We conducted a multicenter, prospective cohort study of all consecutive NDMM patients diagnosed at 4 specialized hematology centers in Montevideo, Uruguay (Hospital Central de las Fuerzas Armadas and Hospital de Clínicas, both public healthcare institutions, Hospital Británico and CASMU-IAMPP, both private healthcare institutions). The inclusion criteria included active disease, being currently on therapy and having provided written informed consent. Patients with monoclonal gammopathy of undetermined significance, smoldering MM, plasma cell leukemia, amyloidosis and HIV infection were excluded. Eligible patients were consecutively enrolled between June 2019 and December 2020, by their own treating physician at each participating center. Thereafter, patients were clinically observed for development of infectious events that required hospitalization for ≥ 24 h for an additional 6 months and before proceeding to autologous stem cell transplantation or until death, whichever occurred first. Demographics, comorbidities, laboratory data and myeloma-specific features were collected on a standardized form. Institutional Review Boards approved this study at each participating institution.

Data on all infectious events that required hospitalization for ≥ 24 h were recorded. The variables analyzed were the infection site, type of isolated microbial agent, infection severity, time to occurrence, and outcome from the infection. We found 7 cases of SARS-CoV-2 infection, which were excluded from the analysis. Catheter-related infections, but no port-a-cath exit site infections, were included in the analysis. The antimyeloma treatments were defined as IMiD-based (i.e., thalidomide or lenalidomide), PI-based (i.e., bortezomib) and IMiD plus PI-based. The choice of therapy and antimicrobial prophylaxis were decided by the treating physician. Comorbidities included in the analysis were diabetes mellitus, chronic pulmonary disease, asthma and heart failure.

The diagnosis of MM was defined according to the International Myeloma Working Group (IMWG) 2014 criteria and staging was performed in adherence to the International Staging System (ISS) recommendations. We defined the infectious event as the presence of a body temperature ≥ 38 ºC, and/or the presence of clinical symptoms or signs of infection. Events were classified as clinically defined (CD) when there was clinical evidence, but microbial isolation was negative; microbiologically defined (MD), when the microbial agent was identified from a blood test and/or other body sources; and fever of unknown origin, when the only clinical sign was fever without microbial isolation. The type of infection (i.e., bacterial, viral or fungal) was defined based on combined clinical, imaging and microbiological findings. Bacterial infections were identified by conventional culture methods and enzyme immunoassay in stools was used to identify the Clostridium difficile infection. Culture-independent methods to identify viral and fungal infections (e.g., respiratory viral panel, serum galactomannan, urine histoplasma antigen) were recorded when available. When the infectious agent was not identified, if the response to empiric antibiotic, antifungal or antiviral therapy was documented, they were classified as bacterial, fungal or viral infection, respectively. Early death was defined as death within the first 6 months from diagnosis. The cause of death (classified as either infectious or non-infectious) was determined by the treating physicians.

Demographics, clinical features and therapies received were summarized using descriptive statistics. The primary study outcome was the number of infectious events that required hospitalization for ≥ 24 h within the first 6 months of the follow-up. Secondary outcomes were the mortality rate at 6 months and its cause. Quantitative variables were described in terms of the median; qualitative variables were described as the absolute percentage. Patients were divided based on the presence or absence of infectious events. Comparisons between subgroups were analyzed using the Chi-square test. Univariate analysis was performed using the Chi-square test to identify possible risk factors for infection; those with a p < 0.05 were selected and included in the multivariate analysis, which was performed using a binary logistic regression model (forward LR). The degree of collinearity between variables was evaluated using the Variance Inflation Factor (VIF) statistic. Clinical and treatment factors evaluated were: age, Eastern Cooperative Oncology Group (ECOG) performance status, smoking habit, comorbidities, myeloma subtype, ISS score, Durie-Salmon stage, anemia (hemoglobin level < 10 g/dl), renal impairment (serum creatinine level ≥ 2 mg/dl), hypercalcemia (serum calcium > 11 mg/dl), presence of osteolytic lesions (one or more on skeletal imaging), lymphopenia (blood lymphocyte count ≤ 1 × 109/L), hypoalbuminemia (serum albumin < 3.5 g/dl), elevated serum lactate dehydrogenase (LDH) (above the upper limit of normal), immunoparesis (decreased serum concentration of any polyclonal immunoglobulin class in serum) and type of therapy. In all cases, p < 0.05 was considered significant. The statistical analysis was performed using the IBM SPSS version 25.0 (Armonk, NY, USA).

A total of 124 patients with NDMM were included (65 males and 59 females). Forty-two (33.9 %) patients were diagnosed at the Hospital de Clínicas, 39 (31.5 %) at the CASMU, 37 (29.8 %) at the Hospital Central de las FF.AA. and 6 (4.8 %) at the Hospital Británico. The median age at diagnosis was 68 years (range, 27 - 88), 75 (60.5 %) patients were ≥ 65 years. One-third of the patients had an ECOG performance status ≥ 2. A total of 67 patients (54 %) were IgG subtype, 33 (26.6 %) IgA, 23 (18.5 %) light chains and 1 non-secretor. Most patients were diagnosed with advanced Durie-Salmon stage III (n = 102, 82.3 %), only 12 patients (9.7 %) were stage II and 10 were stage I (8 %). According to the ISS, 39 were stage 1 (31.5 %), 36 were stage 2 (29 %) and 49 were stage 3 (39.5 %). Bone disease was the most frequent myeloma-defining event (n = 87, 70.2 %), followed by anemia (n = 69, 55.7 %), renal failure (n = 27, 21.8 %) and hypercalcemia (n = 20, 16.1 %). The clinical features of NDMM patients are shown in Table 1.

Infections were found in 54 patients (43.5 %) with a median time to the first infection of 1 month from diagnosis (range 1 - 6 months). A total of 74 infectious events were identified in the 54 patients; 31.5 % (n = 17) has ≥ 2 infectious events. The majority of infectious events (n = 55/74, 74.3 %) occurred in the first 3 months from diagnosis, particularly within the first month (n = 37/74, 50 %). The distribution of infectious episodes over time from the diagnosis is shown in Figure 1.

Figure 1.

Distribution of infectious episodes over time from the diagnosis of multiple myeloma (n = 74).

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The most common site of infection was the urinary tract (n = 29, 39.2 %), followed by the respiratory tract (n = 25 cases, 33.8 %), skin and soft tissue (n = 6, 8.1 %), blood stream (n = 6, 8.1 %), gastrointestinal tract (n = 3, 4.1 %) and central nervous system (n = 2, 2.7 %). In 3 cases (4.1 %), the site of infection was not identified and they were classified as a fever of unknown origin. Respiratory infections were predominantly CD (p < 0.001), whereas urinary tract infections were MD (p < 0.001). The distribution of infected sites is summarized in Figure 2.

Figure 2.

Distribution of infection sites. There was a significant difference in the proportion of microbiologically defined infections (MDIs) and in the proportion of clinically defined infections (CDIs) in patients with respiratory and urinary tract infections (*p < 0.001).

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Overall, 83.1 % of patients received antiviral prophylaxis (100 % of those treated with bortezomib). Prophylaxis with fluoroquinolones, trimethoprim-sulfamethoxazole and fluconazole were used in 6.5 %, 2.4 % and 0.8 %, respectively. The immunization against H. influenza and S. pneumoniae was documented in 50.8 % (n = 63) and 27.4 % (n = 34) of patients, respectively.

In the 74 infectious events, the microbial agent was isolated in 45 (60.8 %) cases; 6 (13.3 %) had more than one microorganism isolated. Bacterial infections represented 94.6 % of the episodes. Viral and fungal infections were infrequent. Gram-negative bacteria represented 71.4 % (n = 35/49) and Gram-positive bacteria, 26.5 % (n = 13/49) of the MD cases. One case corresponded to mycobacterium infection (2 %, 1/49). The most frequent pathogen was Escherichia coli (37.3 %), followed by Klebsiella pneumoniae (11.8 %) and Staphylococcus aureus (11.8 %) (Table 2). The major sources for microorganism isolation were urine (59.1 %), blood culture (18.2 %) and bronchoalveolar lavage (9.1 %).

According to the univariate analysis, the factors associated with a higher risk for bacterial infection in the first 6 months from diagnosis were: ECOG performance status ≥ 2 (p = 0.029); smoking habit (p = 0.022); ISS 3 (p = 0.002); creatinine ≥ 2 mg/dl (p < 0.001); dialysis (p = 0.002); hypercalcemia (p = 0.013) and; serum albumin < 3.5 g/dl (p = 0.026) (Table 3). An age ≥ 65 years, the gender, presence of co-existing comorbidities, such as diabetes, respiratory and cardiac diseases, Durie-Salmon stage III, non-IgG MM subtype, presence of anemia, osteolytic lesions, immunoparesis and lymphopenia did not show significant differences between those who developed infections versus those who did not (Table 1).

To analyze the effect of the MM therapy on the rate of infection, we categorized cases according to the drug for which the regimen was based (i.e., PI-based, IMiD-based and the combination of both). The PI-based therapy was administered in 79 cases (63.7 %), IMiD-based therapy in 16 cases (12.9 %) and a combination of both in 21 patients (16.9 %). The remaining cases were treated with conventional chemotherapy (Table 1). According to therapy type, we did not find a significant difference in the risk of infection (Table 3).

In the multivariate logistic regression analysis (Table 3), the factors with an independent prognostic value for the development of bacterial infections were an ECOG performance status ≥ 2 (0.008) and creatinine ≥ 2 mg/dl (p = 0.003). There was no collinearity among the factors (VIF < 2 in all cases).

The rate of infection was 32.8 % in the absence of risk factors, 44.4 % with 1 risk factor, and 100 % with 2 risk factors (p < 0.001, Figure 3). Analysis of risk factors associated with fungal and viral infections was not performed, given the small sample size.

Figure 3.

Infection rates corresponding to the number of independent risk factors. The two risk factors are the ECOG performance status ≥ 2 and creatinine ≥ 2 mg/dl.

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Overall, 18.9 % (n = 14/74) of infectious events resulted in admission to the intensive care unit. A total of 14 (11.3 %) patients died within 6 months of their diagnosis; 7 (50 %) of these deaths were due to infectious complications.