Blood Cancer Journal www.nature.com/bcj ARTICLE OPEN A simple score to predict early severe infections in patients with newly diagnosed multiple myeloma Cristina Encinas 1,34, José-Ángel Hernandez-Rivas2,34, Albert Oriol 3, Laura Rosiñol4, María-Jesús Blanchard5, José-María Bellón 1, Ramón García-Sanz 6, Javier de la Rubia 7, Ana López de la Guía8, Ana Jímenez-Ubieto9, Isidro Jarque 10, Belén Iñigo11, Victoria Dourdil12, Felipe de Arriba 13, Clara Cuéllar Pérez-Ávila9, Yolanda Gonzalez14, Miguel-Teodoro Hernández15, Joan Bargay16, Miguel Granell 17, Paula Rodríguez-Otero18, Maialen Silvent19, Carmen Cabrera20, Rafael Rios21, Adrián Alegre 22, Mercedes Gironella23, Marta-Sonia Gonzalez24, Anna Sureda25, Antonia Sampol 26, Enrique M. Ocio27, Isabel Krsnik28, Antonio García29, Aránzazu García-Mateo30, Joan-Alfons Soler31, Jesús Martín 32, José-María Arguiñano33, María-Victoria Mateos 6, ✉ Joan Bladé 4, Jesús F. San-Miguel 18, Juan-José Lahuerta 9,35, Joaquín Martínez-López 9,35 and GEM/PETHEMA (Grupo Español de Mieloma/Programa para el Estudio de la Terapéutica en Hemopatías Malignas) cooperative study group © The Author(s) 2022 Infections remain a common complication in patients with multiple myeloma (MM) and are associated with morbidity and mortality. A risk score to predict the probability of early severe infection could help to identify the patients that would benefit from 1234567890();,: preventive measures. We undertook a post hoc analysis of infections in four clinical trials from the Spanish Myeloma Group, involving a total of 1347 patients (847 transplant candidates). Regarding the GEM2010 > 65 trial, antibiotic prophylaxis was mandatory, so we excluded it from the final analysis. The incidence of severe infection episodes within the first 6 months was 13.8%, and majority of the patients experiencing the first episode before 4 months (11.1%). 1.2% of patients died because of infections within the first 6 months (1% before 4 months). Variables associated with increased risk of severe infection in the first 4 months included serum albumin ≤30 g/L, ECOG > 1, male sex, and non-IgA type MM. A simple risk score with these variables facilitated the identification of three risk groups with different probabilities of severe infection within the first 4 months: low-risk (score 0–2) 8.2%; intermediate-risk (score 3) 19.2%; and high-risk (score 4) 28.3%. Patients with intermediate/high risk could be candidates for prophylactic antibiotic therapies. Blood Cancer Journal (2022)12:68 ; https://doi.org/10.1038/s41408-022-00652-2 INTRODUCTION a significant cause of morbidity and mortality in MM, particularly Multiple myeloma (MM) is a malignant proliferation of mature within the first months of therapy [4–6]. Early mortality is related clonal plasma cells, which are responsible for the secretion of an to myeloma progression, especially in elderly patients [7] and excess of clonal immunoglobulins. The disease is commonly infections can additionally increase the risk of early-related associated with the suppression of normal immunoglobulins myeloma mortality because of the delay or adjustment of doses. (Immunoparesis), leading to severely impaired humoral immunity; Recent advances in treatments have improved the survival of in addition, patients with MM also show dysfunctional cellular and patients with MM [8–10]. However, myeloma treatments, includ- innate immunity [1]. This complex failure of immunosurveillance ing new biological agents, might also impact the immune system, mechanisms also leaves patients highly vulnerable to viral (10-fold either positively or negatively, increasing the risk of infection increase) and bacterial (7-fold increase) infections [2, 3], which are [11–15]. The most common side-effect in this context is cytopenia, 1 Hospital General Universitario Gregorio Marañón (HGUGM), IiSGM, Madrid, Spain. 2Hospital Universitario Infanta Leonor, Madrid, Spain. 3Hospital Universitario Germans Trias i Pujol, Badalona (Barcelona), Barcelona, Spain. 4Hospital Clinic, CIBERONC, Barcelona, Spain. 5Hospital Universitario Ramón y Cajal, Madrid, Spain. 6University Hospital of Salamanca (HUS/IBSAL), CIBERONC and Cancer Research Institute of Salamanca-IBMCC (USAL-CSIC), Salamanca, Spain. 7Hospital Universitario Doctor Peset, Valencia, Spain. 8Hospital Universitario la Paz, Madrid, Spain. 9Hospital Universitario 12 de Octubre, CIBERONC, Madrid, Spain. 10Hospital Universitario la Fe, CIBERONC, Valencia, Spain. 11Hospital Clínico San Carlos, Madrid, Spain. 12Hospital Clínico Universitario “Lozano Blesa”, Zaragoza, IIS Aragón, Spain. 13Hospital J.M. Morales Meseguer, Murcia, Spain. 14Hospital Universitario Dr. Josep Trueta, Girona, Spain. 15Hospital Universitario de Canarias, San Cristóbal de La Laguna, Spain. 16Hospital Son Llatzer, Palma de Mallorca, Spain. 17Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. 18Clínica Universidad de Navarra, CIMA, IDISNA; CIBERONC, Pamplona, Spain. 19Hospital Donostia, San Sebastián, Spain. 20Complejo Hospitalario de Cáceres, Cáceres, Spain. 21Hospital Universitario Virgen de las Nieves, Granada, Spain. 22Hospital Universitario de la Princesa y Hospital Universitario Quirónsalud, Madrid, Spain. 23 Hospital Vall D’Hebron, Barcelona, Spain. 24Hospital Universitario de Santiago, Santiago de Compostela, Spain. 25ICO-L’Hospitalet, IDIBELL, Universitat de Barcelona, Barcelona, Spain. 26Hospital Universitario Son Espases, Palma de Mallorca, Spain. 27Hospital Universitario Marqués de Valdecilla, (IDIVAL). Universidad de Cantabria, Santander, Spain. 28 Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain. 29Hospital Universitario Arnau de Vilanova, Lleida, Spain. 30Hospital General de Segovia, Segovia, Spain. 31 Hospital Parc Taulí, Sabadell (Barcelona), Barcelona, Spain. 32Complejo Hospitalario Regional Virgen del Rocío, CIBERONC, Sevilla, Spain. 33Complejo Hospitalario de Navarra, Pamplona, Spain. 34These authors contributed equally: Cristina Encinas, José-Ángel Hernández-Rivas. 35These authors jointly supervised this work: Juan-José Lahuerta, Joaquín Martínez-López. ✉email: jmarti01@ucm.es Received: 11 January 2022 Revised: 21 February 2022 Accepted: 21 March 2022 C. Encinas et al. 2 which is associated with increased susceptibility to bacterial and the final analysis, although it did allow us to compare the incidence of viral infections, particularly when a high dose of chemotherapy early severe infection with GEM2005 > 65 where prophylaxis was not followed by autologous stem cell transplant is administered [12]. mandatory, with both trials in transplant-ineligible populations. Infectious Corticosteroids are included in most drug combinations for MM, events were graded according to the National Cancer Institute–Common but they have well-established immunosuppressive effects [6]. Toxicity Criteria for adverse events (NCI-CTCAE), version 4.0. We considered early severe infection as an infection occurring in the first 4 months and Similarly, proteasome inhibitors (PIs) induce T-cell dysfunction and when it was grade ≥3 (as is considered by NCI-CTCAE) and, in the case of are associated with an increased risk for varicella-zoster virus (VZV) pneumonia, irrespective of the grade of severity. We also evaluated the reactivation [16, 17]. Immunomodulatory drugs (IMiDs) may have a demographics, clinical and/or biological variables to test for associations protective effect by enhancing natural killer (NK) and T-cell with a higher risk of early severe infection. In addition, we tested the function, but they are associated with cytopenia, and there is prediction value of previously published scores [24] for infection in evidence that their use is accompanied by an increase in serious patients with MM. infections [11, 18–21]. Finally, CD38-targeting monoclonal anti- bodies (CD38 MAbs) reduce the number of NK and immunosup- Patients pressive regulatory T-cells and are associated with a higher A total of 1347 newly diagnosed patients with symptomatic MM who had number of infections (e.g., increased risk of VZV infection, and a received at least one treatment dose were analyzed in this post hoc study. higher risk of hepatitis B virus reactivation) [22, 23]. The median age of patients was 62 years (range 25–88) and the median The incidence of severe infection in patients with MM seems to follow-up was 81.7 months. Five-hundred patients who were ineligible for be higher during the first months after the diagnosis [2, 4, 5, 24]. autologous transplant and aged ≥65 years were included in trials GEM2005 > 65 [33] and GEM2010 > 65 [34], and 847 patients who were Several reports have indicated that the administration of transplant candidates and aged < 65 years were included in trials prophylactic antibiotics or the use of vaccination protocols before GEM2005 < 65 [35] and GEM2012 < 65 [36]. All patients were diagnosed beginning myeloma treatment reduces the frequency and severity according to the International Myeloma Working Group criteria [37] and of early infections, but their use remains controversial [25–28]. provided written informed consent before the screening. The trials were Recent results of the TEAMM study have shown that the addition registered on ClinicalTrials.gov; data were reviewed by an external clinical of prophylactic levofloxacin to active myeloma treatment during research organization and centrally assessed, and the efficacy and safety the first 12 weeks of therapy significantly reduces febrile episodes have been previously reported [33–36]. The main clinical and biological and deaths versus placebo [29, 30]. characteristics of patients included in the analysis are summarized in Table 1. Risk scores to predict the probability of infection could help in Antibiotic prophylaxis was not mandatory in GEM2005 < 65, GEM2005 > 65 or GEM2012 < 65 (antibiotics were administered at the discretion of the identifying patients at higher risk of infection who may benefit trial center), whereas in GEM2010 > 65 a prophylactic antibiotic was used from individualized prophylactic antibiotic treatments. Along this as per protocol during the first 3 months. line, a scoring system was developed in a sub-study of the phase 3 FIRST clinical trial [31], which characterized treatment-emergent Outcomes and variables analyzed infections in transplant-ineligible elderly patients treated with The primary outcomes were the early severe infection incidence and the lenalidomide or thalidomide. Results showed that Eastern clinical and biological variables associated with an increased risk of severe Cooperative Group Oncology (ECOG) performance status [32] ≥ 2, infection, which were used to build a score to predict the risk of early β2microglobulin (B2M) ≥ 6 mg/L, lactate dehydrogenase >200 U/L, severe infection. Secondary outcomes included (1) to identify the number and hemoglobin <11 g/dL were significantly associated with a of patients with at least one infection in the series, focusing on the first high risk of infections [24]. Based on this model, the benefit of 6 months, and the number, severity, and type of infectious events in the adding prophylactic antibiotics was useful only in a subset of global series and in each of the clinical trials; (2) to compare the incidence patients with a high risk of infections. While the risk score was of early severe infection between the transplant-ineligible populations, GEM2005 > 65, without antibiotic prophylaxis, and GEM2010 > 65, with externally validated in three independent data sets (MM-003, MM- mandatory antibiotic prophylaxis; and finally (3) to determine the mortality 009, and MM-01024), the results have not been confirmed in other due to infection and the impact of experiencing a severe infection on series and, particularly, in the transplant-candidate setting. overall survival (OS). The present study aimed to analyze the rate of severe infection Most of the continuous variables were dichotomized before their in a large series of newly diagnosed transplant-eligible and inclusion in the analysis using clinical criteria and the area under the -ineligible patients with MM treated with novel agents in the receiver operating characteristic (ROC). The following characteristics were context of prospective clinical trials of the Spanish Myeloma analyzed: age (≤75 vs >75, >55 vs ≤55 years old), sex, ECOG 0–1 vs >1, Group (PETHEMA, Grupo Español de Mieloma, GEM). Furthermore, β2microglobulin (β2 M) in mg/L ( < 5.5 vs >5.5, <6 vs >6, ≤3 vs >3), serum we aimed to identify the clinical and biological variables lactate dehydrogenase (normal or higher than the upper limit of the associated with the risk of early severe infection that could be normal range), staging according to Durie–Salmon staging system [37, 38], staging according to the International Staging System (ISS) [37, 39, 40] 1–2 used to generate a score for identifying patients at higher risk of versus 3, high versus standard risk cytogenetic abnormalities [41], early severe infection in all subsets of MM in the era of new monoclonal component (≤40 g/L vs >40 g/L), type of involved paraprotein agents. (IgA vs non-IgA), hemoglobin level (≤11 g/dL vs >11 g/dL), serum albumin level (≤30 g/L vs >30 g/L), risk of early infection using FIRST score [24] [high-risk (2–5 points) vs low risk (−3–1 points)], presence of bone lytic PATIENTS AND METHODS lesions, autologous transplant and presence of extramedullary disease. Study design Platelet level, creatinine, calcium, C-reactive protein (CRP) in blood, and The present study was designed to develop a scoring system to predict the plasma cell infiltration in bone marrow were included as continuous variables. Variables were selected by expert assessment and were risk of early severe infection in patients with MM. For this purpose, we evaluated with univariate and multivariate models based on their clinical analyzed all infectious events in a large series of transplant-eligible and -ineligible patients with newly diagnosed MM treated in four GEM clinical and/or biological relevance. trials: GEM2005 > 65, GEM2010 > 65, GEM2005 < 65, and GEM2012 < 65. The protocols of these studies are included as Tables S1 and S2 in Statistical analysis Supplementary Material [33–36]. We analyzed infectious events focusing All data were entered into the Redcap database [42, 43] (Vanderbilt on the first 6 months in an attempt to harmonize the population of University, Nashville, TN, USA). Statistical analysis was performed with the patients analyzed and avoid post-transplant period bias of the GEM2005 < SPSS Statistics for Windows program, version 25.0 (IBM Corp., Armonk, NY, 65 and GEM2012 < 65 trial, where the autologous transplant was USA). Continuous variables are represented by means and standard performed after 6 cycles of induction. Regarding the GEM2010 > 65 trial, deviation. For categorical variables, the results are expressed in frequencies antibiotic prophylaxis was mandatory during the first 3 months (oral and percentages. Normality analysis was performed using graphical tests levofloxacin, 500 mg daily), and therefore, we elected to exclude it from and the Kolmogorov–Smirnov test. Blood Cancer Journal (2022)12:68 C. Encinas et al. 3 To compare the differences between two or more groups, parametric qualitative variables was studied using Pearson’s chi-square test or Fisher’s tests (Student’s t or ANOVA) or non-parametric tests (Mann–Whitney or exact test. Time to infection was measured using cumulative incidence Kruskal–Wallis) were used, as necessary. The association between curves considering death without infection as a competitive event. The evolution of cumulative incidence between groups was compared using the Pepe and Mori test. Univariate and multivariate logistic regression was performed to Table 1. Main clinical characteristics of the patients. calculate the odds ratio (OR) for severe infections at 4 months with a 95% confidence interval (CI). In addition, we built a predictive model Variables Number of including variables of clinical relevance and variables that showed a patients (%) statistical association (p < 0.1) in the univariate analysis. Model calibration Total of patients 1347 (100) was performed with the Hosmer–Lemeshow test, and its discrimination Protocol GEM05 > 65 259 (19.2) was assessed by calculating the area under the ROC curve (AUC). The coefficients of the logistic regression models were converted into a GEM05 < 65 389 (28.9) simplified score to facilitate their application in clinical practice, dividing GEM2010 > 65 241 (17.9) each coefficient by the coefficient with the lowest value and rounding it to GEM2012 < 65 458 (34.0) an integer. Subsequently, the incidence of severe infection within the first 4 months was estimated based on the score, and the sub-hazard ratio (sHR, Sex Male 703 (52.2) competing risk regression) was calculated for the different groups. Two- Female 644 (47.8) tailed tests were used, and results with p < 0.05 were considered statistically significant. Age (years) >75 168 (12.5) ≤75 1179 (87.5) >55 771 (57.2) RESULTS ≤55 576 (42.8) Infectious events Focusing on the first 6 months, 327/1347 patients (24.3%) ECOG PS 0–1 788 (58.5) experienced at least one infection (227 patients with one >1 559 (41.5) infectious event, 74 patients with two, 19 patients with 3, and Hb (g/dL) ≤11 760 (56.4) seven patients with >3 infectious events). 161/1347 patients >11 587 (43.6) (12.5%) experienced at least one severe infection (49.2% of all the patients with any-grade infection reported). ISS Stage 1–2 997 (74.0) Data on the number, severity, and type of infectious events in 3 350 (26.0) the global series and by clinical trials are shown in Table 2. Most Monoclonal ≤40 509 (37.8) infectious events were respiratory infections with 273 events Component (g/L) (59.1% of total infectious events), including 96 events (21.7%) of >40 838 (62.2) pneumonia. There were 40 events (8.7%) considered fever Bone lytic lesion Yes 1160 (86.1) episodes, and 38 events (8.2%) considered urinary tract infections. A total of 13 events (2.8%) were catheter infections, and 11 events Extramedullary disease Yes 237 (17.6) (2.4%) were bacteremia episodes. Regarding the infectious Score FIRST High risk (2 to 5) 465 (34.5) pathogens documented during the first 6 months after treatment Low risk (-3 to 1) 882 (65.5) initiation, results were available in 50 infectious events (10.8% of LDH Normal 1142 (84.8) the total), and 56% of events in which a pathogen was documented were bacterial infections (Table S3 in Supplementary High-risk cytogenetic Yes 240 (20.2) Material). Figure 1 shows the distribution of infectious events per abnormalities NA 157 month in this period: 357 (77.3%) of 462 any-grade infectious Albumin (g/L) ≤30 268 (19.9) events and 162 (78.3%) of 207 severe infectious events occurred Type MM Non-IgA 991 (73.6) within the first 4 months of treatment. Comparative analysis of the transplant-ineligible patients IgA 356 (26.4) showed that the incidence of early severe infection was higher ECOG PS Eastern Cooperative Oncology Group Performance Status, Hb (HR 2.57, p < 0.001) in the GEM2005 > 65 trial than in the Hemoglobin, NA not available, GEM2010 > 65 trial (Fig. 2), where antibiotic prophylaxis in the β2 M β2microglobulin, ISS Stage International Staging System Stage, LDH first 3 months was mandatory. Accordingly, patients enrolled in lactate dehydrogenase, IgA Immunoglobulin A, MM Multiple Myeloma. the GEM2010 > 65 trial (n = 241) were excluded from the risk Table 2. Rate of any-grade and severe infection by clinical trial, by most frequent type of infections in the first 6 months. Protocol N Events (%) Severe (%^) RTIs/Pneumonia (%^) UTI (%^) Febrile syndrome (%^) BSI (%^) GEM05 > 65 103 (22.3) 37 (35.9) 57 (55.3)/23 (22.3) 11 (10.7) 14 (13.6) 0 (0) GEM05 < 65 143 (31.0) 65 (45.5) 106 (74.1)/36 (25.2) 10 (7.0) 3 (2.1) 5 (3.5) GEM10 > 65* 48 (10.3) 16 (33.3) 18 (37.5)/5 (17.9) 1 (2.1) 6 (12.5) 0 (0) GEM12 < 65 168 (36.4) 89 (53.2) 92 (54.8)/32 (19) 16 (9.5) 17 (10.1) 19 (11.3) Total 462 (100) 207 (44.8¶) 273 (59.1¶)/96 (21.7¶) 38 (8.2¶) 40 (8.7¶) 24 (5.2¶) N events (%): number of any-grade infectious events by protocol and in the global series (percentage of total any-grade infectious events), Severe: number of severe infectious events by protocol and in the global series. RTIs/Pneumonia: number of any-grade respiratory tract infections/Pneumonia by protocol and in the global series; UTI: any-grade urinary tract infections by protocol and in the global series, BSI Bloodstream infections, including bacteremia and catheter infection by protocol and in the global series. (%^) percentage of total infectious events in each protocol. ¶ Percentage of total any-grade infectious events. *In GEM10 > 65, antibiotic prophylaxis was mandatory during the first 3 months. Blood Cancer Journal (2022)12:68 C. Encinas et al. 4 Severe infectious events 160 Non-severe infectious events 140 120 71 Number of infectious events 100 80 32 60 34 23 25 40 72 22 50 20 39 38 34 22 0 1 2 3 4 5 6 Months of treatment Fig. 1 Distribution of the number of infectious events per month from treatment. Fig. 2 Cumulative incidence of severe infections comparing non-candidate transplant patients. Fig. 3 Cumulative incidence. A Cumulative incidence of severe infection and B mortality by infection. score final analysis (n = 1106) due to the use of antibiotic If we consider the 4 CTs, a total of 59 patients died in the first prophylaxis. The cumulative incidence of serious infections at 6 months of treatment (46 patients in the first 4 months), of them, 6 months was 13.8%, and 11.3% experienced the first episode 16 patients died by infection in the first 6 months of treatment within the first 4 months (Fig. 3A). (1.2%) and 13 patients in the first 4 months (1%). If GEM2010 > 65 Blood Cancer Journal (2022)12:68 C. Encinas et al. 5 A B 100 100 Patients(%) Patients(%) 60 60 P=0.021 P=0.6574 40 40 0 0 0 6 12 18 24 30 36 42 48 0 6 12 18 24 30 36 42 48 Month of treatment Month of treatment Number at risk Number at risk No infetion 1315 962 827 727 671 636 586 500 415 1327 1117 1029 953 899 856 794 675 561 Infection 20 309 397 438 427 421 397 337 279 8 154 195 212 199 201 189 162 133 Fig. 4 Impact on overall survival of infection. A Impact on overall survival of any-grade infection and B severe infection. groups with different probabilities of early severe infection: 8.2% Table 3. Univariate logistic regression analysis. in the low-risk group (0–2 points), 19.2% in the intermediate-risk group (3 points) (sHR 2.34, 95% CI 1.59–3.45, p < 0.001) and 28.3% Variables Odds Ratio p-value 95% Number Confidence of in the high-risk group (4 points) (sHR 3.89, 95%CI, 2.16–6.99 p < interval patients 0.001) (Fig. 5A). Then, when we compared the low versus intermediate/high-risk groups, the probability of early severe ECOG PS 0–1 1.84 0.001 1.26–2.68 1103 infection was 8.2% and 20.6%, respectively (sHR 2.58, 95% CI vs > 1 1.80–3.70, p < 0.0001) (Fig. 5B). Finally, we tested the GEM- Age > vs ≤ 55 1.19 0.354 0.82–1.72 1106 PETHEMA score only in the group of transplant-eligible patients, Female vs 0.65 0.026 0.44–0.95 1106 and the results were reproducible (AUC = 0.62, 95% CI, 0.56–0.67). male Monoclonal 1.42 0.065 0.98–2.05 1106 Component > DISCUSSION vs ≤ 40 g/L In the present study, we sought to evaluate risk factors Albumin > 2.32 <0.001 1.55–3.48 1102 associated with an early severe infection in a large population vs ≤ 30 g/L of patients with newly diagnosed MM (both young and elderly) non-IgA type 1.38 0.166 0.87–2.19 1106 treated in clinical trials with therapies based on PIs and IMiDs. MM vs IgA Our results show that a relevant number of MM patients, ECOG PS Eastern Cooperative Group Oncology Performance Status, IgA including those treated with novel drugs, develop infections, Immunoglobulin A, MM Multiple Myeloma. especially within the first 4 months from the initiation of treatment. In addition, of the total number of infections, almost half of them were considered as serious, which is consistent with is not considered, 13 patients died by infection in the first the results of other series [2, 4, 24]. 6 months of treatment and 11 patients in the first 4 months, as is Although an improvement in early mortality rate is expected shown in Fig. 3B. Six had respiratory tract infections, of which five with the introduction of new agents that achieve rapid tumor were pneumonia. Infection of any grade did not affect OS control as compared with conventional chemotherapy (~5%) [4], (p = 0.660) (Fig. 4A); however, severe infection had an impact on our results show that the presence of severe infections still has an OS (p = 0.021) in our series (Fig. 4B). impact on the survival of patients. The cumulative incidence of severe infection after excluding GEM-PETHEMA and FIRST scores patients enrolled in the GEM2010 > 65 trial (total n = 1106) was Initially, we tested the reproducibility of the FIRST score [24] in our 13.8% in the first 6 months. Notably, most patients had their first three clinical trials (GEM2010 > 65 trial was excluded from the final serious infection within 4 months of starting treatment. While the analysis). We found no significant differences in the incidence of mortality associated with infection in the first 6 months was low early severe infection between the low or high-risk group (11.0% (1.2%), and no differences in mortality were observed between vs. 13.0%, respectively, p = 0.347). Similarly, no differences were GEM2010 > 65 and the other three CTs, it is important to note that observed for the group of transplant-eligible (13.3% vs. 13.0% p = most of the deaths occurred in the first 4 months (1%). Even 0.255) and -ineligible (6.5% vs. 10.5% p = 0.50) patients, or when though infection of any degree did not affect OS, severe infection the protocols were analyzed separately. significantly influenced survival. A total of 126 patients experienced a severe infection in the first Of note, about one out of five infections in our analysis involved 4 months of treatment. Tables 3, 4 show the results of the the lower respiratory tract in the form of pneumonia. Regarding univariate and multivariate logistic analysis of the variables respiratory events by protocol, it is interesting to note that they associated with a higher risk of early severe infection in the first were lower in patients treated in the GEM2010 > 65 trial [34], 4 months. Four variables were selected in the multivariate analysis where the administration of prophylactic antibiotics was manda- (AUC = 0.64, 95% CI: 0.58–0.68): albumin ≤30 g/L (OR 2.12, p < tory per protocol during the first 3 months. 0.001), ECOG > 1 (OR 1.73, p = 0.005), male sex (OR 1.50, p = 0.037) In line with our results, a post hoc analysis of the FIRST clinical and non-IgA MM type (OR 1.49, p = 0.091). trial [31] revealed that the number of infections was higher during We then generated a score, termed GEM-PETHEMA, to predict the first 4 months of therapy. In total, 21% of the patients the risk of infection. The weight of each variable with a higher risk experienced a grade ≥3 infection in the first 18 months of the of early severe infection in the multivariate analysis was given 1 therapy, with more than half (56%) occurring in the first 4 months. point (Table 4). The score facilitated the identification of three risk ECOG status, β2 M, lactate dehydrogenase, and hemoglobin levels Blood Cancer Journal (2022)12:68 C. Encinas et al. 6 Table 4. Multivariate logistic regression analysis. Variables Odds ratio p-value 95% Confidence interval Weight (points) Albumin ≤ 30 g/L 2.12 <0.001 1.40–3.20 1 ECOG PS > 1 1.73 0.005 1.18–2.54 1 Male sex 1.50 0.037 1.02–2.20 1 Non-IgA type MM 1.49 0.091 0.93–2.39 1 ECOG PS Eastern Cooperative Oncology Group Performance Status, IgA Immunoglobulin A, MM Multiple Myeloma. score Number of patients Number of patients Number of patients A (%) (%) without severe (%) with at least 1 infection during first severe infection 4 months during first 4 months 50 0-2 (Low-risk) 813 (100) 746 (91.8) 67 (8.2) 3 (Intermediate- 240 (100) 194 (80.8) 46 (19.2) risk) 40 4 (High-risk) 46 (100) 33 (71.7) 13 (28.3) 30 Total 1099 (100) 973 (88.5) 126 (11.5) Incidence (%) 20 sHR 3.89 P<0-0001 CI 95% (2.16-6.99) sHR 2.34 P<0.0001 CI 95% (1.59-3.45) 10 0 0 1 2 3 4 Months B score Number of patients Number of patients Number of patients (%) (%) without severe (%) with at least 1 infection during first severe infection 50 4 months during first 4 months 0-2(Low-risk) 813 (100) 746 (91.8) 67 (8.2) 40 3-4 (Intermediate 286 (100) 227 (79.4) 59 (20.6) and high-risk) 30 Total 1099 (100) 973(88.5) 126 (11.5) Incidence (%) 20 sHR 2.58 P<0.0001 CI 95% (1.80-3.70) 10 0 2 3 4 Months Fig. 5 Cumulative incidence of early severe infection according to risk group by Score GEM. A Three risk groups with different probabilities of early severe infection. B Two risk group when intermediate and high risk were grouped. sHR sub-Hazard ratio, CI 95% confidence interval. are defined high- or low-risk groups, with 24% versus 7% of early infection as compared with only 8% in those at low-risk. severe infection risk, respectively [24]. This score [24] was Importantly, the GEM score is valid for both young and elderly developed in elderly patients, but there is a lack of data in populations. younger patients. Moreover, when we tested the FIRST score [24] The TEAMM study [29, 30] has shown that the use of in our series, we found no significant association with a higher risk prophylactic levofloxacin (500 mg, daily) during the first 4 months of early severe infection either in the group of transplant-eligible in newly treated patients with MM reduced febrile episodes and and -ineligible candidates, and this lack of congruence of our deaths, and only a low number of mild adverse events were score and that of Dumontet et al. in elderly patients should be reported, without antibiotic-resistant organisms and healthcare- answered in future studies. associated infections [29, 30]. Although this information is of We searched for a new, simple, and easily applicable score in interest, physicians may be concerned about over-treatment with transplant-eligible and -ineligible candidates that could be used to the risk of inducing antibiotic-resistant strains. A strength of our define groups of patients with a higher risk of acquiring an score system is that it could help to individualize the prophylactic infection. The combination of low albumin levels (≤30 g/L), antibiotics regimen, for use only in the intermediate- and high-risk performance status according to the ECOG scale (ECOG > 1), male group of patients. sex, and non-IgA type MM (1 point each) classified the patients Our study has several limitations. First, the results were into three risk groups, and those at intermediate- and high-risk generated from a post hoc analysis, as the design of the included had a 20% and 30% probability, respectively, of early serious clinical trials did not consider the incidence of infections as the Blood Cancer Journal (2022)12:68 C. Encinas et al. 7 main endpoint. The patients were selected by the inclusion and 5. Huang CT, Liu CJ, Ko PS, Liu HT, Yu YB, Hsiao LT, et al. Risk factors and char- exclusion criteria, and it is necessary to reproduce this score in acteristics of blood stream infections in patients with newly diagnosed multiple both the real world with patients and clinical trials. Second, the myeloma. BMC Infect Dis. 2017;17:33. treatment regimens and the characteristics of the patients (eligible 6. Bladé J, Rosiñol L. Renal, hematologic and infectious complications in multiple myeloma. Best Pr Res Clin Haematol. 2005;18:635–52. vs. ineligible for the hematopoietic transplant) were heteroge- 7. Rodríguez-Otero P, Mateos MV, Martínez-López J, Martín-Calvo N, Hernández MT, neous. Third, we included in the descriptive analysis the patients Ocio EM, et al. Early myeloma-related death in elderly patients: development of a treated in the GEM2010 > 65 trial, as it was the only trial in which clinical prognostic score and evaluation of response sustainability role. Leukemia. antibiotic prophylaxis was mandatory. Comparative analysis 2018;32:2427–34. revealed that despite a moderately toxic regimen, particularly 8. Kumar SK, Dispenzieri A, Lacy MQ, Gertz MA, Buadi FK, Pandey S, et al. Continued for patients >80 years of age, those treated with this scheme had improvement in survival in multiple myeloma: changes in early mortality and significantly fewer early severe infections than peers belonging to outcomes in older patients. Leukemia. 2014;28:1122–8. the GEM2005 > 65, also elderly patients, but with non-mandatory 9. Kristinsson SY, Anderson WF, Landgren O. Improved long-term survival in mul- antibiotic prophylaxis; however, we elected to exclude the former tiple myeloma up to the age of 80 years. Leukemia. 2014;28:1346–8. 10. Kristinsson SY, Landgren O, Dickman PW, Derolf AR, Björkholm M. Patterns of trial from the final univariate and multivariate analysis to avoid survival in multiple myeloma: a population-based study of patients diagnosed in bias because of the prophylactic antibiotics. Fourth, in the three Sweden from 1973 to 2003. J Clin Oncol. 2007;25:1993–9. clinical trials used to generate our score, antibiotic prophylaxis was 11. de la Rubia J, Cejalvo MJ, Ribas P. Infectious complications in patients with newly not mandatory and was at the discretion of each participating diagnosed multiple myeloma: a complication from the past? Leuk Lymphoma. center and, this information has not been collected in the clinical 2016;57:258–68. trials databases, but in general, antibiotic prophylaxis was not 12. Nucci M, Anaissie E. Infections in patients with multiple myeloma in the era of performed. Fifth, patients undergoing autologous hematopoietic high-dose therapy and novel agents. Clin Infect Dis. 2009;49:1211–25. stem cell transplantation frequently experience infections during 13. Teh BW, Harrison SJ, Slavin MA, Worth LJ. Epidemiology of bloodstream infec- the transplant period due to post-chemotherapy aplasia and tions in patients with myeloma receiving current era therapy. Eur J Haematol. 2017;98:149–53. mucositis, characteristic of conditioning treatments with high 14. Teh BW, Harrison SJ, Worth LJ, Thursky KA, Slavin MA. Infection risk with doses of melphalan. In the case of the GEM2005 < 65 and immunomodulatory and proteasome inhibitor-based therapies across treatment GEM2012 < 65 trial, this was performed after 6 cycles of induction, phases for multiple myeloma: A systematic review and meta-analysis. Eur J and so only the severe infections occurring in the first 6 months of Cancer. 2016;67:21–37. treatment were considered. Sixth, the potential impact of 15. Teh BW, Worth LJ, Harrison SJ, Thursky KA, Slavin MA. Risks and burden of viral comorbidities, immunoparesis, and the cumulative dose of respiratory tract infections in patients with multiple myeloma in the era of corticosteroids on the infection risk were not evaluated. Finally, immunomodulatory drugs and bortezomib: experience at an Australian Cancer anti-CD38 monoclonal antibodies (mAbs) were not taken part in Hospital. Support Care Cancer. 2015;23:1901–6. the treatment in these trials. It is well known the increased risk of 16. Basler M, Lauer C, Beck U, Groettrup M. The proteasome inhibitor bortezomib enhances the susceptibility to viral infection. J Immunol. 2009;183:6145–50. infections with these mAbs, and a score including age, LDH, 17. Wongsaengsak S, Kopel J, Behera TR, Chakraborty R, Ball S. Infection risk with albumin, and ALT at baseline has been also built to identify carfilzomib in multiple myeloma: a systematic review and meta-analysis of ran- patients at higher risk of infections when they receive anti-CD38 domised controlled trials. Br J Haematol. 2020;190:e95–e97. mAbs [44, 45]. As the GEM-PETHEMA group is involved in new 18. Offidani M, Corvatta L, Polloni C, Gentili S, Brioni A, Visani G, et al. Infectious trials with anti-CD38 mAbs, this score will be evaluated and if new complications in patients with multiple myeloma treated with new drug com- risk factors emerge, the model could be revisited. binations containing thalidomide. Leuk Lymphoma. 2011;52:776–85. The strengths of the study include the multicenter nature of the 19. Ying L, YinHui T, Yunliang Z, Sun H. Lenalidomide and the risk of serious infection trials, the inclusion of a large number of patients to establish in patients with multiple myeloma: a systematic review and meta-analysis. differences according to the variables analyzed, the prior Oncotarget. 2017;8:46593–600. 20. Teh BW, Harrison SJ, Worth LJ, Spelman T, Thursky KA, Slavin MA. Risks, severity publication in peer review journals, the continuous updating of and timing of infections in patients with multiple myeloma: a longitudinal cohort the databases, and the results comparable with prior studies study in the era of immunomodulatory drug therapy. Br J Haematol. related to infections in patients with MM. 2015;171:100–8. In conclusion, our study confirms that a high proportion of 21. Chen M, Zhao Y, Xu C, Wang X, Zhang X, Mao B. Immunomodulatory drugs and serious infections occur within the first 4 months. 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All authors collected the data; CE, and thalidomide versus bortezomib and prednisone in elderly patients with JAHR, and JML wrote the manuscript. All authors have reviewed and provided final untreated multiple myeloma: a randomised trial. Lancet Oncol. 2010;11:934–41. approval of the manuscript. 34. Mateos M-V, Martínez-López J, Hernández M-T, Ocio E-M, Rosiñol L, Martínez R, et al. Sequential vs alternating administration of VMP and Rd in elderly patients with newly diagnosed MM. Blood. 2016;127:420–5. COMPETING INTERESTS 35. Rosiñol L, Oriol A, Teruel AI, Hernández D, López-Jiménez J, de la Rubia J, et al. The authors declare no competing interests. Superiority of bortezomib, thalidomide, and dexamethasone (VTD) as induction pretransplantation therapy in multiple myeloma: a randomized phase 3 PETHEMA/GEM study. Blood. 2012;120:1589–96. ADDITIONAL INFORMATION 36. Rosiñol L, Oriol A, Rios R, Sureda A, Blanchard MJ, Hernández MT, et al. 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