MM-198 Anti-BCMA Therapy in Multiple Myeloma: A Single-Center Experience

Context: Triple class exposed/refractory multiple myeloma (MM) represents an unmet medical need because there is no standard of care and overall survival (OS) does not exceed 9 months. B-cell maturation antigen (BCMA) has appeared as an interesting target to treat MM. Objective: To indirectly compare the time to access therapy and hospitalization as well as the toxicity and efficacy of BCMA bispecific monoclonal antibodies (BiAbs) and CAR-T. Design: An observational retrospective study was designed including MM patients treated with BCMA CAR-T or BiAbs in clinical trials at the Hospital of Salamanca (October 2018–April 2022). Patients or Other Participants: Forty-nine patients were treated with BCMA therapy. Intervention: N/A. Main Outcome Measures: The time to access the treatment and hospitalization, global responses, cytokine release syndrome (CRS), neurotoxicity, infections, progression-free survival (PFS), and OS. Results: Twenty-seven patients (55.1%) received CAR-T and 22 (44.9%) received BiAbs. Thirty-nine (79.6%) patients were triple exposed and 28 (57.1%) were triple refractory. Patients who received BiAbs were treated earlier (12 vs. 56 days;P<0.001) and were hospitalized for less time (13 vs. 21 days;P=0.018). Overall response rate was superior in CAR-T patients (100% vs. 52.4%;P<0.001) as was percentage of CR (70.4% vs. 47.6%;P=0.110). Incidence of CRS was higher in the CAR-T group than the BiAbs group (92.6% vs. 68.2%;P=0.028) as were the percentages of grade 4 neutropenia (92.6% vs. 22.7%;P<0.001) and thrombocytopenia (70.4% vs. 9.1%;P<0.001). Infections were more frequent in the BiAbs group (especially between the first and third month of treatment initiation, 55.6% vs. 14.8%;P=0.004), including COVID-19 infection (50.0% vs. 29.6%;P=0.002). With a median follow-up of 14.3 months (1.1–41.8), PFS was superior in patients treated with CAR-T (18.9 vs. 6.1 months;P=0.045) as was OS (not reached vs. 25.5 months;P=0.016). Conclusions: The times to access therapy and hospitalization were shorter in patients treated with BiAbs. The incidences of CRS and cytopenia were higher in the CAR-T group, but mid-term and COVID-19 infections were more frequent in the BiAbs group. Response, PFS, and OS were superior in patients treated with CAR-T than those treated with BiAbs.

Psychometric Properties of the Functional Impairment Checklist (FIC) as a Disease-Specific Patient-Reported Outcome Measure (PROM) in Previously Hospitalized COVID-19 Survivors with Long-COVID.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus is associated with a plethora of long-lasting symptoms (long-COVID). The presence of long-COVID symptoms causes decreased functionality. This study described the psychometric properties of the Functional Impairment Checklist (FIC), a disease-specific patient-reported outcome measure (PROM) used for evaluating the functional consequences of SARS in previously hospitalized COVID-19 survivors with long-COVID symptoms. The LONG-COVID-EXP-CM is a multicenter cohort study including patients hospitalized with COVID-19 during the first wave of the pandemic in five hospitals in Madrid. A total of 1969 (age: 61 ± 16 years, 46.4% women) COVID-19 survivors with long-COVID completed the FIC at a long-term follow-up after hospitalization (mean: 8.4 ± 1.5 months). Internal consistency (Cronbach alpha value), reliability (item-internal consistency, item-discriminant validity), construct validity (exploratory factor analysis), floor effect and ceiling effect were calculated. The mean time for fulfilling the FIC was 62 ± 11 s. The Cronbach's alpha values reflecting the internal consistency reliability were 0.864 for FIC-symptoms and 0.845 for FIC-disability. The correlation coefficient between the FIC-symptoms and FIC-disability scale was good (r: 0.676). The ceiling effect ranged from 2.29% to 9.02%, whereas the floor effect ranged from 38.56% to 80.19%. The exploratory factor analysis showed factor loadings from 0.514 to 0.866, supporting good construct validity. Women exhibited greater limitations in all physical symptoms and disability-related domains of the FIC compared with men (all, p < 0.001). Further, younger patients (those aged <45 years) self-reported lower physical symptoms and disability-related domains than older patients. In conclusion, this study indicates that the FIC has good psychometric properties to be used as a specific-disease PROM to measure function and disability in COVID-19 survivors with long-COVID.

Psychometric properties of the Spanish version of the EuroQol-5D-5L in previously hospitalized COVID-19 survivors with long COVID.

The EuroQol 5-dimensions 5-levels (EQ-5D-5L) is a generic patient-reported outcome measures (PROM) used for evaluating health-related quality of life (HRQoL). No data on its psychometric properties in COVID-19 survivors is available. We aimed to describe internal consistency, test-retest reliability, and construct validity of the EQ-5D-5L in people with long-COVID. Ninety-three (n = 93) individuals previously hospitalized due to COVID-19 with post-COVID symptoms completed the EQ-5D-5L questionnaire twice one year after hospital discharge in a three-week interval. Internal consistency (Cronbach alpha and Omega value), test-retest reliability (kappa and ICC2,1) and construct validity (factor analysis), and floor/ceiling effects were calculated. No ceiling effect was observed in any dimension whereas the floor effect ranged from 53.76 to 94.62%. The overall Cronbach's α value was 0.75 (95%CI 0.64-0.83) and the Omega ω value was 0.77 (95%CI 0.66-0.84), showing good internal consistency of the questionnaire. Further, Cronbach's alpha values the of each dimension ranged from 0.63 to 0.77 whereas those for Omega values ranged from 0.70 to 0.79. The test-retest reliability of the total score was excellent (ICC2,1 0.86, 95%CI 0.798-0.911). The agreement percentage ranged from 85.13 to 96.77%; but kappa coefficients ranged from fair (κ: 0.37) to good (κ: 0.61). The factor analysis showed factor loadings from 0.585 to 0.813 supporting good construct validity. The EQ-5D-5L has good psychometric properties to be used as a PROM to assess HRQoL in hospitalized COVID-19 survivors with long-COVID.

Effective high-throughput RT-qPCR screening for SARS-CoV-2 infections in children.

Systematic SARS-CoV-2 testing is a valuable tool for infection control and surveillance. However, broad application of high sensitive RT-qPCR testing in children is often hampered due to unpleasant sample collection, limited RT-qPCR capacities and high costs. Here, we developed a high-throughput approach ('Lolli-Method') for SARS-CoV-2 detection in children, combining non-invasive sample collection with an RT-qPCR-pool testing strategy. SARS-CoV-2 infections were diagnosed with sensitivities of 100% and 93.9% when viral loads were >106 copies/ml and >103 copies/ml in corresponding Naso-/Oropharyngeal-swabs, respectively. For effective application of the Lolli-Method in schools and daycare facilities, SEIR-modeling indicated a preferred frequency of two tests per week. The developed test strategy was implemented in 3,700 schools and 698 daycare facilities in Germany, screening over 800,000 individuals twice per week. In a period of 3 months, 6,364 pool-RT-qPCRs tested positive (0.64%), ranging from 0.05% to 2.61% per week. Notably, infections correlated with local SARS-CoV-2 incidences and with a school social deprivation index. Moreover, in comparison with the alpha variant, statistical modeling revealed a 36.8% increase for multiple (≥2 children) infections per class following infections with the delta variant. We conclude that the Lolli-Method is a powerful tool for SARS-CoV-2 surveillance and can support infection control in schools and daycare facilities.

Surveillance Web System and Mouthwash-Saliva qPCR for Labor Ambulatory SARS-CoV-2 Detection and Prevention.

This study provides a safe and low-cost in-house protocol for RT-qPCR-based detection of SARS-CoV-2 using mouthwash-saliva self-collected specimens to achieve clinical and epidemiological surveillance in a real-time web environment applied to ambulatory populations. The in-house protocol comprises a mouthwash-saliva self-collected specimen, heat virus inactivation, and primers to target virus N-gene region and the human RPP30-gene. Aligning with 209 SARS-CoV-2 sequences confirmed specificity including the Alpha variant from the UK. Development, validation, and statistical comparison with official nasopharyngeal swabbing RT-qPCR test were conducted with 115 specimens of ambulatory volunteers. A web-mobile application platform was developed to integrate a real-time epidemiological and clinical core baseline database with mouthwash-saliva RT-qPCR testing. Nine built-in algorithms were generated for decision-making on testing, confining, monitoring, and self-reports to family, social, and work environments. Epidemiological and clinical follow-up and SARS-CoV-2 testing generated a database of 37,351 entries allowing individual decision-making for prevention. Mouthwash-saliva had higher sensitivity than nasopharyngeal swabbing in detecting asymptomatic and mild symptomatic cases with 720 viral copy number (VCN)/mL as the detection limit (Ct = 37.6). Cycling threshold and viral loading were marginally different (p = 0.057) between asymptomatic (35 Ct ± 2.8; 21,767.7 VCN/mL, range 720-77,278) and symptomatic (31.3 Ct ± 4.5; 747,294.3 VCN/mL, range 1433.6-3.08 × 106). We provided proof-of-concept evidence of effective surveillance to target asymptomatic and moderate symptomatic ambulatory individuals based on integrating a bio-safety level II laboratory, self-collected, low-risk, low-cost detection protocol, and a real-time digital monitoring system. Mouthwash-saliva was effective for SARS-CoV-2 sampling for the first time at the community level.

Does timing matter on tocilizumab administration? Clinical, analytical and radiological outcomes in COVID-19.

INTRODUCTION: While there are no pharmacological treatments with proven efficacy for coronavirus disease 2019 (COVID-19), tocilizumab has emerged as a candidate therapy. Some aspects of this therapy are still unknown, including the optimal timing of administration. OBJECTIVE: This observational study aimed to compare the 90-day mortality in two cohorts of patients when the drug was administered within the first 10 days from onset of symptoms or after day 11. METHODS: Patients hospitalised with severe COVID-19 pneumonia who had received tocilizumab were divided into two groups according to when the medication was administered. The primary outcome was 90-day mortality. Secondary outcomes were 30-day mortality, clinical improvement on a 6-item scale by day 6, biomarker improvement by day 6, radiological image improvement by day 10 and SaO₂ quotient by day 6. The results in the two groups were compared. Additionally, adverse events relating to tocilizumab were recorded. RESULTS: A total of 112 patients were analysed. Both groups were epidemiologically comparable. The results obtained in the primary efficacy variable of the study (90-day mortality) showed a statistically significant difference in the subgroups according to the time of administration of tocilizumab (18.6% vs 5.0%, p=0.048). There was clinical improvement in 24.1% of patients at 6 days, with similar behaviour in both subgroups. No statistically significant differences were found in the percentage of patients who achieved radiological improvement at 10 days or in the other inflammatory parameters, with the exception of significant reductions in lactate dehydrogenase and C-reactive protein. Administration of tocilizumab was not associated with relevant adverse events. CONCLUSION: To our knowledge, this is the first report of data regarding the timing of administration of tocilizumab in patients with COVID-19 pneumonia. A strategy involving tocilizumab administration after 10 days from onset of symptoms may decrease mortality. Further randomised controlled trials are needed to confirm this emerging hypothesis.

Ozone therapy for patients with COVID-19 pneumonia: Preliminary report of a prospective case-control study.

BACKGROUND: There is still no specific treatment strategies for COVID-19 other than supportive management. DESIGN: A prospective case-control study determined by admittance to the hospital based on bed availability. PARTICIPANTS: Eighteen patients with COVID-19 infection (laboratory confirmed) severe pneumonia admitted to hospital between 20th March and 19th April 2020. Patients admitted to the hospital during the study period were assigned to different beds based on bed availability. Depending on the bed the patient was admitted, the treatment was ozone autohemotherapy or standard treatment. Patients in the case group received ozonated blood twice daily starting on the day of admission for a median of four days. Each treatment involved administration of 200 mL autologous whole blood enriched with 200 mL of oxygen-ozone mixture with a 40 µg/mL ozone concentration. MAIN OUTCOMES: The primary outcome was time from hospital admission to clinical improvement. RESULTS: Nine patients (50%) received ozonated autohemotherapy beginning on the day of admission. Ozonated autohemotherapy was associated with shorter time to clinical improvement (median [IQR]), 7 days [6-10] vs 28 days [8-31], p = 0.04) and better outcomes at 14-days (88.8% vs 33.3%, p = 0.01). In risk-adjusted analyses, ozonated autohemotherapy was associated with a shorter mean time to clinical improvement (-11.3 days, p = 0.04, 95% CI -22.25 to -0.42). CONCLUSION: Ozonated autohemotherapy was associated with a significantly shorter time to clinical improvement in this prospective case-control study. Given the small sample size and study design, these results require evaluation in larger randomized controlled trials. CLINICAL TRIAL REGISTRATION NUMBER: NCT04444531.

Potential Role of Oxygen-Ozone Therapy in Treatment of COVID-19 Pneumonia.

BACKGROUND Pneumonia caused by coronavirus originated in Wuhan, China in late 2019 and has spread around the world, becoming a pandemic. Many patients deteriorate rapidly and require intubation and mechanical ventilation, which is causing the collapse of healthcare systems in many countries. Coronavirus infection is associated with extensive lung inflammation and microvascular thrombosis, which can result in hypoxia. It can also cause severe and lasting harm in other organs, including the heart and kidneys. At present, there is no proven and efficacious treatment for this new disease. Consequently, there is a growing tendency to use novel methods. Ozone therapy consists of administration of a mixture of oxygen and ozone (a molecule consisting of 3 oxygen atoms). The potential benefits of this therapy include reduced tissue hypoxia, decreased hypercoagulability, renal and heart protection, modulated immune function, improved phagocytic function, and impaired viral replication. CASE REPORT We report rapidly improved hypoxia with associated decreases in inflammatory markers and D-dimer immediately after 1-4 sessions of oxygen-ozone (O2-O3) therapy in 3 patients with COVID-19 pneumonia who presented with respiratory failure. Invasive mechanical ventilation was not required in these 3 patients. All patients were discharged home on days 3-4 after O2-O3 therapy. CONCLUSIONS O2-O3 therapy appears to be an effective therapy for COVID-19 patients with severe respiratory failure. Large controlled clinical trials are required to study the efficacy and safety of using O2-O3 therapy compared with the standard supportive case in patients with COVID-19 in terms of the need for invasive ventilation and length of hospital and intensive care unit stays.