Introduction: For decades corticosteroids (steroids) have been essential in treating patients with multiple myeloma (MM). However, the role of steroids in the era of novel therapies is uncertain. Considering the unfavourable toxicity profile of steroids, the phase 2 REST study investigated the efficacy of a quadruplet regimen with limited steroids (dexamethasone) in patients with newly diagnosed MM who were ineligible for autologous stem cell transplantation. Patients were treated with isatuximab-bortezomib-lenalidomide-dexamethasone; dexamethasone was omitted after two cycles, bortezomib was omitted after eight cycles and isatuximab was omitted after 18 cycles. Efficacy was comparable with full-dose steroid regimens. This study aimed to investigate the impact of omitting dexamethasone on patient-reported steroid toxicity. Methods: Patients completed two patient-reported outcomes questionnaires: the Steroid-Symptom Questionnaire for patients with MM (SSQ-MM) and the European Organization for Research and Treatment of Cancer (EORTC) Quality of life – Core 30 (QLQ-C30) at day 1 and 22 of cycles 1 and 2 (with dexamethasone) and cycles 4 and 5 (without dexamethasone). Frailty was assessed for each patient using the patient-reported frailty phenotype based on responses to five of the EORTC QLQ-C30 items. The SSQ-MM Total score calculated by the patients´ responses to 19 of the 20 items of SSQ-MM assessed steroid toxicity. Mean change from baseline and mean score differences between time points with dexamethasone compared to without dexamethasone were estimated using linear mixed model of repeated measures (LMRM). Statistically significant estimates (p-value <0.05) were interpreted using Benjamini-Hoechberg procedure to avoid type I errors and minimal important difference to ensure clinical relevance. The proportion of patients developing steroid toxicity during cycles with and without dexamethasone were compared using mixed effect logistic regression, and statistical significance was assessed with a p-value of <0.05. The impact of steroid toxicity on other health-related quality of life (HRQL) domains was investigated with LMRM including a Gaussian random intercept for each patient with adjustments using Benjamini-Hoechberg procedure. Results: 51 patients were included with a median age of 77 years (range 70-88). 16 patients (31%) were 80 years or older. Eight patients (16%) were ECOG 2 or more and 21 patients (41%) were frail according to the patient-reported frailty phenotype. Questionnaire completion rate was 88%. Assessed by SSQ-MM Total, we found an overall impact of dexamethasone on steroid toxicity as the overall p-value of <0.001 was significant after adjustment using Benjamini-Hoechberg. Mean score differences in steroid toxicity between time points with dexamethasone compared to time points without dexamethasone were not statistically significant (Cycle 1 day 22 (C1D22) compared to C4D1; p-value 0.07, C2D1 compared to C5D1; p-value 0.25 and C2D22 compared to C5D22; p-value 0.21). At C1D22 and C2D22, patients reported clinically meaningful greater steroid toxicity compared to baseline (p-values <0.01), and sensitivity analysis revealed significantly more patients reported steroid toxicity at C1D22 (16 out of 38) compared to C4D22 (2 out of 29, p-value 0.004). Steroid toxicity was associated with impaired physical, emotional and social functioning and greater fatigue, pain, appetite loss and insomnia. Conclusions: Steroids are included in most myeloma-targeted therapies. However, growing evidence shows similar disease responses with steroid-limited treatments. Overall, we found a statistical significant difference in steroid toxicity during cycles with dexamethasone compared to cycles without dexamethasone. A clinically meaningful increase in steroid toxicity from C1D1 (baseline) to C1D22 (also confirmed with sensitivity analysis) and C2D22 was observed. Steroid toxicity also negatively impacted several HRQL domains.

BACKGROUND:Adding anti-CD38 monoclonal antibodies to standard therapies can improve outcomes in patients with multiple myeloma. Long-term treatment with corticosteroids increases the risk of infection. We aimed to evaluate the safety and activity of isatuximab, weekly bortezomib, lenalidomide, and limited dexamethasone in patients with newly diagnosed multiple myeloma ineligible for autologous haematopoietic stem-cell transplantation (HSCT). METHODS:REST is an academic, multicentre, single-arm, phase 2 trial of adults with newly diagnosed multiple myeloma and measurable disease as defined by International Myeloma Working Group criteria, ineligible for high-dose melphalan and autologous HSCT, Eastern Cooperative Oncology Group performance status of 0-3 (with 3 only allowed if related to myeloma). In 28-day cycles, patients received isatuximab (10 mg/kg intravenously on days 1, 8, 15, and 22 of cycle 1, and days 1 and 15 of cycles 2-18), bortezomib (1·3 mg/m2 subcutaneously on days 1, 8, and 15 of cycles 1-8), and lenalidomide (25 mg orally on days 1-21, until progressive disease). Dexamethasone was given 20 mg orally on days 1, 8, 15 and 22, limited to the two first cycles only. The primary endpoint was measurable residual disease (MRD)-negative complete response, assessed by next-generation flow cytometry (sensitivity 1·0 × 10-5), during or after 18 cycles of study treatment. MRD was tested in all patients who had at least complete response before cycle 19 and in all patients who had at least very good partial response at cycle 19. All patients enrolled initiated treatment and were included in the analyses. This trial is registered with ClinicalTrials.gov (NCT04939844); the primary endpoint is reported in this Article, and follow-up is ongoing. FINDINGS:Between June 30, 2021 and Jan 19, 2023, we assessed for eligibility and recruited 51 patients (27 [53%] females and 24 [47%] males), with a median age of 77 years (IQR 73·5-80). 39 participants completed 18 cycles of treatment on protocol, of whom two had discontinued treatment but not protocol. At a median follow-up of 27·0 months (IQR 23·0-33·7), MRD-negative complete response was observed in 19 (37% [95% CI 25·3-51·0]) patients, with a median treatment duration of 22 months (IQR 15·2-28·8; range 1·4-35·1). Disease progression or death had occurred in 18 (35%) of 51 patients, and eight (16%) patients had died. During the first 18 cycles of study treatment, the most common adverse events of grade 3 or 4 were neutropenia (28 [55%] patients), infections (21 [41%] patients), and thrombocytopenia (11 [22%] patients). 48 serious adverse events of grade 3 or higher were reported in 27 (53%) patients. A total of 14 (27%) patients discontinued treatment before cycle 19, most commonly because of progressive disease (eight [16%]) and adverse events (four [8%]). Two deaths (one due to pneumonia and one due to sepsis) were assessed as possibly related to study treatment. INTERPRETATION:Isatuximab, weekly bortezomib, and lenalidomide with limited dexamethasone was active and safe as initial therapy for older patients with multiple myeloma ineligible for autologous HSCT. A modified quadruplet regimen in which dexamethasone is omitted after two cycles can be used in this patient population. FUNDING:Sanofi.

Background: Standard therapies for patients with newly diagnosed multiple myeloma (NDMM) who are ineligible for autologous stem cell transplantation (ASCT) have been lenalidomide-dexamethasone (Rd), bortezomib-lenalidomide-dexamethasone (VRd) or bortezomib-melphalan-prednisone (VMP). The benefit of adding an anti-CD38 monoclonal antibody (mAb) to the standard treatments of VMP and Rd has been demonstrated in two large phase 3 studies, achieving overall response rates (ORR) of 90.9% and 92.9% in the daratumumab-VMP arm and the daratumumab-Rd arm, respectively (Facon, 2019, Mateos, 2018). Isatuximab is an anti-CD38 mAb approved in combination with pomalidomide-dexamethasone and carfilzomib-dexamethasone to treat relapsed/refractory MM. The drug has also shown clinical responses as combination therapy to treat NDMM (Trudel, 2019). Corticosteroids have been the backbone of most myeloma-targeted therapies since the discovery of their effectiveness. Due to the continuous treatment paradigm, the cumulative dose of corticosteroids in patients is substantial. Steroids inflict reduction in both short- and long-term quality of life and increase patients' receptiveness to infections. Infections are one of the main reasons for complications and death during active first line treatment and the rate rises with age (Mothy, 2019). Instead of reducing or removing corticosteroids, isatuximab will replace corticosteroids to evaluate the effectiveness and safety of the novel regime of isatuximab-bortezomib-lenalidomide. Aim: The study will evaluate isatuximab (Isa) in combination with bortezomib (V) and lenalidomide (R) with minimal dexamethasone (d) as first-line treatment in transplant-ineligible patients. The primary endpoint is the number of patients who achieve measurable residual disease negative (Euroflow NGF 10 -5) complete response during and/or after 18 cycles of study treatment. Secondary endpoints include progression free survival, overall survival, overall response rate, safety evaluations and patient-reported outcome. Methods: The REST study is an academic, single arm, open-label, phase 2 study of NDMM patients ineligible for ASCT. 51 patients are included and receive Isa-VRd (Isa: 10 mg/kg IV Days 1, 8, 15, 22 during cycle 1, Q2W cycle 2-18; V: 1, 3 mg/m 2 SC Days 1, 8, 15 during cycle 1-8; R: 25 mg PO Days 1-21 during all cycles; d: 20 mg PO Days 1, 8, 15, 22 only for the first 2 cycles), all 28-day cycles. Results: Recruitment was completed in January 2023. Baseline characteristics, safety summary and preliminary results can be found in Table 1. The median age is 77 years, range 70-88 years. Twenty-nine patients developed 60 grade >3 non-hematological adverse events (AE), including infections (n=26), syncope (n=5), diarrhea (n=4), skeletal pain (n=4), arrhythmias (n=3), acute renal failure (n=3), increased transaminases (n=3), venous thromboembolism (n=2), arthritis (n=2), gastrointestinal hemorrhage (n=2), peripheral sensory neuropathy (n=2), edema (n=1), hyperglycemia (n=1), rash (n=1) and opiate intoxication (n=1). At a median follow up of 12 months, the ORR was 100% (51/51) with very good partial response or better at80.3% (41/51). Forty-four patients are still on study. One patient died from septicemia with staphylococcus aureus, four patients discontinued due to disease progression, one patient due to poor compliance and one patients for safety reasons judged by the investigator. Conclusions: Isa-VRd in the transplant ineligible population with a median age of 77 years has a tolerable safety profile. Isa-VRd is showing encouraging preliminary efficacy in NDMM ineligible for transplant. Follow-up is ongoing. Acknowledgements: Sanofi funded this research.

Background: The aetiology of multiple myeloma (MM) is unknown but various environmental exposures are suspected as risk factors. We present the first paper analysing the geographical distribution of MM in Denmark at the municipal level to investigate variations that could be explained by environmental exposures.Methods: Patients diagnosed with MM in Denmark during 2005-2020 were identified from nationwide registries and grouped into the 98 Danish municipalities based on residence. The age- and sex-standardised incidence rate (SIR) of each municipality was compared to the national incidence in a funnel plot with 95% control limits. Differences in SIRs of rural, suburban, and urban areas were evaluated with incidence rate ratios.Results: In total, 5243 MM patients were included. Overall, we found a heterogeneous geographical distribution of MM and a potential hotspot in southern Denmark. This hotspot contains three municipalities with SIRs above the 95% control limit assuming considerably higher rate of MM compared to the national incidence rate. A significant higher SIR was found in rural areas compared to urban areas.Conclusion: The geographical distribution of MM in Denmark indicates that the risk of developing MM depends on place of residence probably due to environmental factors.

Topic: 14. Myeloma and other monoclonal gammopathies - Clinical Background: Standard therapies for newly diagnosed multiple myeloma (NDMM) patients who are ineligible for autologous stem-cell transplantation (ASCT) have been lenalidomide-dexamethasone (Rd), bortezomib-lenalidomide-dexamethasone (VRd) or bortezomib-melphalan-prednisone (VMP). The benefit of adding an anti-CD 38 monoclonal antibody (mAb) to the standard treatments of VMP and Rd has been demonstrated in two large phase 3 studies (Facon, 2019. Mateos, 2018). Isatuximab is an anti-CD38 mAb approved in combination with pomalidomide-dexamethasone and carfilzomib-dexamethasone to treat relapsed/refractory MM, and has also shown clinical responses as combination therapy to treat NDMM (Trudel, 2019). Corticosteroids have been the backbone of most myeloma-targeted therapies since the discovery of their effectiveness. Due to the continuous treatment paradigm, the cumulative dose of corticosteroids in patients is substantial. Steroids inflict reduction in both short- and long-term quality of life and increase patients’ receptiveness for infections. Infections are one of the main reasons for complications and death during active first line treatment and the rate rises with age (Mothy, 2019). Both steroid-free regimens and regimens with reduced corticosteroids have demonstrated improved safety and similar efficacy as regimens containing steroids (O´Donnell, 2018. Rajkumar, 2010. Richardson, 2005). Aims: The study evaluates isatuximab (Isa) in combination with bortezomib (V) and lenalidomide (R) with minimal dexamethasone (d) as first-line treatment in transplant-ineligible patients. The primary endpoint is the number of patients who achieve measurable residual disease negative (Euroflow NGF 10-5) complete response during and/or after 18 cycles of study treatment. Secondary endpoints include progression free survival, overall survival, overall response rate, safety evaluations and patient-reported outcome. Methods: The REST study is an academic, single arm, open-label, phase 2 study (ClinicalTrial.gov; NCT04939844) of NDMM patients ineligible for ASCT. The patients receive Isa-VRd (Isa:10 mg/kg IV Days 1, 8, 15, 22 during cycle 1, QW cycle 2-18; V: 1,3 mg/m2 SC Days 1,8,15 during cycle 1-8; R: 25 mg PO Days 1-21 during all cycles; d: 20 mg PO Days 1,8,15,22 only for the first 2 cycles), all 28-day cycles. Results: As of January 31, 2023, recruitment is completed with 51 patients enrolled. Baseline characteristics can be found in Table 1. At data-cutoff, the median number of cycles started by patients was 9 (range 1-21) and the median duration of exposure was 34 (range 1-76) weeks. 46 patients were still on study, 1 patient died of staphylococcus aureus septicemia, 3 patients discontinued due to disease progression and 1 patient for poor compliance (after 1 cycle). 23 patients developed 43 grade ≥3 non-hematological adverse events (AE), including infections (n=16), vasovagal syncope (n=5), bone pain (n=3), acute renal failure (n=3), diarrhea (n=3), increased transaminases (n=3) peripheral neuropathy (n=2), maculopapular rash (n=1), venous thromboembolism (n=1), reduced general condition (n=1), opiate intoxication (n=1), arthritis (n=1) and gastrointestinal hemorrhage (n=1). 2 patients have discontinued study treatment before cycle 19 due to drug toxicity or adverse events (all grade 2 or lower). At a median follow up of 8 months, 39 patients was evaluated for response. The ORR was 97% (38/39 patients) and the ≥very good partial response rate was 66.6% (26/39 patients). Summary/Conclusion: Isa-VRd in the transplant ineligible population has a tolerable safety profile and is showing encouraging preliminary efficacy in NDMM ineligible for transplant. Follow-up is ongoing. Table 1:Acknowledgements: Sanofi sponsors the REST study. Keywords: Monoclonal antibody, Minimal residual disease (MRD), Multiple myeloma

Background: In the HOVON 126/NMSG 21.13 trial non-transplant eligible newly diagnosed multiple myeloma (NTE-NDMM) patients were treated with 9 induction cycles of ixazomib, thalidomide and dexamethasone (ITd), followed by randomization between either ixazomib or placebo until progression or unacceptable toxicity. The overall response rate and PFS data have been previously published. Aims: We here present the long-term PFS2 and overall survival data. Methods: Patients were treated with 9 induction cycles (28 days) of ixazomib (4mg on day 1, 8 and 15), thalidomide (100mg on day 1-28) and dexamethasone (40mg on day 1, 8, 15 and 22), followed by maintenance with either ixazomib or placebo (4mg, both on day 1, 8 and 15, every 28 days). Patients were classified as fit, intermediate fit or frail, based on a modified IMWG frailty index which incorporated age, the Charlson Comorbidity Index (CCI) and the WHO performance as a proxy for (instrumental) Activities of Daily Living (iADL) (scoring WHO 0 as 0 points, WHO 1 as 1 point, and WHO 2-3 as 2 points). Results:From registration: 143 eligible patients were included in the study. After a median follow-up (FU) of 67.4 months (m), the median PFS was 14.3m (95% CI 11.5-16.8), median PFS2 was 34.6m (30.7-41.5) and median OS was 58.3m (50.5-65.0). There was no difference in PFS between frailty subgroups. In contrast, median PFS2 and OS were longer in fit patients (PFS2: 49.1m (34.6-74.1), OS: NR (66.6-NR)) versus intermediate-fit (30.1m (25.1-39.0); 51.2m (32.3-63.9) resp.) and frail patients (30.9m (24.0-42.3); 50.5m (32.9-59.4) resp.). From randomization: 78 (55%) patients were randomized, 39 patients in each arm. After a median FU of 60 months from randomization, there was no difference in PFS between the ixazomib-arm (median 9.5m; 95% CI 5.5-14.8) and the placebo-arm (8.4m; 3.0-13.8). Median PFS2 was 39.8m (28.8-60.0) for patients on ixazomib, as compared to 28.7m (22.8-43.2) for patients in the placebo arm, although this difference was not statistically significant. Median OS was not reached for the ixazomib arm and was 50.7m (41.3-58.1) for the placebo arm (HR 0.39; 95% CI 0.19-0.78, p=0.008). In both arms 32 (82%) patients received 2nd line treatment. With the caveat of low numbers and heterogeneous treatment regimens, more patients in the ixazomib arm received daratumumab-lenalidomide-dexamethasone (4 patients, 13%) and panobinostat-bortezomib-dexamethasone (6 patients, 19%), compared to the placebo arm (2 patients (6%) and 3 patients (9%) respectively). In order to explain the difference in OS, subsequent lines of therapy are currently being investigated. Image:Summary/Conclusion: With longer FU, we here confirm that ixazomib maintenance therapy did not improve PFS, compared to placebo. However, PFS2 tends to be longer and OS was superior in patients treated with ITd followed by maintenance with ixazomib versus placebo.

Background: The severe, acute respiratory syndrome, coronavirus 2 (SARS-CoV-2), leading to coronavirus-19 (COVID-19), was detected for the first time in Wuhan, China in December 2019. In general, governments and health authorities have taken precautions during the COVID-19 pandemic to reduce viral spread and protect vulnerable citizens. Patients with multiple myeloma (MM) have an increased risk of being infected with COVID-19 and developing a fatal course due to the MM-related immunodeficiency (Glenthøj, A et al. PMID: 32939853). To some extent, the COVID-19 pandemic has changed standard of care towards extended use of oral regimens and limiting hospital visits (Terpos E et al.PMID: 32444866).

In general, governments and health authorities have taken precautions during the COVID-19 pandemic to reduce the viral spread and protect vulnerable citizens. Patients with multiple myeloma (MM) have an increased risk of being infected with COVID-19 and developing a fatal course due to the related immunodeficiency. We investigated how Danish patients with MM reported their quality of life (QoL) pre-COVID and during COVID, in an ongoing longitudinal QoL survey. The responses given during the first and second wave of the COVID-19 pandemic were pooled, analyzed and compared to the same period the year before. We hypothesized that locking down the society would have caused deteriorated QoL and that patients living alone and those under the age of 65 would be particularly affected by the situation. Surprisingly, our study showed the opposite. Statistically significant and clinically relevant differences were primarily found during the first lock down and represented reduced fatigue, improved role functioning, decreased insomnia and improved physical health summaries in patients below 65 years of age. These results indicate that Danish patients with MM might have felt protected and safe by COVID restrictions. Otherwise, the questionaries used in QoL-MM survey may not have been able to capture the impact of the COVID-19 pandemic. Importantly, this indicates that QoL survey data obtained in clinical studies, in countries with highly developed health-care systems using standard questionnaires during the pandemic, allow room for interpretation without being adjusted for the impacts of the pandemic.

Kazimierz Groen1,2, Fredrik H. Schjesvold3,4, Bronno van der Holt5, Mark-David Levin6, Maarten R. Seefat1,2, Markus Hansson7, Maria B.L. Leys8, Josien C. Regelink9, Anders Waage10, Damian Szatkowski11, Per Axelsson12, Trung Hieu Do13, Asta Svirskaite14, Ellen van der Spek15, Einar Haukas16, Dorota Knut-Bojanowska17, Paula F. Ypma18, Cecilie H. Blimark19, Ulf-Henrik Mellqvist20, Niels W.C.J. van de Donk1,2, Pieter Sonneveld21, Anja Klostergaard22, Annette J. Vangsted23, Niels Abildgaard24,*, Sonja Zweegman1,2,*

Immunotherapy is being thoroughly tested for hematological malignancies. In myelodysplastic syndromes (MDS), greatest focus has been towards vaccines and checkpoint inhibitors (CI). The cancer types, where CI has shown the greatest clinical benefit, are the ones that carry a high mutational burden. Mutations create neoantigens, that can be presented on HLA molecules, and are suggested to be the main mediator of immunogenic cancer cell elimination. MDS carry comparably few mutations in their malignant cells. Therefore, it remains doubtful whether the malignant cells in MDS can be sufficiently immunogenic to generate an adequate immune response when treated with CI. In this study we investigated T cell responses to personal neoantigens in patients with MDS. We ran DNA and RNA sequencing data, from mesenchymal stem cells and CD34+ cells in 15 patients with MDS, through an MHC binding prediction algorithm, to create personal libraries of neo-peptides corresponding to the individual patients’ mutations. Bone marrow samples from the patients were screened for T cell binding to peptide-MHC-multimers (pMHC) coupled with a DNA-barcode, allowing us to look for T cell reactivity against more than 1000 pMHC in parallel. T cell responses were then validated using functional analysis. Current results indicate that several neoepitopes in MDS are indeed immunogenic and are recognized by cytotoxic T cells in the bone marrow. Interestingly, many of the same neoepitopes are also recognized by T cells in healthy donors, but in contrary to the patient samples, neoepitope binding T cells from healthy donors are not functionally active. To our knowledge, this is the first time neoantigens have been detected and functionally verified in the context of MDS. These findings could lead to further explorations into personal neoepitope vaccines, currently tested in other malignancies, and suggests a role for CI in MDS, possibly combined with specific neoepitope targeting. Copy Number Variations Predict Poor Survival in Patients with Idiopathic Cytopenia of Undetermined Significance (ICUS) and are Associated with Macrocytosis SU Mikkelsen,1,2 S Safavi,3 JW Hansen,1,2,4 K Dimopoulos,5 C O’Rourke,2 MK Andersen,3 JB Andersen,2 and K Grønbæk1,2,4 1Department of Hematology, Rigshospitalet; 2BRIC, University of Copenhagen; 3Department of Clinical Genetics, Rigshospitalet; 4DanStem, University of Copenhagen; 5Department of Clinical Biochemistry, Rigshospitalet Approximately half of ICUS patients have somatic mutations associated with increased risk of progression. The cause of cytopenia in the remaining ICUS patients is unknown. We hypothesize that uniparental disomy (UPD) and submicroscopic copy number variations (CNVs; gains and deletions) are present in ICUS patients and may be associated with prognosis. Patients (n=154) referred with ICUS (2008-2017) were included if cytopenia persisted for >6 months, cytogenetics was normal and BM morphology was not diagnostic. SNP-A was performed on DNA from MNCs or granulocytes using Illumina Infinium-CytoSNP-850K and analyzed with GenomeStudio-v1.1 (Illumina). Only dels>30 markers, gains>90 markers and UPD>5Mb were reported. A total of 33 CNVs/UPDs (excluding delY) were detected in 27/154 patients (18%). Mutations were present in 12/27 patients (44%) with CNVs/UPDs. Twenty-six deletions or UPDs (del/UPD) were detected in 21/154 patients (14%) of whom 11/21 (52%) harbored mutations. After a median follow-up of 25 months (range, 2-114), median OS was 67 months (95%CI:19-not reached) in patients with del/UPD and not reached in patients without (p=0.003), Fig.1. The association with poor OS was also significant when including gains (p=0.02), however, the impact seemed driven by del/UPD, and here results with del/UPD are presented. In multivariate analysis, del/UPD (HR=2.7, 95%CI:1.22-5.9, p=0.014) and deep anemia (hgb<6.2) (HR=2.2, 95%CI:1.104.4, p=0.025) were independent adverse prognostic factors for OS, Fig.2. Interestingly, an almost identical pattern was observed between macrocytosis (MCV>100fL) and del/UPD indicating a linked impact on survival. Patients with del/UPD had significantly higher MCV (p=0.005) and Pferritin (p=0.03). Importantly, macrocytosis was not associated with deep anemia (p=0.317). To our knowledge, this is the first study investigating CNVs/UPDs in ICUS patients. Our results suggest that SNP-A can aid the prognostics in ICUS by identifying submicroscopic structural variations as risk markers for poor OS. A possible role of macrocytosis as a surrogate marker should be explored. Figure 2. Forest plot with hazard ratios (HR). Deletions or UPD (Deletions_UPD) and macrocytosis were not included in the same model due to multicollinearity. Cox proportional hazard regression models were used to estimate HRs and associated 95% CIs. Anemia: hgb < 6.2 mM; Mutations: Somatic mutations with a VAF ≥ 5%. Figure 1. Kaplan-Meier survival curves for patients with deletions or UPD (del/UPD) and patients without del/UPD. Median overall survival (OS) was compared using a stratified log-rank test. X axis: Time from first visit (study inclusion) in months. Oral vitamin C supplementation to myeloid cancer patients on azacitidine treatment: Normalization of plasma vitamin C induces epigenetic changes L.Gillberg,1,2 A.D.Ørskov,1,2 A.Nasif,3 H.Ohtani,4 Z.Madaj,4 J.W.Hansen,1,2,7 N.Rapin,2 J.B. Mogensen,1,2 M.Liu,4 I.H.Dufva,5 J.Lykkesfeldt,6 P.Hajkova,3 P.A.Jones,4 K.Grønbæk1,2,7 1Dept. of Haematology, Rigshospitalet. 2BRIC, University of Copenhagen; 3MRC London Institute of Medical Sciences (LMS), Imperial College, London, UK; 4Van Andel Research Institute, Grand Rapids, Michigan, USA; 5Department of Haematology, Herlev University Hospital; 6Department of Veterinary and Animal Sciences, University of Copenhagen; and 7The Danish Stem Cell Center (Danstem), University of Copenhagen, Denmark. Abstract Purpose: Hematological cancer patients are often vitamin C deficient, and vitamin C is essential for the TET-induced conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC); the first step in active DNA demethylation. Here, we investigated whether oral vitamin C supplementation can correct vitamin C deficiency, enhance the 5hmC/5mC ratio and upregulate expression of viral defense genes in myeloid cancer patients treated with DNA methyltransferase inhibitors (DNMTis). Experimental design: A randomized, placebo-controlled clinical trial in myeloid cancer patients performed during 3 cycles of DNMTi-treatment (5-azacitidine, 100 mg/m2/d for 5 days in 28-day cycles) supplemented by oral dose of 500 mg vitamin C (n=10) or placebo (n=10) daily during the last 2 cycles (Figure 1). Results: Fourteen patients were deficient in plasma vitamin C (<23 μM) and four of the remaining six patients were taking vitamin supplement at inclusion. Global DNA methylation was significantly higher in patients with severe vitamin C deficiency (<11.4 μM; P=0.004). Oral supplementation restored plasma vitamin C levels to the normal range in all patients in the vitamin C arm (P=0.0004). We show for the first time that global 5hmC/5mC levels were significantly increased in patients receiving vitamin C compared to placebo (P=0.041). Additionally, preliminary data suggest that vitamin C supplement may increase the upregulation of viral defense genes in DNMTi naïve patients. Conclusions: Normalization of plasma vitamin C by oral supplementation may enhance the biological effects of DNMTis in patients and prompts the investigation of the clinical efficacy of vitamin C supplementation to DNMTis in a large randomized, placebocontrolled trial.Purpose: Hematological cancer patients are often vitamin C deficient, and vitamin C is essential for the TET-induced conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC); the first step in active DNA demethylation. Here, we investigated whether oral vitamin C supplementation can correct vitamin C deficiency, enhance the 5hmC/5mC ratio and upregulate expression of viral defense genes in myeloid cancer patients treated with DNA methyltransferase inhibitors (DNMTis). Experimental design: A randomized, placebo-controlled clinical trial in myeloid cancer patients performed during 3 cycles of DNMTi-treatment (5-azacitidine, 100 mg/m2/d for 5 days in 28-day cycles) supplemented by oral dose of 500 mg vitamin C (n=10) or placebo (n=10) daily during the last 2 cycles (Figure 1). Results: Fourteen patients were deficient in plasma vitamin C (<23 μM) and four of the remaining six patients were taking vitamin supplement at inclusion. Global DNA methylation was significantly higher in patients with severe vitamin C deficiency (<11.4 μM; P=0.004). Oral supplementation restored plasma vitamin C levels to the normal range in all patients in the vitamin C arm (P=0.0004). We show for the first time that global 5hmC/5mC levels were significantly increased in patients receiving vitamin C compared to placebo (P=0.041). Additionally, preliminary data suggest that vitamin C supplement may increase the upregulation of viral defense genes in DNMTi naïve patients. Conclusions: Normalization of plasma vitamin C by oral supplementation may enhance the biological effects of DNMTis in patients and prompts the investigation of the clinical efficacy of vitamin C supplementation to DNMTis in a large randomized, placebocontrolled trial. Figure 1. Study design. Days 1, 5, and 28: before 500 mg vitamin C/placebo exposure. Day 32: after short-term vitamin C/placebo exposure. Days 56, 60, and 84: after longerterm vitamin C/placebo exposure. DEPRESSION AND ANXIETY IN HODGKIN LYMPHOMA SURVIVORS: A DANISH NATIONWIDE COHORT STUDY OF 896 PATIENTS Andreas Kiesbye Øvlisen1,2, Lasse Hjort Jakobsen1,2, Kristian Hay Kragholm3, Martin Hutchings4, Christian Bjørn Poulsen5, Henrik Frederiksen6, Danny Stoltenberg7, Martin Bøgsted1,2, Lene Sofie Granfelt Østgård8, Marianne Tang Severinsen1,2,3, Tarec Christoffer El-Galaly1,2,3. 1. De

Purpose The quality of patient-reported outcome (PRO) data can be compromised by non-response (NR) to scheduled questionnaires, particularly if reasons for NR are related to health problems, which may lead to unintended bias. The aim was to investigate whether electronic reminders and real-time monitoring improve PRO completion rate. Methods The population-based study "Quality of life in Danish multiple myeloma patients" is a longitudinal, multicentre study with consecutive inclusion of treatment-demanding newly diagnosed or relapsed patients with multiple myeloma. Education of study nurses in the avoidance of NR, electronic reminders, 7-day response windows and real-time monitoring of NR were integrated in the study. Patients complete PRO assessments at study entry and at 12 follow-up time points using electronic or paper questionnaires. The effect of the electronic reminders and real-time monitoring were investigated by comparison of proportions of completed questionnaires before and after each intervention. Results The first 271 included patients were analysed; of those, 249 (85%) chose electronic questionnaires. Eighty-four percent of the 1441 scheduled PRO assessments were completed within the 7-day response window and 11% after real-time monitoring, achieving a final PRO completion rate of 95%. A significant higher proportion of uncompleted questionnaires were completed after the patients had received the electronic reminder and after real-time monitoring. Conclusions Electronic reminders and real-time monitoring contributed to a very high completion rate in the study. To increase the quality of PRO data, we propose integrating these strategies in PRO studies, however highlighting that an increase in staff resources is required for implementation.

Immunoparesis (hypogammaglobulinemia) is associated to an unfavorable prognosis in newly diagnosed Multiple myeloma (MM) patients. However, this finding has not been validated in an unselected population-based cohort. We analyzed 2558 newly diagnosed MM patients in the Danish Multiple Myeloma Registry representing the entire MM population in Denmark from 2005-2013. Two-thousand two hundred and fifty three patients (90%) presented with reduction below lower normal levels of at least one uninvolved immunoglobulin. Using multivariable Cox regression we found that high age, high ISS score, high LDH and IgA MM were associated to both shorter overall survival and progression free survival. Furthermore, bone marrow plasma cell% was associated to short progression free survival. Immunoparesis had no independent significant effect on OS (HR 0.9 (95% CI: 0.7; 1.0; p = 0.12)). Likewise, the number of suppressed immunoglobulins or the relative degree of suppressed uninvolved immunoglobulins from lower normal level (quantitative immunoparesis) was not associated to OS in the multivariable analysis. However, quantitative immunoparesis with at least 25% reduction (from lower normal level) of uninvolved immunoglobulins was associated to shorter PFS for the entire population. The impact of quantitative immunoparesis on PFS was present irrespective of calendar periods 2005-2008 and 2009-2013. Our population-based study does not confirm that immunoparesis at diagnosis is an independent prognostic factor regarding OS. However, quantitative immunoparesis is associated to a shorter PFS.

Infections after chemotherapy often cause significant morbidity in patients with acute myeloid leukaemia (AML). Chitotriosidase (CHIT) and mannose-binding lectin (MBL) are part of the innate immune system. Polymorphism in the CHIT-coding gene (CHIT1) may be associated with Gram-negative sepsis in children with AML, and polymorphism in the MBL-coding gene (MBL2) seems to modify the risk of infections in several patient groups. The purpose of this study was to investigate the possible associations between polymorphisms in CHIT1, MBL2 and sepsis in adult patients treated with high-dose chemotherapy for AML. We included 190 patients treated with 526 cycles of chemotherapy. The follow-up period was 6 months from the diagnosis of AML. Prophylactic antibiotics were not used. We identified 604 febrile episodes with 246 episodes of sepsis. Thirty-two patients (17%) either died from infection or infection was a major concomitant factor for death. No significant associations between CHIT1 polymorphism and sepsis (P = 0.85) or death caused by sepsis (P = 0.14) were found. Furthermore, no significant associations between MBL2 polymorphism and sepsis (P = 0.76) or death caused by sepsis (P = 0.24) were observed. The severe and long-lasting neutropenia and mucositis after chemotherapy may explain why the MBL system does not protect against sepsis in patients with AML. Replacement therapy with recombinant MBL is not likely to decrease the risk of sepsis in patients with AML.