**5. Infections associated with use of novel agents**

Infections represent a significant cause of morbidity and a leading cause of death in patients with MM [13, 53]. The novel therapies that have been introduced over the past decade have improved the survival of patients with MM [53, 109]. Consequently, management of disease complications such as infections has become an important issue as patients with MM survive longer [53]. The pattern of infection and the risk factors for infection in MM patients have shifted due to the evolution of new therapies and the widespread use of HSCT [13, 43].

Several studies have shown that the use of immunomodulatory agents such as thalidomide and lenalidomide and proteasome inhibitors such as bortezomib, particularly if they are used in drug combinations that include corticosteroids in the treatment of MM at any stage, induction, relapse, or maintenance, are associated with increased risk of infectious complications, thus making the use of antimicrobial prophylaxis with fluoroquinolones, acyclovir, cotrimoxazole, and fluconazole essential [13, 52, 110, 111]. Also, in a meta-analysis that included 13 clinical trials, with 2402 patients participating, the use of daratumumab and elotuzumab in the treatment of R/R-MM was associated with myelosuppression in the form of neutropenia and lymphopenia and subsequent risk of infectious complications such as pneumonia [109].

#### **5.1. Infections associated with use of thalidomide**

Thalidomide is not significantly myelotoxic, so the risk of infection in patients with MM receiving thalidomide alone is very low [14]. However, severe infections have been encountered once thalidomide is used in combination with other drugs in the treatment of MM. Therefore, antibiotic prophylaxis is needed once thalidomide is used in combination with other drugs such as dexamethasone [112].

#### **5.2. Infections associated with use of lenalidomide**

Lenalidomide has more potent costimulatory effects on CD4+ and CD8+ cells than thalidomide, and it causes neutropenia as part of myelosuppression, which is highest during the initial cycles of therapy and then it decreases thereafter [14, 31, 113].

Serious infections and even deaths have been encountered with the use of lenalidomide [31]. Several studies have shown the following results once lenalidomide is combined with dexamethasone: (1) various infections are prone to occur, and (2) these infectious complications may be severe to the extent that the patients need hospitalization to receive G-CSF and IV antimicrobial therapy, (3) respiratory tract infections are common, and (4) viral infections such as VZV may be encountered requiring treatment as well as prophylaxis with acyclovir [14, 82, 113–116].

**5.7. Infections associated with use of elotuzumab**

**6. Infections related to HSCT in MM**

failure [140, 141].

Elotuzumab can cause neutropenia, lymphopenia, and hyperglycemia [129–132]. Several studies have shown that its use in the treatment of patients with MM is associated with the

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Corticosteroids predispose to infectious complications by causing immune suppression and hyperglycemia [13, 14, 39]. The following infections have been reported in patients with MM receiving corticosteroid therapy: (1) *Candida albicans* and *non-albicans Candida*; (2) *Mycobacteriaceae*; (3) viruses such as HSV, VZV, CMV, and respiratory viruses; (4) encapsulated bacteria such as *Staphylococcus aureus*, *Streptococcus pneumonia*, *Pseudomonas aeruginosa*, and *Enterobacter aerogenes*; and (5) PJP [13, 14, 39]. The use of bisphosphonates in patients with

Prior to the era of novel therapies for MM, studies in patients with HMs receiving autologous HSCT showed that there was no significant difference in incidence, type of infection, and clinical course of infection between patients with MM and patients with other HMs [134, 135]. However, a recent study showed that in-hospital mortality in patients with MM receiving autologous HSCT was approximately 1.5% and that there was no significant difference in mortality between elderly individuals and young patients [136]. Nevertheless, elderly patients were more likely to develop complications such as pneumonia, septic shock, acute respiratory failure needing endotracheal intubation, acute renal failure, and cardiac arrhythmias [136].

In patients with MM having dialysis-dependent renal failure are at higher risk of FN and infectious complications such as septic shock compared to patients without renal failure [137]. Patients with MM subjected to autologous HSCT are at higher risk of developing bacterial meningitis, which is associated with high rates of mortality and morbidity [138]. MM patients having MBL2 (mannan-binding lectin, which is part of the innate immune system that protects against severe infections during autologous HSCT) polymorphism are at risk of severe infections particularly after receiving HD-melphalan and autologous HSCT [139]. In addition to the administration of prophylactic antimicrobials in patients with HR-MM and in recipients of HSCT, strategies to reduce the incidence of infectious complications include administration of IV immunoglobulins and vaccination despite the likelihood of vaccination

During stem cell mobilization, infections related to central venous catheters are likely to occur with predominance of GPB [142]. Conditioning therapy with HD-melphalan causes mucositis and myelosuppression with neutropenia [14]. The use of melphalan is associated with colitis, pneumonia, and bacteremia, and these infections are usually caused by the following encap-

sulated bacteria, *Candida* species and *Aspergillus* species [14].

following infections: pneumonia, sepsis, and even leishmaniasis [129–131, 133].

**5.8. Infections related to corticosteroids and bisphosphonates**

MM is associated with osteomyelitis and osteonecrosis of the jaw [14].

#### **5.3. Infections associated with use of pomalidomide**

Pomalidomide causes neutropenia [44, 116, 117]. When combined with dexamethasone in the treatment of patients with MM, severe infections may develop and pneumonia is a commonly encountered infection [44, 116, 117].

Infection is the second most common cause of death, after disease progression, in MM patients treated with pomalidomide [44]. Patient receiving pomalidomide therapy may have interruption of their scheduled treatment in case of severe infection and may need: G-CSF administration, antimicrobial prophylaxis with quinolones and cotrimoxazole, and even revaccination [44, 116, 117].

#### **5.4. Infections associated with use of bortezomib**

Bortezomib causes decreased lymphocytic count and imbalance in T-lymphocyte subsets due to its potent immunosuppressive effect on T cells [14, 118–120]. Several studies have shown that the use of bortezomib in the treatment of patients with MM is associated with development of the following infectious complications: (1) viral infections such as HSV and VZV infections mainly in patients with IgG type of myeloma, (2) fungal infections, (3) bacterial infections, mainly in IgG type of MM, and (4) TB reactivation, which is more pronounced in patients receiving other drugs, such as thalidomide and cyclophosphamide, in combination with bortezomib [14, 118, 119, 121]. However, one study found that *Epstein–Barr virus* (EBV)-positive B-cells were more susceptible to killing by bortezomib. Hence, the drug could represent a novel strategy for the treatment of certain EBV-associated lymphomas [122].

#### **5.5. Infections associated with use of carfilzomib**

Carfilzomib causes BM suppression that includes lymphopenia [123, 124]. The use of carfilzomib in the treatment of MM has been associated with the following infections: bacterial pneumonia, viral respiratory tract infections, and bacterial sepsis [123, 124].

#### **5.6. Infections associated with use of daratumumab**

Daratumumab has the following effects: neutropenia, lymphopenia, hyperglycemia, and decrease in natural killer cells, which play a major role in the immune clearance of virally infected cells [125, 126]. The use of daratumumab in the treatment of MM patients is associated with the following infections: nasopharyngitis, pneumonia, and viral infections such as VZV [125–128].

#### **5.7. Infections associated with use of elotuzumab**

Serious infections and even deaths have been encountered with the use of lenalidomide [31]. Several studies have shown the following results once lenalidomide is combined with dexamethasone: (1) various infections are prone to occur, and (2) these infectious complications may be severe to the extent that the patients need hospitalization to receive G-CSF and IV antimicrobial therapy, (3) respiratory tract infections are common, and (4) viral infections such as VZV may be encountered requiring treatment as well as prophylaxis with acyclovir

Pomalidomide causes neutropenia [44, 116, 117]. When combined with dexamethasone in the treatment of patients with MM, severe infections may develop and pneumonia is a commonly

Infection is the second most common cause of death, after disease progression, in MM patients treated with pomalidomide [44]. Patient receiving pomalidomide therapy may have interruption of their scheduled treatment in case of severe infection and may need: G-CSF administration, antimicrobial prophylaxis with quinolones and cotrimoxazole, and even revaccination

Bortezomib causes decreased lymphocytic count and imbalance in T-lymphocyte subsets due to its potent immunosuppressive effect on T cells [14, 118–120]. Several studies have shown that the use of bortezomib in the treatment of patients with MM is associated with development of the following infectious complications: (1) viral infections such as HSV and VZV infections mainly in patients with IgG type of myeloma, (2) fungal infections, (3) bacterial infections, mainly in IgG type of MM, and (4) TB reactivation, which is more pronounced in patients receiving other drugs, such as thalidomide and cyclophosphamide, in combination with bortezomib [14, 118, 119, 121]. However, one study found that *Epstein–Barr virus* (EBV)-positive B-cells were more susceptible to killing by bortezomib. Hence, the drug could represent a novel strategy for the treatment of certain EBV-associated lymphomas [122].

Carfilzomib causes BM suppression that includes lymphopenia [123, 124]. The use of carfilzomib in the treatment of MM has been associated with the following infections: bacterial

Daratumumab has the following effects: neutropenia, lymphopenia, hyperglycemia, and decrease in natural killer cells, which play a major role in the immune clearance of virally infected cells [125, 126]. The use of daratumumab in the treatment of MM patients is associated with the following infections: nasopharyngitis, pneumonia, and viral infections such as VZV [125–128].

pneumonia, viral respiratory tract infections, and bacterial sepsis [123, 124].

[14, 82, 113–116].

190 Update on Multiple Myeloma

[44, 116, 117].

**5.3. Infections associated with use of pomalidomide**

**5.4. Infections associated with use of bortezomib**

**5.5. Infections associated with use of carfilzomib**

**5.6. Infections associated with use of daratumumab**

encountered infection [44, 116, 117].

Elotuzumab can cause neutropenia, lymphopenia, and hyperglycemia [129–132]. Several studies have shown that its use in the treatment of patients with MM is associated with the following infections: pneumonia, sepsis, and even leishmaniasis [129–131, 133].

#### **5.8. Infections related to corticosteroids and bisphosphonates**

Corticosteroids predispose to infectious complications by causing immune suppression and hyperglycemia [13, 14, 39]. The following infections have been reported in patients with MM receiving corticosteroid therapy: (1) *Candida albicans* and *non-albicans Candida*; (2) *Mycobacteriaceae*; (3) viruses such as HSV, VZV, CMV, and respiratory viruses; (4) encapsulated bacteria such as *Staphylococcus aureus*, *Streptococcus pneumonia*, *Pseudomonas aeruginosa*, and *Enterobacter aerogenes*; and (5) PJP [13, 14, 39]. The use of bisphosphonates in patients with MM is associated with osteomyelitis and osteonecrosis of the jaw [14].
