%). Index cases were identified for 13 households with 31 exposed contacts. Higher transmission rates were observed in households with aerosol-positive index cases, 10/16 infected (63%), compared to households with aerosol-negative index cases, 4/15 infected (27%) (Chi-square test, p=0.045). Conclusions Covid-19 cases were more likely to exhale SARS-CoV-2-containing aerosol particles close to symptom onset and during singing or talking as compared to breathing. This study supports that individuals with SARS-CoV-2 in exhaled aerosols are more likely to transmit covid-19.

Transmission of respiratory viruses is a complex process involving emission, deposition in the airways, and infection. Inhalation is often the most relevant transmission mode in indoor environments. For severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the risk of inhalation transmission is not yet fully understood. Here, we used an indoor aerosol model combined with a regional inhaled deposited dose model to examine the indoor transport of aerosols from an infected person with novel coronavirus disease (COVID-19) to a susceptible person and assess the potential inhaled dose rate of particles. Two scenarios with different ventilation rates were compared, as well as adult female versus male recipients. Assuming a source strength of 10 viruses/s, in a tightly closed room with poor ventilation (0.5 h−1), the respiratory tract deposited dose rate was 140–350 and 100–260 inhaled viruses/hour for males and females; respectively. With ventilation at 3 h−1 the dose rate was only 30–90 viruses/hour. Correcting for the half-life of SARS-CoV-2 in air, these numbers are reduced by a factor of 1.2–2.2 for poorly ventilated rooms and 1.1–1.4 for well-ventilated rooms. Combined with future determinations of virus emission rates, the size distribution of aerosols containing the virus, and the infectious dose, these results could play an important role in understanding the full picture of potential inhalation transmission in indoor environments.

Background: Recent advances have improved survival in multiple myeloma (MM; Kumar et al. Leukemia. 2014); however, the disease remains incurable. Patients with triple-class refractory MM have a median overall survival (OS) of only 9.2 months (Ghandi et al. Leukemia. 2019). These patients and those with poor-risk features, such as high-risk cytogenetics, have few treatment options and represent a patient group with a very poor prognosis and high unmet medical need. Melflufen is a lipophilic peptide-conjugated alkylator that rapidly delivers a highly cytotoxic payload into myeloma cells through peptidase activity. Meflufen is taken up by myeloma cells and immediately cleaved by peptidases into hydrophilic alkylator payloads that induce irreversible DNA damage and apoptosis. This updated analysis of the ongoing HORIZON study in patients with MM refractory to pomalidomide (pom) and/or daratumumab (dara) includes a subgroup analysis of patients with triple-class refractory (no response or progression on or within 60 days of last dose to at least 1 IMiD, 1 proteasome inhibitor [PI], and 1 anti-CD38 monoclonal antibody) and high-risk cytogenetics at baseline (NCT02963493). Methods: Patients with relapsed refractory MM (RRMM) must have received ≥2 prior lines, been exposed to an IMiD and PI, and be refractory to pom and/or dara. Patients receive 40-mg melflufen intravenously on day 1 of each 28-day cycle and 40-mg weekly dexamethasone (dex; 20 mg for patients aged ≥75 years) until progressive disease (PD) or unacceptable toxicity. The primary endpoint is overall response rate (ORR; ≥ partial response [PR]; investigator assessed per International Myeloma Working Group criteria). Secondary endpoints include safety, clinical benefit rate (CBR; ≥ minimal response), progression-free survival (PFS), OS, and duration of response (DOR). Results: As of 6 May 2019, 121 patients were treated. The median age was 64 years (range, 35-86), median time since diagnosis was 6.2 years (range, 0.7-25), 29% of patients had International Staging System stage 3 disease, and 62% with available cytogenetic data (n=81) had high-risk cytogenetics at study entry. The median number of prior lines was 5 (2-12). All patients were pom or dara refractory and received prior PIs and IMiDs; 74% were triple-class refractory. With a median follow-up of 10.8 months, 29% of patients were on ongoing treatment. Of 86 patients (71%) who discontinued treatment, 69% discontinued due to PD, 20% due to adverse events (AEs), and 12% for other reasons. In total, 113 patients had available response data. ORR was 28%; 1 patient achieved stringent complete response (sCR), 9% very good PR (VGPR), and 19% PR. CBR was 40%. Median PFS for all patients treated (N=121) was 4.0 months (95% CI, 3.7-4.6), median OS was 11.2 months (95% CI, 8.1-13.9), and median DOR was 4.4 months (95% CI, 3.6-8.3). Efficacy was examined in poor-risk patient subsets with available response data. ORR was 20% in patients with triple-class refractory disease (n=83). ORR in patients with high-risk cytogenetics was 28%. Median DOR was 3.6 months in responders with triple-class refractory disease. DOR in patients with high-risk cytogenetics was 5.1 months. Treatment-related grade 3 and grade 4 AEs were reported in 24% and 49% of patients, respectively. Most common (≥5%) grade 4 AEs were thrombocytopenia (36%) and neutropenia (31%). The incidence of treatment-related grade 3/4 nonhematologic AEs was low; most commonly pneumonia (3%), fatigue (2%), and upper respiratory tract infection (2%). Treatment-related serious AEs occurred in 20% of patients. No treatment-related deaths were reported. Conclusion: Melflufen continues to show promising activity (ORR, 28%) in patients with late-stage RRMM refractory to dara and/or pom and was generally well tolerated, with infrequent nonhematologic AEs and, of the 121 patients treated, 14% discontinued due to AEs. Additionally, melflufen has comparable efficacy in subsets of patients with poor-risk features, including triple-class refractory and high-risk cytogenetics, relative to the overall HORIZON patient population. Melflufen plus dex is being further investigated vs pom plus dex in the OCEAN phase 3 study (OP-103; NCT03151811) in patients with RRMM refractory to lenalidomide. Disclosures Mateos: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; EDO: Membership on an entity's Board of Directors or advisory committees; Pharmamar: Membership on an entity's Board of Directors or advisory committees. Oriol:Janssen: Consultancy; Takeda: Consultancy, Speakers Bureau; Celgene Corporation: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Larocca:Amgen: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rodriguez Otero:Kite Pharma: Consultancy; BMS: Honoraria; Celgene Corporation: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy; Janssen: Consultancy, Honoraria. Bladé:Jansen, Celgene, Takeda, Amgen and Oncopeptides: Honoraria. Cavo:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; novartis: Honoraria; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; bms: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hassoun:Celgene: Research Funding; Janssen: Research Funding; Novartis: Consultancy. Leleu:Sanofi: Honoraria; Oncopeptide: Honoraria; Takeda: Honoraria; Karyopharm: Honoraria; Amgen: Honoraria; Carsgen: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Janssen: Honoraria; BMS: Honoraria; Merck: Honoraria. Amor:Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Maisel:Texas Oncology: Employment; Amgen: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Verastem: Honoraria, Speakers Bureau. Paner:Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Cellectar: Consultancy, Honoraria; Dova: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Rush University Medical Center: Employment; Cellectar: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Harmenberg:Oncopeptides: Consultancy, Equity Ownership. Byrne:Oncopeptides: Consultancy; Takeda: Consultancy. Thuresson:Oncopeptides: Employment, Equity Ownership. Zubair:Oncopeptides: Employment, Equity Ownership. Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: This is a phase 2 investigational study of melflufen in RRMM