Systemic Amyloid Light Chain (AL) Amyloidosis Patient Experience Research

Background: There is limited empirical evidence exploring the patient experience and treatment needs in AL-amyloidosis. Many patients experience delays in receiving a diagnosis and research suggests they suffer from a lack of support and information about the condition, worsening the impact of the disease on their quality-of-life. In June 2021 the EMA granted marketing authorisation for daratumumab in combination with bortezomib, cyclophosphamide and dexamethasone (DBCd) to treat adults with newly diagnosed AL-amyloidosis. Previously, patients have been treated with off-label therapies for multiple myeloma. Objective(s): To develop greater understanding of the diagnosis, management of the disease, and impact on patients and carers, in the UK. Method(s): A literature review and focus groups with adults living with AL-amyloidosis and a carer. Group 1 consisted of 3 adults, group 2 of 3 adults plus 1 carer. Groups were semi-structured;discussion topics included the patient journey, impact of disease, and COVID-19. Result(s): Despite delays to diagnosis, ongoing relationships with consultants fostered good communication with patients. In the treatment pathway, patients prioritised extension of life and quality-of-life, even if side-effects from treatment impaired quality-of-life. Participants spoke highly of their healthcare teams and experiences with the National Amyloidosis Centre. Impacts on daily life and emotional well-being tended to be more prominent among patients with a more complex disease pathway. For patients, time to diagnosis, ongoing communication with a trustworthy consultant, treatment outcomes and support was important. Although generally satisfied, suggestions for change across the diagnostic and treatment pathway were recommended. Striving for consistency of care and communication was paramount, and treatment impacts on day-to-day life (e.g., through minimising side-effects and convenient administration) should be prioritised. Conclusion(s): Results have the power to better inform healthcare decisions and the development of specific treatments, prioritising interventions that align with the unmet needs and preferences of people living with AL-amyloidosis. Copyright © 2022

Clinical, Laboratory Profile, Treatment and Outcome Of Primary Amyloidosis in the Era Of Novel Agents: An Experience from a Tertiary Care Hospital

Introduction: Diagnosis of AL amyloidosis requires demonstration of amyloid in affected tissues along with clonal plasma cells in bone marrow or presence of monoclonal light chains in blood. With the availability of serum light chain assay and immunophenotyping by flow cytometry, more cases of AL amyloidosis are being diagnosed. Here we present our experience of AL amyloidosis diagnosis and treatment in the era of modern diagnostics and therapy. Aims & Objectives: We aimed to describe the clinical presentations, laboratory features, treatment and outcomes of patients with AL amyloidosis in a single center using standard diagnostic tests and treatment with novel agents. Material(s) and Method(s): A retrospective analysis of AL amyloidosis patients, diagnosed in our hospital, a tertiary care center from January 2016 to June 2022 was conducted. The data was collected from departmental database. All statistical analyses were done by SPSS version 17. Result(s): Diagnosis of AL amyloidosis was done in 31 patients. Median age of presentation was 61 years. 25 (80.6%) were males. Major symptoms were pedal edema (38.7%) and shortness of breath (32.3%). Twenty four (77.4%) presented with ECOG PS >= 2. Most common systems involved were cardiac (54.8%) and renal (54.8%). Fourteen (45.2%) had two or more systems involvement while 17 (54.8%) had single system involvement. Lambda monoclonal light chain was present in 83.9% and kappa monoclonal light chain in 16.1%. Median M-protein was 0.59 g/dL (range 0-2 g/dL) and median bone marrow plasma cells were 6% (range-1-18%). Eighteen patients were treated;cyclophosphamide, bortezomib and dexamethasone (CyBORD) in 12/18 (66.7%) and bortezomib + dexamethasone in 6/18 (33.3%). Among 18 patients followed up with median follow up of 9 months (range 1-64 months), six expired;three due to COVID, two due to cardiac arrhythmia (during first cycle) and one due to relapse and rest 12 were alive. Among the 12 patients who were alive 6 were in complete hematological response. Conclusion(s): Our study presents the spectrum of clinical manifestations, management and outcomes of primary amyloidosis in Indian context. There is a need to increase the awareness among the physicians about amyloidosis so that early diagnosis can be made and timely treatment can be done with novel agents to improve the dismal historical results.

Seroconversion After COVID 19 Vaccination And Disease In Adults With Hematological Diseases

Introduction: Patients with hematological diseases have impaired humoral immunity secondary to disease itself and due to its treatment. Treatment can be either steroids, chemotherapy and chemoimmunotherapy. The immune response to covid 19 vaccine or disease may be significant impaired in haematological diseases. Aims & Objectives: None of the approved vaccine available in India (Covaxin, covishield and sputnik) has been approved for hemato oncology and transplant patients but most of our patients had received either of these vaccines as per national recommendations. Hereby we did retrospective study to look for antibody response in haematological diseases. Material(s) and Method(s): We retrospectively analysed the serological response to covid 19 disease and vaccination in 50 patients. Patients were divided into myeloid malignancies (Acute myeloid leukemia and MDS) n = 11, lymphoid malignacies n = 12 (CLL N = 8, Non Hodgkin Lymphoma n = 3, Pre B ALL n = 1), plasma cell dyscrasis (n = 8) (Multiple myeloma n = 6, AL amyloidosis n = 2), ITP N = 10 (patients on steroids, rituximab), MPNs n = 6 (CML N = 5, ET N = 1), AIHA N = 3. The complete history including the history of covid 19 diseases and covid vaccination was taken. Treatment history of the patient and antibody formation was analysed. Result(s): SARS COV2 IgG antibody was tested in a total of 50 patients. Overall antibody response was present in 90.1% patients. The total igG antibody in myeloid malignancies was 482.45 (12-2000) u/ml, while MPN, lymphoid malignancies, plasma cell dyscrasis had median antibody 140.04 u /ml (0.2-250), 47.9.9u/ml (3.04-200), 1416.9u/ml (20-40,000) respectively. 2 patients with plasma cell dyscrasis and 2 patients with CML had no antibody formation. The benign disorders including itp on steroids and rituximab had median antibody of 262.72 u/ml (6.54-1358) and AIHA had 281.6 (45- 400) u/ml. The results are shown in table 1. Conclusion(s): This Study demonstrates low immunogenicity, mainly in patients with lymphoproliferative disorders, as well as with certain drugs, including mainly anti-CD20 antibodies, Bruton tyrosine kinase inhibitors. However, better humoral response rates are seen in plasma cell dyscrasis on treatment. (Table Presented).

54. Congresso Nazionale SIBioC

The proceedings contain 328 papers. The topics discussed include: laboratory medicine: not only resilience;evaluation of the k-index in inflammatory diseases of the central nervous system in the pediatric patient;urinary microbial signature by 16S RRNA analysis in bladder cancer patients;evaluation of Quantiferon SARS-CoV-2 interferong (INF G) release assay in two cohort of BNT162B vaccinated fragile patients;machine learning as a tool for laboratory medicine, to realize truly personalized care;the need of informatic standardization in the management of laboratory test semantics;tele-consultation in the management of systemic light chain (AL) amyloidosis: the PAVIA amyloidosis center experience;laboratory assessment of the anticoagulant activity of the direct oral anticoagulants (DOACS);platelet function testing current practice among laboratories: how, when, why and to whom;and evaluation of hypercoagulability in patients with multiple myeloma using experimental parameters of rotational thromboelastometry: MAXV, MAXVT, AUC.

Systemic AL Amyloidosis With an Undetectable Plasma Cell Dyscrasia: A Rare Entity

Introduction: AL Amyloidosis is characterized by a plasma cell dyscrasia that can be detected in 99% by monoclonal protein on abnormal serum free light chain (sFLC) concentrations or immunofixation electrophoresis (IFE). Case Description: A 47-year-old man was admitted to the emergency department and afterward to the intensive care unit due to severe COVID-19-associated pneumonia. Initial laboratory studies showed: hemoglobin 12.1 g/dL, creatinine 2 mg/dL, albumin 1.69 g/ dL, AST 20 U/L, ALT 19 UI, urine analysis with no erythrocytes, urine protein/creatinine ratio 4.9 g/g, HbA1c 5.5%, C3 150 mg/dL, C4 35 mg/dL. Serological testing for hepatitis B, C, HIV, ANA, and anti-PLA2R were negative. After three months of hospitalization, the patient was discharged home and lost his outpatient follow-up. He returned five months later with a nephrotic syndrome. Laboratory studies showed: creatinine 1.47 mg/dL, urine proteins 5.7g/day, sFLC lambda 90.1 mg/L (8.3-27), sFLC kappa 43 mg/L (6.7-22.4), sFLC ratio 0.48 (0.31-1.56), urine and serum protein electrophoresis negative, urine and serum IFE negative. We performed a renal biopsy, consistent with amyloidosis with positivity for Congo red staining. Immunofluorescence reported light chain restriction +++ for lambda (figure 1) and was negative for IgG, IgM, IgA, C1q, C3c, kappa, and albumin. A bone biopsy reported no evidence of plasmatic cell neoplasia and was negative for Congo red staining. An echocardiogram showed no evidence of amyloid affection. Hematology stratified the patient as low risk, so they started protocol for autologous stem cell transplantation as definitive treatment but decided to consider CyBorD as induction therapy. Discussion(s): This case illustrates a patient with systemic AL amyloidosis without evidence of plasma cell dyscrasia by conventional techniques. It could be explained because the hematologic disease is so subtle that it goes undetected. The parameter for response in his follow-up will be the improvement of proteinuria, as we cannot measure classic criteria of hematologic response. Figure 1.

A Case of Renal Amyloidosis (AD) Presented as Orthostatic Hypotension

Introduction: Neurogenic hypotension can happen in the context of immunoglobulin light chain AD. The most serious feature is autonomic nervous system impairment, mainly characterized by severe refractory orthostatic hypotension. Amyloid deposition may be found in many organs and the patient can presents with cardiac, gastrointestinal, renal, and neurological symptoms, but rarely hypotension only. Here we describing a patient who presented with sever orthostatic hypotension, found to have renal AD. Case Description: 67 year old male with past medical history of type 2 diabetes, chronic kidney disease, coronary artery disease, colon cancer, and history of COVID-19 infection who presents to nephrology clinic after being referred by primary care provider for elevated Creatinine to 2.5 mg/dl (baseline around 1.2 mg/dl). on clinic visit found to have severe orthostatic hypotension. blood pressure (BP) supine 121/80 mmHg, heart rate (HR) 87 beat per minute (BPM) ;sitting 106/70 mmHg, HR-92 BPM;standing: 92/59 mmHg, HR-100 BPM, no other abnormalities on physical examination. and was admitted to the hospital for evaluation. upon admission to the hospital, pateint received IV fluid, found to have 11 gram protein on 24 hour urine collection laboratory work up showed positive ANA, immunofixation was positive for lambda chain. Fat pad biopsy without signs of AD. Bone marrow biopsy results were inconclusive. Renal biopsy was performed, findings consistent with AL AD. pateint to start treatment with hematology Discussion: The amyloidoses are a group of disorders in which soluble proteins deposit extracellularly in tissues as insoluble fibrils, causing organ dysfunction that is usually progressive. Renal amyloid is a major source of morbidity in affected individuals. When the kidney is involved, renal insufficiency is common, accounting for 47% of cases in a study. Proteinuria has been reported with full nephrotic syndrome in 25-68%. it usually progress to end stage renal disease if left untreated. in our case we are describing an unusual presentation of renal AD, in which the symptoms were orthostatic hypotension. renal function was below baseline but was improving with volume replacement, pateint was felt to have prerenal acute kidney injury. the significant amount of proteinuria prompted further testing. We feel that nephrotic syndrome from amyloid should be considered when patient presented with orthostatic hypotension.

CLINICAL, LABORATORY PROFILE, TREATMENT AND OUTCOME OF PRIMARY AMYLOIDOSIS IN THE ERA OF NOVEL AGENTS: AN EXPERIENCE FROM A TERTIARY CARE HOSPITAL IN INDIA

Background: Diagnosis of AL amyloidosis requires demonstration of amyloid in affected tissues along with clonal plasma cells in bone marrow or presence of monoclonal light chains in blood. With increasing awareness among physicians and availability of proper diagnostics, more cases of AL amyloidosis are being diagnosed. Here we present our experience of AL amyloidosis diagnosis and treatment in the era of modern diagnostics and therapy with novel agents. Aims: We aimed to describe the clinical presentations, laboratory features and outcomes of patients with AL amyloidosis in a single center using standard diagnostic tests and treatment with novel agents. Methods: A retrospective analysis of AL amyloidosis patients, diagnosed in our hospital, a tertiary care center in India from January 2016 to December 2021. The data was collected from departmental database. All statistical analyses were done by SPSS version 17. Results: Diagnosis of AL amyloidosis was done in 27 patients. Median age of presentation was 59 years. 22 (81.5%) were males. Major symptoms were pedal edema (37%), shortness of breath (22.2%), frothy urine (11.1%) and fatigue (11.1%). Twenty two (81.5%) presented with ECOG PS ≥ 2. Most common system involved was renal in 16 (59.2%), followed by cardiac in 13 (48.1%) and gastro-intestinal in 9 (33.3%). Fifteen (55.6%) had two or more system involvement while 12 (44.4%) had single system involvement. Lambda monoclonal light chain was present in 22/27 (81.5%) and kappa monoclonal light chain was present in 5/27 (18.5%). Median Hb was 11.6 g/dl (range 6.7- 14.8 g/dl), median M-protein was 0.69 g/dL (range 0-2 g/dL) and median bone marrow plasma cells were 7% (range- 1-18%). Fourteen patients were treated;cyclophosphamide, bortezomib and dexamethasone (CyBORD) in 10/14 (71.4%) and bortezomib + dexamethasone in 4/14 (28.6%). Among 14 patients followed up with median follow up of 13 months (range 6-60 months), 5 expired;3 due to COVID, one due to cardiac arrhythmia (during first cycle) and one due to relapse and rest 9 were alive. Among the 9 patients who were alive 6 were in complete hematological response and 3 were in partial response after 6 cycles of therapy. Summary/Conclusion: Our study presents the spectrum of clinical manifestations, management and outcomes of primary amyloidosis in Indian context. There is a need to increase the awareness among the physicians about amyloidosis so that early diagnosis can be made and timely treatment can be done with novel agents to improve the dismal historical results.

HIGH RESPONSES RATES WITH SINGLE AGENT BELANTAMAB MAFODOTIN IN RELAPSED SYSTEMIC AL AMYLOIDOSIS

Background: Systemic AL amyloidosis is an incurable relapsing plasma cell disorder. Despite therapeutic advances, there are no approved treatments for relapse disease. Treatment is often challenging due to underlying organ dysfunction. Belantamab mafodotin is an antibody-drug conjugate targeting B-cell maturation antigen with approval for relapsed refractory myeloma. In multiply pre-treated myeloma, the DREAMM-2 phase II trial showed an overall response rate of 32% for those with 2.5 mg/kg dose administered every three weeks with 2/3rd patients reporting keratopathy. A small case series of 6 patients with relapsed AL amyloidosis (Zhang et al , ASH 2021) was recently reported and a phase 2 trial is recruiting for patients with refractory amyloidosis (NCT04617925). Aims: We report our initial results using Belantamab monotherapy for the treatment of patients with AL amyloidosis with relapsed disease. Methods: Data for consecutive patients who were administered Belantamab at a specialist referral centre, National Amyloidosis Centre, University College London, was analysed. Results: Eleven patients were included 8 male, 3 female. Median age at Belantamab initiation was 65 (range 42-74) years. Eight patients had λ AL-type and three κ AL-type. At diagnosis, median involved free light-chain concentration was 534 (range 73-7181) mg/l. A median of two organs involved at baseline (range 1-3): 4 had cardiac involvement (half Mayo stage 2;half Mayo stage 3a) and 8 had renal involvement. The median prior lines of therapy was 3 (range 2-5) with all exposed to prior immunomodulatory drugs, proteasome inhibitors and 73% to anti-CD38 antibody treatments. Thirty-six percent had relapsed after melphalan-conditioned autologous stem cell transplantation. A median of 3 cycles of belantamab were delivered (range 1-8). The most frequent adverse event was ocular toxicity which was experienced in 8 patients (grade 1-3), necessitating dose modification of the three-weekly schedule. One patient developed transient grade 1 dyspnoea and liver dysfunction. No patients developed cytopenias, unlike previous reports (Zhang et al , 2021), nor infections beyond COVID (2 patients mild with no hospital admissions). The majority of the cohort required dose reduction either at initiation (patient 4, due to end stage renal failure;patient 11, post-renal transplant) or during therapy (n=5;three to 1.9mg/kg, two to 1.25mg/kg) due to ocular toxicity. Only one patient remained on the standard dose of 2.5mg/kg for >3 cycles. Ocular toxicity improved after treatment interruption (drug intervals 4-6 weeks) and no patients required complete treatment cessation. One patient is too early to assess response. Haematological responses (PR or better) were seen in 7 patients with 3 complete responses and two very good partial responses (VGPR) which are ongoing. Both renal patients (patients 4 and 11) commenced a dose of 1.25mg/kg and sustained a VGPR with no additional toxicity. Patient 3 had a 42% reduction in sFLC after two doses but then a prolonged gap due to keratopathy and has lost the response. There were no cardiac or renal toxicities observed. Summary/Conclusion: Belantamab mafodotin demonstrates significant activity in patients with heavily pre-treated AL amyloidosis with 70% achieving a ≥PR. Apart from keratopathy requiring dose modification, no other substantial toxicity was observed. Two patients with renal impairment (stage V CKD and ESRD) and one patient post-renal transplant tolerated treatment with no additional toxicity. Belantamab mafodotin shows promise in treatment of relapsed AL and needs further prospective trials.

[Interest of daratumumab in refractory AL amyloidosis in a 96-year-old patient]. / Intérêt du daratumumab dans l'amylose AL réfractaire chez une patiente de 96ans.

Systemic immunoglobulin light-chain (AL) amyloidosis is characterized by deposition of amyloid fibrils of light chains produced by clonal CD38+plasma cells, resulting in organ dysfunction. Cardiac involvement has a major prognostic value. Antiplasma cell chemotherapy reduces the synthesis of immunoglobulin light chains (precursors of amyloid deposits). We describe a case of AL amyloidosis in a 95-year-old patient. Our patient responded poorly to treatment with rituximab, cyclophosphamide-bortezomib-dexamethasone, and rituximab-bendamustine. Finally, the anti-CD38 antibody daratumumab was associated with the best hematologic responsiveness without significant adverse effects. In conclusion, our case suggests that daratumumab is an effective and well-tolerated alternative to chemotherapy in the treatment af AL amyloidosis in very elderly patients.

Morphological changes in organs after infection with SARS-CoV-2 against the background of AL-amyloidosis

The article describes a clinical case of death of a 57-year-old patient from idiopathic AL-amyloidosis after infection with SARS-CoV-2. Histological examination revealed signs of pneumonia with symptoms of pneumosclerosis, histologically determined di-apedesic hemorrhages, necrosis and desquamation of the alveolar epithelium, along the contours of the alveolar passages, al-veolar sacs — hyaline membranes. In many areas, the histoarchitectonics of the pulmonary parenchyma was sharply disturbed, connective tissue was determined in the alveolar passages, in the lumens of the alveoli. The interalveolar septa were thickened due to the proliferation of connective tissue. Positive Congo red staining was visualized mainly in the perivascular and interalveo-lar septa, along the vessels;in the heart — between cardiomyocytes, in the kidneys — in the capillary loops of the glomeruli, base-ment membranes of individual tubules of the cortical layer, in the walls of blood vessels. Thus, the cause of death of the patient was the severe course of infection with SARS-CoV-2;the presence of a concomitant disease in the form of idiopathic AL-amyloi-dosis of internal organs and chronic diseases, obviously, aggravated the patient’s condition and contributed to the onset of death.

COVID-19 and Light Chain Amyloidosis, Adding Insult to Injury.

Light chain (AL) amyloidosis is a potentially fatal disease of monoclonal plasma cells that leads to accumulation of light chain amyloid fibrils, organ damage, and the manifestations of clinical disease. Meanwhile, coronavirus disease 2019 (COVID-19) is a disease caused by infection with the severe acute respiratory syndrome coronavirus 2 virus, with the potential to cause severe systemic illness and death. There is significant overlap in the demographics and comorbidities observed in AL amyloidosis and those associated with highest risk for severe morbidity and mortality due to COVID-19. This overlap creates unique challenges in caring for patients with AL amyloidosis, which are further compounded by the immunosuppressive nature of anti-plasma cell therapies, the need for frequent clinical assessments, and the exclusion of AL amyloidosis patients from initial COVID-19 vaccine trials. Herein, we highlight many of the relevant concerns related to COVID-19 and the treatment of AL amyloidosis, summarize a general approach for AL amyloidosis management amidst the ongoing COVID-19 pandemic, and discuss current guidance about COVID-19 vaccination of patients with AL amyloidosis.

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

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

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.

Cardiac Amyloid Reaching for Extended Survival (CARES): Study Design of Two Placebo-Controlled, Double-Blind, Randomized, International Phase 3 Trials Assessing Cael-101 in Patients with Mayo Stage Iiia or Stage IIIb AL Amyloidosis

Background: Light-chain amyloidosis (AL-A) is a rare, severe, progressive, systemic disorder with high mortality caused by immunoglobulin (Ig) light chains that misfold and aggregate into amyloid fibrils that deposit in multiple organs, leading to progressive organ dysfunction/damage and death. Prognosis is poor for patients with cardiac involvement (characterized by high levels of cardiac troponin T and N-terminal brain natriuretic peptide). Median survival is 24 and 4 months for Mayo Stage IIIa and IIIb AL-A, respectively, based on the 2013 European Modification of the 2004 Mayo Staging system. For most patients, standard of care (SOC) is anti-plasma cell dyscrasia (PCD) therapy to suppress plasma cell proliferation, halt generation of amyloidogenic free light chains, and stop deposition of new amyloid fibrils and further organ decline. However, a critical need exists for therapies that accelerate the removal of deposited fibrils. CAEL-101 is a monoclonal antibody that binds to misfolded Ig light chains in amyloid fibrils. In Phase 1 and 2, CAEL-101 (with and without concurrent PCD SOC) was well tolerated up to 1000 mg/m 2. Preliminary Phase 2 data (NCT04304144) suggest improvements in cardiac and renal biomarkers in some patients. Objective: To evaluate the efficacy and safety of CAEL-101 versus placebo when administered concurrently with SOC anti-PCD therapy in treatment-naïve patients with cardiac AL-A, Mayo Stages IIIb (NCT04504825;Study 1) or IIIa (NCT04512235;Study 2). Methods: These international, multicenter, double-blind, randomized, phase 3 trials, initiated in 2020, are enrolling patients at over 70 sites in 14 countries. Newly diagnosed adults with AL-A stage IIIb or IIIa based on the 2013 European Modification of 2004 Mayo Staging (Wechalekar AD et al. Blood 2013;121:3420. Dispenzieri A, et al. J Clin Oncol. 2004;22:3751), measurable hematologic disease, and histopathological diagnosis of amyloidosis with cardiac involvement are eligible. Patients cannot have any other form of amyloidosis, symptomatic orthostatic hypotension, or supine systolic blood pressure <90 mmHg. Patients in Mayo Stages IIIb (N=111) and IIIa (N=267) are randomized 2:1 to receive once-weekly intravenous infusions of CAEL-101 (1000 mg/m 2) or placebo for 4 weeks, followed by maintenance dosing every 2 weeks. In these event-driven studies, treatment will continue to a minimum of 54 deaths for Study 1 and 77 deaths for Study 2 (a minimum treatment duration of 12 months is expected). Patients will receive concurrent anti-PCD therapy per the institutional protocol for SOC and will be followed to death from any cause or until end of study (Figure). The primary endpoint is overall survival (defined as the time from first dose of study drug to date of death, with censoring at last known living date), and will be analyzed via time-to-event log-rank statistics. Functional, quality of life, and echocardiography measures are targeted secondary endpoints. Results: Patient baseline characteristics and demographics are presented (Table). As of July 17, 2021, 9/13 (69.2%) patients in Study 1 and 23/39 (59%) patients in Study 2 have received at least 4 doses of CAEL-101 concurrently with anti-PCD therapy. Discussion: These ongoing trials will evaluate the efficacy and safety of CAEL-101 as first-in-class treatment to reduce amyloid burden in patients with cardiac AL-A. Notably, Study 1 (Mayo Stage IIIb) is the first randomized, placebo-controlled efficacy clinical trial to formally assess the effects of a pharmacological in this severely ill population. Because the median expected survival for Mayo Stage IIIb patients is far shorter than for Mayo Stage IIIa patients, the resulting sample size required for the Mayo Stage IIIB study is less (111 patients) than for the Mayo Stage IIIA study (267 patients). Importantly, these studies include patients identified as Stage III and IV based on the 2012 Mayo staging system (Kumar S. et al. J Clin Oncol. 2012;30:989). These trials are ongoing in a challenging environment. The approval of daratumumab i 2021 changed the landscape and modified the SOC, requiring appropriate protocol amendments. While the COVID pandemic affected all people, it had a greater impact on patients with AL amyloidosis, a rare disease that can only be treated effectively by a coordinated team of experts at centers of excellence. [Formula presented] Disclosures: Wechalekar: Alexion, AstraZeneca Rare Disease: Consultancy;Caelum Biosciences: Other: Clinical Trial Funding;Janssen: Consultancy;Celgene: Honoraria;Takeda: Honoraria;Amgen: Research Funding. Silowsky: Caelum Biosciences: Current Employment. Daniel: Caelum Biosciences: Current Employment. Harnett: Caelum Biosciences: Current Employment. Spector: Caelum Biosciences: Current Employment. Sobolov: Caelum Biosciences: Current Employment. Quarta: Alexion, AstraZeneca Rare Disease: Current Employment. Kurman: Caelum Biosciences: Other: Medical Monitor. Tulchinskiy: Caelum Biosciences: Consultancy. Bhattacharyya: Alexion, AstraZeneca Rare Disease: Current Employment. Liedtke: Karyopharm: Membership on an entity's Board of Directors or advisory committees;Kite: Membership on an entity's Board of Directors or advisory committees;Celgene: Membership on an entity's Board of Directors or advisory committees;Sanofi: Membership on an entity's Board of Directors or advisory committees;Takeda: Membership on an entity's Board of Directors or advisory committees;GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees;Pfizer: Honoraria;Oncopeptides: Membership on an entity's Board of Directors or advisory committees;Kura Oncology: Membership on an entity's Board of Directors or advisory committees;Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees;Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees;Alnylam: Membership on an entity's Board of Directors or advisory committees;Caelum: Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial Funding.

Neutralizing Antibody Responses Against Sars-Cov-2 in Patients with Plasma Cell Disorders Who Are on Active Treatment after Two Doses of mRNA Vaccination

Background Patients (Pts) with multiple myeloma (MM) experience prolonged immunosuppression due to the incurable nature of the disease and corresponding treatment modalities. Due to this many MM pts with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) require hospitalization, with an increased mortality rate over healthy adults. Two mRNA vaccines against (SARS-CoV-2): BNT162b2 & mRNA-1273 were approved under an emergency use authorization (EUA) by the Food and Drug Administration (FDA) due to the high efficacy in preventing SARS-CoV-2. The aim of this study was to analyze the antibody (Abs) response in all pts with plasma cell disorders (PCD) including MM, AL-Amyloidosis, and smoldering myeloma (SMM) who are on active treatment. Patients & Methods All pts (MM, AL-Amyloidosis, and SMM) on active treatment who received SARS-CoV-2 mRNA vaccine were identified at the University of Kansas Health System between January 2021 to July 2021and reviewed retrospectively. Descriptive analyses were performed on available data for patient characteristics. Abs against SARS-CoV-2 were measured using methodology approved by the FDA (enzyme-linked immunosorbent assay;cPass SARS-CoV-2 Neutralizing Antibody Detection Kit;GenScript, Piscataway, NJ). We stratified pts into clinically relevant responders (>250 IU/mL), partial responders (50-250 IU/mL), and non-responders (<50 IU/mL) Results A total of 118 pts were identified in our analysis and are described in Table 1. Of the total pts, 102 (86%) had MM, 13 (11%) pts had AL-Amyloidosis, and 3 (3%) pts had SMM. Median age was 69 years (45-95), 96 pts (81%) were Caucasian, and 57 (48%) were male. Median lines of prior treatment was 2 (1-13). Active PCD patients were treated with single-agent therapy in 60 pts (51%), doublet-based therapy in 5 pts (4%), and triplet-based therapy in 51 pts (43%). Daratumumab based therapy was utilized in 59 pts (50%). All pts included received two doses of either BNT162b2 or mRNA-1273. At the time of abs testing 82 patients (69%) were in a very good partial response (VGPR) or better, 29 pts (25%) were in partial response, while 7 pts (6%) had stable disease. Five pts (4%) had COVID-19 infection prior to the vaccine. The median time between thesecond dose of the vaccine and testing for Abs was 100 days (34-190). Only 46 pts (39%) developed an adequate response, 36 pts (30.5%) had a partial response, while 36 (30.5%) did not respond to the vaccine. Low Ab levels were seen in all PCD subtypes with the following mean levels: SMM :25.4 (5.4- 36.9) IU/mL, MM 148 (0- >250) IU/mL, and AL- Amyloidosis 92.35 (range 0- >250) IU/mL. Among the 5 pts with COVID-19 infection prior to the vaccination, full Abs response was observed in 4 pts, and 1 patient had no Abs response. Type of treatment did not affect the response to treatment in any clinically meaningful way. The odds ratio of achieving a clinically relevant Abs response was higher in pts with absolute lymphocyte counts>0.5 K/uL (p=0.01) and IgG levels> 400 mg/dL (p=0.04) and lower in pts receiving treatments with daratumumab combinations or anti-BCMA therapy (p<0.0001). Higher levels of anti-SARS-CoV-2 Abs were observed in pts with ≥ VGPR (mean≈147 IU/mL) compared to <VGPR (mean≈ 119 IU/mL). However, in this dataset, this difference was not statistically significant (p=0.17). Conclusion mRNA vaccine Ab response is lower in PCD pts getting active treatment compared with the general population. For PCD patients on active treatment, mRNA vaccine produced full antibody responses and partial responses in 39% and 30.5% of pts, respectively. anti-SARS-CoV-2 abs are especially low for patients on daratumumab combinations or anti-BCMA therapy, low lymphocytes, and low IgG levels at the time of vaccination. Some PCD may not develop anti-SARS-CoV-2 abs despite vaccination and/or previous COVID-19 infection. Therefore, checking anti-SARS-CoV-2 abs may be clinically useful in identifying patient's response. Further prospective studies should ascertain the value of a 3 rd vaccine dose in this population. [Fo mula presented] Disclosures: Mahmoudjafari: Omeros: Membership on an entity's Board of Directors or advisory committees;GSK: Membership on an entity's Board of Directors or advisory committees;Incyte: Membership on an entity's Board of Directors or advisory committees. McGuirk: Astelllas Pharma: Research Funding;Juno Therapeutics: Consultancy, Honoraria, Research Funding;EcoR1 Capital: Consultancy;Gamida Cell: Research Funding;Magenta Therapeutics: Consultancy, Honoraria, Research Funding;Fresenius Biotech: Research Funding;Bellicum Pharmaceuticals: Research Funding;Novartis: Research Funding;Pluristem Therapeutics: Research Funding;Allovir: Consultancy, Honoraria, Research Funding;Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau;Novartis: Research Funding. Atrash: Jansen: Research Funding, Speakers Bureau;AMGEN: Research Funding;GSK: Research Funding.

The impact of COVID-19 in the management of AL amyloidosis and Immunoglobulin Deposition Disease: A single-center experience.

INTRODUCTION: Patients with AL amyloidosis and immunoglobulin deposition diseases (IDD) are vulnerable during the COVID-19 pandemic due to the immune compromise from the plasma cell disorder and therapy-related immune defects. We describe a local experience in providing care for patients with AL amyloidosis and IDD. METHOD: Patient treatment and disease status since the beginning of the pandemic on March 11, 2020, as declared by WHO, were collected and analyzed. RESULTS: Ninety-six patients with AL amyloidosis and IDD were included. Four patients with IDD and 22 patients with systemic AL amyloidosis were receiving treatment during the pandemic. Since the pandemic, patients' treatments were discontinued if they achieved VGPR or better postinduction. Seven patients discontinued all treatment after achieving VGPR, and others required treatment modifications. 28 patients have been tested for COVID-19, and all tests have been negative. Three patients died since the pandemic, two from organ complications of systemic AL amyloidosis and one from an unrelated cause. CONCLUSION: The management of AL amyloidosis and IDD must be individualized on the clinical characteristics, centers' access to care under the pandemic restrictions, and the epidemiological aspects of the outbreak.