Comprehensive analysis of clinical outcomes, infectious complications and microbiological data in newly diagnosed multiple myeloma patients: a retrospective observational study of 92 subjects.

Patients with multiple myeloma (MM) have an increased risk of sepsis due to underlying disease- and treatment-related immunosuppression. However, data on sepsis incidence, causative pathogens, and impact on outcomes in newly diagnosed MM (NDMM) are limited. We conducted a retrospective observational study of 92 NDMM patients who developed sepsis between 2022 and 2023 at a tertiary care center in Italy. Patient characteristics, sepsis criteria [Quick Sequential Organ Failure Assessment, Systemic Inflammatory Response Syndrome (SIRS)], microbiology results, and associations with progression-free survival (PFS) were analyzed. In this cohort of 92 critically-ill patients, pathogenic organisms were identified via microbiological culture in 74 cases. However, among the remaining 18 culture-negative patients, 9 exhibited a SIRS score of 2 and another 9 had a SIRS score of 4, suggestive of a clinical presentation consistent with sepsis despite negative cultures. Common comorbidities included renal failure (60%), anemia (71%), and bone disease (83%). Gram-negative (28%) and Gram-positive (23%) bacteria were frequent causative organisms, along with fungi (20%). Cox Univariate analyses for PFS showed statically significant HR in patients with albumin ≥ 3.5 vs < 3.5 (HR = 5.04, p < 0.001), Karnofsky performance status ≥ 80 vs < 80 (HR = 2.01, p = 0.002), and early-stage vs late-stage disease by International Staging System (HR = 4.76 and HR = 12.52, both p < 0.001) and Revised International Staging System (R-ISS III vs R-ISS I, HR = 7.38, p < 0.001). Sepsis is common in NDMM and associated with poor outcomes. Risk stratification incorporating sepsis severity, comorbidities, and disease stage may help guide preventive strategies and optimize MM management.

Multiple myeloma with Echinococcus granulosus infection diagnosed by detection of oligoclonal bands: A case report.

RATIONALE: Isoelectric focusing electrophoresis (IFE) is currently recognized as the gold standard for detecting oligoclonal bands (OCBs) in cerebrospinal fluid (CSF). To the best of our knowledge, however, no study has reported on type III OCBs using IFE. In this paper, we report on a rare case of multiple myeloma (MM) with Echinococcus granulosus infection diagnosed by IFE. PATIENT CONCERNS: A 71-year-old man complained of weakness of the right lower extremity accompanied with fever (temperature range 37.8°C-38.2°C) for more than 6 months. DIAGNOSES: MM with E granulosus infection. INTERVENTIONS: The IFE results identified a unique monoclonal band, indicating that the patient may have MM in conjunction with a distinct pathogen infection. He received anthelmintic treatment and bortezomib-thalidomide-dexamethasone therapy. OUTCOMES: The patient was followed up for 15 months. During that time, his temperature returned to normal, his Medical Research Council Grading of Muscle Power scale became 5, and his vital signs stabilized. LESSONS: Detection of OCB type III indicated that the patient was diagnosed with MM accompanied by E granulosus infection. Thus, IFE of CSF may be an auxiliary diagnostic method for MM in the future.

The nutrition risk index is associated with bacteremia within 30 days after autologous stem cell transplantation in patients with multiple myeloma.

OBJECTIVES: To assess whether the nutrition risk index (NRI) is associated with the risk of bacteremia within the first days after autologous stem cell transplantation (ASCT) in patients with multiple myeloma (MM). MATERIALS AND METHODS: Retrospective cohort study of adult patients with MM taken to ASCT at the Hospital Universitario San Ignacio (Bogotá, Colombia) between 2005 and 2019. The outcome of interest was the incidence of bacteremia at 30 days. Multivariate analysis was used to identify whether the NRI was associated with bacteremia, controlling by different confounding variables. RESULTS: One hundred and twenty-four patients with a median age of 58.5 years (IQR: 54-64) were included. 47.1% were in stage ISS III. 36.0% had moderate or severe malnourishment (NRI < 97.5). 11.2% presented bacteremia in the first 30 days after transplantation. In the univariate analysis, the NRI < 97.5 was associated with bacteremia (OR: 1.88; 95% CI: 1.30-2.72, P = .001); however, this association was not significant in the multivariate analysis, unlike the presence of mucositis (OR: 11.59; 95% CI: 1.9-68.3, <0.01), one or more previous lines of therapy (OR: 12.0; 95% CI: 2.1-67.4; P < .01), and duration of aplasia (OR: 1.70; 95% CI: 1.2-2.4, P < .01). CONCLUSIONS: Patients with moderate or severe malnourishment have a higher incidence of bacteremia in the 30 days post-ASCT in patients with MM. Additional risk factors associated with bacteremia include the presence of mucositis, one or more previous lines of therapy, and the duration of aplasia.

Alterations of gut microbiome accelerate multiple myeloma progression by increasing the relative abundances of nitrogen-recycling bacteria.

BACKGROUND: Gut microbiome alterations are closely related to human health and linked to a variety of diseases. Although great efforts have been made to understand the risk factors for multiple myeloma (MM), little is known about the role of the gut microbiome and alterations of its metabolic functions in the development of MM. RESULTS: Here, in a cohort of newly diagnosed patients with MM and healthy controls (HCs), significant differences in metagenomic composition were discovered, for the first time, with higher bacterial diversity in MM. Specifically, nitrogen-recycling bacteria such as Klebsiella and Streptococcus were significantly enriched in MM. Also, the bacteria enriched in MM were significantly correlated with the host metabolome, suggesting strong metabolic interactions between microbes and the host. In addition, the MM-enriched bacteria likely result from the regulation of urea nitrogen accumulated during MM progression. Furthermore, by performing fecal microbiota transplantation (FMT) into 5TGM1 mice, we proposed a mechanistic explanation for the interaction between MM-enriched bacteria and MM progression via recycling urea nitrogen. Further experiments validated that Klebsiella pneumoniae promoted MM progression via de novo synthesis of glutamine in mice and that the mice fed with glutamine-deficient diet exhibited slower MM progression. CONCLUSIONS: Overall, our findings unveil a novel function of the altered gut microbiome in accelerating the malignant progression of MM and open new avenues for novel treatment strategies via manipulation of the intestinal microbiota of MM patients. Video abstract.

Fecal Microbiota Taxonomic Shifts in Chinese Multiple Myeloma Patients Analyzed by Quantitative Polimerase Chain Reaction (QPCR) and 16S rRNA High-Throughput Sequencing.

BACKGROUND Increasing evidence has suggested that gut flora play an important role in tumor progression and prognosis. However, the relationship between fecal microbiota and hematologic malignancy requires further investigation. This study aimed to characterize the relationship of the fecal microbial community in multiple myeloma (MM) patients. MATERIAL AND METHODS A total of 40 MM patients and healthy controls (n=17) were retrospectively collected from the First Affiliated Hospital of Sun Yat-sen University between October 2018 and May 2019. The fecal samples were collected for 16S rRNA high-throughput sequencing for the fecal microbial community, as well as diversity and correlation analysis. Furthermore, 21 MM patients and their family members were selected for the matched pair analysis to confirm the fecal microbiota taxonomic changes by qRT-PCR assay. RESULTS Diversity analysis showed that diversity measured by Shannon index was lower in MM patients compared with healthy controls. At the phylum level, higher abundances of Proteobacteria but lower abundances of Actinobacteria were identified in the MM group in comparison with the healthy control group. At the genus level, the proportion of Bacteroides, Faecalibacterium, and Roseburia was significantly higher in the MM group. The matched pair analysis showed that Pseudomonas aeruginosa and Faecalibacterium were significantly more abundant in the MM group. Further analysis on prognostic risk factors revealed that the Faecalibacterium prausnitzii level was significantly correlated with ISS stage. CONCLUSIONS Our study highlights the imbalanced composition and diversity of the gastrointestinal microbiome in MM patients, which could be further used as a potential biomarker for MM risk screening, therapeutic strategies, and prognostic prediction.

Early infectious complications after autologous hematopoietic cell transplantation for multiple myeloma.

BACKGROUND: The spectrum of infectious complications in autologous hematopoietic cell transplant recipients (AHCT) with multiple myeloma has not been well described in the recent era of novel agent induction and improved supportive care. METHODS: We conducted a retrospective cohort study of 413 adult myeloma AHCT recipients at our institution from 2007-2016 to describe the cumulative incidence and risk factors for various infections and FN occurring within the first 100 days after AHCT. Additionally, landmark analysis was done among 404 patients who survived at least 100 days after transplant admission to estimate the association of infections with subsequent non-relapse mortality (NRM), overall survival (OS), and relapse-free survival (RFS). RESULTS: Cumulative incidences (95% CI) of infection events by day 100 were: FN 43% (38-48), any infection 21% (17-25), bacterial 17% (14-21), viral 4% (3-7) and fungal 1% (0.5-3), central line-associated blood stream infection 3% (2-6), and Clostridium difficile colitis 6% (4-8). Patients with infection had a longer initial transplant hospitalization (median 17 vs 16 days, P < 0.01), more readmissions (31% vs 8%, P < 0.01), and spent more days in hospital in first 100 days (median 18 vs 16 days, P < 0.01). A 100-day mortality was low and similar between groups (2% vs 1%, P = 0.28). In landmark analysis of 404 100-day survivors, OS was worse among patients with early infections (hazard ratio 1.54 [1.03-2.30], P = 0.03), although there was no difference in NRM and RFS. CONCLUSIONS: Notwithstanding advances in supportive care, early infectious complications remain a relevant source of morbidity and require attention in myeloma AHCT recipients.

Gastrointestinal Microbiome and Mycobiome Changes during Autologous Transplantation for Multiple Myeloma: Results of a Prospective Pilot Study.

Microbiome dysbiosis has been associated with adverse outcomes of hematopoietic cell transplantation (HCT). We hypothesized that exposure to high-dose melphalan and antimicrobials in patients undergoing autologous HCT for plasma cell disorders results in oral and gastrointestinal microbial dysbiosis, which in turn is associated with regimen-related toxicities. We conducted a prospective study describing the longitudinal changes in oral and gastrointestinal bacteriome and mycobiome in this patient population. Our findings show that microbiome composition present at baseline is associated with the incidence and severity of post-transplantation nausea, vomiting, and culture-negative neutropenic fever, as well as with the rate of neutrophil engraftment. We also have evidence of an association between the microbial communities at count nadir and the development of regimen-related gastrointestinal toxicities commonly observed after exposure to high-dose melphalan. Although bacteriome diversity largely recovers within 1 month after transplantation, we observed a continuous decrease in oral and gastrointestinal mycobiome diversity, suggesting that the mycobiome requires a longer time to recover compared with the bacteriome.

Infectious complications and NK cell depletion following daratumumab treatment of Multiple Myeloma.

Treatment with Daratumumab (Dara), a monoclonal anti-CD38 antibody of IgG1 subtype, is effective in patients with multiple myeloma (MM). However, Dara also impairs the cellular immunity, which in turn may lead to higher susceptibility to infections. The exact link between immune impairment and infectious complications is unclear. In this study, we report that nine out of 23 patients (39%) with progressive MM had infectious complications after Dara treatment. Five of these patients had viral infections, two developed with bacterial infections and two with both bacterial and viral infections. Two of the viral infections were exogenous, i.e. acute respiratory syncytial virus (RSV) and human metapneumovirus (hMPV), while five consisted of reactivations, i.e. one herpes simplex (HSV), 1 varicella-zoster (VZV) and three cytomegalovirus (CMV). Infections were solely seen in patients with partial response or worse. Assessment of circulating lymphocytes indicated a selective depletion of NK cells and viral reactivation after Dara treatment, however this finding does not exclude the multiple components of viral immune-surveillance that may get disabled during this monoclonal treatment in this patient cohort. These results suggest that the use of antiviral and antibacterial prophylaxis and screening of the patients should be considered.

Low frequency of CD3+CD4+CD161+ T cells correlates with the occurrence of infections in refractory/relapsed multiple myeloma patients receiving lenalidomide plus low-dose dexamethasone treatment.

The aim of this study was to explore the predictive implications of the composition of immune cell populations prior to lenalidomide plus high-dose dexamethasone (Len-Dex) initiation for the occurrence of infections. We prospectively examined immune cell populations in peripheral blood taken at baseline of lenalidomide plus low-dose dexamethasone (Len-dex) therapy and reviewed clinical and microbiology records in 90 patients with refractory/relapsed multiple myeloma (RRMM). Risk factors for infection were analyzed using logistic regression. During a median of 11 cycles of Len-dex treatment, 52 (57.8%) patients experienced at least 1 infection episode. Of a total of 92 episodes of infection, 58 (63%) episodes were clinically defined, 29 (31.5%) episodes were microbiologically defined, and 5 (5.4%) episodes were fever of unknown origin. Severe episodes were more frequently observed during the first 3 cycles. After adjusting for risk factors for infection based on univariate analyses, multivariate analyses showed that lower Hb (< 10 g/dL) was a clinically independent factor associated with occurrence of infections. Lower frequency (P = 0.044) and absolute count (P = 0.014) of circulating CD3+CD4+CD161+ cells prior to Len-dex treatment were also associated with the occurrence of infection, especially during the first 3 cycles of Len-dex therapy. In addition to several clinical predictive factors, we found that CD3+CD4+CD161+ cells may provide additional information for predicting the occurrence of infection in the early period of Len-dex therapy.

Immunomodulatory drugs and the risk of serious infection in multiple myeloma: systematic review and meta-analysis of randomized and observational studies.

The effect of immunomodulatory drugs (IMiDs) on serious infection remains uncertain. We therefore conducted a systematic review and meta-analysis to assess the possible impact of IMiDs on serious infection in patients with multiple myeloma (MM). We searched randomized controlled trials (RCTs) and observational studies from databases that addressed the effect of IMiDs on serious infection in patients with MM. We pooled data from RCTs and observational studies separately and used the GRADE approach to rate the quality of evidence. Rates in patients with individual IMiDs at different treatment status ranged from 7.00 to 23.00%. The use of thalidomide- or lenalidomide-based regimen induction therapy for autologous stem cell transplantation (ASCT)-ineligible patients suggests increase in serious infection (RR = 1.59, 95% CI 1.31-1.93, p < 0.01). Compared to conventional therapy, IMiDs' induction in ASCT-eligible patients significantly decreases the risk of serious infection (RR = 0.82, 95% CI 0.72-0.94, p < 0.01). Lenalidomide-based therapy was associated with a significant increase in risk of serious infection in patients treated compared with conventional therapy (RR = 2.45, 95% CI 1.57-3.83, p < 0.01). The current evidence suggests that patients with MM treated with IMiDs are at a high risk of serious infection.

Risk factors for blood stream infections in multiple myeloma: A population-based study of 1154 patients in Denmark.

OBJECTIVES: Multiple myeloma (MM) patients are at high risk of developing infections. The risk factors for blood stream infections (BSI) in MM patients are, however, less described. The aim of this study was to analyze the epidemiology of and risk factors for BSI in an unselected MM population. METHODS: Nationwide Danish MM data of 1154 patients diagnosed from 2010 to 2013 were linked with nationwide data on blood cultures (BCs; from 2010 to 2016) to assess the peak period of having a BC taken and BC positive for pathogenic microorganisms. RESULTS: The highest number of BC was taken in the period from day -30 to day +180 from date of MM diagnosis. Risk factors for having a BC sampling within the peak period were as follows: immunoparesis (HR 1.5 [1.1-2.1]; P = .007), ISS-III (HR 1.3 [1.0-1.7]; P = .035), high creatinine (HR 1.4 (1.0-2.0); P = .046), and high lactate dehydrogenase (LDH) (HR 2.8 (1.6-4.7; P < .001). Risk factors for positive BC during the peak period were ISS-III (HR 2.0 (1.1-3.7); P = .023) and high LDH (HR 3.4 [1.1-10.3]; P = .028). CONCLUSIONS: Our results show that MM patients with aggressive disease presentation are at the highest risk of developing BSI. Furthermore, our study implies that MM is diagnosed in relation to a serious infection for a large number of patients.

DYSFUNCTION OF VARIOUS ORGAN SYSTEMS INDUCED BY SEPSIS WITH UNDERLYING SEVERE MYELOMIC DISEASES AND PROSTATE CANCER (CASE REPORT).

A 65-year-old male patient, unconscious, was admitted into the clinic by the Ambulance. From the patient's medical history it was revealed that several hours before the admission in the clinic the following symptoms were present: shortness of breath, fever, hypotonia, consciousness inhibition, because of which emergency brigade was called and was brought by the Emergency Brigade. The history is loaded by chronic pathologies: myeloma disease, prostate cancer, ciliary arrhythmia, heart failure; received several courses of polichemotherapy, last ten days has been treated for pneumonia with antibiotics of ceftriaxone group in outpatient setting. It is also noteworthy that for the last three months dysfunction of musculoskeletal system with muscle weakness, restricted motion has been present. Clinically there was present dysfunction syndrome of several organs: disorder of function of several organs that required emergency intervention, recovery chance was very low, correlation with morbidity in PIRO was high. By investigation it is known, that as SIRS aggravates, and turns into septic shock, lethal index increases, especially when the underlying severe diseases are present. On basis of certain data we can conclude that the severity of the disease may have some compatibility with results, although it is alteration of further clinical status of initial stage that has the closest compatibility with results. Sepsis toward MODS experiences progress with lethal results. Mortality rate in the patients with acute respiratory deficiency increases from 50% to 80%. In most patients with sepsis syndrome, who have 3 or more organs damaged, lethality is more than 90%. In this certain case organ systems that are mostly involved in the process during the sepsis, are respiratory, blood, renal and cardiovascular systems, were all involved , in the mentioned case a reasonable symptomatic and pathognomic treatment and the appropriate measures led to the recovery of the above mentioned patient. Sepsis syndrome is developed when the balance between the substances that contribute to the inflammation and anti-inflammatory substances is violated. By the mentioned case there is sepsis - induced polyorganic insufficiency with underlying severe somatic pathological condition, with violation of hemodynamics. Clinically the insufficiency of all the organic systems developed at the background of cardio-respiratory-cerebral insufficiency, with functional insufficiency of all the organ systems and violation of buffer system. With reasonable pathognomic and symptomatic treatment eradication of vicious circle was possible. The patient was discharged from the clinic with positive clinic-laboratory recovery. The condition is stable. Neurological status -contact, adequate, with high capacity to work, and with an achievement of 2 year remission.

Monoclonal IgG in MGUS and multiple myeloma targets infectious pathogens.

Subsets of mature B cell neoplasms are linked to infection with intracellular pathogens such as Epstein-Barr virus (EBV), hepatitis C virus (HCV), or Helicobacter pylori. However, the association between infection and the immunoglobulin-secreting (Ig-secreting) B proliferative disorders remains largely unresolved. We investigated whether the monoclonal IgG (mc IgG) produced by patients diagnosed with monoclonal gammopathy of undetermined significance (MGUS) or multiple myeloma (MM) targets infectious pathogens. Antigen specificity of purified mc IgG from a large patient cohort (n = 244) was determined using a multiplex infectious-antigen array (MIAA), which screens for reactivity to purified antigens or lysates from 9 pathogens. Purified mc IgG from 23.4% of patients (57 of 244) specifically recognized 1 pathogen in the MIAA. EBV was the most frequent target (15.6%), with 36 of 38 mc IgGs recognizing EBV nuclear antigen-1 (EBNA-1). MM patients with EBNA-1-specific mc IgG (14.0%) showed substantially greater bone marrow plasma cell infiltration and higher ß2-microglobulin and inflammation/infection-linked cytokine levels compared with other smoldering myeloma/MM patients. Five other pathogens were the targets of mc IgG: herpes virus simplex-1 (2.9%), varicella zoster virus (1.6%), cytomegalovirus (0.8%), hepatitis C virus (1.2%), and H. pylori (1.2%). We conclude that a dysregulated immune response to infection may underlie disease onset and/or progression of MGUS and MM for subsets of patients.

Infectious complications in multiple myeloma receiving autologous stem cell transplantation in the past 10 years.

Infection is one of the main causes of early-treatment mortality in multiple myeloma (MM) patients during autologous stem cell transplantation (autoSCT). In the present study, we sought to determine the incidence of, and risk factors for, infection during hospital stays after autoSCT. We retrospectively evaluated 324 autoSCT events that occurred in 285 MM patients between 2006 and 2015, and reviewed the clinical characteristics of patients and history of infections. Sixty-eight infection events occurred, including bacteremia (24), other bacterial infections (7), as well as infections caused by Cytomegalovirus (17), Herpes simplex virus (12), Varicella zoster virus (3), Aspergillus (3) and Pneumocystis jiroveci (2). There was no significant difference in number of infections in the 2006-2010 and 2011-2015 periods (P = 0.194). Risk factors for bacteremia included higher beta-2 microglobulin levels at diagnosis [≥3.5 mg/L; adjusted odds ratio (aOR) 3.544 (95% CI 1.070-11.736), P = 0.038] and previous bortezomib treatment [aOR 4.270 (95% CI 1.389-13.125), P = 0.011]. In-hospital mortality occurred in 1.2% of all cases and all were infection-related. In conclusion, infection was the main cause of in-hospital mortality in patients who underwent autoSCT. Bacteremia was the most common type of microbiologically confirmed infection, and was associated with higher beta-2 microglobulin levels and previous bortezomib treatment.