EBV-related lymphoproliferative disease in Wiskott-Aldrich Syndrome patient

Case: Wiskott-Aldrich Syndrome (WAS) is a rare X-linked inborn error of immunity caused by mutations in the WAS gene. It is classically characterized by immunodeficiency, eczema, and micro-thrombocytopenia. It has been known since the 1960s that patients with WAS have an increased risk of lymphoproliferative disease though the exact incidence remains unknown in the American population. Limited case reports have discussed EBV-related lymphoproliferative disease in patients with WAS. We present a case of a 9-year-old boy with known WAS complicated by eczematous rash, thrombocytopenia, recurrent ear infections, and monoclonal gammopathy who was found to have submandibular EBV-associated lymphoid hyperplasia with associated lung and retroperitoneal lymphadenopathy. Family had been offered treatment with hematopoietic stem cell transplant but declined multiple times in the past. Earlier in the year, he presented with possible MIS-C with negative SARS-CoV-2 PCR. He presented to our hospital with mastoiditis and lymphadenopathy. Physical examination showed severe eczema on hands and tender right mastoid. Laboratory evaluation showed thrombocytopenia, elevated IgG of 6290, IgA of 744, IgE of 827, low IgM of 41, and 14% response to pneumococcal titers. He was empirically treated with intravenous antibiotics. ENT performed right postauricular incision and drainage and the culture grew Hemophilus influenza. Throughout his hospital stay, his submandibular lymphadenopathy became more prominent despite treatment. Core needle biopsy of right submandibular lymph node was suggestive of EBV-associated lymphoid hyperplasia. EBV PCR and antibodies were both positive. CT chest, abdomen, and pelvis revealed multifocal pulmonary lymphadenopathy and a diffuse, bilateral nodularity as well as retroperitoneal and mesenteric lymphadenopathy. He was given four doses of weekly Rituximab, which successfully decreased EBV viremia below linear detectability. Immunoglobulin replacement therapy (IgRT) was initiated. Bronchoalveolar lavage and lung biopsy were performed and are results are currently pending. Discussion(s): We present a case of a 9-year-old boy with known WAS awaiting transplant who was found to have submandibular EBV-associated lymphoid hyperplasia with associated lung and retroperitoneal lymphadenopathy. While lymphoproliferative disease is a known complication of WAS, EBV-related lymphoproliferative disease in WAS patients has only been reported as case reports and remains a rare but known complication of patient with WAS.Copyright © 2023 Elsevier Inc.

Kidney Limited Complement-Mediated Thrombotic Microangiopathy- a Challenging Case

Introduction: Complement-mediated thrombotic microangiopathy (CM-TMA) is a rare disease characterized by microangiopathic hemolytic anemia (MAHA), thrombocytopenia and organ injury. The absence of hemolysis and thrombocytopenia is rare. We present a case of kidney limited CM-TMA successfully treated with eculizumab. Method(s): A 36 year-old man with poorly controlled hypertension, obesity, CKD (baseline creatinine (sCr) 2,6mg/dL, albuminuria 150mg/g), hyperlipidemia, obstructive sleep apnea, hyperuricemia, SARS-CoV-2 infection 3 months earlier, and family history of CKD of unknown etiology (father started kidney replacement therapy (KRT) at young age) presented to the ER with high blood pressure and right hemiplegy. Head CT scan showed left thalamo-capsular hemorrhage. Oftalmologic exam was normal. Laboratory findings were: hemoglobin (Hb) 12.5g/dL, elevated white cell count (17.900/uL), platelet count 214.000/uL, sCr 4.3mg/dL, lactate dehydrogenase (LDH) 303U/L. Urine dipstick revealed protein+ and Hb++. Chest X-ray showed signs of pneumonia. The patient was admitted in ICU and mechanically ventilated. After 3 weeks, renal function recovered to its baseline (sCr 1.5mg/dL, no proteinuria) without KRT, and the patient was transferred to the medical ward. Several infectious complications prolonged hospital stay. After 3 months, a new mild SARS-CoV-2 infection was detected. At this time: Hb 9.9g/dL, platelets 220.000/uL, sCr 2.2mg/dL. Six days later the patient showed Hb 9.5 g/dL, without reticulocytosis, platelets 195.000/uL, sCr 6.3mg/dL, LDH 348U/L, normal haptoglobin, no schizocytes on blood smear. After 3 days, the patient was anuric and sCr increased to 10mg/dL, prompting KRT. Kidney ultrasound showed no abnormalities. Autoimmunity study was negative, normal C3/C4, no monoclonal gammopathy, and negative viral serologies. Kidney biopsy (KB) was performed as the etiology of AKI remained unclear. Light microscopy revealed thickned glomerular capillary walls with subendothelial expansion forming double contouring, arteriolar intimal expansion and fibrin thrombi occluding the vascular lumina. Scarse C3 deposition was observed in capillary walls. Since the morphological features were consistent with TMA, secondary causes were excluded and primary causes also investigated: ADAMTS13 activity, complement factor B and I were within normal range, slight decrease of factor H with normal anti factor H antibody. The molecular studies of complement genes were performed by NGS-based gene panel revealing a rare heterozygous missense mutation on gene CFB, c.1189G>A (p.Asp397Asn), described as a genetic risk factor of CM-TMA in the presence of a trigger. Result(s): Treatment with eculizumab was started and the patient showed signs of kidney recovery allowing KRT suspension 1 month later (sCr 5.53mg/dL). Of note, the patient never presented MAHA or thrombocytopenia. After 5 months, renal function improved to sCr 3.9mg/dL. Conclusion(s): We report a case of CM-TMA with isolated kidney injury without laboratory hallmarks of TMA. Patients usually require a secondary trigger for the disease to manifest, and in this case SARS-CoV-2 infection may have been the causative agent. A mutation in gene CFB may have predisposed the patient to the outcome. KB was crucial for diagnosis and prompted the treatment with eculizumab with partial recovery without the need for chronic KRT. No conflict of interestCopyright © 2023

Demonstrating New-onset orWorsened Sudomotor Function post COVID-19

Objective: Identify if SARS-CoV-2 virus is triggering and/or worsening dysautonomia by reviewing the function of autonomic patients pre-COVID-19 and post-COVID-19 infection, as well as new onset autonomic patients post-COVID-19 infection. Background: Autonomic dysfunction may be part of acute and long COVID-19 infection. Design/Methods: Six participants were enrolled and divided into two groups. The first group of 4 volunteers reported worsened autonomic symptoms post-COVID-19 infection. These individuals had first autonomic test prior to COVID-19 pandemic outbreak (July 2019- December 2019). Autonomic function testing was repeated in these participants, 6 months to 1- year post-COVID-19 infection (June, 2021). The second group of 2 volunteers reported newonset autonomic symptoms post-COVID-19 infection and were tested March-May, 2021. All participants were screened for known causes of autonomic dysfunction and had normal neurophysiological studies (EMG/NCS), no hypertension/hyperlipidemia or thyroid dysfunction, no diabetes/prediabetes, no vitamin deficiencies, no history of HIV, hepatitis, or syphilis, no prior radiation or chemical exposure and no evidence of monoclonal gammopathy, or autoimmune condition. Participants were diagnosed with COVID-19 via PCR testing, and tested again via SARS-CoV-2 capsid-antibody test. Results: All volunteers were female (age: 21-37y) and endorsed orthostatic intolerance. Gastrointestinal symptoms (5/6), new-onset paresthesias, drier skin (3/6), and sexual dysfunction (2/6) were reported. Dysgeusia reported in 50%, but was not demonstrated on neurological examination. Parasympathetic autonomic function remained stable 6-months to 1- year post-COVID-19 infection and not demonstrated in participants with new-onset symptoms. Sympathetic-adrenergic dysfunction as new-onset orthostatic hypotension and abnormalities on blood-pressure response to Valsalva was found in 50% of participants. Sympathetic cholinergic (sudomotor) dysfunction was demonstrated in ALL participants. Worsened, or new-onset, sudomotor dysfunction was demonstrated in those with mild or normal sudomotor function on pre-COVID-19 autonomic testing Conclusions: Sudomotor dysfunction was demonstrated as worsened or new-sequelae to COVID-19 infection. COVID-19 may be responsible for new-onset or worsened small-fiber neuropathy in this sample.

Are we looking for Monoclonal Gammopathy of Renal Significance ( MGRS )? An audit of investigations in current clinical practice

Monoclonal gammopathy of unknown significance (MGUS) is a premalignant condition defined as the presence of a monoclonal protein with no evidence of plasma cell/B-cell-related malignancy. The risk of progression from MGUS to a related malignancy is approximately 1% per year. MGUS patients are closely monitored for signs of progression allowing for rapid initiation of treatment. In 2012, the International Kidney and Monoclonal Gammopathy Research Group (IKMG) introduced the term Monoclonal Gammopathy of Renal Significance (MGRS). MGRS is the clonal proliferation of a nephrotoxic monoclonal protein without meeting the criteria for any other plasma cell/B-cell malignancy. The diagnosis of MGRS allows for the initiation of urgent treatment required to prevent further deterioration in renal function. Updated diagnostic criteria from the IKMG made renal biopsy essential for diagnosis of MGRS. Consequently, the IKMG set out an algorithm to guide clinicians on when to consider a renal biopsy. The parameters measured to evaluate the need for a renal biopsy include urine albumin creatinine ratio (ACR). This audit was conducted in the Clatterbridge Cancer Centre Liverpool (CCC-L) a leading cancer centre in the Northwest of England. Urine ACR was chosen as the parameter to audit as it is a cheap, non-invasive, quantitative investigation. The primary outcome of this audit is to assess the number of MGUS patients who had an ACR measured at diagnosis in the Myeloma clinic from January 2014 to December 2020. Data were collected retrospectively from electronic clinic letters and notes. The date of diagnosis was defined as the date of clinic letter in which diagnosis was first confirmed. Patients were considered to have had an ACR performed at diagnosis if ACR was measured between 28 days prior to and post the date of diagnosis. ACR performed during disease was defined as any ACR measured from 28 days prior to date of diagnosis and date of death/data collection. Data from 503 patients (249 females, 254 males) were analysed. The median age at diagnosis was 73. Table 1 shows data for patients who had an ACR measurement performed at diagnosis and during disease. There is a trend towards greater compliance to measuring ACR at diagnosis in successive years from 2014 to 2019 (Table 1). This trend reverses in 2020 when only 40.0% of patients had an ACR measured at diagnosis. For all patients where ACR was performed during disease;56.8% ( n = 179) had the highest ACR measurement of <3.0 mg/mmol with only 14.0% ( n = 44) having the highest ACR measurement of >30.0 mg/mmol. If ACR was performed at diagnosis it was more commonly repeated if the value was higher;the frequencies with which ACR was repeated were 85.7% ( n = 12), 65.1% ( n = 28) and 28.4% ( n = 31) when ACR value at diagnosis was >30.0 mg/mmol, 3.0-30.0 mg/mmol and <3.0 mg/mmol respectively. This audit has shown an increased recognition for the importance of ACR measurement with increased compliance year on year. A likely hypothesis for the reduced measurements in 2020 is the need for remote clinic appointments during the Coronavirus 2019 (Covid-19) pandemic. Following IKMG guidelines 14.0% ( n = 44) of patients would be advised to have a renal biopsy due to their ACR measurement of >30.0 mg/ mmol. Further evaluation of this patient cohort is required to audit compliance with other parameters suggested by the IKMG. A diagnostic pathway to be used at the earliest opportunity for MGUS patients may then be developed..

POS-531 MONOCLONAL GAMMOPATHY PRESENTING AS ACUTE PSEUDOHYPERPHOSPHATEMIA IN A MAINTENANCE HEMODIALYSIS PATIENT: A RARE PRESENTATION

Introduction: Phosphorus is an essential component of many macromolecules found in bone, lipid membranes, and DNA. It circulates in serum as phosphate. Phosphate level is mainly determined by kidney function. Other factors such as 1, 25 vitamin D3, thyroid hormone and low phosphorous intake can increase renal absorption of phosphate. Hyperphosphatemia presents when serum phosphate is above 4.5 mg/dl (1.45 mmol/L). The phosphate target for hemodialysis (HD) patients is 5.5 mg/dl (1.77 mmol/L) or less. Serum phosphate is commonly measured through the colorimetric method and can also be measured isotopically. Depending on the method used to measure the serum phosphate, many factors have been reported to produce falsely elevated levels. Methods: 52-year-old female with past medical history of end stage renal disease on HD, heart failure with severely reduced ejection fraction secondary to ischemic cardiomyopathy status post left ventricular assist device (LVAD), type 2 diabetes, hypertension, upper gastrointestinal bleeding, anemia, was admitted at a rehabilitation center after a hospital stay due to COVID-19 infection and E. faecium bacteremia secondary to a drive-line infection of the LVAD which was treated with daptomycin. On admission, the patient was found to have a phosphorus level of 6.3 mg/dl, PTH 265 pg/mL, corrected calcium 10 mg/dl, and hemoglobin 9.1 g/dL. Results: Patient was started on oral Sevelamer tablets 800 mg every 8 hours and underwent regular full HD sessions. However, the hyperphosphatemia persisted. Sevelamer was increased to 1600 mg every 8 hours, and she was maintained on a strict low phosphorous renal diet. Four days later while on the new regimen, the phosphorous increased to 12.2 mg/dl. She remained asymptomatic. Hemolysis and hyperbilirubinemia were excluded. A serum protein electrophoresis revealed a monoclonal spike in the gamma region with gamma % of 38.5 (normal range 11-20), gamma globulin 3.0 g/dL (normal range 0.6 – 1.6 g/dL), and quantification of the abnormal protein of 0.41 g/dL (5.3% total). Serum immunofixation showed a probable IgG Lambda monoclonal band. A serum free light chain assay demonstrated a Kappa light chain free serum of 548.9 mg/L (normal range 3.3 – 19.4 mg/L) and Lambda light chain free serum 549.7 mg/L (normal range 5.7 – 26.3 mg/L). Patient was diagnosed with a monoclonal gammopathy, and the elevated phosphorus deemed to be pseudohyperphosphatemia secondary to paraproteinemia. Conclusions: Colorimetric assay with phosphomolybdate ultraviolet (UV) is commonly used for measurement of serum phosphate. The ammonium molybdate reacts with the phosphate to form a cloudy complex, UV absorbance is measured at a specific wavelength. Several factors have been reported to cause falsely high phosphate such as hyperlipidemia, hyperbilirubinemia, hemolysis, liposomal amphotericin B, recombinant tissue plasminogen activator, heparin sulfate, and gammopathies. The paraproteinemia present in monoclonal gammopathies creates a cloudier sample which increases the absorbance of UV light leading to spurious elevation of serum phosphate. Although hyperphosphatemia is a common finding in dialysis patients, the presence of persisting or worsening hyperphosphatemia in a compliant patient taking phosphorous binders and adhering to a low phosphorus diet should raise concern for pseudohyperphosphatemia. No conflict of interest

Geriatric oncological patients in the pandemic: What are we currently doing differently in practice as compared to the past?

Patients with multiple myeloma (MM), monoclonal gammopathies (MGUS/SMM) and other hemato-oncological (hem-onc) diseases frequently present with disease- and treatment related immunosuppression and bear an increased risk for infections and infection-related mortality. Measures to reduce the infection risk, such as antibiotic and antiviral prophylaxis as well as vaccinations are important elements in the management of these pts. During the COVID-19 pandemic many hem-onc pts have been infected with the SARS-CoV-2 virus, and a large proportion had to be hospitalized. Many required intensive care treatment. Mortality rates were higher compared to those of the general population, highlighting the need to boost pts' immune system against SARS-CoV-2. Although millions of people have already been vaccinated with one of the several COVID-19 vaccines, data on the immune response in MM and other hem-onc pts are limited. First reports indicate suboptimal antispike protein or neutralizing antibody response, leaving several pts potentially unprotected. Yet, the immunological correlates of protection are incompletely understood. Factors associated with poor humoral immune response to the vaccine against SARS-CoV-2 were active or relapsing/progressive disease as well as concomitant therapy. A diminished antibody response in MM pts treated with daratumumab or lymphoma patients undergoing treatment with CD20-antibody or BTK-/bcl2-inhibitors was shown. These data mandate monitoring of humoral and cellular immune response to SARS-Cov-2-vaccination in our pts in order to define the correlates of protection in this pt population. Eventually, it is necessary to assure sufficient protection or to consider additional measures such as discontinuation of MM/lymphoma therapy, if possible, and/or additional doses with the same or other COVID-19 vaccines. In those failing to respond, prophylactic treatment with neutralizing monoclonal antibody cocktails, which is not yet approved, may be considered. However, pts lacking adequate immune response to SARS-CoV-2 will be required to adhere to measures for infection risk reduction until the end of the pandemic is reached. At this meeting, we will report our experiences with COVID-19 in hemonc pts at our center and data on the immune response of pts with certain hem-onc diseases after vaccination against SARS-CoV-2. Furthermore, we will discuss current recommendations regarding this vulnerable pt population during the COVID-19 pandemic.

CD19+ B Lymphocytes Are Predictive for Anti-Sars-Cov-2 Vaccination Response in Multiple Myeloma Patients

Introduction: Up to now,reliable results regarding the efficacy of anti-SARS-CoV-2 vaccines in patients with multiple myeloma (MM), especially under current myeloma-directed therapy, are scarcely available. Here, we report an analysis describing the level of post-vaccination antibody titers after the 1 stand 2 ndanti-SARS-CoV-2 vaccination depending on therapy, remission status, and B- and T-cell numbers in patients with MM and related plasma cell neoplasia. Methods: This observational single-center study included patients aged ≥18 years with diagnoses of MM, monoclonal gammopathies of clinical significance (MGCS), or systemic light-chain amyloidosis (AL) who were eligible for Anti-SARS-CoV-2 vaccination according to the International Myeloma Society recommendations. Patients with prior COVID-19 infections were excluded. Samples were analyzed for the presence of SARS-CoV-2 specific antibodies using the quantitative anti-spike IgG (SARS-CoV-2 spike RBD IgG, cut off ≥ 0.8 BAU/ml) according to manufacturer's recommendations. SARS-CoV-2 spike protein antibody titer (SP-AbT) were evaluated after at least 7 days after the 1 stand 2 ndvaccination, respectively. This study was performed between January 1 - July 15, 2021, at the University Medical Center Hamburg-Eppendorf, Germany, as part of the COVIDOUT trial (NCT04779346). All patients provided written informed consent. Aims of this study were to evaluate a possible correlation between SP-AbT and CD19+ B lymphocyte count, as well as to identify other factors impacting vaccination response. Results: 82 patients who received SARS-CoV-2 vaccines (including 67 patients with mRNA-, 8 with vector-based vaccines and 4 heterologous vaccinations) were included. 74 patients had diagnosis of MM, 4 of MGCS/smoldering MM and 4 of AL. Median age was 68 years (range 35-85) and 49 patients were male. In total, 37 patients (45.1%) received anti-CD38- and 2 (2.4%) anti-SLAMF7-targeting therapies at the time of vaccination, 52 (63.4%) patients received immunomodulatory drug (IMID)-based treatments and 13 patients (15.9%) were under active surveillance. 59% of patients had newly diagnosed and 41% refractory or relapsed disease. In total, 75.6% of all patients were in deep remissions (very good partial remission or better). Assessment of anti-SARS-CoV-2 antibody titers took place in median 23 days (range [r] 8-63 days) after the 1 stand 21 days (r: 6-53) after the 2 ndvaccination. A positive SARS-CoV-2 SP-AbT was detected in 31.9% of assessable patients with an overall median SP-AbT of 0 BAU/ml (r: 0-10328, mean 202.36) after the 1 stvaccination and increased up to 88.9% (median SP-AbT of 216.87 BAU/ml, r: 0-25720, mean 2139.29) after 2 ndvaccination. Of the patients not showing positive SP-AbT after the 1 stvaccination, 80.9% became positive after 2 ndvaccination, while 19.1 % remained negative. Median SP-AbT titer was significantly lower compared to patients who became positive already after 1 stvaccination (51.04 vs. 2191.87 BAU/ml, p<0.0001). Regarding immune status, a CD19+ B cell count of median 33.5/µl (r: 1-696/µl) was seen in the overall patient cohort;in patients with negative SP-AbT, median CD19+ B cell numbers were significantly lower compared to patients with positive titers (median CD19+ B cells: 2.0 vs. 52.5/µl, p=0.005). Overall, CD19+ B lymphocyte numbers correlate significantly with positive SP-AbT results and were identified as predictive factor in multivariate analysis. The previously suggested threshold of 30 CD19+ B cells/µl as being predictive for SP-AbT development could be validated. SP-AbT concentration was significantly lower with older age. Furthermore, median SP-AbT were significantly lower in patients with current anti-CD38 directed therapy (median SP-AbT: 1085.4 vs. 62.05 BAU/ml, p < 0.005). Conclusions: In spite of immunodeficiency and immunosuppressive therapy, most MM patients develop SP-AbT. However, about 11% of MM patients failed to develop SP-AbT after full vaccination, and thus remain on risk for COVID-19. Higher counts of CD19+ B lymphocytes, ith a threshold of 30 CD19+ B lymphocytes/µl, are predictive for SP-AbT formation and may further help to identify patients at higher risk of insufficient vaccination response in whom control of vaccination success and potential third vaccination are particularly important. Disclosures: Bokemeyer: GlaxoSmithKline: Research Funding;Inside: Research Funding;IO Biotech: Research Funding;Eisai: Research Funding;Daiichi Sankyo: Research Funding;Gilead Sciences: Research Funding;Blueprint Medicine: Research Funding;BerGenBio: Research Funding;Janssen-Cilag: Research Funding;Isofol Medical: Research Funding;AOK Health insurance: Consultancy;GSO: Consultancy;Bayer Schering Pharma: Consultancy;Gylcotope GmbH: Research Funding;ADC Therapeutics: Research Funding;Apellis Pharmaceuticals: Research Funding;Amgen: Research Funding;Alexion Pharmaceuticals: Research Funding;Agile Therapeutics: Research Funding;Merck Serono: Consultancy, Other: Travel accomodation;Lilly/ImClone: Consultancy;Merck Sharp Dohme: Consultancy, Honoraria;AstraZeneca: Honoraria, Research Funding;BMS: Honoraria, Other: Travel accomodation, Research Funding;Bayer: Honoraria, Research Funding;Roche: Honoraria, Research Funding;Sanofi: Consultancy, Honoraria, Other: Travel accomodation;Merck KGaA: Honoraria;Abbvie: Research Funding;Boehringer Ingelheim: Research Funding;Celgene: Research Funding;Astellas: Research Funding;Karyopharm Therapeutics: Research Funding;Lilly: Research Funding;Millenium: Research Funding;MSD: Research Funding;Nektar: Research Funding;Rafael Pharmaceuticals: Research Funding;Springworks Therapeutics: Research Funding;Taiho Pharmaceutical: Research Funding;Pfizer: Other. Sinn: Incyte: Honoraria, Research Funding;Pfizer: Honoraria;Servier: Consultancy, Honoraria, Research Funding;Amgen: Consultancy, Research Funding;Astra Zenica: Consultancy, Research Funding;MSD: Consultancy, Research Funding;Sanofi: Consultancy;Bayer: Research Funding;BMS: Honoraria, Research Funding. Leypoldt: GSK: Consultancy, Other: Meeting attendance;Sanofi: Consultancy;Abbvie: Other: Meeting attendance. Weisel: Adaptiv Biotec: Consultancy;Abbvie: Consultancy;BMS: Consultancy, Honoraria, Research Funding;Celgene: Consultancy, Honoraria, Research Funding;Amgen: Consultancy, Honoraria, Research Funding;GSK: Consultancy, Honoraria;Janssen: Consultancy, Honoraria, Research Funding;Karyopharm: Honoraria;Novartis: Honoraria;Oncopeptides: Consultancy, Honoraria;Pfizer: Honoraria;Roche: Honoraria;Takeda: Honoraria;Sanofi: Consultancy, Honoraria, Research Funding.

COVID-19 in Patients with Monoclonal Gammopathy of Undetermined Significance (MGUS): An Observational Retrospective Study

Introduction. Monoclonal Gammopathy of Undetermined Significance (MGUS) is a pre-malignant plasma cell disorder reported in approximately 3% of individuals aged > 50 years, characterized by a low risk (about 1% per year) of evolution into “overt” myeloma or other lymphoproliferative diseases. It is classified as IgM-MGUS (15%) and non-IgM-MGUS (80-85%). MGUS is usually asymptomatic, but a higher risk of deep venous thrombosis and infection has been reported. In March 2020, “Coronavirus Disease 2019” (COVID-19) outbreak has been declared a pandemic by the World Health Organization. Regarding outcome of COVID-19 in patients with plasma cell dyscrasia, many papers have been published about multiple myeloma (MM), reporting a higher fatality rate respect to general population, while few data are available about the outcome of SARS-CoV-2 infection in patients with MGUS. Methods. We collected clinical data on MGUS Apulian patients with SARS- CoV-2 infection, tested by RT-PCR on nasopharyngeal swabs between March 1st, 2020 and April 30st, 2021. Among 1454 MGUS patients followed at our center, 91 were found SARS-CoV-2 positive, enrolled in this observational, retrospective study and compared with 182 age and sex-matched normal controls. Clinical data collected regarded: symptoms, hospitalization, hospitalization in intensive care unit, death. Calculations were carried out using Stata MP17. Results. Mean age of whole group (n. 273) was 65,3+/-13,3 years (range: 29-89), with no statistically-significant differences (p=0,734) observed between MGUS-group (65,6+/-13,3;range: 29-89 years) and controls-group (65,2+/- 13,4;range: 29-89 years). Mean number of comorbidities in the whole group was 1,2+/-1,2 (range: 0-5) and no statistically-significant differences (p=0,844) were found between MGUS-group (1,3+/-1,3;range: 0-5) and control group (1,2+/- 0,9;range: 0-3). About MGUS-subtypes, the most frequent was IgG-kappa (n=36;39,6%), followed by IgG-lambda (n=27;29,7%) and IgM-kappa (n=6;6,6%). Regarding MGUS risk-stratification, application of Mayo Clinic model identified 22 patients (24,2%) with low risk, 22 (24,2%) with low-intermediate risk, and 3 (3,3%) with high-intermediate risk;in 44 patients (48,3%) this data was missing. Immunoparesis was present in 13 cases (14,3%) and absent in 55 (60,4%), missing in 23 (25,3%). No patient developed MM or a lymphoproliferative disease progression during and immediately after COVID-19. Rates of symptoms (59,3% vs 56%), hospitalization (20,9% vs 14,3%), hospitalization in intensive care unit (11% vs 8,8%) and death (8,8% vs 5,5%) were slightly higher in MGUS group than controls (Table 1), but these differences were not statistically significant. A statistically significant association (p<0,05), was observed between higher age and death in both groups. Lastly, incidence of SARS-CoV-2 infection in MGUS patients (6,2%) was not statistically significant different from that observed in the population of the Puglia region (5,8%) in the same period. Conclusions. To our knowledge, this report is the largest study of patients with MGUS and SARS-CoV-2 infection to date. In our study patients with MGUS did not show an increased incidence of this infection compared to the general population and did not appear to represent a risk factor for poor outcome in COVID-19. [Formula presented] Disclosures: No relevant conflicts of interest to declare.

Monoclonal Gammopathy of Undetermined Significance and COVID-19: Results from the Population-Based Iceland Screens Treats or Prevents Multiple Myeloma Study (iStopMM)

Introduction Multiple myeloma (MM) patients have an increased risk of severe coronavirus disease 2019 (COVID-19) when infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Monoclonal gammopathy of undetermined significance (MGUS) precedes MM and related disorders and affects 4.2% of the general population over the age of 50 years. MM and MGUS are associated with immune dysfunction that is believed to contribute to the development of severe COVID-19. Currently, no systematic data on MGUS and COVID-19 have been published. We conducted a large population-based cohort study to evaluate whether MGUS was associated with SARS-CoV-2 infection and the development of severe COVID-19. Methods Data on all SARS-CoV-2 test results and COVID-19 severity was acquired from the COVID-19 Outpatient Clinic at Landspitali - The National University Hospital of Iceland. The first case of COVID-19 in Iceland was diagnosed on February 28 th, 2020. Since then, the Icelandic authorities have followed an aggressive strategy of SARS-CoV-2 testing and contact tracing. All SARS-CoV-2-positive individuals were immediately contacted and those with active infection were enrolled into telehealth monitoring consisting of repeated standardized interviews conducted by a nurse or physician. If clinical deterioration was detected, patients were assessed in person at the COVID-19 Outpatient Clinic and admitted if needed. Study participants were included from the Iceland Screens Treats or Prevents Multiple Myeloma study (iStopMM). The study is an ongoing population-based screening study for MGUS and randomized trial of follow-up strategies. Out of the 148,708 Icelanders who were born 1976 and earlier and were alive on September 9 th 2016, 80,759 (54%) provided informed consent for study participation and 75,422 (94%) of those provided a blood sample for MGUS screening by serum protein electrophoresis (SPEP) and free light chain (FLC) assay. MGUS was determined by current criteria using SPEP and FLC assay data. Individuals who had died, been diagnosed with MM and related disorders, or were undergoing treatment for smoldering MM prior to February 28 th were excluded. First, the association of MGUS and testing positive for SARS-CoV-2 was evaluated. We used a test negative design and included participants who had been tested at least once for SARS-CoV-2 between February 28 th and December 31 st, 2020. The association of MGUS and a positive test for SARS-CoV-2 was assessed using logistic regression, adjusted for sex and age. Next, the association of MGUS and severe COVID-19 was evaluated. Those who tested positive for SARS-CoV-2 were included unless they were hospitalized or living in a nursing home at diagnosis. Participants were followed until discharge from telehealth monitoring or until considered having severe COVID-19. Severe COVID-19 was defined as the composite outcome of the need for outpatient visit or hospital admission and death and as the composite outcome of hospital admission and death. Logistic regression was then performed adjusting for sex and age. Results Of the 75,422 individuals screened for MGUS, 32,047 (42%) were tested for SARS-CoV-2 during the study period of whom 1,754 had MGUS (5.5%). Those with MGUS were older (mean age 66.3 vs 59.1 p<0.001) and more likely to be male (50% vs 41% p<0.001). In total, 1,100 (3.4%) of the participants tested positive for SARS-CoV-2 of whom 65 had MGUS. After adjusting for sex and age, MGUS was not found to be associated with testing positive for SARS-CoV-2 (odds ratio (OR): 1.05;95% confidence interval (CI): 0.81-1.36;p=0.72;Table;Figure A). Of those who tested positive for SARS-CoV-2, a total of 230 had the composite outcome of requiring an outpatient visit or hospital admission, and death, and 117 had the composite outcome of hospital admission and death. After adjusting for age and sex, MGUS was not found to be associated with either endpoint (OR: 0.99;95%CI: 0.52-1.91;p=0.99 and OR: 1.13;95%CI: 0.52-2.46;p=0.76;Table;Figure B) Conclusions: In this large population-bas d study that included 75,422 individuals screened for MGUS, we did not find MGUS to be associated with SARS-CoV-2 susceptibility or COVID-19 severity. This is contrary to MM which is preceded by MGUS. These findings suggest that immunosuppression in MGUS differs significantly from that of MM and are important since they can inform management and recommendations for individuals with MGUS. [Formula presented] Disclosures: Kampanis: The Binding Site: Current Employment. Hultcrantz: Intellisphere LLC: Consultancy;Daiichi Sankyo: Research Funding;Curio Science LLC: Consultancy;Amgen: Research Funding;GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding. Durie: Amgen, Celgene/Bristol-Myers Squibb, Janssen, and Takeda: Consultancy;Amgen: Other: fees from non-CME/CE services. Harding: The Binding Site: Current Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Landgren: Amgen: Honoraria;Janssen: Honoraria;Celgene: Research Funding;Janssen: Other: IDMC;Janssen: Research Funding;Takeda: Other: IDMC;Amgen: Research Funding;GSK: Honoraria. Kristinsson: Amgen: Research Funding;Celgene: Research Funding.

BNT162b2 mRNA COVID-19 Vaccination (BNTCV) in Patients (Pts) Having Hematological Malignancies (HM): Early tolerance with telemedicine application connecting and antibody anti-Spike IgG response (AcAS)

Pts with HM and particularly those under therapy or with secondary immune deficiency have been reported to have a low or delayed specific immune response. In addition, pts receiving rituximab for either HM or auto-immune disease presented a low specific antibody response. Daratumumab, an anti-CD38 moAb was demonstrated to lower normal plasma cells and to reduce polyclonal IgA, M and E in pts with multiple myeloma (MM). It is fundamental to evaluate the early post-vaccination tolerance and the level of seroconversion for such pts. Patients' population. 194 pts having HM and followed at the Institute (IC), received at least 2 doses of BNTCV (BioNTech Pfizer, Paris, France) by IM route with 3 weeks between the 2 doses. Currently, analysis was performed on 147 pts, including 63 pts with non-Hodgkin lymphoma (NHL), 18 with B-chronic lymphocytic leukemia (CLL), 34 with MM, 14 with monoclonal gammopathy of undetermined significance (MGUS) and 18 with myeloproliferative disorder (MPD). Mean age was 69 years-old (range 27-92). Follow-up of early tolerance in pts using a telemedicine application. 43 pts vaccinated at the IC received Thess®, a telemedicine system connecting the patient to the IC, developed by La Valeriane Inc. (Montpellier, France, www.thess-corp.fr) 24/24h, 7days. Local pain (<1 day) was common and transient, particularly reported after the 2nd dose. Only 4/43 patients reported significant adverse events through telemedicine and followed by a medical call, including mainly severe asthenia for 2 days or more, fever (>38°C) for at least 2 days, headache, or general pain. The satisfaction survey of monitoring system was good. In addition, adherence to vaccination was excellent with only one refusal out of the 194 pts. AcAS follow-up IgG AcAS and IgG+M AcAS were analyzed in the serum 3 to 4 weeks after the 1st dose and 4-8 weeks after the 2 nd dose and every 2 months, respectively by SARS-CoV-2 IgG II Quant ® Assay with a threshold of positivity at 50 AU/mL (Abbott, Rungis, France) and Elecsys ® Anti-SARS-CoV-2 S (Roche Diagnostics, Meylan, France) with a threshold of positivity at 0.8 U/mL. 270 samples were analyzed in duplicate with the 2 assays, by 2 independent labs. Data were reported and statistically analyzed by the clinical research team. 17 results were discordant including 12 with Abbott IgG test undetectable and Roche IgG+M detectable, and 5 with Abbott test detectable and Roche undetectable. After the first dose of BNTCV, 72/147 (49%) pts were seroconverted, including 7/18 (39%) with CLL, 27/63 (43%) with NHL, 10/14 (71%) with MGUS, 17/34 (50%) with MM and 11/18 (61%) with SMD. The median levels of the AcAS response for pts were 0 (range 0-40 000 AU/mL) for the AdviseDX test as compared to 12 normal subjects (mean 257 AU/mL, range 226-283), and 0 U/mL (range 0-2500) for the Elecsys test. 49/75 (65%) of untreated pts were seroconverted after the 1 st dose as compared to 26/72 (36%) of treated patients (p<0.001), with rituximab or ibrutinib as negative factors in addition to low gammaglobulin level (<5g/L, p=0.019), similarly to the IgG level. Analysis of CRP levels, circulating lymphocyte counts, and lymphocyte subpopulations will be performed. After the second dose of BNTCV, 50 pts have currently been tested, with only 25 additional pts seroconverted. The median levels of the AcAS response for pts were 310 AU/mL (range 62-11760) for the AdviseDX test as compared to 12 normal subjects (mean 6725 AU/mL, range 3002-9787), and 1250 U/mL (range 0.87-2500) for the Elecsys test. The 25 patients who were not seroconverted after the 2nd dose received a 3rd dose of BNTCV, including 8 with MM, 9 with NHL, 5 with CLL, 1 with MGUS (with polyneuropathy under daratumumab) and 2 with SMD. Currently, 9 pts were tested after the 3 rd dose. AcAS levels were respectively 268 AU/mL for 1 MM treated by daratumumab, 103 and 313 AU/mL for 2 MM under carfilzomib, 1622 AU/mL for 1 untreated SMD, 29100 AU/mL for 1 untreated MGUS, 537 AU/mL for 1 CLL and 2 negative NHL. In conclusion, there is a need to follow AcAS for pts aving HM including SMD after BNTCV aiming to adapt vaccine strategy including a 3 rd dose and eventual recall. As some pts are always negative after a 3 rd dose, vaccination strategy could be discussed by using different combinations of vaccine or the addition of immune adjuvant in a more personalized medicine. In addition, the usage of telemedicine connecting system may help to follow the early tolerance and to improve the pts' adherence. Disclosures: Rossi: NPO Petrovax Pharm: Consultancy;LEO Pharma: Consultancy;EUSA Pharma: Consultancy;E-SANA Inc: Other: Co-founder of E-SANA Inc.