Infection Events in Patients With Newly Diagnosed Multiple Myeloma With Anti-cd38 Monoclonal Antibody-based First Line Regimens: A Multicentric Italian Experience

Infection Events in Patients With Newly Diagnosed Multiple Myeloma With Anti-cd38 Monoclonal Antibody-based First Line Regimens: A Multicentric Italian Experience | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Infection Events in Patients With Newly Diagnosed Multiple Myeloma With Anti-cd38 Monoclonal Antibody-based First Line Regimens: A Multicentric Italian Experience angela rago, francesca Fioritoni, CARMINE Liberatore, Stefano Pulini, and 16 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6779049/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 11 Oct, 2025 Read the published version in Annals of Hematology → Version 1 posted 10 You are reading this latest preprint version Abstract Introduction : Multiple myeloma (MM) is a malignancy characterized by the clonal proliferation of plasma cells. MM accounts for 1% of all neoplastic diseases and is the second most common hematologic malignancy after lymphoma. Infection is a significant cause of morbidity and mortality in newly diagnosed multiple myeloma (NDMM) patients, responsible for about 45% of early deaths especially in elderly patients and within the first months of therapy. Available treatments for MM, such as anti-CD-38 monoclonal antibody (CD38 MAbs), proteasome inhibitors, immunomodulatory agents (lenalidomide, thalidomide and glucocorticoids), demonstrated an improvement in the outcome of NDMM patients, however, predispose to increasing risk of infection. Daratumumab (Dara), an anti-CD38 MAbs is an important new agent in the therapeutic armamentarium of MM. Dara is approved for NDMM or relapsed/refractory MM (RRMM). The use of Dara has improved patient outcomes but has changed the frequency and epidemiology of infections. We retrospectively reviewed data of 472 patients who received Dara-containing regimen for NDMM treated in 10 centers members of the European Myeloma Network Italy (EMN-I) between 2020 and 2023, to study the incidence of IE. Of 472 patients, 148 (31.3%) (148 patients) encountered experienced infectious complications during therapy. No differences were found among the 3 above mentioned groups of patient. In our experience, the introduction of dara in the induction phase did not increase the frequency, degree and duration of infections in the 3 cohorts. Even though the difference was not statistically significant, we observed an earlier onset of IE in the D-VTD group as compared to the others. Further studies are warranted to define further the incidence of infections in these categories of patients, and identify factors associated with a higher risk profile for infection. This will also help understanding the role of infectious prophylaxis in the clinical management of NDMM. multiple myeloma infection disease monoclonal antibody Figures Figure 1 Figure 2 Figure 3 INTRODUCTION Multiple myeloma (MM) is a malignancy characterized by the abnormal proliferation of clonal plasma cells and accounts for 1% of neoplastic diseases, being the 2nd most common hematologic malignancy after lymphoma. Median age at diagnosis is 69 years [ 1 , 2 ]. MM is associated with the suppression of normal immunoglobulin synthesis and processing, leading to impaired humoral immunity. In addition, patients with MM also show dysfunctional cellular and innate immunity [ 3 ]. Infection is a significant cause of morbidity and mortality in newly diagnosed multiple myeloma (NDMM) patients, responsible for about 45% of early deaths, especially in patient’ population and within the first months of therapy [ 4 ]. Compared to the normal population, MM patients have a 7-fold increased risk of developing an infection in the course of their disease. When considering only viral infection, this risk increases up to 10-fold. Despite advances in the treatment of MM, the disease remains incurable and characterized by subsequent phases of progression, after the initial therapy. In recent decades, significant therapeutic advancements have dramatically shifted the treatment paradigm, leading to increased survival and quality of life [ 1 ]. Available treatments, such as anti-CD-38 monoclonal antibody (CD38 MAbs), proteasome inhibitors, immunomodulatory agents (lenalidomide, glucocorticoids), have have demonstrated improvements in the outcome of NDMM patients; however, they predispose to an increased risk of infection [ 5 , 7 ]. Corticosteroids, which are critical components for treating MM, have well-established immunosuppressive effects. Similarly, proteasome inhibitors (PIs) induce T-cell dysfunction associated with an increased risk for varicella-zoster virus (VZV) reactivation [ 7 , 8 ].Immunomodulatory drugs (IMiDs) may have a protective effect by enhancing natural killer (NK) and T-cell function but they are associated with cytopenia, and there is evidence that their use is associated with an increase in infection rate [ 4 , 9 – 10 ].Finally, anti-CD38 monoclonal antibodies (MAbs) reduce the number of NK and immunosuppressive regulatory T-cells and their use is associated with a higher frequency of VZV infection and hepatitis B virus reactivation [ 10 , 11 ]. Daratumumab (Dara), an anti-CD38 MAbs is approved for NDMM or relapsed/refractory multiple myeloma (RRMM). The use of Dara has improved patients’ outcomes but has also modified the frequency and epidemiology of infections [ 11 – 14 ].To address this issue, we conducted a real-world retrospective analysis including a large series of NDMM patients, treated in ten Italian centers with the aim to evaluate the number, the type, and the risk of infectious events (IE) associated with the use of Dara in the induction phase of NDMM transplant-eligible and transplant ineligible patients. Patients and Methods Of 472 patients treated with Dara based regimens between 2020 and 2023, to evaluated the number, the type and risk of infection events. The patients were divided into three study cohorts according to the regimens received: cohort A, receiving Daratumumab, bortezomib, melphalan and dexamethasone, Dara-VMP; cohort B, receiving Daratumumab, Lenalidomide and dexamethasone (Dara-RD); cohort C, receiving daratumumab, bortezomib, thalidomide, and dexamethasone (Dara-VTD). The study was approved by the local Ethical Committees. The diagnosis was made according to the International Myeloma Working Group (IMWG) consensus criteria; prognostic risks and fitness were evaluated by ISS and frailty score, respectively [ 15 , 16 ]. Baseline demographic characteristics, induction regimen and events are shown in Table 1 . Infectius events (IE) Antibiotic and antiviral prophylaxis were not routinely administered. Pre-specified hematologic and biochemical parameters including neutrophils and lymphocytic count, and immunoglobulin levels were also collected. Neutropenia was defined as an absolute neutrophil count < 0.5 x 10 9 /L, lymphopenia as an absolute lymphocyte count < 0.5 x 10 9 /L. Each infection episode was classified as either microbiologically defined (MDI), clinically defined (CDI), or fever of unknown focus (FUF) according to definitions of the International Immunocompromised Host Society [ 17 ]. Severity of infections was graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE), version 5.10 Pre-existing comorbidities were scored using the Charlson comorbidity index (CCI). Infectious diseases were classified based on the World Health Organization’s International Statistical Classification of Diseases–10th Revision (ICD-10) [ 18 ]. According to ICD-10, infections are divided in non-serious or serious, with the latter requiring hospitalization. Non-serious infections are categorized in upper respiratory or urinary tract infections, diarrhea disease, and skin infections. Serious infections are grouped in pneumonia, sepsis, urinary tract infections, and other Statistical Analysis Baseline clinical and infection characteristics were summarized using median and range (min, max) for continuous variables and percentages for categorical variables. To determine clinical and treatment associated risk factors for infection, univariate analysis was performed with first episode of infection (MDI, CDI, FUF) and MDI as the main outcomes of interest. MDI was evaluated as it constitutes a proven infection. In univariate analysis non-parametric tests were performed for comparisons between groups (Chi-Squared and Fisher Exact test in case of categorical variables, Mann-Whitney and Kruskal-Wallis test in case of continuous variables). Survival curves (OS and PFS) were estimated according to the Kaplan-Meier product-limit method and were tested for significant differences using the log-rank test. All tests were 2-sided, accepting p < 0.05 as indicating a statistically significant difference and confidence intervals were calculated at 95% level. All analysis were performed using the R software. RESULTS Cohort Dara-VMP Baseline characteristics of this cohort are summarized in Table 1 . This cohort included 20 patients ineligible for autologous transplant. Median age was 74 years, (range 69–76); 12 and 8 were males and females, respectively. Two of 20 (10%) aged 65 years. ISS stage at diagnosis was: I (n = 3), II (n = 8), III (n = 3) and UNK in 6 patients. Five patients were judged fit, 6 unfit and 2 frail; fitness status was unknown in 7 patients. At baseline, the median haemoglobin (Hb) level was 11.15 g/dL (10.2–12), β2m 3.7 mg/dL (2.9–4.6), median monoclonal component (CM) was 3.96 g/dL 0.58–5.28), LDH were 187 (139–238). The white blood cell (WBC) was 6.000 x 10 9 /L (range 4–11 x 10 9 /L), absolute neutrophil count was 4.325 x 10 9 /L (range 2.7–6.9 x 10 9 /L), absolute lymphocyte count was 1.3 x 10 9 /L (range 1-2.4 x10 9 /L). Plasma cell infiltration was 70% (range 60–90). The cytogenetic analysis at diagnosis was present in 19/20 (95%) patients and of 7/19 (37%) had a high risk cytogenetic. The Immunoglobulin (Ig) dosage at diagnosis was: IgG 488 (range 331-1.019), IgA 114 (range 30-1705) and IgM 10 (range 7–24). Arterial hypertension (n = 3), cardiomyopathy (n = 9) and diabetes (n = 1) werethe most common comorbidities reported. Antiviral and antibacterial prophylaxis was given to 14/20 (70%) 13/20 (65%) patients, respectively. We considered all the prophylaxis interventions as given at any time points during the therapy. Number, type of infectious events (IE) and their severity are shown in Table 2 . The IE were fever (n = 4), respiratory infectious (n = 1) and unk (n = 15). The grade of IE was 1 (n = 2), 2 (n = 1), 3(n = 1), 4 (n = 1), and UNK (n = 15). The median time to IE occurrence was 48 days (7-161) and the median number of Dara-VMP cycles was 4 (3–8). The median duration of IE was 6 (5–6) days. The Ig level when IE was diagnosed was IgG 440 (360–460), IgA 23 (8–30) and 9 (7–10). The WBC count at time of IE was 4.7 x 10 9 /L (range 3.4–8.1) and absolute neutrophil count was 2.8 x 10 9 /L (range 2.5–3.2). Cohort Dara-RD We reviewed the data on the 80 NDMM patients with IE and treated with Dara-RD regimen. The baseline characteristics of this cohort are summarized in Table 1 . At diagnosis, the median age was 74 ys, (range 71–77). Patients who were ineligible for autologous transplant and aged 65 years 46/80 patient were male and 33/80 were female. ISS stage at diagnosis was I (n = 28), II (n = 13), III (n = 18) and UNK in 21 patients. The fitness status was fit in 38 patients, unfit in 19 patients, frail in 4 patients and UNK in 19 patients. The median haemoglobin (Hb) level was 11.6 g/dL (9.9–13.5), β2m 3.7 mg/dL (2.5–4.7), median monoclonal component (CM) was 2.25 g/dL (1.06–3.58), LDH were 163 (131–189). The WBC was 2.410 (4–11) and neutrophil count median was 3 x10 9 /L (1.080–51450). The Ig dosage at diagnosis was: IgG 53 (range 20–466), IgA 15 (range 0–40) and IgM 1 (range 0–17). The cytogenetic analysis at diagnosis was present in 68/80 (85%) patients and of 19/80 (28%) had a high risk cytogenetic. At diagnosis, the most common comorbidities were: arterial hypertension (n = 28), cardiomyopathy (n = 10) and diabetes (n = 1). Over time, antiviral prophylaxis with acyclovir was done in 58/80 (72%) and antibacterial prophylaxis in 57/80 (98%) patients. Data regarding the number, severity and type of infectious events (IE) in this cohort are shown in Table 2 . The 4 IE were: covid infection (n = 16), cmv reactivation (n = 3), pneumoniae (n = 26), fever episodes (n = 3), and unk (n = 25). The grade of IE was 1 (n = 19), 2 (n = 20), 3(n = 6), 4 (n = 3), 5 (n = 3) and UNK (n = 29). The time to IE was 48 days (7-161) and the number of Dara-2 4. The median duration of IE was 14 (7–23) days. The immunoglobulin level at the time of IE was: IgG 238 (range 6-347), IgA 8(range 0–32) and IgM 5 (range 0–15). The WBC count at time of IE was 1490 (4-3585) and absolute neutrophil count was 1 x 10 9 /L (4-1.8). Cohort Dara-VTD We reviewed the data on the 48 NDMM patients with IE and treated with Dara-VTD regimen. The baseline characteristics of this cohort are summarized in Table 1 . At diagnosis, in this group, the median age was 62 ys, (range 57–67); 35/48 patient were male and 13/48 were female. ISS stage at diagnosis was: I (n = 14), II (n = 8), III (n = 5) and UNK in 21 patients. Th fitness status was: fit in 29 patients, and UNK in 19 patients. The median haemoglobin (Hb) level was 11.5 g/dL (10.7-13.15), β2m 3.3 mg/dL (2.1–5.3), median CM was 2.2 g/dL (1.-4.9), LDH were 157 (132–209). The WBC medium was 3.8 x 10 9 /L (range 7-6.5), neutrophil count was 4.1 x 10 9 /L (range 2-6.2) and absolute lymphocyte count was 1.4 x 10 9 /L (range 0.6–2.2 x10 9 /L). The Ig dosage at diagnosis was : IgG 56 (range 32–883), IgA 1 (range 0–14) and IgM 0 (range 0–5). The cytogenetic analysis at diagnosis was present in 45/48 (93%) patients and of 8/48 (16%) had a high risk cytogenetic. At diagnosis, the most common comorbidities were arterial hypertension (n = 9), cardiomyopathy (n = 5) and diabetes (n = 1). Over time, antiviral prophylaxis with acyclovir was done in 29/48 (60%) and antibacterial prophylaxis in 29/48 (60%) patients. Data on the number, severity and type of IE in this cohort are shown in Table 2 . The IE were: covid infection (n = 5), cmv reactivation (n = 2), pneumoniae (n = 15), fever episodes (n = 3), and unk (n = 19). The grade of IE was 1 (n = 10), 2 (n = 8), 3(n = 9), 4 (n = 1) and UNK (n = 20). The time to IE onset was 59 days (18–147) and the median number of Dara-VTD cycles was 3 (range 2–4) The duration of IE was 14 (9–26) days. The median duration of IE was 14 (7–23) days. The Ig level at the time of IE was: IgG 178 (5-492), IgA 5 (0–19) and IgM 6 (0–12). The WBC count at time of IE was 2460 (8-5530) and absolute neutrophil count was 1.3 x10 9 /L (range 8-3.6 x10 9 /L). Comparison between the three cohorts Table 1 and Table 2 show the characteristics of the whole patients’ population. At baseline, statistically significant differences were identified between the Dara VTD cohort and the other two cohorts in terms of age and fitness, as expected. In addition, patients in Cohort B had statistically significant lower median nadir absolute neutrophil count (ANC) (median 3 x 10 9 /L, range 1-5.1 x 10 9 /L), compared to the other two cohort (p = 0.043). Furthermore, at baseline, patients in Cohort C had a significantly lower Ig dosage IgG = p 0.025; IgA = p < 0.001; IgM = p 0.004 (Fig. 1 and Fig. 2). The type of prophylaxis and IE was listed in Table 2 . The onset of IE was different between TE and NTE patients: 48 days in cohort A and B versus 59 days in cohort C (p < 0.001). No differences were present in the grade and in the duration of IE. In all groups there was seen a statistically significant reduction of the IgA level at the time of the IE (p = 0.006), while no differences were present for IgG and IgM level in treatment 3 groups. Moreover, a significant difference in neutropenia (p = 0.002) and lymphocytopenia pre and post IE (p = 0.006) resulted in all three groups. Median 24 months-PFS was 68.3% (95%CI: 54.7, 85.4), Fig. 1. On the other hand, the median OS was not significantly different in three cohort groups at 12 and 24 months (p = 0.13; Fig. 3). Discussion Treatment of MM include treatment options including CD-38-targeting agents. CD38 is a transmembrane glycoprotein that is expressed on MM cells and also, at lower levels, on normal lymphoid cells, myeloid cells, and some non-hematopoietic tissues. The high expression of CD38 on MM cells potentially makes it a therapeutic target for the treatment of MM. CD38 is highly expressed on NK cells, therefore daratumumab depletes the NK cells reservoir. Prior studies have shown that the decline in NK cells after a Dara infusion can be rapid and can occur at very early stages during therapy. In mice, NK impairment and/or depletion increases susceptibility to viral infections. Our study is the first to estimate the comparative risk for types of infections and the number of infectious events (IE) associated with the use of Dara in the induction phase of transplant-eligible and ineligible NDMM patients in a real-world setting treated with the Dara combo. Significant advances in MM therapeutics in the last two decades have led to improved survival outcomes but infections remain a major cause of morbidity and early mortality. 1,2 Infection risk often depends on disease-related immunoparesis, co-morbidities, and systemic therapy. The incidence of severe infection in patients with MM seems to be higher during the first months after diagnosis [ 2 , 4 – 5 ]. Patterns of infections have evolve over the time, as the myeloma treatment strategies continues to change, with new therapeutic classes such as proteasome inhibitors (PI), immuno-modulatory drugs (IMiD) [ 3 ] and anti-CD38Mabs being introduced. We retrospectively evaluated 148 patients with NDMM managed in nine Italian Hematology Centers receiving D-VTD, D-RD and D-VMP as induction therapy on between 2020 and 2023. Overall, 148 developed an infection of any grade, substantially comparable to the risk reported in MM patients undergoing induction therapy. The overall risk of infection with dara treatment is 38%, being upper respiratory tract infections the most common; our reported rate is slightly lower. A meta-analysis from 5 phase III randomized trials, demonstrated that adding the anti-CD38 Mab, daratumumab to standard MM regimens resulted in a higher incidence of all grades of infection (with a risk ratio (RR) of 1.27), and any-grade pneumonia (with a RR of 1.63) [ 5 ].Several reports have indicated that the administration of prophylactic antibiotics or the use of vaccinations before beginning myeloma treatment reduces the frequency and severity of early infections, but their use remains controversial. In our study, there was no difference on antiviral and antimicrobial prophylaxis in the 3 treatment groups. Furthermore, the median time to IE was similar between the 3 groups D-VMP 161 (104–243), D-RD 157 (97–370) and D-VTD 82 (44–184) days. (p = 0.064). The type of IE was upper respiratory tract infection in 81/105 patients (77%), covid infection 12/105 patients (11%), herpes simplex and varicella zoster virus (VZV) in 2/105 patients (1.9%), abdominal infection 3/105 patients (2.8%) and infection of urinary tract 2/105 patients (1.9%) of any grade. No differences were present in the grade and in the duration of IE between the three studied groups. We attempted to identify predictors of IE in order to stratify the risk and inform prophylaxis management. In our experience, no significant differences were found between the three treatment groups in terms of incidence, type and degree of infections, while significant differences were found between baseline IgA, IgM levels, neutropenia and lymphopenia at the time of the IE. The risk of infection may be associated with neutropenia, hypogammaglobulinemia, and NK cell depletion. The risk of neutropenia during dara treatment depends on whether monotherapy or a combination regimen is used. In patients treated with combination regimens, the risk of neutropenia is largely higher, ranging from 28 to 48%, and is highest with DRd [ 8 – 11 ]. Lymphopenia is a well-recognized risk factor for infections in MM [ 15 ].Grade 3 or 4 lymphopenia occurs with IMIDs and bortezomib [ 12 , 16 ] at rates of 3 to 6% [ 17 – 18 ].The development and persistence of severe lymphopenia in patients receiving dara-based regimens is not uncommon and is associated with risk of serious infections, and worst outcomes in certain subsets of patients. Therefore, close monitoring, prophylactic measures, should be adopted especially in patients with pretreatment lymphopenia. In our experience, the introduction of dara in the induction phase did not lead to an increase in the number, degree and duration of IE in the group of 3 treatments, even if we highlighted a non-statistically significant difference in the time to onset of IE in the D-VTD group. In addition, we have highlighted a significant difference in IgA and IgM level and neutropenia and lymphocytopenia prior and post IE in 3 treatment group. A larger cohort of patients are needed to confirm our results and to evaluate tailored prophylaxis in different dara treatment groups. Further studies and registries with long-term follow-up are warranted to better identify patients at higher risk for infection and to clarify the potential benefits of infectious prophylaxis in the clinical management of NDMM treated with Dara combinations. Declarations Data availability No datasets were generated or analysed during the current study. No funding was received for conducting this study. Consent to Participate statement to clearly indicate that informed consent to participate was obtained from all human participants. 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Supplementary Files Tables1.docx Tables2.docx Cite Share Download PDF Status: Published Journal Publication published 11 Oct, 2025 Read the published version in Annals of Hematology → Version 1 posted Editorial decision: Revision requested 01 Jul, 2025 Reviews received at journal 01 Jul, 2025 Reviews received at journal 26 Jun, 2025 Reviewers agreed at journal 17 Jun, 2025 Reviewers agreed at journal 12 Jun, 2025 Reviewers agreed at journal 12 Jun, 2025 Reviewers invited by journal 04 Jun, 2025 Editor assigned by journal 04 Jun, 2025 Submission checks completed at journal 04 Jun, 2025 First submitted to journal 29 May, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6779049","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":466788833,"identity":"161e4930-da56-4a92-93a9-e853c8d5d80b","order_by":0,"name":"angela rago","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABCElEQVRIiWNgGAWjYLCCBxCKEUhbgFkHGAwIaEmAUMxAdRJgvUAtBPRAtbBJQLUwH2DAYw3/7PaLDxJqGPL5+xcfq/jxRyKfX+zwgwMMBX9wapG4c6bYIOEYg+WMG8/Sbva2SVjOnJ1mgN9hN3LSJBLYgO64ccbsBm+DhIHB7QT8WuRv5KT/SPjHYCAP1FL45w9IS/oHvFoMbqQfY0hsAyo532PGzMMG0pKD3xbDGznMEol9EgaGN9iSpWXbJAwkZ+cUHEgwMMapRe5G+sMPH77ZGMidP3zw45s/Ngb80umbP3z4I4fb+ww8ICeAYiQBSTABu1ooYH8AofkP4FU2CkbBKBgFIxgAAP2YVu4SwuWeAAAAAElFTkSuQmCC","orcid":"","institution":"ASL ROMA 1, Santo Spirito Hospital of Rome","correspondingAuthor":true,"prefix":"","firstName":"angela","middleName":"","lastName":"rago","suffix":""},{"id":466788835,"identity":"c4b51262-86d9-43cd-8c0e-25e5ee73a3e5","order_by":1,"name":"francesca Fioritoni","email":"","orcid":"","institution":"Azienda Ospedaliero Universitaria delle Marche","correspondingAuthor":false,"prefix":"","firstName":"francesca","middleName":"","lastName":"Fioritoni","suffix":""},{"id":466788836,"identity":"5e2c2a94-67d4-418b-b1d9-e5967965c762","order_by":2,"name":"CARMINE Liberatore","email":"","orcid":"","institution":"Azienda Ospedaliero Universitaria delle Marche","correspondingAuthor":false,"prefix":"","firstName":"CARMINE","middleName":"","lastName":"Liberatore","suffix":""},{"id":466788838,"identity":"7b3a88c4-0139-4184-acac-4a20b65b65b0","order_by":3,"name":"Stefano Pulini","email":"","orcid":"","institution":"Azienda Ospedaliero Universitaria delle Marche","correspondingAuthor":false,"prefix":"","firstName":"Stefano","middleName":"","lastName":"Pulini","suffix":""},{"id":466788839,"identity":"c03130d9-4014-47c0-bdcd-959fc067c15e","order_by":4,"name":"Francesca Fazio","email":"","orcid":"","institution":"Ematologia, Azienda Ospedaliera Universitaria Policlinico Umberto I","correspondingAuthor":false,"prefix":"","firstName":"Francesca","middleName":"","lastName":"Fazio","suffix":""},{"id":466788840,"identity":"d479105b-b6ab-4e1f-a602-6373946b23f4","order_by":5,"name":"Maria teresa petrucci","email":"","orcid":"","institution":"Ematologia, Azienda Ospedaliera Universitaria Policlinico Umberto I","correspondingAuthor":false,"prefix":"","firstName":"Maria","middleName":"teresa","lastName":"petrucci","suffix":""},{"id":466788841,"identity":"fcd60cce-a02f-4b9e-acf2-0331cd471884","order_by":6,"name":"Valerio De Stefano","email":"","orcid":"","institution":"Agostino Gemelli University Polyclinic","correspondingAuthor":false,"prefix":"","firstName":"Valerio","middleName":"","lastName":"De Stefano","suffix":""},{"id":466788842,"identity":"7ab0c992-7a09-40d2-b727-c6248efce968","order_by":7,"name":"Elena Rossi","email":"","orcid":"","institution":"Agostino Gemelli University Polyclinic","correspondingAuthor":false,"prefix":"","firstName":"Elena","middleName":"","lastName":"Rossi","suffix":""},{"id":466788843,"identity":"8711ee9e-47e4-4dd2-bcb7-f2abce98c816","order_by":8,"name":"Tommaso Za","email":"","orcid":"","institution":"Agostino Gemelli University Polyclinic","correspondingAuthor":false,"prefix":"","firstName":"Tommaso","middleName":"","lastName":"Za","suffix":""},{"id":466788844,"identity":"cf37ed9f-50da-4735-9c72-893b36fb8d3a","order_by":9,"name":"Francesca Di Landro","email":"","orcid":"","institution":"Agostino Gemelli University Polyclinic","correspondingAuthor":false,"prefix":"","firstName":"Francesca","middleName":"Di","lastName":"Landro","suffix":""},{"id":466788845,"identity":"62a0b913-990d-4e7c-9e21-d246fcc483e8","order_by":10,"name":"Laura De Padua","email":"","orcid":"","institution":"UOC Ematologia, Trapianto di cellule staminali e Terapia genica, Ospedale F. Spaziani, Frosinone","correspondingAuthor":false,"prefix":"","firstName":"Laura","middleName":"","lastName":"De Padua","suffix":""},{"id":466788846,"identity":"c04ac626-6e69-44f0-89e6-7304ee6e97aa","order_by":11,"name":"Massimo Offidani","email":"","orcid":"","institution":"Azienda Ospedaliero Universitaria delle Marche","correspondingAuthor":false,"prefix":"","firstName":"Massimo","middleName":"","lastName":"Offidani","suffix":""},{"id":466788847,"identity":"5a85947f-7a9a-49c0-bf84-47d23ac339c9","order_by":12,"name":"sonia More","email":"","orcid":"","institution":"Azienda Ospedaliero Universitaria delle Marche","correspondingAuthor":false,"prefix":"","firstName":"sonia","middleName":"","lastName":"More","suffix":""},{"id":466788848,"identity":"dd7fdc8a-800f-4db1-bc3c-093ee023a236","order_by":13,"name":"Annibali ombretta","email":"","orcid":"","institution":"Università Campus Bio-Medico","correspondingAuthor":false,"prefix":"","firstName":"Annibali","middleName":"","lastName":"ombretta","suffix":""},{"id":466788849,"identity":"f28a8abf-2a9d-43a0-89c7-2d826472c23a","order_by":14,"name":"Valeria Tomarchio","email":"","orcid":"","institution":"Università Campus Bio-Medico","correspondingAuthor":false,"prefix":"","firstName":"Valeria","middleName":"","lastName":"Tomarchio","suffix":""},{"id":466788850,"identity":"cf8c325b-8ca8-49cf-a959-6a08cb801e64","order_by":15,"name":"Maria Antonietta Tafuri","email":"","orcid":"","institution":"Università Campus Bio-Medico","correspondingAuthor":false,"prefix":"","firstName":"Maria","middleName":"Antonietta","lastName":"Tafuri","suffix":""},{"id":466788851,"identity":"3958a8ea-59b8-4ee6-bb42-34b2c10e0b0e","order_by":16,"name":"Alfonso Piciocchi","email":"","orcid":"","institution":"GIMEMA Data Center, Fondazione GIMEMA Franco Mandelli Onlus","correspondingAuthor":false,"prefix":"","firstName":"Alfonso","middleName":"","lastName":"Piciocchi","suffix":""},{"id":466788852,"identity":"1c067de6-af96-4251-9c99-1c786facccba","order_by":17,"name":"Luca Franceschini","email":"","orcid":"","institution":"Dipartimento di Oncologia-Ematologia Fondazione Policlinico Tor Vergata, Roma","correspondingAuthor":false,"prefix":"","firstName":"Luca","middleName":"","lastName":"Franceschini","suffix":""},{"id":466788853,"identity":"ee2ad350-9a9c-45df-8d05-f6bff79ffe10","order_by":18,"name":"Alessia Fiorini","email":"","orcid":"","institution":"UOC Ematologia, Ospedale Santa Rosa, Viterbo","correspondingAuthor":false,"prefix":"","firstName":"Alessia","middleName":"","lastName":"Fiorini","suffix":""},{"id":466788854,"identity":"343bc587-6670-4c9c-8b78-243bc8d793a5","order_by":19,"name":"Tommaso Caravita di Toritto","email":"","orcid":"","institution":"ASL ROMA 1, Santo Spirito Hospital of Rome","correspondingAuthor":false,"prefix":"","firstName":"Tommaso","middleName":"Caravita di","lastName":"Toritto","suffix":""}],"badges":[],"createdAt":"2025-05-29 19:23:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6779049/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6779049/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00277-025-06645-y","type":"published","date":"2025-10-11T15:57:42+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":84276753,"identity":"9194d985-b6eb-4275-aa2f-d1b5dff00c01","added_by":"auto","created_at":"2025-06-10 05:42:41","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":68457,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version\u003c/p\u003e","description":"","filename":"figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-6779049/v1/a330e404b3f036e84ea10ccd.png"},{"id":84276750,"identity":"3e062611-5c7b-473d-9dc6-bf1f0ec22087","added_by":"auto","created_at":"2025-06-10 05:42:41","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":67414,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version\u003c/p\u003e","description":"","filename":"figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-6779049/v1/518c5b700ed01116c89d9ea0.png"},{"id":84277432,"identity":"4fc38427-e01d-4ddb-892f-bec9864d803f","added_by":"auto","created_at":"2025-06-10 06:02:12","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":51691,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version\u003c/p\u003e","description":"","filename":"figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-6779049/v1/639b07e1c90f3fa76082e95f.png"},{"id":93419723,"identity":"969fed19-cdbb-4c27-a3e1-198bc66a5025","added_by":"auto","created_at":"2025-10-13 16:06:32","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":823211,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6779049/v1/6a656244-f091-498c-85f5-8d4143285444.pdf"},{"id":84276749,"identity":"ac3cb65f-6e00-4e69-b0d8-e6ebe317bed3","added_by":"auto","created_at":"2025-06-10 05:42:41","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":26824,"visible":true,"origin":"","legend":"","description":"","filename":"Tables1.docx","url":"https://assets-eu.researchsquare.com/files/rs-6779049/v1/8face610c3ef1eb581da855b.docx"},{"id":84276752,"identity":"fb7647d1-d4f7-4158-aec5-8a1911f7915f","added_by":"auto","created_at":"2025-06-10 05:42:41","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":19591,"visible":true,"origin":"","legend":"","description":"","filename":"Tables2.docx","url":"https://assets-eu.researchsquare.com/files/rs-6779049/v1/e67da66dc65169b0d7e0fe78.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eInfection Events in Patients With Newly Diagnosed Multiple Myeloma With Anti-cd38 Monoclonal Antibody-based First Line Regimens: A Multicentric Italian Experience\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eMultiple myeloma (MM) is a malignancy characterized by the abnormal proliferation of clonal plasma cells and accounts for 1% of neoplastic diseases, being the 2nd most common hematologic malignancy after lymphoma. Median age at diagnosis is 69 years [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. MM is associated with the suppression of normal immunoglobulin synthesis and processing, leading to impaired humoral immunity. In addition, patients with MM also show dysfunctional cellular and innate immunity [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Infection is a significant cause of morbidity and mortality in newly diagnosed multiple myeloma (NDMM) patients, responsible for about 45% of early deaths, especially in patient\u0026rsquo; population and within the first months of therapy [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Compared to the normal population, MM patients have a 7-fold increased risk of developing an infection in the course of their disease. When considering only viral infection, this risk increases up to 10-fold. Despite advances in the treatment of MM, the disease remains incurable and characterized by subsequent phases of progression, after the initial therapy. In recent decades, significant therapeutic advancements have dramatically shifted the treatment paradigm, leading to increased survival and quality of life [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Available treatments, such as anti-CD-38 monoclonal antibody (CD38 MAbs), proteasome inhibitors, immunomodulatory agents (lenalidomide, glucocorticoids), have have demonstrated improvements in the outcome of NDMM patients; however, they predispose to an increased risk of infection [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Corticosteroids, which are critical components for treating MM, have well-established immunosuppressive effects. Similarly, proteasome inhibitors (PIs) induce T-cell dysfunction associated with an increased risk for varicella-zoster virus (VZV) reactivation [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].Immunomodulatory drugs (IMiDs) may have a protective effect by enhancing natural killer (NK) and T-cell function but they are associated with cytopenia, and there is evidence that their use is associated with an increase in infection rate [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].Finally, anti-CD38 monoclonal antibodies (MAbs) reduce the number of NK and immunosuppressive regulatory T-cells and their use is associated with a higher frequency of VZV infection and hepatitis B virus reactivation [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Daratumumab (Dara), an anti-CD38 MAbs is approved for NDMM or relapsed/refractory multiple myeloma (RRMM). The use of Dara has improved patients\u0026rsquo; outcomes but has also modified the frequency and epidemiology of infections [\u003cspan additionalcitationids=\"CR12 CR13\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].To address this issue, we conducted a real-world retrospective analysis including a large series of NDMM patients, treated in ten Italian centers with the aim to evaluate the number, the type, and the risk of infectious events (IE) associated with the use of Dara in the induction phase of NDMM transplant-eligible and transplant ineligible patients.\u003c/p\u003e"},{"header":"Patients and Methods","content":"\u003cp\u003eOf 472 patients treated with Dara based regimens between 2020 and 2023, to evaluated the number, the type and risk of infection events. The patients were divided into three study cohorts according to the regimens received: cohort A, receiving Daratumumab, bortezomib, melphalan and dexamethasone, Dara-VMP; cohort B, receiving Daratumumab, Lenalidomide and dexamethasone (Dara-RD); cohort C, receiving daratumumab, bortezomib, thalidomide, and dexamethasone (Dara-VTD). The study was approved by the local Ethical Committees. The diagnosis was made according to the International Myeloma Working Group (IMWG) consensus criteria; prognostic risks and fitness were evaluated by ISS and frailty score, respectively [\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e]. Baseline demographic characteristics, induction regimen and events are shown in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\n\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003eInfectius events (IE)\u003c/h2\u003e\n \u003cp\u003eAntibiotic and antiviral prophylaxis were not routinely administered. Pre-specified hematologic and biochemical parameters including neutrophils and lymphocytic count, and immunoglobulin levels were also collected. Neutropenia was defined as an absolute neutrophil count\u0026thinsp;\u0026lt;\u0026thinsp;0.5 x 10\u003csup\u003e9\u003c/sup\u003e/L, lymphopenia as an absolute lymphocyte count\u0026thinsp;\u0026lt;\u0026thinsp;0.5 x 10\u003csup\u003e9\u003c/sup\u003e/L.\u003c/p\u003e\n \u003cp\u003eEach infection episode was classified as either microbiologically defined (MDI), clinically defined (CDI), or fever of unknown focus (FUF) according to definitions of the International Immunocompromised Host Society [\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e]. Severity of infections was graded according to the National Cancer Institute\u0026rsquo;s Common Terminology Criteria for Adverse Events (CTCAE), version 5.10 Pre-existing comorbidities were scored using the Charlson comorbidity index (CCI).\u003c/p\u003e\n \u003cp\u003eInfectious diseases were classified based on the World Health Organization\u0026rsquo;s International Statistical Classification of Diseases\u0026ndash;10th Revision (ICD-10) [\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e]. According to ICD-10, infections are divided in non-serious or serious, with the latter requiring hospitalization. Non-serious infections are categorized in upper respiratory or urinary tract infections, diarrhea disease, and skin infections. Serious infections are grouped in pneumonia, sepsis, urinary tract infections, and other\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n \u003ch2\u003eStatistical Analysis\u003c/h2\u003e\n \u003cp\u003eBaseline clinical and infection characteristics were summarized using median and range (min, max) for continuous variables and percentages for categorical variables. To determine clinical and treatment associated risk factors for infection, univariate analysis was performed with first episode of infection (MDI, CDI, FUF) and MDI as the main outcomes of interest. MDI was evaluated as it constitutes a proven infection. In univariate analysis non-parametric tests were performed for comparisons between groups (Chi-Squared and Fisher Exact test in case of categorical variables, Mann-Whitney and Kruskal-Wallis test in case of continuous variables). Survival curves (OS and PFS) were estimated according to the Kaplan-Meier product-limit method and were tested for significant differences using the log-rank test. All tests were 2-sided, accepting p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 as indicating a statistically significant difference and confidence intervals were calculated at 95% level. All analysis were performed using the R software.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n \u003ch2\u003eCohort Dara-VMP\u003c/h2\u003e\n \u003cp\u003eBaseline characteristics of this cohort are summarized in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. This cohort included 20 patients ineligible for autologous transplant. Median age was 74 years, (range 69\u0026ndash;76); 12 and 8 were males and females, respectively. Two of 20 (10%) aged\u0026thinsp;\u0026lt;\u0026thinsp;65 years and 18/20 (90%)\u0026thinsp;\u0026gt;\u0026thinsp;65 years. ISS stage at diagnosis was: I (n\u0026thinsp;=\u0026thinsp;3), II (n\u0026thinsp;=\u0026thinsp;8), III (n\u0026thinsp;=\u0026thinsp;3) and UNK in 6 patients. Five patients were judged fit, 6 unfit and 2 frail; fitness status was unknown in 7 patients. At baseline, the median haemoglobin (Hb) level was 11.15 g/dL (10.2\u0026ndash;12), \u0026beta;2m 3.7 mg/dL (2.9\u0026ndash;4.6), median monoclonal component (CM) was 3.96 g/dL 0.58\u0026ndash;5.28), LDH were 187 (139\u0026ndash;238). The white blood cell (WBC) was 6.000 x 10\u003csup\u003e9\u003c/sup\u003e/L (range 4\u0026ndash;11 x 10\u003csup\u003e9\u003c/sup\u003e/L), absolute neutrophil count was 4.325 x 10\u003csup\u003e9\u003c/sup\u003e/L (range 2.7\u0026ndash;6.9 x 10\u003csup\u003e9\u003c/sup\u003e/L), absolute lymphocyte count was 1.3 x 10\u003csup\u003e9\u003c/sup\u003e/L (range 1-2.4 x10\u003csup\u003e9\u003c/sup\u003e/L). Plasma cell infiltration was 70% (range 60\u0026ndash;90). The cytogenetic analysis at diagnosis was present in 19/20 (95%) patients and of 7/19 (37%) had a high risk cytogenetic. The Immunoglobulin (Ig) dosage at diagnosis was: IgG 488 (range 331-1.019), IgA 114 (range 30-1705) and IgM 10 (range 7\u0026ndash;24). Arterial hypertension (n\u0026thinsp;=\u0026thinsp;3), cardiomyopathy (n\u0026thinsp;=\u0026thinsp;9) and diabetes (n\u0026thinsp;=\u0026thinsp;1) werethe most common comorbidities reported. Antiviral and antibacterial prophylaxis was given to 14/20 (70%) 13/20 (65%) patients, respectively. We considered all the prophylaxis interventions as given at any time points during the therapy.\u003c/p\u003e\n \u003cp\u003eNumber, type of infectious events (IE) and their severity are shown in Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e. The IE were fever (n\u0026thinsp;=\u0026thinsp;4), respiratory infectious (n\u0026thinsp;=\u0026thinsp;1) and unk (n\u0026thinsp;=\u0026thinsp;15). The grade of IE was 1 (n\u0026thinsp;=\u0026thinsp;2), 2 (n\u0026thinsp;=\u0026thinsp;1), 3(n\u0026thinsp;=\u0026thinsp;1), 4 (n\u0026thinsp;=\u0026thinsp;1), and UNK (n\u0026thinsp;=\u0026thinsp;15). The median time to IE occurrence was 48 days (7-161) and the median number of Dara-VMP cycles was 4 (3\u0026ndash;8). The median duration of IE was 6 (5\u0026ndash;6) days. The Ig level when IE was diagnosed was IgG 440 (360\u0026ndash;460), IgA 23 (8\u0026ndash;30) and 9 (7\u0026ndash;10). The WBC count at time of IE was 4.7 x 10\u003csup\u003e9\u003c/sup\u003e/L (range 3.4\u0026ndash;8.1) and absolute neutrophil count was 2.8 x 10\u003csup\u003e9\u003c/sup\u003e/L (range 2.5\u0026ndash;3.2).\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eCohort Dara-RD\u003c/h3\u003e\n\u003cp\u003eWe reviewed the data on the 80 NDMM patients with IE and treated with Dara-RD regimen. The baseline characteristics of this cohort are summarized in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. At diagnosis, the median age was 74 ys, (range 71\u0026ndash;77). Patients who were ineligible for autologous transplant and aged\u0026thinsp;\u0026lt;\u0026thinsp;65 years were 7/80 (8.8%) and 73/80 (91%) aged\u0026thinsp;\u0026gt;\u0026thinsp;65 years 46/80 patient were male and 33/80 were female. ISS stage at diagnosis was I (n\u0026thinsp;=\u0026thinsp;28), II (n\u0026thinsp;=\u0026thinsp;13), III (n\u0026thinsp;=\u0026thinsp;18) and UNK in 21 patients. The fitness status was fit in 38 patients, unfit in 19 patients, frail in 4 patients and UNK in 19 patients. The median haemoglobin (Hb) level was 11.6 g/dL (9.9\u0026ndash;13.5), \u0026beta;2m 3.7 mg/dL (2.5\u0026ndash;4.7), median monoclonal component (CM) was 2.25 g/dL (1.06\u0026ndash;3.58), LDH were 163 (131\u0026ndash;189). The WBC was 2.410 (4\u0026ndash;11) and neutrophil count median was 3 x10\u003csup\u003e9\u003c/sup\u003e/L (1.080\u0026ndash;51450). The Ig dosage at diagnosis was: IgG 53 (range 20\u0026ndash;466), IgA 15 (range 0\u0026ndash;40) and IgM 1 (range 0\u0026ndash;17). The cytogenetic analysis at diagnosis was present in 68/80 (85%) patients and of 19/80 (28%) had a high risk cytogenetic. At diagnosis, the most common comorbidities were: arterial hypertension (n\u0026thinsp;=\u0026thinsp;28), cardiomyopathy (n\u0026thinsp;=\u0026thinsp;10) and diabetes (n\u0026thinsp;=\u0026thinsp;1). Over time, antiviral prophylaxis with acyclovir was done in 58/80 (72%) and antibacterial prophylaxis in 57/80 (98%) patients.\u003c/p\u003e\n\u003cp\u003eData regarding the number, severity and type of infectious events (IE) in this cohort are shown in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e. The 4 IE were: covid infection (n\u0026thinsp;=\u0026thinsp;16), cmv reactivation (n\u0026thinsp;=\u0026thinsp;3), pneumoniae (n\u0026thinsp;=\u0026thinsp;26), fever episodes (n\u0026thinsp;=\u0026thinsp;3), and unk (n\u0026thinsp;=\u0026thinsp;25). The grade of IE was 1 (n\u0026thinsp;=\u0026thinsp;19), 2 (n\u0026thinsp;=\u0026thinsp;20), 3(n\u0026thinsp;=\u0026thinsp;6), 4 (n\u0026thinsp;=\u0026thinsp;3), 5 (n\u0026thinsp;=\u0026thinsp;3) and UNK (n\u0026thinsp;=\u0026thinsp;29). The time to IE was 48 days (7-161) and the number of Dara-2 4. The median duration of IE was 14 (7\u0026ndash;23) days. The immunoglobulin level at the time of IE was: IgG 238 (range 6-347), IgA 8(range 0\u0026ndash;32) and IgM 5 (range 0\u0026ndash;15). The WBC count at time of IE was 1490 (4-3585) and absolute neutrophil count was 1 x 10\u003csup\u003e9\u003c/sup\u003e/L (4-1.8).\u003c/p\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003eCohort Dara-VTD\u003c/h2\u003e\n \u003cp\u003eWe reviewed the data on the 48 NDMM patients with IE and treated with Dara-VTD regimen. The baseline characteristics of this cohort are summarized in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. At diagnosis, in this group, the median age was 62 ys, (range 57\u0026ndash;67); 35/48 patient were male and 13/48 were female. ISS stage at diagnosis was: I (n\u0026thinsp;=\u0026thinsp;14), II (n\u0026thinsp;=\u0026thinsp;8), III (n\u0026thinsp;=\u0026thinsp;5) and UNK in 21 patients. Th fitness status was: fit in 29 patients, and UNK in 19 patients. The median haemoglobin (Hb) level was 11.5 g/dL (10.7-13.15), \u0026beta;2m 3.3 mg/dL (2.1\u0026ndash;5.3), median CM was 2.2 g/dL (1.-4.9), LDH were 157 (132\u0026ndash;209). The WBC medium was 3.8 x 10\u003csup\u003e9\u003c/sup\u003e/L (range 7-6.5), neutrophil count was 4.1 x 10\u003csup\u003e9\u003c/sup\u003e/L (range 2-6.2) and absolute lymphocyte count was 1.4 x 10\u003csup\u003e9\u003c/sup\u003e/L (range 0.6\u0026ndash;2.2 x10\u003csup\u003e9\u003c/sup\u003e/L). The Ig dosage at diagnosis was : IgG 56 (range 32\u0026ndash;883), IgA 1 (range 0\u0026ndash;14) and IgM 0 (range 0\u0026ndash;5). The cytogenetic analysis at diagnosis was present in 45/48 (93%) patients and of 8/48 (16%) had a high risk cytogenetic. At diagnosis, the most common comorbidities were arterial hypertension (n\u0026thinsp;=\u0026thinsp;9), cardiomyopathy (n\u0026thinsp;=\u0026thinsp;5) and diabetes (n\u0026thinsp;=\u0026thinsp;1). Over time, antiviral prophylaxis with acyclovir was done in 29/48 (60%) and antibacterial prophylaxis in 29/48 (60%) patients.\u003c/p\u003e\n \u003cp\u003eData on the number, severity and type of IE in this cohort are shown in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e. The IE were: covid infection (n\u0026thinsp;=\u0026thinsp;5), cmv reactivation (n\u0026thinsp;=\u0026thinsp;2), pneumoniae (n\u0026thinsp;=\u0026thinsp;15), fever episodes (n\u0026thinsp;=\u0026thinsp;3), and unk (n\u0026thinsp;=\u0026thinsp;19). The grade of IE was 1 (n\u0026thinsp;=\u0026thinsp;10), 2 (n\u0026thinsp;=\u0026thinsp;8), 3(n\u0026thinsp;=\u0026thinsp;9), 4 (n\u0026thinsp;=\u0026thinsp;1) and UNK (n\u0026thinsp;=\u0026thinsp;20). The time to IE onset was 59 days (18\u0026ndash;147) and the median number of Dara-VTD cycles was 3 (range 2\u0026ndash;4) The duration of IE was 14 (9\u0026ndash;26) days. The median duration of IE was 14 (7\u0026ndash;23) days. The Ig level at the time of IE was: IgG 178 (5-492), IgA 5 (0\u0026ndash;19) and IgM 6 (0\u0026ndash;12). The WBC count at time of IE was 2460 (8-5530) and absolute neutrophil count was 1.3 x10\u003csup\u003e9\u003c/sup\u003e/L (range 8-3.6 x10\u003csup\u003e9\u003c/sup\u003e/L).\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eComparison between the three cohorts\u003c/h3\u003e\n\u003cp\u003eTable\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e and Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e show the characteristics of the whole patients\u0026rsquo; population. At baseline, statistically significant differences were identified between the Dara VTD cohort and the other two cohorts in terms of age and fitness, as expected. In addition, patients in Cohort B had statistically significant lower median nadir absolute neutrophil count (ANC) (median 3 x 10\u003csup\u003e9\u003c/sup\u003e/L, range 1-5.1 x 10\u003csup\u003e9\u003c/sup\u003e/L), compared to the other two cohort (p\u0026thinsp;=\u0026thinsp;0.043). Furthermore, at baseline, patients in Cohort C had a significantly lower Ig dosage IgG\u0026thinsp;=\u0026thinsp;p 0.025; IgA\u0026thinsp;=\u0026thinsp;p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; IgM\u0026thinsp;=\u0026thinsp;p 0.004 (Fig.\u0026nbsp;1 and Fig.\u0026nbsp;2).\u003c/p\u003e\n\u003cp\u003eThe type of prophylaxis and IE was listed in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e. The onset of IE was different between TE and NTE patients: 48 days in cohort A and B versus 59 days in cohort C (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). No differences were present in the grade and in the duration of IE. In all groups there was seen a statistically significant reduction of the IgA level at the time of the IE (p\u0026thinsp;=\u0026thinsp;0.006), while no differences were present for IgG and IgM level in treatment 3 groups. Moreover, a significant difference in neutropenia (p\u0026thinsp;=\u0026thinsp;0.002) and lymphocytopenia pre and post IE (p\u0026thinsp;=\u0026thinsp;0.006) resulted in all three groups.\u003c/p\u003e\n\u003cp\u003eMedian 24 months-PFS was 68.3% (95%CI: 54.7, 85.4), Fig.\u0026nbsp;1. On the other hand, the median OS was not significantly different in three cohort groups at 12 and 24 months (p\u0026thinsp;=\u0026thinsp;0.13; Fig.\u0026nbsp;3).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eTreatment of MM include treatment options including CD-38-targeting agents. CD38 is a transmembrane glycoprotein that is expressed on MM cells and also, at lower levels, on normal lymphoid cells, myeloid cells, and some non-hematopoietic tissues. The high expression of CD38 on MM cells potentially makes it a therapeutic target for the treatment of MM. CD38 is highly expressed on NK cells, therefore daratumumab depletes the NK cells reservoir. Prior studies have shown that the decline in NK cells after a Dara infusion can be rapid and can occur at very early stages during therapy. In mice, NK impairment and/or depletion increases susceptibility to viral infections.\u003c/p\u003e \u003cp\u003eOur study is the first to estimate the comparative risk for types of infections and the number of infectious events (IE) associated with the use of Dara in the induction phase of transplant-eligible and ineligible NDMM patients in a real-world setting treated with the Dara combo. Significant advances in MM therapeutics in the last two decades have led to improved survival outcomes but infections remain a major cause of morbidity and early mortality.\u003csup\u003e1,2\u003c/sup\u003e Infection risk often depends on disease-related immunoparesis, co-morbidities, and systemic therapy. The incidence of severe infection in patients with MM seems to be higher during the first months after diagnosis [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Patterns of infections have evolve over the time, as the myeloma treatment strategies continues to change, with new therapeutic classes such as proteasome inhibitors (PI), immuno-modulatory drugs (IMiD) [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] and anti-CD38Mabs being introduced. We retrospectively evaluated 148 patients with NDMM managed in nine Italian Hematology Centers receiving D-VTD, D-RD and D-VMP as induction therapy on between 2020 and 2023. Overall, 148 developed an infection of any grade, substantially comparable to the risk reported in MM patients undergoing induction therapy. The overall risk of infection with dara treatment is 38%, being upper respiratory tract infections the most common; our reported rate is slightly lower. A meta-analysis from 5 phase III randomized trials, demonstrated that adding the anti-CD38 Mab, daratumumab to standard MM regimens resulted in a higher incidence of all grades of infection (with a risk ratio (RR) of 1.27), and any-grade pneumonia (with a RR of 1.63) [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].Several reports have indicated that the administration of prophylactic antibiotics or the use of vaccinations before beginning myeloma treatment reduces the frequency and severity of early infections, but their use remains controversial.\u003c/p\u003e \u003cp\u003eIn our study, there was no difference on antiviral and antimicrobial prophylaxis in the 3 treatment groups. Furthermore, the median time to IE was similar between the 3 groups D-VMP 161 (104\u0026ndash;243), D-RD 157 (97\u0026ndash;370) and D-VTD 82 (44\u0026ndash;184) days. (p\u0026thinsp;=\u0026thinsp;0.064). The type of IE was upper respiratory tract infection in 81/105 patients (77%), covid infection 12/105 patients (11%), herpes simplex and varicella zoster virus (VZV) in 2/105 patients (1.9%), abdominal infection 3/105 patients (2.8%) and infection of urinary tract 2/105 patients (1.9%) of any grade. No differences were present in the grade and in the duration of IE between the three studied groups. We attempted to identify predictors of IE in order to stratify the risk and inform prophylaxis management. In our experience, no significant differences were found between the three treatment groups in terms of incidence, type and degree of infections, while significant differences were found between baseline IgA, IgM levels, neutropenia and lymphopenia at the time of the IE. The risk of infection may be associated with neutropenia, hypogammaglobulinemia, and NK cell depletion. The risk of neutropenia during dara treatment depends on whether monotherapy or a combination regimen is used. In patients treated with combination regimens, the risk of neutropenia is largely higher, ranging from 28 to 48%, and is highest with DRd [\u003cspan additionalcitationids=\"CR9 CR10\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Lymphopenia is a well-recognized risk factor for infections in MM [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].Grade 3 or 4 lymphopenia occurs with IMIDs and bortezomib [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] at rates of 3 to 6% [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].The development and persistence of severe lymphopenia in patients receiving dara-based regimens is not uncommon and is associated with risk of serious infections, and worst outcomes in certain subsets of patients. Therefore, close monitoring, prophylactic measures, should be adopted especially in patients with pretreatment lymphopenia. In our experience, the introduction of dara in the induction phase did not lead to an increase in the number, degree and duration of IE in the group of 3 treatments, even if we highlighted a non-statistically significant difference in the time to onset of IE in the D-VTD group. In addition, we have highlighted a significant difference in IgA and IgM level and neutropenia and lymphocytopenia prior and post IE in 3 treatment group. A larger cohort of patients are needed to confirm our results and to evaluate tailored prophylaxis in different dara treatment groups. Further studies and registries with long-term follow-up are warranted to better identify patients at higher risk for infection and to clarify the potential benefits of infectious prophylaxis in the clinical management of NDMM treated with Dara combinations.\u003c/p\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo datasets were generated or analysed during the current study.\u003c/p\u003e\u003cp\u003eNo funding was received for conducting this study.\u003c/p\u003e\n\u003cp\u003eConsent to Participate statement to clearly indicate that informed consent to participate was obtained from all human participants. \u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003ePalumbo A, Bringhen S, Ludwig H, Dimopoulos MA, Bladé J, Mateos MV, Rosiñol L, Boccadoro M, Cavo M, Lokhorst H, Zweegman S, Terpos E, Davies F, Driessen C, Gimsing P, Gramatzki M, Hàjek R, Johnsen HE, Leal Da Costa F, Sezer O, Spencer A, Beksac M, Morgan G, Einsele H, San Miguel JF, Sonneveld P. 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N Engl J Med. 1996; 11;335 :91-7. \u003c/li\u003e\n \u003cli\u003eEncinas C.\u003csup\u003e \u003c/sup\u003e, José-Ángel Hernandez-Rivas, Albert Oriol\u003csup\u003e \u003c/sup\u003e, Rosiñol\u003csup\u003e \u003c/sup\u003e\u003csup\u003e \u003c/sup\u003eL., Blanchard\u003csup\u003e M.J.\u003c/sup\u003e, José-María Bellón\u003csup\u003e \u003c/sup\u003e\u003csup\u003e1\u003c/sup\u003e, Ramón García-Sanz\u003csup\u003e \u003c/sup\u003e\u003csup\u003e6\u003c/sup\u003e, Javier de la Rubia\u003csup\u003e \u003c/sup\u003e\u003csup\u003e7\u003c/sup\u003e, Ana López de la Guía\u003csup\u003e \u003c/sup\u003e\u003csup\u003e8\u003c/sup\u003e, Ana Jímenez-Ubieto\u003csup\u003e \u003c/sup\u003e\u003csup\u003e9\u003c/sup\u003e, Isidro Jarque\u003csup\u003e \u003c/sup\u003e\u003csup\u003e10\u003c/sup\u003e, Belén Iñigo\u003csup\u003e \u003c/sup\u003e\u003csup\u003e11\u003c/sup\u003e, Victoria Dourdil\u003csup\u003e \u003c/sup\u003eFelipe de Arriba\u003csup\u003e \u003c/sup\u003e\u003csup\u003e13\u003c/sup\u003e, Clara Cuéllar Pérez-Ávila\u003csup\u003e \u003c/sup\u003e\u003csup\u003e9\u003c/sup\u003e, Yolanda Gonzalez\u003csup\u003e \u003c/sup\u003e\u003csup\u003e14\u003c/sup\u003e, Miguel-Teodoro Hernández\u003csup\u003e \u003c/sup\u003e\u003csup\u003e15\u003c/sup\u003e, Joan Bargay\u003csup\u003e \u003c/sup\u003e\u003csup\u003e16\u003c/sup\u003e, Miguel Granell\u003csup\u003e \u003c/sup\u003e\u003csup\u003e17\u003c/sup\u003e, Paula Rodríguez-Otero\u003csup\u003e \u003c/sup\u003e\u003csup\u003e18\u003c/sup\u003e, Maialen Silvent\u003csup\u003e \u003c/sup\u003e\u003csup\u003e19\u003c/sup\u003e, Carmen Cabrera\u003csup\u003e \u003c/sup\u003e\u003csup\u003e20\u003c/sup\u003e, Rafael Rios\u003csup\u003e \u003c/sup\u003e\u003csup\u003e21\u003c/sup\u003e, Adrián Alegre\u003csup\u003e \u003c/sup\u003e\u003csup\u003e22\u003c/sup\u003e, Mercedes Gironella\u003csup\u003e \u003c/sup\u003e\u003csup\u003e23\u003c/sup\u003e, Marta-Sonia Gonzalez\u003csup\u003e \u003c/sup\u003e\u003csup\u003e24\u003c/sup\u003e, Anna Sureda\u003csup\u003e \u003c/sup\u003e\u003csup\u003e25\u003c/sup\u003e, Antonia Sampol\u003csup\u003e \u003c/sup\u003e\u003csup\u003e26\u003c/sup\u003e, Enrique M Ocio\u003csup\u003e \u003c/sup\u003e\u003csup\u003e27\u003c/sup\u003e, Isabel Krsnik\u003csup\u003e \u003c/sup\u003e\u003csup\u003e28\u003c/sup\u003e, Antonio García\u003csup\u003e \u003c/sup\u003e, Aránzazu García-Mateo\u003csup\u003e \u003c/sup\u003e\u003csup\u003e30\u003c/sup\u003e, Joan-Alfons Soler\u003csup\u003e \u003c/sup\u003e, Jesús Martín\u003csup\u003e \u003c/sup\u003e\u003csup\u003e32\u003c/sup\u003e, José-María Arguiñano\u003csup\u003e \u003c/sup\u003e\u003csup\u003e33\u003c/sup\u003e, María-Victoria Mateos\u003csup\u003e \u003c/sup\u003e\u003csup\u003e6\u003c/sup\u003e, Joan Bladé\u003csup\u003e \u003c/sup\u003e\u003csup\u003e4\u003c/sup\u003e, Jesús F San-Miguel\u003csup\u003e \u003c/sup\u003e\u003csup\u003e18\u003c/sup\u003e, Juan-José Lahuerta\u003csup\u003e \u003c/sup\u003e\u003csup\u003e9\u003c/sup\u003e, Joaquín Martínez-López\u003csup\u003e \u003c/sup\u003e\u003csup\u003e34\u003c/sup\u003e; GEM/PETHEMA (Grupo Español de Mieloma/Programa para el Estudio de la Terapéutica en Hemopatías Malignas) cooperative study group A simple score to predict early severe infections in patients with newly diagnosed multiple myeloma Blood Cancer 2022;12:68. \u003c/li\u003e\n \u003cli\u003eBlimark C., Erik Holmberg , Ulf-Henrik Mellqvist , Ola Landgren , Magnus Björkholm , Malin Hultcrantz , Christian Kjellander , Ingemar Turesson , Sigurdur Y Kristinsson. Multiple myeloma and infections: a population-based study on 9253 multiple myeloma patients Haematologica 2015; 100:107-13\u003c/li\u003e\n \u003cli\u003eNucci M. , Anaissie E. Infections in patients with multiple myeloma in the era of high-dose therapy and novel agents Oct Clin Infect Dis 2009; 49:1211-25\u003c/li\u003e\n \u003cli\u003eCaro J.\u003csup\u003e \u003c/sup\u003e, Marc Braunstein\u003csup\u003e \u003c/sup\u003e, Louis Williams\u003csup\u003e \u003c/sup\u003e, Benedetto Bruno\u003csup\u003e \u003c/sup\u003e, David Kaminetzky\u003csup\u003e \u003c/sup\u003e, Ariel Siegel\u003csup\u003e \u003c/sup\u003e, Beatrice Razzo\u003csup\u003e \u003c/sup\u003e, Serge Alfanari\u003csup\u003e \u003c/sup\u003e, Gareth J Morgan\u003csup\u003e \u003c/sup\u003e, Faith E Davies\u003csup\u003e \u003c/sup\u003e, Eileen M Boyle Inflammation and infection in plasma cell disorders: how pathogens shape the fate of patients Leukemia 2022; 36:613-624.\u003c/li\u003e\n \u003cli\u003eThierry Facon\u003csup\u003e \u003c/sup\u003e, Shaji K Kumar\u003csup\u003e \u003c/sup\u003e, Torben Plesner, Robert Z Orlowski\u003csup\u003e \u003c/sup\u003e, Philippe Moreau\u003csup\u003e \u003c/sup\u003e, Nizar Bahlis\u003csup\u003e \u003c/sup\u003e, Supratik Basu\u003csup\u003e \u003c/sup\u003e, Hareth Nahi\u003csup\u003e \u003c/sup\u003e, Cyrille Hulin\u003csup\u003e \u003c/sup\u003e, Hang Quach\u003csup\u003e \u003c/sup\u003e, Hartmut Goldschmidt\u003csup\u003e \u003c/sup\u003e, Michael O'Dwyer\u003csup\u003e \u003c/sup\u003e\u003csup\u003e12\u003c/sup\u003e, Aurore Perrot\u003csup\u003e \u003c/sup\u003e\u003csup\u003e13\u003c/sup\u003e, Christopher P Venner\u003csup\u003e \u003c/sup\u003e\u003csup\u003e14\u003c/sup\u003e, Katja Weisel\u003csup\u003e \u003c/sup\u003e\u003csup\u003e15\u003c/sup\u003e, Joseph R Mace\u003csup\u003e \u003c/sup\u003e\u003csup\u003e16\u003c/sup\u003e, Noopur Raje\u003csup\u003e \u003c/sup\u003e\u003csup\u003e17\u003c/sup\u003e, Mourad Tiab\u003csup\u003e \u003c/sup\u003e\u003csup\u003e18\u003c/sup\u003e, Margaret Macro\u003csup\u003e \u003c/sup\u003e\u003csup\u003e19\u003c/sup\u003e, Laurent Frenzel\u003csup\u003e \u003c/sup\u003e\u003csup\u003e20\u003c/sup\u003e, Xavier Leleu\u003csup\u003e \u003c/sup\u003e\u003csup\u003e21\u003c/sup\u003e, Tahamtan Ahmadi\u003csup\u003e \u003c/sup\u003e\u003csup\u003e22\u003c/sup\u003e, Jianping Wang\u003csup\u003e \u003c/sup\u003e\u003csup\u003e23\u003c/sup\u003e, Rian Van Rampelbergh\u003csup\u003e \u003c/sup\u003e\u003csup\u003e24\u003c/sup\u003e, Clarissa M Uhlar\u003csup\u003e \u003c/sup\u003e\u003csup\u003e25\u003c/sup\u003e, Brenda Tromp\u003csup\u003e \u003c/sup\u003e\u003csup\u003e26\u003c/sup\u003e, Maria Delioukina\u003csup\u003e \u003c/sup\u003e\u003csup\u003e25\u003c/sup\u003e, Jessica Vermeulen\u003csup\u003e \u003c/sup\u003e, Saad Z Usmani\u003csup\u003e \u003c/sup\u003e\u003csup\u003e27\u003c/sup\u003e Daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone alone in newly diagnosed multiple myeloma (MAIA): overall survival results from a randomised, open-label, phase 3 trial Lancet Oncol 2021;22:1582-1596. \u003c/li\u003e\n \u003cli\u003eNizar J Bahlis\u003csup\u003e \u003c/sup\u003e, Meletios A Dimopoulos\u003csup\u003e \u003c/sup\u003e, Darrell J White\u003csup\u003e \u003c/sup\u003e\u003csup\u003e3\u003c/sup\u003e, Lotfi Benboubker\u003csup\u003e \u003c/sup\u003e\u003csup\u003e4\u003c/sup\u003e, Gordon Cook\u003csup\u003e \u003c/sup\u003e\u003csup\u003e5\u003c/sup\u003e, Merav Leiba\u003csup\u003e \u003c/sup\u003e\u003csup\u003e6\u003c/sup\u003e, P Joy Ho\u003csup\u003e \u003c/sup\u003e\u003csup\u003e7\u003c/sup\u003e, Kihyun Kim\u003csup\u003e \u003c/sup\u003e\u003csup\u003e8\u003c/sup\u003e, Naoki Takezako\u003csup\u003e \u003c/sup\u003e\u003csup\u003e9\u003c/sup\u003e, Philippe Moreau\u003csup\u003e \u003c/sup\u003e\u003csup\u003e10\u003c/sup\u003e, Jonathan L Kaufman\u003csup\u003e \u003c/sup\u003e\u003csup\u003e11\u003c/sup\u003e, Maria Krevvata\u003csup\u003e \u003c/sup\u003e, Christopher Chiu\u003csup\u003e \u003c/sup\u003e\u003csup\u003e12\u003c/sup\u003e, Xiang Qin\u003csup\u003e \u003c/sup\u003e\u003csup\u003e12\u003c/sup\u003e, Linda Okonkwo\u003csup\u003e \u003c/sup\u003e\u003csup\u003e13\u003c/sup\u003e, Sonali Trivedi\u003csup\u003e \u003c/sup\u003e\u003csup\u003e12\u003c/sup\u003e, Jon Ukropec\u003csup\u003e \u003c/sup\u003e\u003csup\u003e14\u003c/sup\u003e, Ming Qi\u003csup\u003e \u003c/sup\u003e\u003csup\u003e12\u003c/sup\u003e, Jesus San-Miguel\u003csup\u003e \u003c/sup\u003e\u003csup\u003e15\u003c/sup\u003e Daratumumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: extended follow-up of POLLUX, a randomized, open-label, phase 3 study. Leukemia 2020 ;34:1875-1884.\u003c/li\u003e\n \u003cli\u003eStephanos Vassilopoulos\u003csup\u003e \u003c/sup\u003e, Athanasios Vassilopoulos\u003csup\u003e \u003c/sup\u003e, Markos Kalligeros\u003cem\u003e\u003csup\u003e \u003c/sup\u003e\u003c/em\u003e\u003csup\u003e1\u003c/sup\u003e, Fadi Shehadeh\u003csup\u003e \u003c/sup\u003e\u003csup\u003e1\u003c/sup\u003e, Eleftherios Mylonakis\u003csup\u003e \u003c/sup\u003e Cumulative Incidence and Relative Risk of Infection in Patients With Multiple Myeloma Treated With Anti-CD38 Monoclonal Antibody-Based Regimens: A Systematic Review and Meta-analysis. Open Forum Infect Dis 2022 31;9(11)\u003c/li\u003e\n \u003cli\u003eKoichi Yanaba\u003csup\u003e \u003c/sup\u003e, Ayumi Yoshizaki, Eiji Muroi, Toshihide Hara, Fumihide Ogawa, Kazuhiro Shimizu, Shinichi SatoThe proteasome inhibitor bortezomib inhibits T cell-dependent inflammatory responses J Leukoc Biol Jul 2010;88(1):117-22.\u003c/li\u003e\n \u003cli\u003eH Quach , D Ritchie , AK Stewart , P Neeson , S Harrison, MJ Smyth , HM Prince. Mechanism of action of immunomodulatory drugs (IMiDS) in multiple myeloma Leukemia 2009; 12;24:22–32.\u003c/li\u003e\n \u003cli\u003eShahzad Raza\u003csup\u003e \u003c/sup\u003e, Rachael A Safyan\u003csup\u003e \u003c/sup\u003e, Suzanne Lentzsch\u003csup\u003e \u003c/sup\u003e Immunomodulatory Drugs (IMiDs) in Multiple Myeloma. Curr Cancer Drug Target 2017; 17:846-857.\u003c/li\u003e\n \u003cli\u003eAbigail Colley, Timothy Brauns , AnnE. Sluder , MarkC. Poznansky , Yohannes Gemechu Immunomodulatory drugs: a promising clinical ally for cancer immunotherapy Volume 30, Issue 8, 2024, 765-780\u003c/li\u003e\n \u003cli\u003eWentao Li\u003csup\u003e \u003c/sup\u003e, Lin Liang\u003csup\u003e \u003c/sup\u003e, Qianjin Liao\u003csup\u003e \u003c/sup\u003e, Yanling Li\u003csup\u003e \u003c/sup\u003e, Yanhong Zhou\u003csup\u003e \u003c/sup\u003eCD38: An important regulator of T cell function Biomed Pharmacother 2022; 153:113395\u003c/li\u003e\n \u003cli\u003eLakshman A, Rajkumar SV, Buadi FK, Binder M, Gertz MA, Lacy MQ, Dispenzieri A, Dingli D, Fonder AL, Hayman SR, Hobbs MA, Gonsalves WI, Hwa YL, Kapoor P, Leung N, Go RS, Lin Y, Kourelis TV, Warsame R, Lust JA, Russell SJ, Zeldenrust SR, Kyle RA, Kumar SK. Risk stratification of smoldering multiple myeloma incorporating revised IMWG diagnostic criteria Blood Cancer J. 2018;12;8(6):59. \u003c/li\u003e\n \u003cli\u003eGahagan A, Maheshwari S, Rangarajan S, Ubersax C, Tucker A, Harmon C, Pasala MS, Bal S, Godby K, Ravi G, Costa LJ, Williams GR, Bhatia S, Giri S.J Evaluating concordance between International Myeloma Working Group (IMWG) frailty score and simplified frailty scale among older adults with multiple myeloma. Geriatr Oncol.2024; 15:102051. \u003c/li\u003e\n \u003cli\u003eChhay Lim\u003csup\u003e \u003c/sup\u003e, Priyadarshini Sinha, Simon J Harrison\u003csup\u003e \u003c/sup\u003e, Hang Quach\u003csup\u003e \u003c/sup\u003e, Monica A Slavin\u003csup\u003e \u003c/sup\u003e\u003csup\u003e5\u003c/sup\u003e, Benjamin W Teh Epidemiology and Risks of Infections in Patients With Multiple Myeloma Managed With New Generation Therapies Clin Lymphoma Myeloma Leu 2021 ;21:444-450.\u003c/li\u003e\n \u003cli\u003eWorld Health Organization’s International Statistical Classification of Diseases–10th Revision (ICD-10).\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"annals-of-hematology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"aohe","sideBox":"Learn more about [Annals of Hematology](http://link.springer.com/journal/277)","snPcode":"277","submissionUrl":"https://submission.nature.com/new-submission/277/3","title":"Annals of Hematology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"multiple myeloma, infection disease, monoclonal antibody","lastPublishedDoi":"10.21203/rs.3.rs-6779049/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6779049/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eIntroduction\u003c/strong\u003e: Multiple myeloma (MM) is a malignancy characterized by the clonal proliferation of plasma cells. MM accounts for 1% of all neoplastic diseases and is the second most common hematologic malignancy after lymphoma. Infection is a significant cause of morbidity and mortality in newly diagnosed multiple myeloma (NDMM) patients, responsible for about 45% of early deaths especially in elderly patients and within the first months of therapy. Available treatments for MM, such as anti-CD-38 monoclonal antibody (CD38 MAbs), proteasome inhibitors, immunomodulatory agents (lenalidomide, thalidomide and glucocorticoids), demonstrated an improvement in the outcome of NDMM patients, however, predispose to increasing risk of infection. Daratumumab (Dara), an anti-CD38 MAbs is an important new agent in the therapeutic armamentarium of MM. Dara is approved for NDMM or relapsed/refractory MM (RRMM). The use of Dara has improved patient outcomes but has changed the frequency and epidemiology of infections. We retrospectively reviewed data of 472 patients who received Dara-containing regimen for NDMM treated in 10 centers members of the European Myeloma Network Italy (EMN-I) between 2020 and 2023, to study the incidence of IE. Of 472 patients, 148 (31.3%) (148 patients) encountered experienced infectious complications during therapy. No differences were found among the 3 above mentioned groups of patient. In our experience, the introduction of dara in the induction phase did not increase the frequency, degree and duration of infections in the 3 cohorts. Even though the difference was not statistically significant, we observed an earlier onset of IE in the D-VTD group as compared to the others. Further studies are warranted to define further the incidence of infections in these categories of patients, and identify factors associated with a higher risk profile for infection. This will also help understanding the role of infectious prophylaxis in the clinical management of NDMM.\u003c/p\u003e","manuscriptTitle":"Infection Events in Patients With Newly Diagnosed Multiple Myeloma With Anti-cd38 Monoclonal Antibody-based First Line Regimens: A Multicentric Italian Experience","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-10 05:42:36","doi":"10.21203/rs.3.rs-6779049/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-07-01T17:12:35+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-01T16:24:15+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-06-26T04:32:49+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"130693701752614233455597695373089795629","date":"2025-06-17T15:00:04+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"28339656428168055440905599866093918566","date":"2025-06-12T06:26:25+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"259316271304226177817725669207698146899","date":"2025-06-12T04:43:22+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-06-04T18:01:56+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-06-04T14:49:43+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-06-04T14:48:52+00:00","index":"","fulltext":""},{"type":"submitted","content":"Annals of Hematology","date":"2025-05-29T19:13:25+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"annals-of-hematology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"aohe","sideBox":"Learn more about [Annals of Hematology](http://link.springer.com/journal/277)","snPcode":"277","submissionUrl":"https://submission.nature.com/new-submission/277/3","title":"Annals of Hematology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"43ace01b-46a4-4857-b6ff-07511916a840","owner":[],"postedDate":"June 10th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-10-13T16:01:21+00:00","versionOfRecord":{"articleIdentity":"rs-6779049","link":"https://doi.org/10.1007/s00277-025-06645-y","journal":{"identity":"annals-of-hematology","isVorOnly":false,"title":"Annals of Hematology"},"publishedOn":"2025-10-11 15:57:42","publishedOnDateReadable":"October 11th, 2025"},"versionCreatedAt":"2025-06-10 05:42:36","video":"","vorDoi":"10.1007/s00277-025-06645-y","vorDoiUrl":"https://doi.org/10.1007/s00277-025-06645-y","workflowStages":[]},"version":"v1","identity":"rs-6779049","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6779049","identity":"rs-6779049","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}