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Lung involvement in AL amyloidosis is not very common, but post-mortem data and retrospective studies suggest it is likely underrecognized.To perform a comprehensive evaluation of lung function with pulmonary function tests (PFTs) in patients with newly diagnosed AL amyloidosis.A prospective, non-interventional study of 139 consecutive patients with newly diagnosed AL amyloidosis.PFTs indicated normal breathing physiology in 68% of patients, obstructive in 9% and restrictive in 23%; the latter was associated with worse survival (28.6 vs 76 months for obstructive/normal physiology,Pulmonary dysfunction, as assessed with PFTs, is common and underrecognized in patients with systemic AL amyloidosis, with significant prognostic and potentially therapeutic implications, independent of the degree of cardiac dysfunction or chest-CT findings.

Aim Ubiquitin-Proteasome System (UPS) is of paramount importance regarding the function of the myocardial cell. Consistently, inhibition of this system has been found to affect myocardium in experimental models; yet, the clinical impact of UPS inhibition on cardiac function has not been comprehensively examined. Our aim was to gain insight into the effect of proteasome inhibition on myocardial mechanics in humans. Methods and results We prospectively evaluated 48 patients with multiple myeloma and an indication to receive carfilzomib, an irreversible proteasome inhibitor. All patients were initially evaluated and underwent echocardiography with speckle tracking analysis. Carfilzomib was administered according to Kd treatment protocol. Follow-up echocardiography was performed at the 3rd and 6th month. Proteasome activity (PrA) was measured in peripheral blood mononuclear cells. At 3 months after treatment, we observed early left ventricular (LV) segmental dysfunction and deterioration of left atrial (LA) remodelling, which was sustained and more pronounced than that observed in a cardiotoxicity control group. At 6 months, LV and right ventricular functions were additionally attenuated (P < 0.05 for all). These changes were independent of blood pressure, endothelial function, inflammation, and cardiac injury levels. Changes in PrA were associated with changes in global longitudinal strain (GLS), segmental LV strain, and LA markers (P < 0.05 for all). Finally, baseline GLS < −18% or LA strain rate > 1.71 were associated with null hypertension events. Conclusion Inhibition of the UPS induced global deterioration of cardiac function.

Numerical abnormalities of chromosome 1q (+1q21) are common in patients with newly diagnosed multiple myeloma (MM) but their prognostic impact remains a matter of debate. In addition, the impact of the number of copies of 1q21 is not known. We analyzed 912 consecutive patients with symptomatic MM to evaluate the prognostic implications of +1q21 and of their copy number variations, as assessed by FISH. At the time of initial diagnosis, 249 (27.3%) patients had +1q21, of which 150 (16.4%) had 3 copies and 99 (10.9%) had 4 or more copies. Presence of +1q21 was associated with advanced ISS stage (p = .003), concurrent presence of other cytogenetics aberrations and advanced R-ISS stage (p .001). Patients with +1q21 had inferior PFS (median 34 vs. 20 months, p .001) and OS (median 75 vs. 44 months, p .001) but the copy number of 1q21 had no additional prognostic impact. In multivariate analysis, adjusting for R-ISS, age, treatment and HDM, +1q21 remained an independent prognostic factor both for PFS (p .001) and OS (p = .008). The detrimental prognostic effect of +1q21 was more profound in R-ISS-3 patients, identifying a subgroup with OS of just 16 months (vs. 46 for R-ISS-3 without +1q21, p .001). We further validated our findings in an independent cohort of 272 patients. In conclusion, the presence of +1q21 is associated with more advanced disease, inferior PFS, and OS but especially patients with R-ISS-3 disease and +1q21 have a very poor outcome comprising an ultra-high-risk group.

Immunocompromised patients with hematologic malignancies are more susceptible to COVID-19 and at higher risk of severe complications and worse outcomes compared with the general population. In this context, we evaluated the humoral response by determining the titers of neutralizing antibodies (NAbs) against SARS-CoV-2 in patients with Waldenström macroglobulinemia (WM) after vaccination with the BNT162b2 or AZD1222 vaccine. A US Food and Drug Administration–approved enzyme-linked immunosorbent assay–based methodology was implemented to evaluate NAbs on the day of the first vaccine shot, as well as on days 22 and 50 afterward. A total of 106 patients with WM (43% men; median age, 73 years) and 212 healthy controls (46% men; median age, 66 years) who were vaccinated during the same period at the same center were enrolled in the study (which is registered at www.clinicaltrials.gov as #NCT04743388). Our data indicate that vaccination with either 2 doses of the BNT162b2 or 1 dose of the AZD1222 vaccine leads to lower production of NAbs against SARS-CoV-2 in patients with WM compared with controls on days 22 and 50 (P < .001 for all comparisons). Disease-related immune dysregulation and therapy-related immunosuppression are involved in the low humoral response. Importantly, active treatment with either rituximab or Bruton’s tyrosine kinase inhibitors was proven as an independent prognostic factor for suboptimal antibody response after vaccination. In conclusion, patients with WM have low humoral response after COVID-19 vaccination, which underlines the need for timely vaccination ideally during a treatment-free period and for continuous vigilance on infection control measures.

Background: Carfilzomib, an irreversible proteasome inhibitor approved for the treatment of relapsed/refractory Multiple Myeloma (MM) has been associated with Thrombotic Microangiopathy (TMA). Several pathogenetic mechanisms of carfilzomib-induced TMA have been proposed; however, recently, there has been a shift of focus on the potential contribution of complement dysregulation. Our aim was to explore whether patients with carfilzomib-induced TMA harbor germline variants of complement-related genes, which have been characterized as risk factors for TMA. Methods: We retrospectively recruited consecutive MM patients with carfilzomib-induced TMA and compared them to MM patients who received ≥4 cycles of carfilzomib and did not develop signs/symptoms of TMA, in a 1:2 ratio. Genomic DNA from peripheral blood was analyzed using next generation sequencing (NGS) with a complement-related gene panel; ADAMTS13 activity and soluble C5b-9 were measured using ELISA. Results: Complement-related variants were more common in patients with carfilzomib-induced TMA compared to non-TMA controls, regardless of patient and treatment characteristics; ADAMTS13 activity and C5b-9 were compatible with the phenotype of complement-related TMA. Conclusions: We confirmed the previous findings that implicated complement-related genes in the pathogenesis of carfilzomib-induced TMA. Most importantly, by incorporating a control group of non-TMA MM patients treated with carfilzomib-based regimens and functional complement assays, we enhanced the credibility of our findings.

Contemporary information is sparse on the frequency of skeletal-related events (SREs) in multiple myeloma (MM) patients at a population-based level in the era of novel agents. In this context, we conducted this single-center, prospective, observational study to determine the incidence of SREs among newly diagnosed MMs (NDMM) and to explore the possible correlations with disease characteristics, imaging finding, and patient prognosis. A total of 370 patients with available baseline MRIs were included. Among them, 208 (56%) presented with at least one SRE at diagnosis. Fractures were the most common reported SREs (48%). The incidence of SREs at diagnosis was higher in patients with osteolytic lesions, abnormal MRI pattern, hypercalcemia, and at least 60% bone marrow infiltration by plasma cells. Importantly, the patients with normal MRI pattern, who did not present with SREs at diagnosis, had statistically significant improved median OS in comparison with the patients who had abnormal MRI patterns and/or the presence of SREs at diagnosis (9.3 vs. 6.6 years, p = 0.048). Our data, which represent one of a few systematic reports on the incidence and characteristics of SREs in the era of novel agents, was indicative of a high incidence of SREs at the time of MM diagnosis. Early detection of myeloma bone disease and tailored patient management are essential to optimize patient outcomes.

Introduction: Multiple myeloma (MM) is consistently preceded by two precursor conditions, monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). The distinctions between MGUS, SMM, and MM rely on clinical values with inherent variation relating to tumor burden quantified from bone marrow biopsies, a measure subject to inconsistencies in location, timing, and pathologist interpretation. These challenges limit the potential of current standardized risk criteria and advocate for models that examine precursor disease kinetics. We thus developed a risk model that leverages dynamic changes in markers of precursor disease to improve clinical ability to predict time to disease progression. Methods: To model the evolution of progression risk, we built PANGEA, an international retrospective cohort of precursor patients with baseline and serial time points of clinical and biological variables. This cohort comprises 1095 SMM patients, 254 (23%) of which progressed to MM. Using this cohort, we modeled progression to MM with Cox regression using time-dependent and continuous clinical variables. The model was trained on a subset of data restricted to patients of the Dana-Farber Cancer Institute (DFCI) and validated its performance by computing the c-statistic in a sub-cohort independent from the DFCI training cohort. Results: The PANGEA cohort was first used to validate current models of SMM disease progression. We validated the 20/2/20 International Myeloma Working Group criteria for SMM patients using binary cutoffs of initial measurements (baseline model), and then extended this model, allowing for re-stratification by the 20/2/20 criteria over time (dynamic model). We then assessed whether rates of change in a set of myeloma-specific clinical variables unrestricted to those of the 20/2/20 criteria improved the predictive ability of the model. This improved our progression prediction as indicated by a c-statistic increase of more than 10% with respect to both 20/2/20 models (baseline and dynamic). Specifically, changes in disease indicators such as age and creatinine are highly predictive of imminent disease progression (p-value < 0.01). Finally, we clustered patients based on latent trajectories of these time-varying clinical variables and included the trajectory classes in the Cox regression. The resulting multivariable, dynamic algorithm is a dramatic improvement over current clinical standards in predicting progression from SMM to MM disease. Conclusion: The PANGEA multivariable algorithm’s use of continuous clinical variables enhances progression risk predictions in SMM. These findings demonstrate that disease progression from SMM to MM, which likely occurs by the acquisition of sequential changes to the plasma cell clone, can be tracked by trends in clinical values, thus improving prognostication for precursor patients. Citation Format: Annie Cowan, Habib El-Khoury, Federico Ferrari, Samuel S. Freeman, Robert Redd, Jacqueline Perry, Vidhi Patel, Priya Kaur, Hadley Barr, Katelyn Downey, David Argyelan, Anna V. Justis, David J. Lee, Elizabeth D. Lightbody, Foteini Theodorakakou, Despina Fotiou, Nikolaos Kanellias, Christine Liacos, Gad Getz, Lorenzo Trippa, Catherine Marinac, Efstathios Kastritis, Dimopoulos Meletios, Irene Ghobrial. Predictive modeling of smoldering multiple myeloma progression to multiple myeloma by continuous variable analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2259.

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 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 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 against 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.

Despite significant improvements in myeloma (MM) therapies, patients (pts) refractory to immunomodulatory agents (IMiDs), proteasome inhibitors (PIs) and anti-CD38 monoclonal antibodies (mAbs) have poor prognosis and limited treatment options. Daratumumab (DARA), an anti-CD38 mAb, is active in pts with relapsed/refractory MM through mechanisms that include complement-dependent and antibody-dependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis, apoptosis and immunomodulation. DARA + IMiDs have substantial efficacy, probably through the combination of their immune and microenvironmental effects. The mechanisms of resistance are not fully elucidated but resistance to DARA may be reversed by addition of IMiDs and vice versa, as previously shown (Gavriatopoulou Blood 2019, Nooka Cancer 2019). We prospectively evaluated the combination of DARA + IMiD following refractoriness to both agents, to assess clinical activity but also to longitudinally assess immune cell populations in the peripheral blood (PB) in order to understand the resulting immunomodulation. Consecutive PB samples from 35 pts refractory to an IMiD (LEN or POM) and progressing on DARA monotherapy were analyzed. The last IMiD on which each patient was refractory was added without modulating DARA backbone (RESET). In consenting pts, PB samples were collected at the time of DARA initiation, at progression to DARA monotherapy and IMiD addition, at response and at progression to DARA-IMiD. Samples were viably frozen and analyzed using specific two 8-color panels. Panel 1: CD38-FITC, Granzyme B-PE, CD127-PeCy7, CD25-APC, CD4-APCCy7, CD3-BV510, Lag-3-BV421 and 7-AAD as viability dye; panel 2: CD14-FITC, CD56-PE, CD66-b-PeCy7, CD80-APC, CD45-APCCy7, CD3/CD19-BV510, CD16-BV421 and 7-AAD as viability dye. Pts' median age was 73 years (range 52-86; 66% male); median prior treatment lines were 3 (range 1-16); all had prior exposure and refractoriness to at least one PI; all were refractory to LEN and 51% to POM, 40% had prior ASCT. The IMiD added was the last used prior to DARA, i.e., LEN in 49% (17/35) and POM in 51% (18/35). Median duration of DARA monotherapy prior to RESET was 7.9 months (range 1-38) and 64% responded (≥PR) before progression. Median duration of RESET therapy was 5.5 months (range 0.46 to 23.86) and 43% had ≥PR (≥MR: 60%) [including VGPR: 8.6% (n=3), PR: 34.3% (n=12), MR: 17.1% (n=6), SD/NR: 28.6% (n=10), PD: 11.4% (n=4)]. Median PFS was 5 months (95% CI 1.5-8.4) and median OS was 19 months (95% CI 13.5-24.5). Based on response at 3-month landmark, PFS was 9 months for pts who achieved ≥ PR vs 4 months for < PR (p=0.031). PFS and response to RESET were independent of type or dose of IMiD, prior response to DARA monotherapy or IMiD, number of prior treatments, ISS at diagnosis or at time of RESET. Multivariate flow cytometry analysis showed significant heterogeneity between pts (n=20). After DARA monotherapy there was an increase in CD8+ T cells compared to baseline which persisted throughout DARA-containing therapy with CD4+ T remaining at similar levels at all time-points. Total Tregs reduced after DARA start; however, within Tregs the relative proportion of Lag3+ Tregs tended to increase during DARA monotherapy. NK cell levels were significantly reduced after DARA and remained low throughout DARA therapy, with no recovery after IMiD addition; within NKs, we noticed an increase of CD16-/CD56+ immunomodulatory/cytokine producing and, to a lesser extent, of CD56-/CD16+ cytotoxic subsets compared to mature CD56+/CD16+ NK cells which tended to decrease, especially during DARA monotherapy. Although the samples at response to DARA/IMiD combination are few (n=10), CD56-CD16+ NK cell percentages at the time of progression to DARA were associated with response to DARA/IMiD. Finally, there was a noticeable increase in M1- and a decrease in M2-type macrophage subsets at response to DARA/IMiD. In conclusion, retaining DARA backbone therapy may be associated with clinically relevant activity (ORR 43%, 5 months median PFS) among pts refractory toDARA and IMiD, when these drugs are combined. Longitudinal evaluation of PB immune cell composition showed DARA-specific immunomodulation, which was not altered after addition of IMiDs, but may be related to restoration of sensitivity to the DARA/IMiD combination. Further investigation is in progress to reveal potential immune signatures of clinical relevance. Disclosures Krevvata: Janssen: Current Employment. Gavriatopoulou: Genesis: Honoraria; GSK: Honoraria; Karyopharm: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Amgen: Honoraria. Terpos: Amgen: Consultancy, Honoraria, Research Funding; BMS: Honoraria; Sanofi: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Genesis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; GSK: Honoraria, Research Funding. Dimopoulos: Amgen: Honoraria; BMS: Honoraria; Janssen: Honoraria; Takeda: Honoraria; BeiGene: Honoraria. Kastritis: Pfizer: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Honoraria.

Background: The combination of lenalidomide with dexamethasone (Rd) represents a preferred treatment backbone for newly diagnosed, transplant-ineligible patients (pts) with multiple myeloma (MM), while the addition of a third drug (i.e., daratumumab, bortezomib, carfilzomib or ixazomib) leads to higher response rates and deeper responses. Belantamab mafodotin (belamaf; GSK2857916) is a multi-modal antibody-drug conjugate that has demonstrated a clinically meaningful anti-myeloma activity with a manageable safety profile in heavily pre-treated pts with relapsed or refractory MM. Preclinical evidence suggest a potential synergy between belamaf and lenalidomide; at the same time, these drugs do not have overlapping toxicities. Thus, there is strong rationale for investigating the clinical activity of upfront belamaf in combination with Rd in transplant-ineligible MM pts. Aims: The present analysis evaluates the safety profile of belamaf in 3 different dosing schemes in combination with Rd in treatment-naïve, transplant-ineligible MM pts. Methods: BelaRd (study short title) is an open-label, single-center, phase 1/2 study conducted in Greece, aiming to enroll 66 newly diagnosed, transplant-ineligible MM pts. The study comprises 2 parts. Part 1 will evaluate 3 doses of belamaf (2.5, 1.9, and 1.4 mg/kg) in combination with Rd, each given in an individual cohort of pts, and will determine the recommended phase 2 dose (RP2D). In this part, belamaf will be administered q8w and, depending on toxicity, dosing may be rescheduled to q4w or q12w. In Part 2, a single cohort of pts will be treated with belamaf in the RP2D in combination with Rd to further evaluate the safety and clinical activity of this regimen. Part 2 will also evaluate 2 different sets of guidelines for ocular adverse events (AEs) in 2 separate groups of pts to identify the optimal method for the management of belamaf-related keratopathy. This is the initial safety analysis of Part 1 and includes pts who received ≥1 belamaf dose and were followed up for ≥8 weeks. Results: Overall, as of 16 July 2021 (cut-off date), 18 pts completed the dose-limiting toxicity (DLT) observation period, defined as specific ≥ grade 3 AEs occurring during the first cycle of study treatment, and were included in the safety analysis. The median age was 72 years (range: 65-82), and the majority of pts were male (55.6%). Lytic bone lesions were present in 12 (66.7%) pts; no pts had extramedullary disease. Most pts (9, 50.0%) had Eastern Cooperative Oncology Group performance status 0 followed by those at 1 (8, 44.4%) and 2 (1, 5.6%). Regarding the revised International Staging System, most pts (13, 72.2%) were at stage II, followed by those at stages III (2, 11.1%) and I (3, 16.7%); 3 (16.7%) pts had high-risk cytogenetics, defined as del17p13, t(4;14) or t(14;16). By the cut-off date, pts had received a median of 4 treatment cycles, with 17 (94.4%) pts still being on treatment; 1 (5.6%) pt died due to pneumonia, unrelated to the study treatment. 16 (88.9%) pts experienced ≥1 treatment emergent adverse event (TEAE). In total, 11 (61.1%) pts had ≥1 TEAE grade 3/4, of which 1 was related to belamaf; 1 (5.6%) pt experienced a serious adverse event (SAE). There were 2 cases of dose reduction and 1 case of dose delay. The most common grade 3/4 TEAEs were fatigue (5 pts, 27.8%) and rash (4 pts, 22.7%), all related to lenalidomide. One SAE was reported: pneumonia grade 5 in the 2.5 mg/kg cohort. DLTs were noted in 3 (16.7%) pts: 1 pt with grade 3 fatigue in the 1.4 mg/kg cohort and 1 pt with grade 3 rash in each of the 1.9 and 1.4 mg/kg cohorts, all related to lenalidomide. Regarding belamaf-related ocular AEs, there were 2 cases of superficial punctuate keratopathy (grade 1 and 2 each, both in the 2.5 mg/kg cohort), 10 cases of decreased visual acuity (grade 1 [8 pts, 44.4%]: 4 in the 1.9 mg/kg cohort and 4 in the 1.4 mg/kg cohort; grade 2 [2 pts, 11.1%] in the 2.5 mg/kg cohort), and 1 case of grade 1 blurred vision in 2.5 mg/kg cohort. Conclusions: In the first safety analysis of the BelaRd study no new safety signals for the belamaf-Rd combination were observed. The frequency of ocular AEs was within the anticipated range. This early analysis shows that the triplet combination can be safely administered in treatment-naïve, transplant-ineligible MM pts. 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 Terpos: Novartis: Honoraria; Sanofi: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Genesis: Consultancy, Honoraria, Research Funding; GSK: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; BMS: Honoraria. Gavriatopoulou: Janssen: Honoraria; Takeda: Honoraria; Karyopharm: Honoraria; GSK: Honoraria; Genesis: Honoraria; Sanofi: Honoraria; Amgen: Honoraria. Gkolfinopoulos: Health Data Specialists: Current Employment. Manousou: Health Data Specialists: Current Employment. Dimopoulos: Janssen: Honoraria; Beigene: Honoraria; Takeda: Honoraria; BMS: Honoraria; Amgen: Honoraria.

Introduction: Advances in induction regimens have significantly improved depth of response and duration of remission in multiple myeloma (MM) patients who are eligible for high-dose therapy and autologous stem cell transplantation (ASCT). Proteasome inhibitor-based induction regimens are standard as part of induction and it has been shown not to have any detrimental effect on stem cell (SC) collection and engraftment. Daratumumab (DARA) is an IgG1k monoclonal antibody directed against CD38 with potent antimyeloma activity. Based on the results of prospective studies DARA is now approved as part of induction therapy. Available data indicate a potential impact of DARA on SC collection but there is limited data on engraftment, duration of hospitalization and infection risk. In this retrospective analysis we evaluated the effect of DARA-based induction on ASCT parameters. Methods: The analysis included consecutive newly diagnosed MM patients that received ASCT between 2016 and 2020, as part of their upfront treatment regimen in our institution (Department of Clinical Therapeutics, Athens, Greece). Per institutional protocol, after 4-6 cycles of induction, pts received low dose cyclophosphamide (2.5 g/m2) followed by G-CSF (10 mcg/Kg/day) to mobilize and collect SCs. Plerixafor was administered on-demand in case of poor mobilization and insufficient first day collection. Large volume leukapheresis was performed in pts with low CD34+ counts in order to increase CD34+ yield. Pts received G-CSF 480 μcg once daily from day +4 after SC reinfusion to ANC >1500/mm3. All pts received antiviral and antifungal but no anti-bacterial prophylaxis. Results: 200 eligible pts were included in the analysis; 40 (20%) pts received DARA as part of PI-based upfront treatment and 160 (80%) pts received PI-based upfront treatment without DARA. Baseline demographics (age, gender, performance status) and disease characteristics (ISS and R-ISS stage, cytopenias, eGFR, lytic bone disease etc) were not different between the two groups. Response after induction was also similar (CR+VGPR rate was 93% vs 95% for non-DARA and DARA-containing regimens respectively). Use of DARA at induction was associated with lower total mean number of collected CD 34+ SCs (10.48 x 10^6/kg vs 16.58 x 10^6/kg, p1 day of SC collection (37.5% vs 6.3%, P 500/mm3, p 25x10^9/mm3, p Conclusion: DARA-containing induction before ASCT is associated with poorer mobilization and frequent need for use of plerixafor. However, similar percentage of patients can move to at least a single ASCT. The use of DARA-containing induction was also associated with slightly increased risk of infectious complications, antibiotics use and blood product transfusions but no increase in the risk of D100 mortality. These data point to the need for certain modifications to ASCT protocol for patients treated with DARA-containing regimens at induction, such as preemptive use of plerixafor, and perhaps prophylactic antibiotics. Disclosures Terpos: Amgen: Consultancy, Honoraria, Research Funding; BMS: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Genesis: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; GSK: Honoraria, Research Funding. Gavriatopoulou: Takeda: Honoraria; Karyopharm: Honoraria; Sanofi: Honoraria; GSK: Honoraria; Genesis: Honoraria; Janssen: Honoraria; Amgen: Honoraria. Dimopoulos: Amgen: Honoraria; BMS: Honoraria; Janssen: Honoraria; Takeda: Honoraria; BeiGene: Honoraria. Kastritis: Takeda: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Honoraria; Janssen: Consultancy, Honoraria, Research Funding.

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 On D50, there was further increase in NAbs titers both in controls and AL patients (both p Among AL patients, factors associated with NAb titers on D50 included age (p 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 (p3 months of treatment-free interval (HR:7.75, p 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. Figure 1 Figure 1. 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.

In 2014, the IMWG updated the diagnostic criteria for symptomatic myeloma and in addition to classical "CRAB", implemented "biomarkers of malignancy" (BoM) (FLC ratio>100, more than 1 focal lesion in MRI and bone marrow infiltration of at least 60%). As a result, a subset of patients previously considered as having "smoldering myeloma" were characterized as symptomatic and were eligible to start therapy; these criteria are also adopted in clinical trials. However, the impact of the 2014 IMWG criteria in the overall clinical presentation of symptomatic myeloma patients who start therapy or in the outcomes of patients who present only with biomarkers of malignancy, has not been fully appreciated. We evaluated the characteristics and outcomes of patients who started therapy in the past 5 years, when the 2014 IMWG criteria were implement in our clinical practice and compare their characteristics and outcomes with those of patients that started in an earlier period. To adjust for advances in diagnosis and especially imaging, the analysis included 1007 consecutive patients who started therapy in the Department of Clinical Therapeutics between 1/1/2010 and 31/12/2020. Our prospectively maintained database includes all consecutive patients who start therapy for myeloma. The patients were divided in two cohorts: those that started therapy after 1/1/2015 (after 2014 IMWG criteria implementation) and those that started therapy between 1/1/2010 and 31/12/2014. In these two chronological periods, methods for the assessment of disease were similar except for wider use of ldWBCT after 2013 and more frequent use of conventional CT before 2013. In the 2010-2014 period, 393 patients started therapy vs 614 that started between 2015-2020. Patients in the two groups had similar age (mean 67 vs 66.3, p=0.399) and similar b2-microglobulin levels (7.39 vs 7.33 mg/L, p=0.907) but hemoglobin (mean 10.2 vs 10.6 gr/dl, p=0.016), platelet counts (mean 230 vs 246 x10 9/L, p=0.021), serum albumin (3.6 vs 3.8 gr/dl, p=0.003) were higher in the 2015-2020 era. Although it did not reach statistical significance, mean bone marrow infiltration in trephine biopsy (60.5% vs 57.3%, p=0.056) and eGFR (mean 66.6 vs 62.3 ml/min/ 1.73 m2, p=0.057) were higher and mean serum calcium levels lower (9.9 vs 10.2 mg/dl, p=0.073) in 2015-2020 group, while, serum LDH >ULN (19.6% vs 21.4%, p=0.513) and high risk cytogenetics (20.4% vs 20.8%) were found in similar rates. Accordingly, ISS and R-ISS stage distribution was similar (p=0.496). Per CRAB criteria, hemoglobin < 10 gr/dl was present in 48.9% of patients in the 2010-14 period vs 43.6% in the 2015-2020 (p=0.1), hypercalcemia in 18.2% vs 15% (p=0.185), serum creatinine ≥2 mg/dl in 22% vs 18% (p=0.124) and lytic bone disease in 76.9% vs 76.8%, p=0.973). At least one CRAB was present in 96.4% vs 94% of patients in the two periods (p=0.603). Even in the era before the publication of the 2014 IMWG criteria, 3.6% of patients that started therapy did not fulfill the CRAB criteria of that time; in retrospect, most had at least one BoM present. In the 2015-2020 period, 6% of new patients were considered as symptomatic based on the presence of BoM only. The median follow-up of the 2010-2014 cohort is 63 months and is 25 months for the 2015-2020 group; the 1- and 2-year OS is 83% vs 90% and 75% vs 79% respectively (p=0.057) for the two groups; early mortality (within 3 months from start of therapy) was 7.4% vs 3.9% (p=0.016) respectively. The OS of patients starting therapy based on the presence of BoM only is not reached (3-year OS 87%) vs 59 months (3 year OS: 65%) for patients presenting with CRAB (p=0.051). Because there may be a lead time bias, we also compare the OS of patients with biomarkers of malignancy only vs those with CRAB and ISS-1 disease: OS was similar although with a trend towards better OS for those with BoM. In conclusion, the implementation of the 2014 IMWG diagnostic criteria has resulted in about 6% of newly diagnosed patients starting therapy based only on the presence of BoM. Although the implementation of the criteria has resulted in slightly better clinical presentation (less severe CRAB) and reduced early mortality, most patients still present with disease complications. These data point to the need to develop tools that can identify myeloma patients earlier during their disease course, before they develop devastating complications, in order to further improve their outcomes and quality of life. Disclosures Kastritis: Janssen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Genesis Pharma: Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Gavriatopoulou: Karyopharm: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Genesis: Honoraria; GSK: Honoraria; Amgen: Honoraria. 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: Takeda: Honoraria; BMS: Honoraria; Amgen: Honoraria; Beigene: Honoraria; Janssen: Honoraria.

Introduction Despite the availability of novel agents in treating multiple myeloma (MM), renal impairment (RI) remains a poor prognostic factor, and the median survival of patients (pts) with MM and RI is approximately half of that for MM pts with normal renal function. RI can affect up to 50% of pts with MM at presentation, highlighting the need for effective treatment options for this patient population. Daratumumab, an IgG1 κ human monoclonal antibody that targets CD38, has shown efficacy and a favorable safety profile in pts with relapsed or refractory MM (RRMM). The DARE study assessed the safety and efficacy of daratumumab with dexamethasone in pts with RRMM and severe RI or requiring hemodialysis. Methods DARE is a prospective, open-label, phase 2 study, conducted in eight sites in Greece and Italy. Eligible pts were adults with documented RRMM and severe RI (estimated glomerular filtration rate [eGFR] Results The study has completed accrual and 38 pts were enrolled. The pts' median (range) age was 72 (40-89) years, and most pts were male (29, 76.3%). At baseline, 37 (97.4%) pts had ECOG PS ≤1 and 34 (89.5%) were at International Staging System (ISS) stage III. By revised ISS, 20 (52.6%) and 16 (42.1%) pts were at stages II and III, respectively. Pts had a median (range) of 3 (2-6) prior systemic therapies; thirteen (34.2%) pts had undergone prior autologous stem cell transplantation. The median eGFR at baseline was 13.0 mL/min/1.73m 2 and seventeen (44.7%) pts were on dialysis at the time of enrollment. The median (range) number of cycles given was 8.0 (1.0-38.0), and the median (range) follow-up was 11.3 ( Overall, 19 (50.0%) pts had ≥1 grade 3/4 adverse event (AE), and 10 (26.3%) had ≥1 serious AE (SAE). The most common grade 3/4 AEs were anemia (6 pts, 15.8%), hyperglycemia (5 pts, 13.2%), and hypercalcemia (3 pts, 7.9%). The most common SAE was septic shock (3 pts, 7.9%). Conclusions The administration of daratumumab with dexamethasone in pts with RRMM and severe RI or requiring hemodialysis is safe and effective therapy associated with a median PFS of approximately 12 months; hematologic responses were rapid and observed within one month from treatment initiation and approximately one-fifth of pts achieved a major renal response. Almost half of the pts were on dialysis and the combination was active and safe also for those on dialysis. No new safety signals were observed with daratumumab in pts with RRMM and severe RI or in need of dialysis. Figure 1 Figure 1. Disclosures Kastritis: Janssen: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Genesis Pharma: Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Terpos: Sanofi: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Janssen-Cilag: Consultancy, Honoraria, Research Funding; GSK: Honoraria, Research Funding; Genesis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; BMS: Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Symeonidis: Demo: Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; WinMedica: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GenesisPharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Consultancy, Research Funding; Sanofi/Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Delimpasi: Janssen: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau. Cavo: Bristol-Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, 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; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Adaptive Biotechnologies: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations, Speakers Bureau; Novartis: Honoraria. Zamagni: Janssen: Honoraria; Bristol-Myers-Squibb: Honoraria; Takeda: Honoraria; Amgen: Honoraria. Katodritou: GSK, Amgen, Karyopharm, Abbvie, Janssen-Cilag, Genesis Pharma, Sanofi: Honoraria, Research Funding. Kyrtsonis: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene/Genesis Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria; Sanofi: Membership on an entity's Board of Directors or advisory committees. Hatjiharissi: Gilead: Honoraria; Genesis: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Leonidakis: Health Data Specialists: Current Employment. Manousou: Health Data Specialists: Current Employment. Gavriatopoulou: Sanofi: Honoraria; Genesis: Honoraria; Amgen: Honoraria; Janssen: Honoraria; GSK: Honoraria; Karyopharm: Honoraria; Takeda: Honoraria. Dimopoulos: Amgen: Honoraria; Beigene: Honoraria; Janssen: Honoraria; BMS: Honoraria; Takeda: Honoraria.

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. Figure 1 Figure 1. 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.

Background Recent data suggest a suboptimal antibody response to COVID-19 vaccination in patients with hematological malignancies, especially under immunosuppressive therapy. Herein, we evaluated the development of neutralizing antibodies (NAbs) against SARS-CoV-2 in patients with plasma cell neoplasms after vaccination with either the mRNA BNT162b2 or viral vector AZD1222 vaccine. Methods Serum of both patients and controls was collected on day 1 (D1; before the first BNT162b2 or AZD1222 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 FDA approved-ELISA methodology. Results Patients with MM (n=213), SMM (n=38) and MGUS (n=25) and 226 healthy controls, of similar age and gender, were enrolled in the study (NCT04743388). Two hundred and fifteen patients (77.9%) were vaccinated with the BNT162b2 and 61 (22.1%) with the AZD1222 vaccine. Vaccination with either two doses of the BNT162b2 or one dose of the AZD1222 vaccine leads to lower production of NAbs against SARS-CoV-2 in patients compared with controls both on day 22 and on day 50 (P