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Background: A proportion of patient with monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) will progress to active multiple myeloma (MM). Optimization of follow-up strategies and diagnostic testing is needed to detect those who are at risk of imminent progression since they may benefit from early treatment. There is a considerable need for biomarkers that can accurately reflect disease status and risk of progression to MM. In recent years, circulating tumor plasma cells (CTPC) have gained interest in disease monitoring for their promising prognostic significance and the minimally-invasive nature of blood sampling. Aim: To evaluate the feasibility of using CTPC analysis by next-generation flow cytometry (NGF) for disease monitoring in precursor conditions of MM and early detection of progression to active MM. Methods: Participants were enrolled from the Iceland Screens, Treats, or Prevents Multiple Myeloma study (iStopMM). The study is a population-based screening study for MM precursors and randomized trial of follow-up strategies that enrolled 80,579 Icelanders and screened 75,422 of participants by serum protein electrophoresis (SPEP) and free light chain (FLC) assay. A total of 2/3 of participants who had abnormal screening tests were invited to the study clinic to undergo assessment and testing to detect SMM and MM. All cases of SMM and MM and a random conveniency sample of participants with MGUS were eligible for a flow cytometry sub study. The Euroflow NGF MM-MRD method was used for quantitation of tumor PC in the bone marrow (BM) and CTPC in peripheral blood (PB). Paired BM and PB samples were collected at baseline or after SMM/MM diagnosis at the next scheduled BM sampling during follow-up. The Infinicyt software (Cytognos SL, Salamanca, Spain) was used for flow cytometry data analysis. The limit of detection (LOD) was set at ≥ 20 tumor PC in both BM and PB. The Mann-Whitney U test or the Kruskal-Wallis tests were used to assess statistical significance of differences observed between two or more than two groups, respectively. Results: A total of 189 individuals have been included in the study at this point (90 MGUS, 73 SMM, and 26 MM). The frequency of cases in which CTPC were detected in PB increased (p Conclusion: This is the first study evaluating CTPC in a screened cohort of patients with precursor conditions of MM. We found the frequency of CTPC detection to be lower than has been previously reported in a study by Sanoja-Flores et al. in 2018 using the same NGF method, particularly for MGUS (18% vs 59% [n=150]) and SMM (74% vs 100% [n=26]). This difference can likely be attributed to a higher frequency of patients with less advanced disease in the screened cohort of the iStopMM study, suggested by markedly lower median M-component levels in this study (3.3 vs 6, 7.8 vs 21, and 16.2 vs 27 g/L for MGUS, SMM, and MM, respectively). We found that the number of CTPC progressively increased from MGUS to SMM and MM. Furthermore, a detectable CTPC population by NGF was associated with a higher percentage tumor PC in the BMPC compartment in both MGUS and SMM. A BMPC compartment that is highly dominated by tumor PC (>95%) has been reported to be associated with a higher risk of progression in both MGUS and SMM and in our study a CTPC population was detected in a vast majority of SMM patients with over 95% tumor PC. Taken together, these results confirm that the detection and number of CTPC by NGF is associated with a more advanced disease and that their detection by NGF may have a clinical utility in the follow-up of myeloma precursor disease. Figure 1 Figure 1. Disclosures Durie: Amgen: Other: fees from non-CME/CE services ; Amgen, Celgene/Bristol-Myers Squibb, Janssen, and Takeda: Consultancy. Kristinsson: Amgen: Research Funding; Celgene: Research Funding.

Background: Cancer screening is performed worldwide for several malignancies. Monoclonal gammopathy of undetermined significance (MGUS) precedes multiple myeloma (MM) and related lymphoproliferative disorders (LP). However, less than 5% of all MM patients are diagnosed during their precursor state and individuals who develop MM while being monitored for MGUS have better overall survival and fewer complications, compared to MM patients diagnosed without knowledge of MGUS. Thus, population-based screening for MGUS could identify candidates for early treatment of MM/LPs. To evaluate whether systematic screening is beneficial, we performed the Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) study, the first population-based screening study for MGUS that includes a randomized clinical trial (RCT) of follow-up and treatment strategies. Methods: All living residents of Iceland on September 9th, 2016 who were born before 1976 (N=148,708) were invited to participate. Of those, 80,759 (54.3%) provided informed consent for screening. Serum samples were collected from participants alongside clinical blood sampling in the Icelandic health service between September 2016 and the end of 2020. All samples were shipped to the Binding Site in Birmingham, UK, for screening. Samples were tested for M-proteins by capillary zone electrophoresis and immunofixation electrophoresis performed to confirm and characterize suspected M-proteins. Free light chains (FLCs) were measured using the FreeLite® assay. Individuals with a previous diagnosis of MM/LPs/MGUS (N=237) were excluded. Per protocol and informed consent, participants with MGUS were randomized to one of the three study arms: Arm 1 where participants are not contacted; Arm 2 where individuals are followed based on current guidelines; and Arm 3 where individuals are followed with a more intensive diagnostic and monitoring strategy. Participants who progress are offered early treatment. All participants repeatedly answered questionnaires on quality of life and mental health. Results: A total of 75,422 participants (93.4%) provided a serum sample for screening. Of those, 3,725 (4.9%) had MGUS. The prevalence of MGUS was dependent on age with 2.3%, 6.2%, and 12.9% diagnosed in age groups 40-59, 60-79, and 80-103 years, respectively. The prevalence of MGUS was higher in males, 5.9% vs 4.1% (p The RCT includes 3,487 newly diagnosed MGUS individuals with 1164, 1159, and 1164 individuals in arms 1, 2 and 3, respectively (Table). The median age at diagnosis was 69 years in arms 1 and 2, and 70 years in arm 3. Females constituted 45.9% and the isotypes were IgG (50%), IgA (10%), IgM (18%) and biclonal (8%). The median M-protein concentration was 0.34 g/dL. A total of 428 light-chain MGUS cases were randomized. The demographic distribution was well balanced between the three arms. After a median follow-up of 3 years, 194 patients in the RCT have been diagnosed with any LP: 9 in arm 1, 92 in arm 2, and 133 in arm 3 (p Conclusion: In this large prospective population-based screening study including >75,000 screened persons, we have identified 3,725 individuals with monoclonal gammopathy. In the RCT, after 3 years of follow-up, we show that active screening identifies significantly higher number of individuals with full-blown malignancy and smoldering disease, illustrating the fact that early detection and intervention is achievable. Although our findings are encouraging, until final results of the iStopMM study become available, including data on survival and quality of life, we advise against systematic MGUS screening in healthy individuals. Figure 1 Figure 1. Disclosures Kristinsson: Amgen: Research Funding; Celgene: Research Funding. Kampanis: The Binding Site: Current Employment. Hultcrantz: Curio Science LLC: Consultancy; Daiichi Sankyo: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Intellisphere LLC: Consultancy. Durie: Amgen: Other: fees from non-CME/CE services ; Amgen, Celgene/Bristol-Myers Squibb, Janssen, and Takeda: Consultancy. Harding: The Binding Site: Current Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Landgren: Janssen: Research Funding; Celgene: Research Funding; Janssen: Honoraria; Janssen: Other: IDMC; Amgen: Honoraria; Takeda: Other: IDMC; Amgen: Research Funding; GSK: Honoraria.

We performed a genome-wide association study on 1,292 individuals with abdominal aortic aneurysms (AAAs) and 30,503 controls from Iceland and The Netherlands, with a follow-up of top markers in up to 3,267 individuals with AAAs and 7,451 controls. The A allele of rs7025486 on 9q33 was found to associate with AAA, with an odds ratio (OR) of 1.21 and P = 4.6 x 10(-10). In tests for association with other vascular diseases, we found that rs7025486[A] is associated with early onset myocardial infarction (OR = 1.18, P = 3.1 x 10(-5)), peripheral arterial disease (OR = 1.14, P = 3.9 x 10(-5)) and pulmonary embolism (OR = 1.20, P = 0.00030), but not with intracranial aneurysm or ischemic stroke. No association was observed between rs7025486[A] and common risk factors for arterial and venous diseases-that is, smoking, lipid levels, obesity, type 2 diabetes and hypertension. Rs7025486 is located within DAB2IP, which encodes an inhibitor of cell growth and survival.

Abstract 1264 Background: Recombinant activated coagulation factor VII (rFVIIa) has been increasingly used in non-hemophiliac patients for unapproved indications. We undertook a 10 year nation-wide retrospective survey in order to evaluate the use of rFVIIa in Iceland in patients with intractable extra-cranial hemorrhage. Material and methods: Hospital charts of all patients that received rFVIIa between 1999–2008 at Landspitali, the single institution administering rFVIIa in Iceland, were reviewed and indications, coagulation profiles and clinical outcome were evaluated. This analysis focuses on patients treated off-label for desperate (intractable) extra-cranial hemorrhage (IH), ie only patients in who all other measures were considered to have failed to stop hemorrhage. Results: rFVIIa was used for IH in 55 patients (median age 53 yrs, range; 0–84, 51% males). This included IH in open heart surgery (n=23), non-cardiac surgery (n=7), post-partum hemorrhage (n=9), multitrauma (n=8) and miscellaneous (n=8). A single rFVIIa dose was used in 86% of cases and hemorrhage was considered effectively contained by immediate clinical response to rFVIIa in 81% of the IH cases. Survival at 30 days for all patients was 68%. Out of 55 patients with IH, six died within 24 hours of administration of rFVIIa (five assessed clinically as rFVIIa non-responders) and 11 other patients (total 17 patients, 31%) died within 30 days (six non-responders). The 24-hour mortality in rFVIIa clinical responders and non-responders was 2% and 50% respectively (p=0.0004) and the 30 day mortality was 25% and 60% respectively (p=0.05). The need for transfusion of blood products was significantly decreased (p Conclusion: The majority of unselected consecutive patients receiving rFVIIa as last resort treatment for IH were considered to have favorable immediate clinical response as well as reduced transfusion requirements and normalisation of coagulation parameters. Also, patients deemed with clinical response to rFVIIa may have had lower mortality. Disclosures: Off Label Use: Activated recombinant factor VII for use in desperately bleeding patients.