ABSTRACT
Background: Successful vaccination against SARS-CoV2 is highly effective in preventing serious COVID-19 illness and is particularly recommended for at risk populations including patients with multiple myeloma (MM). However, there is uncertainty to which extent modern intensified therapies targeting plasma cell features might attenuate vaccination responses;some early vaccination recommendations for MM have proposed extended treatment breaks of several weeks to maximise vaccination success. Such an approach can be challenging in UHiR MM and pPCL, where maintaining treatment intensity is hallmark for preventing rapid relapse of the aggressive tumor. To address this uncertainty, we measured post-vaccination serological responses in patients treated uniformly with intensified Dara-VR consolidation and Dara-R maintenance post-ASCT for UHiR NDMM or pPCL in the UK OPTIMUM/MUKnine trial (NCT03188172). Methods: Between Sep 2017 and Jul 2019, 107 patients with UHiR NDMM or pPCL were recruited to OPTIMUM and received intensified post-ASCT consolidation with Dara-VR(d) for 18 cycles followed by maintenance with Dara-R until progression. In an exploratory analysis, centrally stored serum samples available for patients with a completed and documented vaccination history of two doses of an anti-SARS-CoV2 vaccine were analyzed for serological vaccine responses Total IgG/IgA/IgM Anti-SARS-CoV-2 spike glycoprotein was measured by ELISA (MK654;The Binding Site). As per UK national guidance and local availability, patients received two vaccine doses 12 weeks apart of either tozinameran (Pfizer/Biontech) or vaxzevria (AstraZeneca);serum taken at least 3 weeks after patients received their second dose was analyzed. Results were correlated with baseline characteristics and annotated with treatment and response data. Patient with available matched serological and vaccination status data at time of data cut-off (09 JUL 2021) were included. Collection of vaccination status data is ongoing and updated results comprising additional patients enrolled in OPTIMUM, as well as antigen levels, will be presented. Data will also comprise longitudinal antibody level measurements for patient with available sequential material. Results: Serological vaccine response data was available for 40 OPTIMUM patients with documented completed double vaccination status. Median patient age was 58.5 years (range 39-70) and clinical and molecular tumor features were similar to the overall trial safety population. All patients had received their second dose before June 2021. Of the 40 patients, 42.5% had received tozinameran and 57.5% vaxzevria. Baseline characteristics of the two groups were comparable. At time of second vaccine dose, 55% of patients were receiving Dara-VR consolidation treatment and 45% Dara-R maintenance. There was no recommendation to pause trial treatment for purposes of vaccination and no extended times off treatment for this reason were reported. Overall, 72.5% of patients had a positive vaccine antibody level as per manufacturer cut-point for high specificity evidence of antigen exposure (infection or vaccine). The response rate was nominally higher for vaxzevria (91.3%) than for tozinameran (47.1%), a dysbalance that will be further investigated with ongoing extension of the cohort. Of note, 90% of patients analyzed had reached a complete response (CR) of their MM prior to being vaccinated, and the majority of patients not in CR had a positive vaccine response. Response rates were nominally slightly higher in patients in receipt of Dara-R maintenance at time of second dose with 77.8% compared to Dara-VR consolidation with 68.2%. Conclusions: These results show a high serological response rate to COVID-19 vaccination in UHiR MM patients receiving intensified post-ASCT consolidation and maintenance therapy in remission. Findings suggest that continuation of intensified post-ASCT therapy for patients with aggressive tumors and a high risk of relapse are compatible with serological responses to commonly used COVID-19 vaccines. Disclosures: Jen er: Janssen: Consultancy, Honoraria, Speakers Bureau;BMS/Celgene: Consultancy, Honoraria, Speakers Bureau;Takeda: Consultancy;Pfizer: Consultancy. Hall: BMS/Celgene: Research Funding;Janssen: Research Funding. Garg: University Hospital Leicester: Current Employment;Takeda Janssen Novartis Sanofi: Other: Travel Accommodations, Expenses;Amgen Janssen Novartis Sanofi Takeda: Honoraria. Jackson: J and J: Consultancy, Honoraria, Speakers Bureau;GSK: Consultancy, Honoraria, Speakers Bureau;takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau;amgen: Consultancy, Honoraria, Speakers Bureau;celgene BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau;oncopeptides: Consultancy;Sanofi: Honoraria, Speakers Bureau. Pratt: Binding Site: Consultancy;BMS/Celgene: Consultancy;Gilead: Consultancy;Janssen: Consultancy;Takeda: Consultancy;Amgen: Consultancy. Cook: Karyopharm: Consultancy;Sanofi: Consultancy;Takeda: Consultancy, Research Funding;Janssen: Consultancy, Research Funding;BMS/Celgene: Consultancy, Research Funding;Amgen: Consultancy. Drayson: Abingdon Health: Current holder of individual stocks in a privately-held company. Kaiser: BMS/Celgene: Consultancy, Other: Travel support, Research Funding;Janssen: Consultancy, Other: Educational support, Research Funding;GSK: Consultancy;Karyopharm: Consultancy, Research Funding;Pfizer: Consultancy;Amgen: Honoraria;Seattle Genetics: Consultancy;Takeda: Consultancy, Other: Educational support;AbbVie: Consultancy.
ABSTRACT
RATIONALE Multiple case reports and case series have described pneumothorax and pneumomediastinum as a complication of patients hospitalized with COVID-19, particularly among those receiving invasive mechanical ventilation. However, it is not known whether patients with COVID-19 have a uniquely higher incidence of these events compared to historical ARDS (non-COVID-19 ARDS) patients. METHODS We compared barotrauma rates in patients hospitalized with COVID-19 who received invasive mechanical ventilation between March-July 2020 to patients with non-COVID-19 ARDS who received mechanical ventilation in 2016-2018. We defined barotrauma as pneumothorax or pneumomediastinum during mechanical ventilation. RESULTS We analyzed 222 patients with COVID-19 who received invasive mechanical ventilation and 421 patients with ARDS. Barotrauma events occurred in 13.1% of patients with COVID-19 and 9.3% of historical ARDS patients (p = 0.136). Mean tidal volumes were 5.7 and 6.4 mL/kg of predicted body weight, plateau pressures were 25.6 and 23.6, PEEP was 11.2 and 8.8, and driving pressures were 14.4 and 14.8 cmH2O, respectively, in COVID-19 and non-COVID-19 ARDS. There were 42 pneumothoraces among COVID-19 patients and 50 among historical ARDS patients (p = 0.144). Incidence rates were 1.7 and 2.7 per 100 ventilator days in COVID-19 and historical ARDS respectively (p=0.808). There were 14 cases of pneumomediastinum among patients with COVID-19 compared to 16 among patients with ARDS (p = 0.152). Overall, pneumothoraces were identified within 24 hours of ipsilateral internal jugular or subclavian line placement in 5.4% (5/92) of events. In both groups, barotrauma was associated with fewer vent-free days at 28 days (3.0 vs 9.2 in COVID-19, p < 0.001 and 7.6 vs 11.5 in historical ARDS, p = 0.0214). Barotrauma was not associated with an increased mortality at discharge for either cohort. For COVID-19 patients only, mean plateau pressure and driving pressure were associated with barotrauma events (28 vs 25 cmH2O, p = 0.0015;16.7 vs 14.0 cmH2O, p ≤ 0.01). Administered tidal volume, PEEP, age, sex, tobacco use, obesity, number of comorbidities, and the presence of lung comorbidities were not associated with barotrauma in either cohort. CONCLUSIONS Both COVID-19 and non-COVID-19 ARDS patients who are mechanically ventilated are at high risk of barotrauma;this was not unique to patients with COVID-19. Barotrauma is associated with prolonged ventilation and fewer ventilator-free days. Despite advances in lung-protective ventilation, barotrauma continues to be a significant source of morbidity in patients mechanically ventilated for respiratory failure.