**4. Infectious complications in MM**

understanding of the biology of the disease and helped in the diagnosis, risk stratification and follow-up of patients, (4) the evolution of new therapeutic strategies such as consolidation and maintenance treatments as well as total and continuous therapy, and (5) improvements in supportive care and antimicrobial therapies [1, 3–12]. Currently, the following novel therapies are available for patients with MM: (1) immunomodulatory agents such as thalidomide, lenalidomide, and pomalidomide; (2) proteasome inhibitors such as bortezomib, carfilzomib, and ixazomib; (3) monoclonal antibodies such as daratumumab and elotuzumab; and (4) histone deacetylase inhibitors such as panobinostat and vorinostat [1, 3, 4, 6, 9, 11]. Unfortunately, despite the remarkable progress achieved in the diagnostics and therapeutics and the plethora of therapeutic modalities, MM remains incurable [1, 4, 5, 7, 11]. The numerous treatment modalities that are available for patients with MM have shown their effectiveness, but they have their own adverse effects including bone marrow (BM) suppression and

The standard induction therapy in patients with newly diagnosed MM is the triplet regimen of bortezomib, lenalidomide, and dexamethasone [4, 16]. Autologous HSCT is the standard of care for transplant-eligible patients either upfront or at relapse [4, 10, 16]. Studies have shown that post-HSCT consolidation and maintenance treatments can further improve the outcome of patients with MM [10, 16, 17]. Monitoring disease response at various stages of treatment is essential and studies have shown that monitoring of minimal residual disease is associated

In patients with MM, several studies have shown that risk factors for early mortality include male gender, age >75 years, poor performance status, presence of comorbid medical conditions such as renal failure and hypertension, low platelet count, low serum albumin level, elevated serum levels of calcium and lactic dehydrogenase, low body mass index, presentation with primary plasma cell leukemia, advanced stage of disease at presentation, and infectious complications [20–25]. Two major studies that included 451 and 299 patients with MM

Despite the use of prophylactic antimicrobials, infections remain a leading cause of mortality and morbidity in patients with MM [26]. In patients with MM, approximately 45% of deaths occurring within 60 days of diagnosis are caused by various infections, predominantly pneu-

In patients with MM, causes of immunosuppression include: (1) the immunosuppressive effects of the disease or the direct immunosuppression caused by tumor cells, particularly in advanced stage or refractory disease, (2) therapeutic interventions to control MM, such

with longer progression-free survival (PFS) and overall survival (OS) [18, 19].

showed that 65 and 45% of early deaths were attributable to infections [20, 21].

infectious complications that may be life-threatening [13–15].

**2. Early mortality in MM**

182 Update on Multiple Myeloma

monia and sepsis [20, 26].

**3. Reduced immunity in patients with MM**

The risk factors for infectious complications in patients with MM can be divided into patientrelated factors, disease-related factors, and treatment-related factors as shown in **Table 1** [13, 14, 38–45]. However, the infections encountered in patients with MM include: (1) bacterial infections, predominantly involving respiratory and urinary tract, caused by *Streptococcus pneumonia*, *Staphylococcus aureus*, *Haemophilus influenzae*, *Klebsiella pneumonia*, *Escherichia coli*,

	- Female gender
	- Old age
	- Poor performance status and poor general condition
	- Presence of comorbid medical conditions
	- Hyperglycemia and uncontrolled diabetes mellitus
	- Renal dysfunction/failure
	- Increased serum ferritin level
	- Active disease
	- Advanced disease; stage III according to international staging system
	- Relapsed and refractory disease
	- Immune dysfunction:
		- Suppression of cellular and humoral immunity including hypogammaglobulinemia

increasingly reported [50]. The incidence of infections in MM patients has bimodal peaks: bacterial infections dominate 4–6 and 70–72 months after the diagnosis, while viral infections

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In patients with MM having active disease, the following types of infections are common: bacteremia, pneumonia, sinusitis, otitis, meningitis, and IFIs [14, 50]. In active disease, Gramnegative bacterial (GNB) particularly encapsulated bacteria and fungi are common causes of

Patients with MM are at high risk of developing infections as infections in these patients have been reported to be 10 times more than that in healthy individuals. Also, the new novel therapies make patients with MM at higher risk of infectious complications than myeloma patients treated with cytotoxic chemotherapy [52, 53]. Even, prior to the diagnosis of MM, there is an underlying immune disturbance, which may predispose to various infections such as VZV, sinusitis, cystitis, and bronchitis that may be encountered during the disease evolution [54].

Neutropenia is a hematologic adverse event of medications characterized by an absolute neutrophil count (ANC) lower than 1500 cells/mL [55]. Neutropenia is a well-recognized complication of cytotoxic chemotherapy. Also, it develops in patients with MM receiving novel therapies or undergoing HSCT [55–57]. Prolonged and severe neutropenia increases the risk of febrile neutropenia (FN) and serious infections that may be life-threatening [57]. Persistent neutropenia causes not only delay in administration of chemotherapy or novel therapies, but also dose reductions in the next cycle of chemotherapy. Nevertheless, once the ANC reaches

FN is a serious effect of chemotherapy, and it has the following adverse consequences: delay in administration of scheduled therapies, costs of hospitalization, and increased risk of morbidity and mortality in immunocompromised individuals [58]. Several studies have shown that the following risk factors for neutropenia and FN in patients with MM: (1) heavily pretreated disease and relapsed and refractory (R/R)-MM, (2) elderly patients with comorbid medical conditions, and (3) use of the following drugs particularly in combination with other agents such as lenalidomide, bendamustine, and the combination of bendamustine, bortezomib and

Management of patients with prolonged neutropenia and FN includes: (1) thorough physical evaluation for the site or source of infection, (2) taking enough cultures and septic screens, (3) administration of prophylactic and empirical antimicrobials, and (4) pre-emptive or prophylactic administration of granulocyte-colony stimulating factor (G-CSF) in patients who are expected to have prolonged or severe neutropenia [58, 59]. However, the choice of empirical antibiotic therapy in patients with HMs having FN depends on the risk stratification of the individual patient [61, 62]. In low-risk (LR) patients with FN, duration of neutropenia is <1 week and there are no comorbid medical conditions; while in high-risk (HR) patients with FN, the duration of neutropenia is >1 week and there are comorbid medical conditions [61, 62]. In case the patient is stratified as LR, oral antibiotics such as ciprofloxacin or levofloxacin are sufficient,

dominate 7–9 and 52–54 months after the diagnosis of MM [13].

infectious complications [14].

dexamethasone [55, 58–60].

**4.1. Neutropenia and febrile neutropenia**

≥1000 cells/mL, scheduled treatment may be resumed [55].

	- High-dose chemotherapy: melphalan, cyclophosphamide
	- Novel therapies:
		- Immunomodulatory agents: thalidomide, lenalidomide, pomalidomide
		- Proteasome inhibitors: bortezomib, carfilzomib
		- Monoclonal antibodies: daratumumab, elotuzumab
	- Neutropenia and lymphopenia
	- Mucositis
	- Presence of central venous catheters
	- Corticosteroids: high dose or prolonged duration of therapy
	- Autologous hematopoietic stem cell transplantation
	- Allogeneic hematopoietic stem cell transplantation

**Table 1.** Risk factors for infectious complications in multiple myeloma.

*Pseudomonas aeruginosa*, and *Enterobacteriaceae*; (2) viral infections caused by *herpes simplex virus* (HSV), VZV, and *cytomegalovirus* (CMV); (3) fungal infections caused by *Candida* species and *Aspergillus* species; and (4) *Pneumocystis jiroveci pneumonia* (PJP) [14, 43, 44, 46–48].

The sites of infections in patients with MM include: (1) upper and lower respiratory tract with otitis, sinusitis, and pneumonia; (2) urinary tract; (3) brain with meningitis; (4) skin with VZV infection; (5) heart with endocarditis; (6) bone and joint infections; and (7) bacteremia [14, 43, 47–51]. Bacterial infections are the most frequent etiological agents. However, invasive fungal infections (IFIs) caused by molds such as *Aspergillus* species and *Fusarium* species have been increasingly reported [50]. The incidence of infections in MM patients has bimodal peaks: bacterial infections dominate 4–6 and 70–72 months after the diagnosis, while viral infections dominate 7–9 and 52–54 months after the diagnosis of MM [13].

In patients with MM having active disease, the following types of infections are common: bacteremia, pneumonia, sinusitis, otitis, meningitis, and IFIs [14, 50]. In active disease, Gramnegative bacterial (GNB) particularly encapsulated bacteria and fungi are common causes of infectious complications [14].

Patients with MM are at high risk of developing infections as infections in these patients have been reported to be 10 times more than that in healthy individuals. Also, the new novel therapies make patients with MM at higher risk of infectious complications than myeloma patients treated with cytotoxic chemotherapy [52, 53]. Even, prior to the diagnosis of MM, there is an underlying immune disturbance, which may predispose to various infections such as VZV, sinusitis, cystitis, and bronchitis that may be encountered during the disease evolution [54].

#### **4.1. Neutropenia and febrile neutropenia**

*Pseudomonas aeruginosa*, and *Enterobacteriaceae*; (2) viral infections caused by *herpes simplex virus* (HSV), VZV, and *cytomegalovirus* (CMV); (3) fungal infections caused by *Candida* species and *Aspergillus* species; and (4) *Pneumocystis jiroveci pneumonia* (PJP) [14, 43, 44, 46–48].

1 Patient-related factors: • Female gender • Old age

184 Update on Multiple Myeloma

• Poor performance status and poor general condition

• Hyperglycemia and uncontrolled diabetes mellitus

• Advanced disease; stage III according to international staging system

○ Suppression of cellular and humoral immunity including hypogammaglobulinemia

○ Immunomodulatory agents: thalidomide, lenalidomide, pomalidomide

• Presence of comorbid medical conditions

• Renal dysfunction/failure • Increased serum ferritin level

• Relapsed and refractory disease

• Immune dysfunction:

3 Treatment-related factors:

• Novel therapies:

• Mucositis

○ Low CD4+ cell count

• Neutropenia and lymphopenia

• Presence of central venous catheters

○ Dysfunction of natural killer cells

• High-dose chemotherapy: melphalan, cyclophosphamide

○ Proteasome inhibitors: bortezomib, carfilzomib ○ Monoclonal antibodies: daratumumab, elotuzumab

• Corticosteroids: high dose or prolonged duration of therapy • Autologous hematopoietic stem cell transplantation • Allogeneic hematopoietic stem cell transplantation

**Table 1.** Risk factors for infectious complications in multiple myeloma.

2 Disease-related factors: • Active disease

The sites of infections in patients with MM include: (1) upper and lower respiratory tract with otitis, sinusitis, and pneumonia; (2) urinary tract; (3) brain with meningitis; (4) skin with VZV infection; (5) heart with endocarditis; (6) bone and joint infections; and (7) bacteremia [14, 43, 47–51]. Bacterial infections are the most frequent etiological agents. However, invasive fungal infections (IFIs) caused by molds such as *Aspergillus* species and *Fusarium* species have been Neutropenia is a hematologic adverse event of medications characterized by an absolute neutrophil count (ANC) lower than 1500 cells/mL [55]. Neutropenia is a well-recognized complication of cytotoxic chemotherapy. Also, it develops in patients with MM receiving novel therapies or undergoing HSCT [55–57]. Prolonged and severe neutropenia increases the risk of febrile neutropenia (FN) and serious infections that may be life-threatening [57]. Persistent neutropenia causes not only delay in administration of chemotherapy or novel therapies, but also dose reductions in the next cycle of chemotherapy. Nevertheless, once the ANC reaches ≥1000 cells/mL, scheduled treatment may be resumed [55].

FN is a serious effect of chemotherapy, and it has the following adverse consequences: delay in administration of scheduled therapies, costs of hospitalization, and increased risk of morbidity and mortality in immunocompromised individuals [58]. Several studies have shown that the following risk factors for neutropenia and FN in patients with MM: (1) heavily pretreated disease and relapsed and refractory (R/R)-MM, (2) elderly patients with comorbid medical conditions, and (3) use of the following drugs particularly in combination with other agents such as lenalidomide, bendamustine, and the combination of bendamustine, bortezomib and dexamethasone [55, 58–60].

Management of patients with prolonged neutropenia and FN includes: (1) thorough physical evaluation for the site or source of infection, (2) taking enough cultures and septic screens, (3) administration of prophylactic and empirical antimicrobials, and (4) pre-emptive or prophylactic administration of granulocyte-colony stimulating factor (G-CSF) in patients who are expected to have prolonged or severe neutropenia [58, 59]. However, the choice of empirical antibiotic therapy in patients with HMs having FN depends on the risk stratification of the individual patient [61, 62]. In low-risk (LR) patients with FN, duration of neutropenia is <1 week and there are no comorbid medical conditions; while in high-risk (HR) patients with FN, the duration of neutropenia is >1 week and there are comorbid medical conditions [61, 62]. In case the patient is stratified as LR, oral antibiotics such as ciprofloxacin or levofloxacin are sufficient, while if the patient belongs to the HR group, intravenous (IV) antibiotics may need to be administered. IV ceftazidime, piperacillin-tazobactam, or a carbapenem can be given as single agents or in combination with either vancomycin or an aminoglycoside [62–65]. However, the fact that there is a recent increase in the incidence of Gram-positive bacteria (GPB) cultured from neutropenic patients with MM has to be taken into consideration [56]. Empirical antifungal therapy can be used in patients with persistent fever despite the use of broad-spectrum antibiotics [61, 62, 66]. In addition, recombinant G-CSF is commonly used to reduce the incidence, duration, and severity of FN [57]. Studies have shown that the use of G-CSF as primary prophylaxis improves quality of life, is cost-effective as it reduces the: days of hospitalization, infectious complications, and incidence of chemotherapy interruptions [58, 59].

patients with MM receiving induction therapy [76]. However, other studies have shown that the addition of doxycycline to ciprofloxacin and the sequential use of levofloxacin followed by ertapenem in patients with MM subjected to autologous HSCT reduce the frequency of FN episodes, bacteremia, and documented bacterial infections without increasing the rate of

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Reactivation of CMV after autologous HSCT performed for patients with MM is relatively common and is mainly encountered in patients receiving tandem rather than single HSCT; HD-melphalan conditioning therapy; and induction with combination therapy particularly bortezomib, thalidomide, and dexamethasone [79]. Also, reactivation of *human herpes virus*-6 is relatively common following autologous HSCT and is usually associated with postengraftment fever [80]. Several studies performed in patients with MM have shown that the risk factors for reactivation of VZV, HSV, and *hepatitis-B virus* (HBV) include (1) progressive disease, (2) treatment with proteasome inhibitors such as bortezomib, (3) treatment with immuno-

Viremia caused by CMV is common and is often associated with fever, while CMV disease with biopsy proven tissue infiltration is rare in patients with MM receiving autologous HSCT [79]. CMV surveillance should be considered in patients with MM subjected to autologous HSCT, particularly those receiving tandem transplants, HD-melphalan and combination therapies for induction [79]. Acyclovir of valacyclovir prophylaxis should be offered to HR patients including recipients of HSCT, patients with progressive disease, and patients treated

Candidemia and IFIs are major complications in patients with HMs who develop prolonged and severe neutropenia. Additionally, IFIs are difficult to diagnose in these severely immunocompromised patients [88–91]. In patients with MM prior to the introduction of novel therapies, IFIs were encountered in patients treated with traditional intensive cytotoxic chemotherapeutic regimens and mortality rates due to IFIs were reaching 60% [91]. In the era of novel therapies, IFIs are associated with mortality rate of approximately 44% and are mainly encountered in MM patients having: (1) progressive disease, (2) ≥ 3 lines of therapy administered, (3) received HSCT, particularly in the early post-transplant period, and (4) history of IFI treated [91–93].

Over the past two decades, the spectrum of *Candida* species infections has shifted to *non-albicans* species, which frequently exhibit decreased susceptibility to fluconazole [89]. Empirical antifungal agents are recommended in patients with HMs having neutropenia and persistent or recurrent fever despite appropriate antibiotic therapy [88]. In patients with candidemia or invasive infection caused by *Candida* species, echinocandins such as caspofungin, liposomal amphotericin-B, and voriconazole are the treatments of choice, while voriconazole is the treatment of choice for IFIs caused by *Aspergillus* species [67, 89, 90, 92]. However, fluconazole is still the most common antifungal agent used for prophylaxis in HR patients and in recipients of HSCT [91, 92].

modulatory agents particularly lenalidomide, and (4) HSCT [81–87].

serious complications [77, 78].

**4.3. Viral infections in MM**

with bortezomib or lenalidomide [81–87].

**4.4. Fungal infections in MM**

#### **4.2. Bacterial and bloodstream infections in MM**

Bloodstream infections (BSIs) are important causes of morbidity and mortality in patients with HMs, and they contribute to delayed administration of planned chemotherapy, increased length of hospitalization, and increased health care costs [29]. The risk factors for bacteremia or bacterial BSIs in patients with HMs include the primary disease, neutropenia induced by intensive chemotherapy, and mucositis due to the cytotoxic effects of chemotherapy on the cells of gastrointestinal tract [67, 68]. In recent years, there has been a shift in prevalence of the causative organisms for bacterial BSIs in patients with HMs from GPB to GNB. Also, there has been increasing frequency of antimicrobial resistance in GNB [69]. Therefore, in patients with HMs having FN, BSIs caused by GNB should initially be treated with non-carbapenem-based anti-pseudomonal therapy taking into consideration the antimicrobial stewardship [67].

In patients with MM undergoing autologous HSCT, mucositis and chemotherapy-induced neutropenia are risk factors for the development of bacteremia [67, 68]. In two retrospective studies on BSIs that included 421 patients with MM, the following results were obtained: (1) the independent risk factors for BSIs were: advanced stage of disease, poor performance status, and receipt of autologous HSCT; (2) GPB, mainly *Streptococcus pneumonia*, were responsible for the majority of BSIs during the induction phase of treatment while GNB, mainly *Escherichia coli*, were responsible for the majority of BSIs in progressive disease; (3) the highest incidence of BSIs was encountered during the first 3 months from the diagnosis and during disease progression; (4) admissions to the intensive care unit were required in 23% of patients with BSIs; and (5) mortality rates due to BSIs were 11.5% in patients with progressive disease and 50% in patients with newly diagnosed MM [29, 70].

Bacteremia may antedate the diagnosis of MM and may be related to the use of venous catheters used during stem cell collection or autologous HSCT [71, 72]. Polymicrobial or multiple microbiologically confirmed infections are frequent and may cause serious consequences in recipients of HSCT [73]. Several studies have shown that the use of ciprofloxacin or levofloxacin prophylaxis in patients with MM undergoing autologous HSCT is associated with significant reduction in the incidence of FN, bacteremia, and pneumonia [68, 74, 75]. On the contrary, a randomized phase III study that included 212 MM patients undergoing induction therapy showed that the prophylactic use of antibiotics did not decrease the incidence of serious bacterial infections, thus obviating the need for the routine use of antibacterial prophylaxis in patients with MM receiving induction therapy [76]. However, other studies have shown that the addition of doxycycline to ciprofloxacin and the sequential use of levofloxacin followed by ertapenem in patients with MM subjected to autologous HSCT reduce the frequency of FN episodes, bacteremia, and documented bacterial infections without increasing the rate of serious complications [77, 78].

#### **4.3. Viral infections in MM**

while if the patient belongs to the HR group, intravenous (IV) antibiotics may need to be administered. IV ceftazidime, piperacillin-tazobactam, or a carbapenem can be given as single agents or in combination with either vancomycin or an aminoglycoside [62–65]. However, the fact that there is a recent increase in the incidence of Gram-positive bacteria (GPB) cultured from neutropenic patients with MM has to be taken into consideration [56]. Empirical antifungal therapy can be used in patients with persistent fever despite the use of broad-spectrum antibiotics [61, 62, 66]. In addition, recombinant G-CSF is commonly used to reduce the incidence, duration, and severity of FN [57]. Studies have shown that the use of G-CSF as primary prophylaxis improves quality of life, is cost-effective as it reduces the: days of hospitalization, infectious

Bloodstream infections (BSIs) are important causes of morbidity and mortality in patients with HMs, and they contribute to delayed administration of planned chemotherapy, increased length of hospitalization, and increased health care costs [29]. The risk factors for bacteremia or bacterial BSIs in patients with HMs include the primary disease, neutropenia induced by intensive chemotherapy, and mucositis due to the cytotoxic effects of chemotherapy on the cells of gastrointestinal tract [67, 68]. In recent years, there has been a shift in prevalence of the causative organisms for bacterial BSIs in patients with HMs from GPB to GNB. Also, there has been increasing frequency of antimicrobial resistance in GNB [69]. Therefore, in patients with HMs having FN, BSIs caused by GNB should initially be treated with non-carbapenem-based anti-pseudomonal therapy taking into consideration the antimicrobial stewardship [67].

In patients with MM undergoing autologous HSCT, mucositis and chemotherapy-induced neutropenia are risk factors for the development of bacteremia [67, 68]. In two retrospective studies on BSIs that included 421 patients with MM, the following results were obtained: (1) the independent risk factors for BSIs were: advanced stage of disease, poor performance status, and receipt of autologous HSCT; (2) GPB, mainly *Streptococcus pneumonia*, were responsible for the majority of BSIs during the induction phase of treatment while GNB, mainly *Escherichia coli*, were responsible for the majority of BSIs in progressive disease; (3) the highest incidence of BSIs was encountered during the first 3 months from the diagnosis and during disease progression; (4) admissions to the intensive care unit were required in 23% of patients with BSIs; and (5) mortality rates due to BSIs were 11.5% in patients with progressive disease

Bacteremia may antedate the diagnosis of MM and may be related to the use of venous catheters used during stem cell collection or autologous HSCT [71, 72]. Polymicrobial or multiple microbiologically confirmed infections are frequent and may cause serious consequences in recipients of HSCT [73]. Several studies have shown that the use of ciprofloxacin or levofloxacin prophylaxis in patients with MM undergoing autologous HSCT is associated with significant reduction in the incidence of FN, bacteremia, and pneumonia [68, 74, 75]. On the contrary, a randomized phase III study that included 212 MM patients undergoing induction therapy showed that the prophylactic use of antibiotics did not decrease the incidence of serious bacterial infections, thus obviating the need for the routine use of antibacterial prophylaxis in

complications, and incidence of chemotherapy interruptions [58, 59].

**4.2. Bacterial and bloodstream infections in MM**

186 Update on Multiple Myeloma

and 50% in patients with newly diagnosed MM [29, 70].

Reactivation of CMV after autologous HSCT performed for patients with MM is relatively common and is mainly encountered in patients receiving tandem rather than single HSCT; HD-melphalan conditioning therapy; and induction with combination therapy particularly bortezomib, thalidomide, and dexamethasone [79]. Also, reactivation of *human herpes virus*-6 is relatively common following autologous HSCT and is usually associated with postengraftment fever [80]. Several studies performed in patients with MM have shown that the risk factors for reactivation of VZV, HSV, and *hepatitis-B virus* (HBV) include (1) progressive disease, (2) treatment with proteasome inhibitors such as bortezomib, (3) treatment with immunomodulatory agents particularly lenalidomide, and (4) HSCT [81–87].

Viremia caused by CMV is common and is often associated with fever, while CMV disease with biopsy proven tissue infiltration is rare in patients with MM receiving autologous HSCT [79]. CMV surveillance should be considered in patients with MM subjected to autologous HSCT, particularly those receiving tandem transplants, HD-melphalan and combination therapies for induction [79]. Acyclovir of valacyclovir prophylaxis should be offered to HR patients including recipients of HSCT, patients with progressive disease, and patients treated with bortezomib or lenalidomide [81–87].

#### **4.4. Fungal infections in MM**

Candidemia and IFIs are major complications in patients with HMs who develop prolonged and severe neutropenia. Additionally, IFIs are difficult to diagnose in these severely immunocompromised patients [88–91]. In patients with MM prior to the introduction of novel therapies, IFIs were encountered in patients treated with traditional intensive cytotoxic chemotherapeutic regimens and mortality rates due to IFIs were reaching 60% [91]. In the era of novel therapies, IFIs are associated with mortality rate of approximately 44% and are mainly encountered in MM patients having: (1) progressive disease, (2) ≥ 3 lines of therapy administered, (3) received HSCT, particularly in the early post-transplant period, and (4) history of IFI treated [91–93].

Over the past two decades, the spectrum of *Candida* species infections has shifted to *non-albicans* species, which frequently exhibit decreased susceptibility to fluconazole [89]. Empirical antifungal agents are recommended in patients with HMs having neutropenia and persistent or recurrent fever despite appropriate antibiotic therapy [88]. In patients with candidemia or invasive infection caused by *Candida* species, echinocandins such as caspofungin, liposomal amphotericin-B, and voriconazole are the treatments of choice, while voriconazole is the treatment of choice for IFIs caused by *Aspergillus* species [67, 89, 90, 92]. However, fluconazole is still the most common antifungal agent used for prophylaxis in HR patients and in recipients of HSCT [91, 92].

#### **4.5. Tuberculosis in patients with MM**

Tuberculosis (TB) is the most common cause of death from a single infectious agent worldwide [94]. In patients with HMs and in recipients of HSCT living in geographic locations that are endemic for TB, these infections are uncommon, but they cause significant morbidity and mortality [95, 96]. Early diagnosis, prompt administration of anti-TB chemotherapy, and adherence to treatment schedules are associated with successful outcome, while delayed management, drug resistance, and presence of disseminated infection are associated with poor prognosis and high mortality rates [95, 96].

**4.6. Bone and joint infections in MM**

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

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

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

initial cycles of therapy and then it decreases thereafter [14, 31, 113].

such as dexamethasone [112].

Bone and joint infections are uncommon in patients with MM. These infections manifest as: osteomyelitis, septic arthritis, and prosthetic joint infections [51, 106]. The pathogens encountered are similar to those cultured in patients without myeloma, although GPB predominate and polymicrobial infections occur less frequently [51]. In patients with MM treated with radiotherapy or IV bisphosphonates, there is a risk of developing osteonecrosis of the jaw [106, 107]. Patients with osteonecrosis of the jaw are at risk for developing infections and often require long-term antimicrobial therapy [108]. Having history of jaw osteonecrosis is not a contraindication for HSCT as the outcome of these patients is not worsened by HSCT itself [108].

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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].

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

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

The incidence of TB infection is higher in patients with MM than in the general population. Also, patients with MM have higher risk of mortality compared to MM patients without TB [97]. The risk factors for TB infection in patients with MM include: (1) the disease itself with its associated immunological abnormalities that include hypogammaglobulinemia as well as abnormal T cell-mediated and humoral immunities, (2) treatment of MM that includes corticosteroids, cytotoxic chemotherapy, and novel therapies such as bortezomib, (3) old age, (4) alcohol use disorder, (5) poor socioeconomic conditions, (6) HSCT, and (7) presence of comorbid medical conditions such as diabetes mellitus and malnutrition [94–104].

TB infections in patients with MM can be primary infections or reactivation of old or latent TB infections [94, 100, 101]. Reactivation of TB may by induced by (1) HD corticosteroids, (2) cytotoxic chemotherapy, (3) administration of novel therapies, and (4) autologous as well as allogeneic HSCT [95, 104]. In patients with MM receiving bortezomib-containing regimens, TB infections are uncommon [94]. In a retrospective analysis of 115 patients with MM treated with bortezomib-based therapy: TB infection was diagnosed in 7% of cases, bortezomib therapy was interrupted in 50% of the patients treated for TB and this affected outcome of patients significantly, but none of the patients died because of uncontrolled TB infection. In these patients, early diagnosis and prompt anti-TB treatment were essential to avoid further worsening of the outcome [94].

TB infections may be diagnosed at the time of diagnosis of MM or may evolve during or after treatment of MM [98–100, 105]. In patients with MM, TB infections have been reported to involve: (1) lungs with pulmonary infiltration, lung nodules, and bronchiectasis; (2) spine causing paraspinal masses and spinal cord compression; and (3) meninges with TB meningitis [98–100, 105]. However, spinal TB is the most serious form of TB infections [100]. TB infections in MM patients may coexist with infections caused by other microorganisms such as *Staphylococcus aureus* [99].

TB infections are 10–40 times more common in recipients of HSCT than in the general population. Also, approximately 80% of *Mycobacterium tuberculosis* infections encountered in recipients of HSCT have been reported in allograft recipients [96, 103, 104]. Patients with MM having latent TB or history of treated TB infection planned for novel therapies or subjected to cytotoxic chemotherapy or HSCT should receive isoniazid prophylaxis to prevent reactivation of their TB infections [95, 96, 101].

#### **4.6. Bone and joint infections in MM**

**4.5. Tuberculosis in patients with MM**

188 Update on Multiple Myeloma

poor prognosis and high mortality rates [95, 96].

[94–104].

worsening of the outcome [94].

as *Staphylococcus aureus* [99].

tion of their TB infections [95, 96, 101].

Tuberculosis (TB) is the most common cause of death from a single infectious agent worldwide [94]. In patients with HMs and in recipients of HSCT living in geographic locations that are endemic for TB, these infections are uncommon, but they cause significant morbidity and mortality [95, 96]. Early diagnosis, prompt administration of anti-TB chemotherapy, and adherence to treatment schedules are associated with successful outcome, while delayed management, drug resistance, and presence of disseminated infection are associated with

The incidence of TB infection is higher in patients with MM than in the general population. Also, patients with MM have higher risk of mortality compared to MM patients without TB [97]. The risk factors for TB infection in patients with MM include: (1) the disease itself with its associated immunological abnormalities that include hypogammaglobulinemia as well as abnormal T cell-mediated and humoral immunities, (2) treatment of MM that includes corticosteroids, cytotoxic chemotherapy, and novel therapies such as bortezomib, (3) old age, (4) alcohol use disorder, (5) poor socioeconomic conditions, (6) HSCT, and (7) presence of comorbid medical conditions such as diabetes mellitus and malnutrition

TB infections in patients with MM can be primary infections or reactivation of old or latent TB infections [94, 100, 101]. Reactivation of TB may by induced by (1) HD corticosteroids, (2) cytotoxic chemotherapy, (3) administration of novel therapies, and (4) autologous as well as allogeneic HSCT [95, 104]. In patients with MM receiving bortezomib-containing regimens, TB infections are uncommon [94]. In a retrospective analysis of 115 patients with MM treated with bortezomib-based therapy: TB infection was diagnosed in 7% of cases, bortezomib therapy was interrupted in 50% of the patients treated for TB and this affected outcome of patients significantly, but none of the patients died because of uncontrolled TB infection. In these patients, early diagnosis and prompt anti-TB treatment were essential to avoid further

TB infections may be diagnosed at the time of diagnosis of MM or may evolve during or after treatment of MM [98–100, 105]. In patients with MM, TB infections have been reported to involve: (1) lungs with pulmonary infiltration, lung nodules, and bronchiectasis; (2) spine causing paraspinal masses and spinal cord compression; and (3) meninges with TB meningitis [98–100, 105]. However, spinal TB is the most serious form of TB infections [100]. TB infections in MM patients may coexist with infections caused by other microorganisms such

TB infections are 10–40 times more common in recipients of HSCT than in the general population. Also, approximately 80% of *Mycobacterium tuberculosis* infections encountered in recipients of HSCT have been reported in allograft recipients [96, 103, 104]. Patients with MM having latent TB or history of treated TB infection planned for novel therapies or subjected to cytotoxic chemotherapy or HSCT should receive isoniazid prophylaxis to prevent reactivaBone and joint infections are uncommon in patients with MM. These infections manifest as: osteomyelitis, septic arthritis, and prosthetic joint infections [51, 106]. The pathogens encountered are similar to those cultured in patients without myeloma, although GPB predominate and polymicrobial infections occur less frequently [51]. In patients with MM treated with radiotherapy or IV bisphosphonates, there is a risk of developing osteonecrosis of the jaw [106, 107]. Patients with osteonecrosis of the jaw are at risk for developing infections and often require long-term antimicrobial therapy [108]. Having history of jaw osteonecrosis is not a contraindication for HSCT as the outcome of these patients is not worsened by HSCT itself [108].
