Report of consensus panel 5 from the 11th international workshop on Waldenstrom's macroglobulinemia on COVID-19 prophylaxis and management.

Consensus Panel 5 (CP5) of the 11th International Workshop on Waldenstrom's Macroglobulinemia (IWWM-11; held in October 2022) was tasked with reviewing the current data on the coronavirus disease-2019 (COVID-19) prophylaxis and management in patients with Waldenstrom's Macroglobulinemia (WM). The key recommendations from IWWM-11 CP5 included the following: Booster vaccines for SARS-CoV-2 should be recommended to all patients with WM. Variant-specific booster vaccines, such as the bivalent vaccine for the ancestral Wuhan strain and the Omicron BA.4.5 strain, are important as novel mutants emerge and become dominant in the community. A temporary interruption in Bruton's Tyrosine Kinase-inhibitor (BTKi) or chemoimmunotherapy before vaccination might be considered. Patients under treatment with rituximab or BTK-inhibitors have lower antibody responses against SARS-CoV-2; thus, they should continue to follow preventive measures, including mask wearing and avoiding crowded places. Patients with WM are candidates for preexposure prophylaxis, if available and relevant to the dominant SARS-CoV-2 strains in a specific area. Oral antivirals should be offered to all symptomatic WM patients with mild to moderate COVID-19 regardless of vaccination, disease status or treatment, as soon as possible after the positive test and within 5 days of COVID-19-related symptom onset. Coadministration of ibrutinib or venetoclax with ritonavir should be avoided. In these patients, remdesivir offers an effective alternative. Patients with asymptomatic or oligosymptomatic COVID-19 should not interrupt treatment with a BTK inhibitor. Infection prophylaxis is essential in patients with WM and include general preventive measures, prophylaxis with antivirals and vaccination against common pathogens including SARS-CoV-2, influenza, and S. pneumoniae.

Report of Consensus Panel 5 from the 11th International Workshop on Waldenstrom's Macroglobulinemia on COVID-19 Prophylaxis and Management

Consensus Panel 5 (CP5) of the 11th International Workshop on Waldenstrom's Macroglobulinemia (IWWM-11;held in October 2022) was tasked with reviewing the current data on the coronavirus disease-2019 (COVID-19) prophylaxis and management in patients with Waldenstrom's Macroglobulinemia (WM). The key recommendations from IWWM-11 CP5 included the following: Booster vaccines for SARS-CoV-2 should be recommended to all patients with WM. Variant-specific booster vaccines, such as the bivalent vaccine for the ancestral Wuhan strain and the Omicron BA.4.5 strain, are important as novel mutants emerge and become dominant in the community. A temporary interruption in Bruton's Tyrosine Kinase-inhibitor (BTKi) or chemoimmunotherapy before vaccination might be considered. Patients under treatment with rituximab or BTK-inhibitors have lower antibody responses against SARS-CoV-2;thus, they should continue to follow preventive measures, including mask wearing and avoiding crowded places. Patients with WM are candidates for pre-exposure prophylaxis, if available and relevant to the dominant SARS-CoV-2 strains in a specific area. Oral antivirals should be offered to all symptomatic WM patients with mild to moderate COVID-19 regardless of vaccination, disease status or treatment, as soon as possible after the positive test and within 5 days of COVID-19-related symptom onset. Co-administration of ibrutinib or venetoclax with ritonavir should be avoided. In these patients, remdesivir offers an effective alternative. Patients with asymptomatic or oligosymptomatic COVID-19 should not interrupt treatment with a BTK inhibitor. Infection prophylaxis is essential in patients with WM and include general preventive measures, prophylaxis with antivirals and vaccination against common pathogens including SARS-CoV-2, influenza and S. pneumoniae.

Recovery after COVID-19 and persisting endothelial cell activation and hypercoagulability-The prospective observational ROADMAP-post COVID-19 study

Background: Hypercoagulable state and endothelial cell activation are common alterations in patients with COVID-19. Nevertheless, the hypothesis of persistent hypercoagulability and endothelial cell activation following recovery from COVID-19 remains an unresolved issue. Aim(s): To investigate the persistence of endothelial cell activation and hypercoagulability after recovery from COVID-19. Patients/ Methods. COVID-19 survivors (n = 208) and 30 healthy individuals were enrolled in this study. Method(s): The following biomarkers were measured: Procoagulant phospholipid-dependent clotting time (PPL-ct), D-Dimer, fibrin monomers (FM), free Tissue factor pathway inhibitor (free-TFP) I, heparinase, and soluble thrombomodulin (sTM). Antibodies against SARS-CoV- 2 (IgG and IgA) were also measured. Result(s): The median interval between symptom onset and screening for SARS-CoV- 2 antibodies was 62 days (IQR = 22 days). Survivors showed significantly higher levels of D-Dimers, FM, TFPI, and heparanase as compared to that of the control group. Survivors had significantly shorter PPL-ct. Elevated D-dimer was associated with older age. Elevated FM was associated with female gender. Elevated heparanase was independently associated with male gender. Decreased Procoag-PPL clotting time was associated with female gender. One out of four of COVID-19 survivors showed increase at least one biomarker of endothelial cell activation or hypercoagulability. Conclusion(s): Two months after onset of COVID-19, a significant activation of endothelial cells and in vivo thrombin generation persists in at least one out of four survivors of COVID-19. The clinical relevance of these biomarkers in the diagnosis and follow-up of patients with long COVID-19 merits to be evaluated in a prospective clinical study.

CLINICAL PROFILE OF COVID-19 INFECTION AND IMMUNE RESPONSE AFTER 3AND6 MONTH VACCINATION AGAINST SARS-COV-2 IN ADULT PATIENTS WITH TRANSFUSION-DEPENDENT THALASSAEMIATHE EXPERIENCE OF A GREEK CENTER

Background: Patients with transfusion-dependent-thalassaemia (TDT) are considered as increased risk population for severe and/or morbid COVID-19 infection. Timely vaccination is the main preventive method for severe COVID-19. Aims: To provide an overview of the clinical profile and outcome of COVID-19 infection in patients with TDT as well as to study the immune response after 3 and 6 months after vaccination against COVID-19 in adult patients with transfusion-dependent thalassaemia. Methods: This analysis focused on the evaluation in TDT patients on the long-term immune response post vaccination and on the course of COVID-19 infection and its correlation with immunization status. Serum was collected at 4 pre-defined time points, namely, just before 1st dose (TP1), 7 weeks after the 1st dose (TP2), 3 months (TP3) and 6 months (TP4) after 2nd dose. Neutralizing antibodies (NAbs) against SARS-CoV-2 were measured using FDA-approved methods. According to manufacturer, the scale of NAbs titer is 0-100%, with ≥30% considered as positive and ≥50% as clinically relevant viral inhibition. Age-matched healthy volunteers (median age: 46 years, range: 24-64 years, 24 males / 53 females) who received mRNA vaccines served as the control group for NAbs evaluation. Results: 340 (170female/170male) TDT patients older than 18 years (mean 43.6±11.5 years) followed in a single unit were included in the analysis. 270 patients (79%) were vaccinated with 2 or 3 doses. Immune response to vaccination was evaluated in 90 patients (median age: 46 years, range: 19-63 years, 40 males / 50 females). NAbs were at the level of non-immunity in all the patients at baseline (TP1) (mean 16.57% ±11.85) and showed a significant increase after the second dose (TP2) mean 86.96%±12.95 (p<0.0001). At TP3 and TP4 Nabs showed a significant decrease but remained in protective levels for the majority of the patients (mean 88.75% ±9.7 and 74.64% ±17.2 respectively(p<0.0001). The kinetics of NAbs were similar to controls except for levels at TP4 (p=0.02) (Figure 1). Up to 10/FEB/2022, 43 TDT patients (median age 43.52 range 18.6-57.9 years) were diagnosed with COVID-19, with 1 of them being infected twice. Of them, 17 were unvaccinated, 18 had received 2 doses of vaccine, while 8 had received 3 doses of the vaccine. The incidence rate was 9.6% and 24.3% for vaccinated and unvaccinated patients, respectively. The severity of the COVID-19 for vaccinated and unvaccinated patients were as follows, respectively, ;Grade 1 (asymptomatic): 0 and 1, Grade 2 (mild symptoms, symptomatic therapy, no COVID19 specific therapy): 23 and 9, Grade 3 (mild symptoms, symptomatic therapy, with COVID19 specific therapy): 1 and 3, Grade 4 (moderate: pneumonia, thrombophlebitis, Hospitalization): 2 and 3, Grade 5 (Hospitalization requiring ICU, death): 0 and 1. Thrombotic event was documented in 1 patient. All patients except one from unvaccinated group are alive. Summary/Conclusion: Immune response to vaccination may wean faster in TDT patients. in Unvaccinated TDT patients were more likely to be infected and to develop more serious COVID-19 infection compared to vaccinated patients. (Figure Presented).

A THIRD BNT162B2 DOSE INDUCES ANTIBODY RESPONSES AGAINST SARS-COV-2 EVEN IN PREVIOUSLY NON-RESPONDERS WITH MULTIPLE MYELOMA

Introduction: Recent data indicate that COVID-19 vaccination leads to a less intense humoral response in patients with multiple myeloma (MM) primarily in those without prior exposure to SARS-CoV-2, as reflected by a lower production of neutralizing antibodies (NAbs), compared with healthy controls. A third BNT162b2 dose in adults aged 60 years and older was associated with significantly increased IgG titers after 10 to 19 days, with no major adverse toxicity. Methods: In this context, we prospectively evaluated the development of NAbs against SARS-CoV-2 (ELISA, cPass™ SARS-CoV-2 NAbs Detection Kit;GenScript, Piscataway, NJ, USA) in patients with MM at 30 days post vaccination with a third dose of the mRNA BNT162b2 vaccine (NCT04743388). Serum samples were collected on the date of the booster dose (just before vaccination) and 4 weeks after. Results: The study population included 167 consecutive MM patients (58% males;median age: 68 years, IQR: 60-75 years) who were vaccinated with the booster BNT162b2 dose between September/October 2021, at the same vaccination center. All patients had been fully vaccinated with the two-dose BNT162b2. At the time of vaccination, the vast majority (93.4%) of patients were receiving anti-myeloma treatment. The booster dose significantly improved the humoral response in MM patients. More specifically, the median (IQR) of NAbs titer reached 96.7% (52.6-97.8%) as compared with 27.1% (13.9%-65.8%) before the third dose (p<0.001). Overall, 114 (68%) patients had less than 50% NAb activity before the third dose. Among them, 75 (65.8%) patients increased their NAb titer to at least 50% after the third dose. Interestingly, the patients who had achieved a NAbs titer of ≥50% at one month after the second vaccine dose were more likely to achieve a NAbs titer of ≥50% at one month after the third dose, as compared with those who had inferior antibody responses after the second dose (p=0.001). Fifty-seven (34%) patients had not developed a sufficient humoral response following the second vaccination (NAbs titer <30%). All of them presented with low NAbs titers before the third dose (median 14.5% (IQR 7.2%-23.3%)). The third vaccine dose boosted the median antibody response to 38.8% (IQR 15.6%-92.3%, p<0.001). At one month after the booster dose, 32/57 (56%) patients showed a NAbs titer above the positivity threshold (≥30%) and 26/57 (45.6%) showed a NAbs titer of ≥50%. In the multivariate analysis, only the presence of a NAbs titer ≥30% at one month after the second dose (Odds Ratio (OR) 9.5, 95% Confidence Interval (CI): 3.3-27.6) and the treatment with anti-BCMA agents (OR 0.03, 95%CI: 0.003-0.27) emerged as significant predictive factors for a NAb titer ≥50% at one month following the third dose. None of patients who were under anti-BCMA therapy achieved a NAbs titer of ≥30% one month after the booster dose. Conclusion: Our study demonstrated that a third BNT162b2 dose in patients with MM optimized the humoral response against SARS-CoV-2, as depicted by the significant increase in NAbs at one month post the booster dose. Importantly, ~46% of patients with suboptimal NAbs responses at one month following the two-dose BNT162b2 vaccination showed NAbs titers over 50% at one month after the booster dose. Taking also into consideration the defective immunity in patients with MM and the current COVID-19 outbreaks, self-protection measures, such as mask wearing and social distancing, remain particularly important. .

COVID-19 AND MYELOMA

The disease- and treatment-induced immunosuppression in MM accounts for a two-fold higher risk for infection with the SARS-CoV-2 virus, an increased risk for a prolonged, severe symptomatic disease, and an increased mortality. Most pts are aware of these risks and show a higher compliance with vaccination recommendations compared to the general population. Several studies revealed differences in the humoral and cellular immune response between pts with MGUS, SMM, and MM, with normal median antibody titers in MGUS, moderately impaired response in SMM, and significantly reduced antibody response in MM, albeit with a wide variation in titers between individual pts. Pts with active, poorly controlled disease and those exposed to CD38 and BCMA-targeting treatments frequently show no or reduced SARS-CoV-2 antibody responses. The EMN issued a consensus that MM pts should ideally be vaccinated before onset of active disease and/or during periods of well controlled disease. A third dose should be administered after an interval of approximately 6 months, and early data in immunocompromised pts show a vaccination response in several previously poorly responding pts after a forth dose. An open question pertains to the role of the interrelationship between the innate, humoral and cellular immune system. Neutralizing antibodies provide the best proxy for protection, although specific thresholds associated with protection against infection are unlikely to be established given the many factors associated with infection control. Antibody titers decline with time from vaccination and more so in vaccinated pts compared to those who have been infected and vaccinated, mandating booster shots in time intervals that need to be established. Pts may present without measurable antibody titers but with detectable cellular immunity or vice versa, although in most reports, correlations between antibody and cellular response were noted. Data suggest that SARSCoV- 2 specific memory B and T cells persist for prolonged periods. One of the threads to patient protection is the substantial mutational activity of the SARS-CoV-2 virus with reduced neutralizing capacity of vaccine induced antibodies against recent variants of concern, particularly the omicron variant, posing vaccinated pts at risk for breakthrough infections. Recent research efforts resulted in new prophylactic treatments for pts with high risk for severe COVID-19 disease (Table 1) that have been shown to reduce the incidence of severe complications. .

Prospective Assessment of Biomarkers of Hypercoagulability in Oncological Patients and Healthcare Workers Following Vaccination Against Sars-Cov-2 with the mRNA Vaccine. the Roadmap-COVID-19-Vaccin Study

Background: COVID-19 has been associated with hypercoagulability, endothelial cell injury and frequent thrombotic complications resulting both from direct effects of the virus on the endothelium and from the ‘cytokine storm’ resulting from the host's immune response. Since the COVID-19 vaccines have been shown to effectively prevent symptomatic infection including hospital admissions and severe disease, the risk of COVID-19-related thrombosis should be expected to (almost) disappear in vaccinated individuals. However, some rare cases of venous thrombosis have been reported in individuals vaccinated with mRNA vaccines. Thus, there is a sharp contrast between the clinical or experimental data reported in the literature on COVID-19 and on the rare thrombotic events observed after the vaccination with these vaccines. This phenomenon raised some scepticism of even some fear about the safety of these vaccines which could compromise the adhesion of the citizens in the vaccination program. Aims: We conducted a prospective observational study, to explore the impact of vaccination with the BNT162b2 (Pfizer/BioNTech) on blood hypercoagulability and endothelial cell activation and to investigate if this is modified by the presence of active cancer. Methods: In total 229 subjects were prospectively included in the study from April to June 2021. Subjects were stratified in three predefined groups: 127 vaccinated patients with active cancer (VOnco group), 72 vaccinated health care workers (VHcw group) and 30 non vaccinated health individuals (Control group). Blood samples were obtained 2 days after the administration of the first dose of BNT162b2 vaccine and collected in Vacutainer® tubes (0.109 mol/L trisodium citrate). Platelet poor plasma (PPP) was prepared by double centrifugation at 2000 g for 20 minutes at room temperature and plasma aliquots were stored at -80°C until assayed. Samples of PPP were assessed for thrombin generation (TG) with PPP-Reagent® (Thrombogram-Thrombinoscope assay with PPP-Reagent®TF 5pM), E-selectin, D-dimers, (D-Di), Tissue Factor (TFa), procoagulant phospholipid-dependent clotting time (Procag-PPL) and von Willebrand factor (vWF), thrombomodulin (TM), tissue factor pathway inhibitor (TFPI), and platelet factor 4 (PF4). All assays were from Diagnostica Stago (France). The upper and lower normal limits (UNL and LNL) for each biomarker were calculated by the mean±2SD for the control group. Results: All vaccinated subjects showed significantly increased levels of PF4 (71% >UNL, p<0.001), D-Dimers (74% >UNL, p<0.01), vWF (60% >UNL, p<0.01), FVIII (62% >UNL, p<0.01) and shorter Procoag-PPL clotting time (96% <LNL, p<0.001), as compared to controls. Thrombin generation showed significantly higher Peak (60% >UNL, p<0.01), ETP (38% >UNL, p<0.01) and MRI (66% >UNL, p<0.01) but no differences in lag-time in vaccinated subjects as compared to the control group. Vaccinated subjects did not show any increase at the levels of TFa, TFPI, TM and E-selectin in comparison with the control group. The studied biomarkers were not significantly different between the VOnco and VHcw groups. Conclusion: The ROADMAP-COVID-19-Vaccine study shows that administration of the first dose of the BNT162b2 vaccine induced significant platelet activation documented by shorter Procoag-PPL associated with increased levels of PF4. Plasma hypercoagulability was less frequent in vaccinated individuals whereas there was no evidence of significant endothelial cells activation after vaccination. Interestingly, the presence of active cancer was not associated with an enhancement of platelet activation, hypercoagulability, or endothelial cell activation after the vaccination. Probably, the generated antibodies against the spike protein or lead to platelet activation in a FcyRIIa dependent manner that results in PF4 release. The implication of the mild inflammatory reaction triggered by the vaccination could be another possible pathway leading to platelet activation. Nevertheless, vaccination does not provoke endothelial activation even n patients with cancer. The findings of the ROADMAP-COVID-19-Vaccine study support the concept administration of mRNA based vaccines does not directly cause a systematic hypercoagulability. Disclosures: Gligorov: Roche-Genentech: Research Funding;Novartis: Research Funding;Onxeo: Research Funding;Daichi: Research Funding;MSD: Research Funding;Eisai: Research Funding;Genomic Heatlh: Research Funding;Ipsen: Research Funding;Macrogenics: Research Funding;Pfizer: Research Funding. Terpos: Novartis: Honoraria;Janssen: Consultancy, Honoraria, Research Funding;Genesis: Consultancy, Honoraria, Research Funding;Celgene: Consultancy, Honoraria, Research Funding;BMS: Honoraria;Amgen: Consultancy, Honoraria, Research Funding;Takeda: Consultancy, Honoraria, Research Funding;Sanofi: Consultancy, Honoraria, Research Funding;GSK: Honoraria, Research Funding. Dimopoulos: Amgen: Honoraria;BMS: Honoraria;Janssen: Honoraria;Beigene: Honoraria;Takeda: Honoraria.

Patients with Multiple Myeloma on Anti-CD38 or Anti-BCMA Based Regimens and Patients with Waldenstrom's Macroglobulinemia Under Rituximab or BTK Inhibitors Have a Poor Humoral Response Following COVID-19 Vaccination

[Formula presented] Introduction: Recent data suggest a suboptimal antibody response to COVID-19 vaccination in patients with hematological malignancies. Herein, we evaluated the development of neutralizing antibodies (NAbs) against SARS-CoV-2 in patients with plasma cell neoplasms (PCNs) after vaccination with either the mRNA BNT162b2 or viral vector AZD1222 vaccine, up to 50 days post their first vaccine dose. Methods: This is an ongoing large prospective study (NCT04743388) evaluating the kinetics of anti-SARS-CoV-2 antibodies after COVID-19 vaccination in healthy subjects and in patients with hematological malignancies or solid tumors. Here we present the data on patients with PCNs in comparison to controls of similar age and gender, who were vaccinated during the same time period (January to March 2021) in Athens (Greece). Major exclusion criteria for both patients and controls included the presence of: (i) autoimmune disorder under immunosuppressive therapy or other active malignant disease;(ii) HIV or active hepatitis B and C infection, (iii) end-stage renal disease and (iv) prior diagnosis of COVID-19. Serum was collected on day 1 (D1;before the first vaccine dose), on day 22 (D22;before the second dose of the BNT162b2 or 3 weeks post the first AZD1222 dose) and on day 50 (D50;4 weeks post second dose of the BNT162b2 or 7 weeks post the first AZD1222 dose). NAbs against SARS-CoV-2 were measured using an FDA approved-ELISA methodology (cPass™ SARS-CoV-2 NAbs Detection Kit, GenScript, Piscataway, NJ, USA). Results: We evaluated 382 patients with PCNs after vaccination with either the BNT162b2 or the AZD1222 vaccine. Patients with MM (n=213), WM (n=106), SMM (n=38) and MGUS (n=25) and 226 healthy controls were enrolled in the study. Of MM/SMM/MGUS patients, 215 (77.9%) were vaccinated with the BNT162b2 and 61 (22.1%) with the AZD1222 vaccine, while out of 106 WM patients 90 (84.9%) were vaccinated with the BNT162b2 and 16 (15.1%) with the AZD1222 vaccine. Vaccination with either two doses of the BNT162b2 or one dose of the AZD1222 vaccine led to lower production of NAbs against SARS-CoV-2 in patients compared with controls both on day 22 and on day 50 (P<0.001 for all comparisons). After the first dose of the vaccine, on D22, the patient group had lower NAb titers compared with controls: the median NAb inhibition titer was 27% (IQR: 15.3-42%) for MM/SMM/MGUS versus 20.5% (IQR: 10-37%) for WM patients versus 38.7% (IQR: 22-54.3%) for controls (P<0.001 for all comparisons). On D50 the median NAb inhibition titer was 62.8% (IQR: 26-88.9%) for MM/SMM/MGUS versus 36% (IQR: 18-78%) for WM patients versus 90% (IQR: 58-96.4%) for controls (P<0.001 for all comparisons). 57.3% MM/SMM/MGUS, 42% WM patients and 81% controls developed NAb titers ≥50% (p<0.001 for patients versus controls). Furthermore, MM patients showed an inferior NAb response compared with MGUS on day 22 (p=0.009) and on day 50 (p=0.003). Importantly, active treatment with either anti-CD38 monoclonal antibodies or belantamab mafodotin and lymphopenia at the time of vaccination were independent prognostic factors for suboptimal antibody response following vaccination in MM (p<0.05). Disease-related immune dysregulation and therapy-related immunosuppression were involved in the low humoral response in patients with WM. Importantly, active treatment with either rituximab or Bruton's Tyrosine Kinase inhibitors (BTKIs) was proven as an independent prognostic factor for suboptimal antibody response following vaccination in WM (p<0.05). Regarding adverse events, 33% and 31.6% patients reported mild reactions after the first and second dose of the BNT162b2 vaccine, respectively;32.8% patients vaccinated with the first dose of AZD1222 also presented with local reactions. Conclusion: Patients with MM and WM have a low humoral response following SARS-CoV-2 vaccination, especially those who are under treatment with anti-CD38-, anti-BCMA-, anti-CD20- or BTKIs-based regimens. This result suggest that these patients have to continue the protective measures ag inst SARS-CoV-2 as they are at high risk for COVID-19. Further studies on the kinetics of immune subpopulations following COVID-19 vaccination will elucidate the underlying immune landscape and determine the potential need for additional booster vaccine doses or protective administration of antibodies against SARS-CoV-2 in MM/WM patients with poor response after full vaccination. Disclosures: Terpos: Janssen-Cilag: Consultancy, Honoraria, Research Funding;BMS: Honoraria;Celgene: Consultancy, Honoraria, Research Funding;Genesis: Consultancy, Honoraria, Research Funding;GSK: Honoraria, Research Funding;Takeda: Consultancy, Honoraria, Research Funding;Sanofi: Consultancy, Honoraria, Research Funding;Novartis: Honoraria;Amgen: Consultancy, Honoraria, Research Funding. Gavriatopoulou: Janssen: Honoraria;Takeda: Honoraria;Sanofi: Honoraria;Karyopharm: Honoraria;Genesis: Honoraria;GSK: Honoraria;Amgen: Honoraria. Kastritis: Amgen: Honoraria, Research Funding;Janssen: Honoraria, Research Funding;Genesis: Honoraria;Takeda: Honoraria;Pfizer: Honoraria. Dimopoulos: Janssen: Honoraria;BeiGene: Honoraria;Takeda: Honoraria;Amgen: Honoraria;BMS: Honoraria.

Kinetics of Anti-Sars-Cov-2 Antibody Responses 3 Months Post Complete Vaccination with BNT162b2;A Prospective Study in 283 Health Workers

Background: Levels of neutralizing antibodies (NΑbs) against SARS-CoV-2 correlate with clinically relevant immune protection from COVID-19. However, a slight decline in antibody titers has become evident even at one month following the second BNT162b2 shot, whereas increased time since the second vaccine dose has been associated with decreased NAb activity against SARS-CoV-2 variants. The aim of this study was to investigate the kinetics of NAbs and anti-S-RBD IgGs after vaccination of health workers with the BNT162b2 mRNA vaccine over a period of up to three months after the second shot. The possible influence of comorbidities, characteristics of the subjects, co-medication, and adverse events was also investigated. Methods: All participants have been enrolled in a large prospective study (NCT04743388) evaluating the kinetics of anti-SARS-CoV-2 antibodies after COVID-19 vaccination. Main inclusion criteria for participation in this study were eligibility for vaccination according to the national program for COVID-19, age above 18 years, and ability to sign the informed consent form. Major exclusion criteria included the presence of active malignant disease, immunosuppressive therapy, and end-stage renal disease. According to National Immunization Program, access to the BNT162b2 mRNA vaccine was available to anyone 18 years of age or older. NΑbs and anti-S-RBD IgG titers were measured on days 1 (before the first vaccine shot), 8, 22 (before the second shot), 36, 50, and three months after the second vaccination (D111), using FDA approved methods, namely, cPass™ SARS-CoV2 NAbs Detection Kit (GenScript, Piscataway, NJ, USA) and Elecsys Anti-SARS-CoV-2 S assay (Roche Diagnostics GmbH, Mannheim, Germany), respectively. Results: In total, 283 health workers (median age 48 years) were included in this study. On D1, immediately before vaccination, the median neutralizing inhibition was 14.2%, while 29 individuals (10.2%) had inhibition levels above the positive threshold of the method (30%). NAbs showed a rapid increase from D8 to D36 on a constant rate of about 3% per day and reached a median (SD) of 97.2% (4.7) at D36. From D36 to D50 a slight decrease in NAbs values was detected and it became more prominent between D50 and D111, when the rate of decline was determined at -0.11 per day. The median (SD) NAbs titers at D111 were 92.7% (11.8). Paired grouped comparisons using the Wilcoxon signed ranks test showed statistically significant differences in inhibition levels between pairs: D36 vs. D50, D36 vs. D111, and D50 vs. D111 (for all three comparisons p<0.001) (Figure A). A similar pattern was also observed for anti-S-RBD antibodies. It is worth mentioning that compared to NAbs, the maximum anti-S-RBD levels were reached two weeks later, i.e., at D36. Interestingly, anti-S-RBDs showed a steeper increase during D22-D36 and a lower decline rate during D36-D111. All consecutive pairs comparison, using Wilcoxon's test, led to p-values<0.001 (Figure B). There was an almost linear relationship between NAbs and anti-S-RBD at D22 (Spearman's rho correlation coefficient equal to 0.718). However, their relationship became non-linear from D36;this is due to the steep increase in anti-S-RBD levels that was observed during the D22-D36 period, while the corresponding increase rate for NAbs was much lower. Also, the decline of anti-S-RBD titers was lower compared to that of NAbs. The composite effect of these functions led to a non-linear pattern. Furthermore, prior COVID-19 and younger age were associated with superior antibody responses over time. Regarding those with previous positive PCR for SARS-CoV-2, significantly higher levels were observed at the initial phase (D1, D8) (Mann-Whitney p-values<0.001) and at D111 (p=0.046). From D50 there was a trend for a slower decline rate for those with previous positive PCR. Younger individuals had higher antibody titers at D36, D50, and D111, which is due to a slower decline in NAbs compared to the older group of participants (for all three comparisons, Wilcoxon's p-values were<0.05) Conclusions: We found a persistent but declining anti-SARS-CoV-2 humoral immunity at 3 months following full vaccination with BNT162b2 in healthy individuals. Our longitudinal study is ongoing to determine the time point of NAbs reduction below the positivity threshold;then a booster vaccine dose might be necessary to maintain humoral immunity against SARS-CoV-2. [Formula presented] Disclosures: Terpos: Amgen: Consultancy, Honoraria, Research Funding;Takeda: Consultancy, Honoraria, Research Funding;Novartis: Honoraria;BMS: Honoraria;Sanofi: Consultancy, Honoraria, Research Funding;Celgene: Consultancy, Honoraria, Research Funding;GSK: Honoraria, Research Funding;Janssen-Cilag: Consultancy, Honoraria, Research Funding;Genesis: Consultancy, Honoraria, Research Funding. Gavriatopoulou: Janssen: Honoraria;Karyopharm: Honoraria;Genesis: Honoraria;Sanofi: Honoraria;GSK: Honoraria;Takeda: Honoraria;Amgen: Honoraria. Dimopoulos: Takeda: Honoraria;Beigene: Honoraria;Amgen: Honoraria;BMS: Honoraria;Janssen: Honoraria.

Poor Neutralizing Antibody Responses in Patients with CLL, NHL and HL after Vaccination Against Sars-Cov-2;A Prospective Study in 132 Patients

Introduction: Recent data suggest a suboptimal antibody response to COVID-19 vaccination in patients with hematological malignancies, especially under therapy with monoclonal antibodies targeting B-cells. Herein, we evaluated the development of neutralizing antibodies (NAbs) against SARS-CoV-2 in patients with chronic lymphocytic leukemia (CLL), Non-Hodgkin Lymphoma (NHL) and Hodgkin's Lymphoma (HL) after vaccination with the mRNA BNT162b2 vaccine, up to 50 days post their first vaccine dose. Methods: This is a large prospective study (NCT04743388) evaluating the kinetics of anti-SARS-CoV-2 antibodies after COVID-19 vaccination in healthy subjects and patients with hematological malignancies. We report here the results in CLL, NHL and HL patients in comparison to age- and gender-matched controls who were vaccinated at the same time period (January to May 2021). After vein puncture, the serum of both patients and controls was collected on day 1 (D1;before the first BNT162b2 dose), on day 22 (D22;before the second dose of the BNT162b2) and on day 50 (D50;3 weeks post second dose of the BNT162b2). Serum was separated within 4 hours from blood collection and stored at -80°C until the day of measurement. NAbs against SARS-CoV-2 were measured using FDA approved methodology (ELISA, cPass™ SARS-CoV-2 NAbs Detection Kit;GenScript, Piscataway, NJ, USA) on the abovementioned timepoints. A NAb titer of at least 30% is considered as positive, according to manufacturer, whereas a NAb titer of at least 50% has been associated with clinically relevant viral inhibition [Walsh et al. N Engl J Med 2020, 383, 2439-50]. Samples of the same individual were measured in the same ELISA plate. Results: We evaluated 132 patients with CLL/Lymphomas after vaccination with the BNT162b2. Patient population included 53 with CLL, 57 with NHL and 22 with HL, while 214 healthy controls, of similar age and gender, were also studied. At the time of vaccination, 30% (n=40) of patients had asymptomatic disease and out of 92 symptomatic patients, 49% (n=45) were on active treatment. Vaccination with two doses of the BNT162b2 led to lower production of NAbs against SARS-CoV-2 in patients compared with controls, both on day 22 and on day 50 (P<0.001 for all comparisons) for all subgroups. After the first dose of the vaccine, on D22, the patient group had lower NAb titers compared with controls: the median NAb inhibition titer was 18% (IQR: 8.5-29%) for patients versus 41.6% (IQR: 25.3-59%) for controls;p<0.001. On D50, the median NAb inhibition titer was 32.5% (IQR: 13.5-93%) for patients versus 94.7% (IQR: 89-97%) for controls;p<0.001. More specifically, only 50.8% (67/132) of the patients versus 98.1% (210/214) of the controls developed NAb titers ≥30% and 43.9% (58/132) of patients versus 95.3% (204/214) titers ≥50% (high protective titers) at day 50 (p<0.0001 for all comparisons;Figure-left part). Importantly, active treatment (which included anti-CD antibodies, Bruton's tyrosine kinase inhibitors, a combination of the above, chemotherapy-only regimens or Bcl-2 inhibitors) was an independent prognostic factor for suboptimal antibody response at day 50 (<50%) in the patient subgroup (p<0.001). Rituximab administration in the last 12 months correlated with decreased antibody response at day 50 (p<0.01). Patients with HL were more likely to achieve humoral responses (>50% at day 50) compared to other disease types (p<0.05;Figure-right part). Disease-related immune dysregulation and therapy-related immunosuppression were therefore involved in the low humoral responses seen in patients. Regarding adverse events, 9% and 9.8% patients reported mild reactions after the first and second dose of the BNT162b2 vaccine, respectively. Conclusion: Patients with CLL/NHL/HL have a low humoral response following SARS-CoV-2 vaccination, particularly patients who are on active treatment with rituximab or BTK inhibitors. These patient subgroups therefore should continue utilizing protective measures against SARS-CoV-2 (masks, social distancing, etc) as they re at high risk for COVID-19. Further studies on the kinetics of immune subpopulations following COVID-19 vaccination will elucidate the underlying immune landscape and determine the potential need for additional booster vaccine doses or protective administration of antibodies against SARS-CoV-2 in CLL/NHL/HL patients with poor response after full vaccination. [Formula presented] Disclosures: Terpos: Sanofi: Consultancy, Honoraria, Research Funding;Novartis: Honoraria;Celgene: Consultancy, Honoraria, Research Funding;Janssen-Cilag: Consultancy, Honoraria, Research Funding;GSK: Honoraria, Research Funding;Genesis: Consultancy, Honoraria, Research Funding;Takeda: Consultancy, Honoraria, Research Funding;BMS: Honoraria;Amgen: Consultancy, Honoraria, Research Funding. Gavriatopoulou: Janssen: Honoraria;GSK: Honoraria;Genesis: Honoraria;Takeda: Honoraria;Sanofi: Honoraria;Amgen: Honoraria;Karyopharm: Honoraria. Baltadakis: Amgen: Honoraria;Bristol-Myers Squibb: Honoraria;Alexion: Honoraria;Astellas: Honoraria;Pfizer: Honoraria, Other: Travel Grants;Gilead: Honoraria;Novartis: Honoraria;Abbvie: Honoraria;Genesis Pharma: Other: Travel Grants;Gilead: Other: Travel Grants;WinMedica: Other: Travel Grants;Baxalta Hellas: Other: Travel Grants. Dimopoulos: BMS: Honoraria;Amgen: Honoraria;Janssen: Honoraria;Takeda: Honoraria;Beigene: Honoraria.

Patients with Multiple Myeloma and Prior COVID-19 Have Superior Antibody Responses Against Sars-Cov-2 Compared with Fully Vaccinated Myeloma Patients with the BNT162b2 Vaccine

Introduction: Recent data suggest a suboptimal antibody response to COVID-19 vaccination in patients with multiple myeloma (MM), especially under treatment. Herein, we evaluated the development of neutralizing antibodies (NAbs) against SARS-CoV-2 in non-vaccinated MM patients who were diagnosed with COVID-19 compared to MM patients after full vaccination with the mRNA BNT162b2 vaccine. Methods: The analysis was performed in the context of an ongoing large prospective study (NCT04743388) evaluating the kinetics of anti-SARS-CoV-2 antibodies after COVID-19 vaccination. We evaluated MM patients diagnosed with COVID-19, confirmed by PCR, matched for age, gender, line of treatment, type of myeloma, type of treatment and response with vaccinated MM patients during the same time period (January - May 2021). Major exclusion criteria for both COVID-19 and vaccine MM groups included the presence of: (i) autoimmune disorder under immunosuppressive therapy or other active cancer;(ii) active HIV, hepatitis B and C infection, and (iii) end-stage renal disease. Serum was collected at 4 th week post confirmed diagnosis for the COVID-19 MM group and at 4 th week post the second BNT162b2 dose for the vaccine MM group. NAbs against SARS-CoV-2 were measured using an FDA approved methodology (cPass™ SARS-CoV-2 NAbs Detection Kit, GenScript, Piscataway, NJ, USA). Results: We evaluated 35 patients with MM and COVID-19 (6 had smoldering MM and 29 symptomatic MM), along with 35 matched MM patients who received the BNT162b2 vaccine. Among COVID-19 MM patients, 13 were diagnosed with mild, 12 with moderate and 10 with severe disease;22/35 patients were hospitalized and 10/35 were intubated. Seven (20%) patients died due to COVID-19. During the disease course 21 patients (60%) were treated with dexamethasone. Type of treatment was not different between COVID-19 positive and vaccinated MM patients. Between the two patient groups, there was no difference in terms of age [median (IQR) 65 (59) for COVID-19 positive versus 66 (74) for COVID-19 vaccinated, respectively, p=0.76], gender [males: 19/35 (54.3%) versus 16/35 (45.7%), respectively, p=0.47), BMI (median 27 versus 26kg/m 2, respectively, p=0.56), asymptomatic disease [6/35 (18.2%) in both groups, p=1], prior lines of treatment [range: 1 to 7 versus 1 to 6, respectively, p=0.99], and type of treatment (p=0.87). Among the COVID-19 MM patients, 6 (20.7%) were in sCR/CR, 6 (20.7%) in VGPR, 12 (41.4%) patients in PR, 2 (6.9%) in MR/SD and one (3.5%) in PD at the time of confirmed infection. Among the vaccinated MM group, 10 (34.5%) patientswere in sCR/CR, 4 (13.8%) in VGPR, 11 (37.9%) in PR, one (3.5%) in MR/SD and one (3.5%) in PD at the time of vaccination (p-value=0.93 for the comparison between COVID-19 and vaccinated MM groups). No differences between COVID-19 and vaccinated MM patients were also noted regarding the median lymphocyte count (1200/μl versus 1400/μl, respectively, p=0.08) and the median immunoglobulin values (IgG 732 mg/dl versus 747 mg/dl, respectively, p=0.29;IgA 9 mg/dl versus 61 mg/dl, respectively, p=0.7;IgM 26 mg/dl versus 25 mg/dl, p=0.97). The incidence of comorbidities was also similar between the two groups (cardiovascular diseases 55.2% versus 44.8%, respectively, p=0.47;diabetes mellitus 66.7% versus 33.3%, p=0.28;chronic pulmonary disease 50% each, p=1.0). Interestingly, patients with MM and COVID-19 showed a superior humoral response compared with vaccinated MM patients. The median (IQR) NAb titers were 87.6% (IQR: 71.6-94) and 58.7% (21.4-91.8) for COVID-19 and for vaccinated MM patients, respectively (p=0.01). In both groups, 27 out of 35 patients were receiving active treatment for MM at the time of NAb evaluation. The median NAb titer was 88% (IQR 71.6%-96.3%) for COVID-19 MM patients and 35.4% (IQR 17.5%-85.5%) for vaccinated MM patients who received anti-myeloma therapy (p=0.001). Importantly, there was no difference in NAb production between COVID-19 and vaccinated MM patients who did not receive any treatment (median NAb titers, 85.1% versus 91 7%, p=0.14). Conclusion: Patients with MM and COVID-19 present a superior NAb response against SARS-CoV-2 compared with fully vaccinated patients with the BNT162b2 vaccine. This finding was more pronounced among patients receiving active treatment for MM. In this context, additional booster doses may be considered for MM patients with poor humoral response after the BNT162b2 vaccine. [Formula presented] Disclosures: Gavriatopoulou: Genesis: Honoraria;Karyopharm: Honoraria;Takeda: Honoraria;Janssen: Honoraria;Sanofi: Honoraria;GSK: Honoraria;Amgen: Honoraria. Terpos: BMS: Honoraria;Celgene: Consultancy, Honoraria, Research Funding;Sanofi: Consultancy, Honoraria, Research Funding;Takeda: Consultancy, Honoraria, Research Funding;Janssen-Cilag: Consultancy, Honoraria, Research Funding;GSK: Honoraria, Research Funding;Novartis: Honoraria;Genesis: Consultancy, Honoraria, Research Funding;Amgen: Consultancy, Honoraria, Research Funding. Kastritis: Amgen: Consultancy, Honoraria, Research Funding;Genesis Pharma: Honoraria;Janssen: Consultancy, Honoraria, Research Funding;Pfizer: Consultancy, Honoraria, Research Funding;Takeda: Honoraria. Dimopoulos: Amgen: Honoraria;BMS: Honoraria;Janssen: Honoraria;Takeda: Honoraria;BeiGene: Honoraria.

The Compass-COVID19-ICU Study: Identification of Factors to Predict the Risk of Intubation and Mortality in Patients with Severe COVID-19

Background: In some patients, SARS-CoV-2 infection induces cytokine storm, hypercoagulability and endothelial cell activation leading to worsening of COVID-19, intubation and death. Prompt identification of patients at risk of intubation or death is un unmet need. Objective: To derive a prognostic score for the risk of intubation or death in patients with critical COVID-19 by assessing biomarkers of hypercoagulability, endothelial cell activation and inflammation and a large panel of clinical analytes. Methods: We conducted a prospective, observational monocentric study enrolling 118 patients with COVID-19 admitted in the intensive care unit. At the 1st day of ICU admission all patients were assessed for the following biomarkers : protein C, protein S, antithrombin, D-Dimer, fibrin monomers, factors VIIa, V, XII, XII, VIII, von Willebrand antigen, fibrinogen, procoagulant phospholipid dependent clotting time, TFPI, thrombomodulin, P-selectin, heparinase, microparticles exposing tissue factor, IL-6, complement C3a, C5a, thrombin generation, prothrombin time, activated partial thromboplastin time, hemogram, platelet count) and clinical predictors. The clinical outcomes were intubation and mortality during hospitalization in ICU. Results: The intubation and mortality rate were 70 % and 18% respectively. Multivariate analysis led to the derivation of the COMPASS- COVID19-ICU score composed of P-Selectin, D-Dimer, free TFPI, TF activity, IL-6 and FXII, age and duration of hospitalization. The score predicted the risk of intubation or death with high sensitivity and specificity (0.90 and 0.92, respectively). Conclusions and Relevance: Critical COVID-19 is related with severe endothelial cell activation and hypercoagulability orchestrated in the context of inflammation. The COMPASS-COVID19-ICU score is an accurate predictive model for the evaluation of the risk of mechanical ventilation and death in patients with critical COVID-19. The assessment with the COMPASS- COVID-19-ICU score is feasible in tertiary hospitals. In this context it could be placed in the diagnostic procedure of personalized medical management and prompt therapeutic intervention. Disclosures: Terpos: Novartis: Honoraria;Janssen: Consultancy, Honoraria, Research Funding;Genesis: Consultancy, Honoraria, Research Funding;Celgene: Consultancy, Honoraria, Research Funding;BMS: Honoraria;Amgen: Consultancy, Honoraria, Research Funding;Takeda: Consultancy, Honoraria, Research Funding;Sanofi: Consultancy, Honoraria, Research Funding;GSK: Honoraria, Research Funding. Dimopoulos: Amgen: Honoraria;BMS: Honoraria;Takeda: Honoraria;Beigene: Honoraria;Janssen: Honoraria.

Antibody Response after Vaccination for Sars-Cov-2 in Patients with AL Amyloidosis and the Impact of Therapy

Patients with lymphoproliferative disorders are at high risk for severe COVID-19. For patients with AL amyloidosis, in which there is also critical organ involvement, this risk may be even higher. Vaccination against SARS-CoV-2 is the best strategy to avoid severe COVID-19, but response to vaccines may be compromised in patients with B-cell lymphoproliferative or plasma cell malignancies, as in AL amyloidosis. Although modest in size, the plasma cell clone in AL may cause immunosuppression while anticlonal therapies further compromise immune responses. To evaluate immunization efficacy, we measured the titers of neutralizing antibodies (NAbs) against SARS-CoV-2 after vaccination with BNT162b2 in patients with AL amyloidosis. As a control group we used volunteers, matched (ratio 1:2) for age and gender, who had no autoimmune or active malignant or infectious disease. Serum was separated within 4 hours from blood collection and stored at -80°C until the day of measurement on (A) day 1 (D1;before the first dose of BNT162b2) (B) day 22 (D22;before the 2nd dose) and (C) day 50 (D50;ie 30 days after the 2nd dose). NAbs against SARS-CoV-2 were measured using FDA approved methodology (cPass™ SARS-CoV-2 NAbs Detection Kit;GenScript, Piscataway, NJ, USA). According to the manufacturer of the assay, a titer ≥ 50% is considered a clinically relevant threshold for viral inhibition. The study included 144 patients with AL amyloidosis, of which 120 had NAbs titers assessed on all time points and were included in the final analysis (53% males;median age: 66, IQR: 57-72 years) and 240 matched controls (53% males;median age: 66, IQR: 57-72 years). 66 (55%) AL patients were on active therapy, 17.5% were on daratumumab (DARA)-based therapy, 52 (43%) had discontinued therapy >3 months from the date of the first shot, 19% had prior exposure to DARA and 94 (78%) were in hematologic remission (CR or VGPR). Prior to the 1st dose (D1), NAb titers were similar between patients and controls (median 14.9% (IQR 7.8-23.1%) vs 14% (IQR 6.8-22.9%), p=0.439);6 AL patients had baseline NAbs >50%, of which 5 reported a history of COVID-19 infection. On D22, there was a significant increase of NAbs titers both in controls and AL patients (both p<0.001);however, median NAb titer was 23.6% (IQR 12.4-37.7%) in AL patients vs 47.5% (IQR 32.1-62.7%) in controls (p<0.001) and 20.5% of AL patients vs 46.7% of controls (p<0.001) developed NAb titers ≥50%. On D50, there was further increase in NAbs titers both in controls and AL patients (both p<0.001) and median NAb titer for AL patients was 83.1% (IQR 41.5-94.9%) vs 95.6% (IQR 91.7-97.2%) in controls (p<0.001);71% of AL patients vs 98% of matched controls (p<0.001) developed NAb titers ≥50%. Among AL patients, factors associated with NAb titers on D50 included age (p<0.001), lymphocyte counts (p<0.001), serum albumin (p<0.001) and amount of proteinuria at the time of vaccination (p=0.047), renal involvement (p=0.047), use of steroids (p<0.001), active treatment (p<0.001), treatment-free interval (p=0.001), remission status (CR/VGPR) (p=0.018). There was no significant association with gender (p=0.092), BMI (p=0.198), IgG (0.099), IgA (p=0.789) or IgM levels (p=0.687), liver (p=0.521) or heart involvement (p=0.141). Patients on therapy had lower NAb titers at D50 (median 50.1% (IQR 25.3-84.1%) vs 91.6% (IQR 74.5-96.5%) for those not on treatment, p<0.001), so that 51% had a D50 NAb titer ≥50% vs 87% of those not on therapy. Current DARA therapy (median 52.1% vs 46.4% without DARA, p=0.486) or prior exposure to DARA (92.1% vs 91.2%, p=0.966) were not associated with D50 NAb titers. Generalized linear models were used for evaluation of multiple factors associated with D50 NAb titers: at least 3 months since the last dose of anticlonal therapy (p<0.001), lymphocyte counts (p=0.001) and serum albumin levels at the time of vaccination (p=0.020) were independent predictors of NAb titers on D50. When seroconversion was defined as a NAb titer ≥50% at D50, then >3 months of treatment-free interva (HR:7.75, p<0.001,) was the strongest factor associated with seconversion. In conclusion, patients with AL amyloidosis have an attenuated response to vaccination with BNT162b2 especially among those on active therapy or with less than 3 months since the last dose of treatment. For such patients, an anamnestic dosing strategy could be considered, especially after completion of anticlonal therapy. [Formula presented] Disclosures: Kastritis: Genesis Pharma: Honoraria;Janssen: Consultancy, Honoraria, Research Funding;Takeda: Honoraria;Pfizer: Consultancy, Honoraria, Research Funding;Amgen: Consultancy, Honoraria, Research Funding. Terpos: Novartis: Honoraria;Janssen: Consultancy, Honoraria, Research Funding;Genesis: Consultancy, Honoraria, Research Funding;Celgene: Consultancy, Honoraria, Research Funding;BMS: Honoraria;Amgen: Consultancy, Honoraria, Research Funding;Takeda: Consultancy, Honoraria, Research Funding;Sanofi: Consultancy, Honoraria, Research Funding;GSK: Honoraria, Research Funding. Gavriatopoulou: Sanofi: Honoraria;GSK: Honoraria;Karyopharm: Honoraria;Takeda: Honoraria;Genesis: Honoraria;Janssen: Honoraria;Amgen: Honoraria. Dimopoulos: Amgen: Honoraria;BMS: Honoraria;Janssen: Honoraria;Takeda: Honoraria;BeiGene: Honoraria.

Safety of Daratumumab Combined with Bortezomib, Cyclophosphamide and Dexamethasone for the Treatment of Patients with Multiple Myeloma Presenting with Extramedullary Disease during the COVID-19 Pandemic

Introduction: Extramedullary disease (EMD) in patients (pts) with multiple myeloma (MM) is a poor prognostic feature which is not curable with currently approved treatments. Consequently, there is a significant unmet need for effective therapies with good safety profiles. Daratumumab with cyclophosphamide, bortezomib and dexamethasone (daraVCD) is a novel treatment combination with a good efficacy profile in pts with EMD based on preclinical synergistic data. Methods: EMN19 is a phase 2, open-label, multicenter study which aims to enroll 40 MM pts presenting with EMD either at diagnosis or following one line of treatment but not refractory to bortezomib-based regimens, from 8 sites in Turkey, Greece and Italy. Pts with bortezomib or daratumumab hypersensitivity, who received previous autologous stem cell transplant (ASCT) ≤12 weeks before Day 1 of treatment Cycle 1, or with previous allogenic stem cell transplant were excluded. Daratumumab was initially administered intravenously at 16 mg/mL, and since July 2020 has been administered subcutaneously at a fixed dose of 1800 mg, weekly during Cycles 1-2, every 2 weeks for Cycles 3-6, and every 4 weeks thereafter. Intravenous bortezomib 1.5 mg/m 2 and oral/intravenous cyclophosphamide 300 mg/m 2 is administered weekly, and oral/intravenous dexamethasone 20 mg is administered on Days 1, 2, 8, 9, 15, 16, 22 and 23. DaraVCD will be administered until progression or unacceptable toxicity unless refractory disease is detected by the end of Cycle 3 (progressive disease [PD] or failure to achieve a confirmed partial response [PR] or better). The present analysis includes pts who initiated study treatment ≥3 months prior to the cut-off date (01 June 2021). Results: In total, 34 patients were screened, 27 patients were enrolled, 2 relapsing patients died during the screening phase due to severe COVID-19 infection, 22 pts were analyzed (59% female;median age 56 years, range 44-77);14 pts (64%) were still on treatment and 8 (36%) discontinued;due to inadequate response after 3 cycles of treatment (n=3, 38%), PD (n=4, 50%), death (n=1, 13%). Fourteen pts (64%) were newly diagnosed and 8 (36%) first relapsed. International Staging System stage at baseline was I, II and III for 8 (36%), 9 (41%) and 5 (23%) pts, respectively. Eastern Cooperative Oncology Group performance status was 0, 1 and 2 for 14 (64%), 7 (32%), and 1 patient (5%), respectively. On average, 3.0 (range 1-20) extramedullary plasmacytomas were observed per patient;most commonly reported sites were thorax (6 pts, 27%), brain, head and lower extremities (4 pts, 18% each). Twenty (91%) pts had ≥1 serious or non-serious treatment-emergent adverse event (TEAE);8 pts (36.4%) experienced ≥1 sTEAEs;COVID-19 infection (n=3, 14%) urinary tract infection (n=2, 9%), infectious myocarditis, hip arthroplasty, pneumonia, cytomegaloviral pneumonia and thrombocytopenia (n=1 each, 4.5%). Thirteen (59%) pts ≥1 Grade 3/4 TEAE;neutropenia observed in 8 pts (36%), followed by thrombocytopenia (n=4, 18%) and COVID-19 infection (n=3, 14%). Overall, 16 (73%) pts missed ≥1 dose of any of the study drugs;2 (9%) pts missed ≥1 dose due to COVID-19 infection (7 doses), 8 (36%) due to COVID-19 vaccination (37 doses), 2 (9%) due to other COVID-19-related issues (65 doses), 10 (46%) due to other safety events (104 doses) and 9 (41%) due to other reasons (25 doses). Overall, 20 cycle delays were observed in 13 (59%) pts, with median (range) delay of 12.0 (4-133) days. Two pts (9%) had a cycle delay due to COVID-19 infection (2 cycles), 1 (5%) due to COVID-19 vaccination (1 cycle), 5 (23%) due to adverse events (8 cycles), 2 (9%) due to ASCT (2 cycles) and 7 (32%) due to other reasons (7 cycles). Total number of missed doses (missed doses due to COVID-19-related issues) were 17 (3) for daratumumab, 53 (11) for bortezomib, 45 (9) for cyclophosphamide and 123 (86) for dexamethasone;238 doses missed in total. No fatalities occurred due to any infection. Conclusions: DaraVCD was associated with a good safety profile in this high ri k MM with EMD patient population. The COVID-19 impact on missed doses was greater for dexamethasone (>60% of missed doses) than other components (~20%), however overall, the pandemic did not significantly affect the patients' safety and data integrity of the study. The enrollment in the study is ongoing, and more safety and efficacy data will become available with the inclusion of additional pts in an updated analysis. Disclosures: Beksac: Amgen,Celgene,Janssen,Takeda,Oncopeptides,Sanofi: Consultancy, Speakers Bureau. Tuglular: GSK: Honoraria, Research Funding;Amgen: Honoraria, Research Funding;Karyopharm: Honoraria, Research Funding;Abbvie: Honoraria, Research Funding;Janssen-Cilag: Honoraria, Research Funding;Genesis Pharma: Honoraria, Research Funding;Sanofi: Honoraria, Research Funding. Cavo: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Novartis: Honoraria;Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;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, EXPENSES, Speakers Bureau;Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;GlaxoSmithKline: Consultancy, Honoraria;AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Bristol-Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Adaptive Biotechnologies: Consultancy, Honoraria. Gay: GSK: 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;AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees;Roche: Membership on an entity's Board of Directors or advisory committees;Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees;Takeda: 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;Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees;Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees;Oncopeptides: Membership on an entity's Board of Directors or advisory committees;Bluebird bio: Membership on an entity's Board of Directors or advisory committees. Katodritou: GSK, Amgen, Karyopharm, Abbvie, Janssen-Cilag, Genesis Pharma, Sanofi: Honoraria, Research Funding. Merante: EMN Italy Medical Monitor: Research Funding. Manousou: Health Data Specialists: Current Employment. Sonneveld: Karyopharm: Consultancy, Honoraria, Research Funding;Janssen: Consultancy, Honoraria, Research Funding;Celgene/BMS: Consultancy, Honoraria, Research Funding;SkylineDx: Honoraria, Research Funding;Takeda: Consultancy, Honoraria, Research Funding;Amgen: Consultancy, Honoraria, Research Funding. Terpos: GSK: Honoraria, Research Funding;Celgene: Consultancy, Honoraria, Research Funding;Genesis: Consultancy, Honoraria, Research Funding;Novartis: Honoraria;Janssen-Cilag: Consultancy, Honoraria, Research Funding;Amgen: Consultancy, Honoraria, Research Funding;BMS: Honoraria;Takeda: Consultancy, Honoraria, Research Funding;Sanofi: Consultancy, Honoraria, Research Funding.