Infections in patients with multiple myeloma

INTRODUCTION — Infection is a major complication and a leading cause of death in patients with multiple myeloma (MM) [1]. The risk of infection is due to a multifactorial immunodeficiency caused by the disease itself and the treatment regimens given during the different phases of therapy [2]. In recent decades, significant progress in the management of MM has occurred, resulting in marked improvement in survival [3]. As a consequence, MM has transformed into a chronic disease with multiple relapses and salvage therapies. As the disease progresses, patients experience cumulative immunosuppression, and the list of possible pathogens and clinical syndromes broadens. The recognition of this cumulative immunosuppression is a major factor in the proper management of infectious complications in MM.

The immune defects, risk of infection, prevention of infection, and evaluation for infection in patients with MM will be reviewed here.

The management of MM and its complications are discussed separately.

●(See "Multiple myeloma: Overview of management".)

●(See "Multiple myeloma: Initial treatment".)

●(See "Multiple myeloma: Treatment of first or second relapse".)

●(See "Multiple myeloma: Treatment of third or later relapse".)

●(See "Treatment protocols for multiple myeloma".)

EPIDEMIOLOGY — The rate of infection in patients with MM is much higher than in the general population, with bacterial and viral infections predominating. A population-based study involving 9253 MM patients and 34,931 matched controls without hematologic malignancy was conducted in Sweden between 2004 and 2007 [4]. Patients with MM had a sevenfold higher risk of infection compared with controls. The risk was 11-fold greater during the first year following diagnosis. The most common infections were meningitis, septicemia, pneumonia, osteomyelitis, cellulitis, and pyelonephritis. The risk of viral infections was 10-fold higher overall and 18-fold during the first year. Influenza infection and herpes zoster were the most frequent viral infections.

Another study from Sweden evaluated the annual incidence of invasive pneumococcal disease (IPD) among patients with MM and in the general population before the introduction of the pneumococcal conjugate vaccine in the infant vaccination program [5]. The rate of IPD was 149-fold higher among MM patients (2238 cases per 100,000 persons compared with 15 per 100,000 individuals in the general population). Likewise, a population-based cohort study conducted in the Netherlands, reported the highest incidence of IPD (3299 cases per 100,000 persons) in patients with MM [6].

Infection occurs during all phases of therapy for MM, but the incidence, pathogens, and clinical syndromes differ according to treatment regimen and stage. For patients eligible for autologous hematopoietic cell transplantation (HCT), the usual treatment consists of induction (three to four cycles of a two- to three-drug regimen), followed by consolidation with autologous HCT. After HCT, treatment regimens may include a post-consolidation phase, with or without maintenance therapy. For patients who are not eligible for HCT, the induction phase is applied for a fixed period, followed by maintenance therapy until disease progression or intolerance. Upon relapse, different salvage regimens are employed [7].

Untreated patients — The immunodeficiency in newly diagnosed MM patients is multifactorial. The primary defect is B cell immunodeficiency, manifested by hypogammaglobulinemia and an increased risk of infection caused by encapsulated bacteria, including Streptococcus pneumoniae and Haemophilus influenzae [5]. Lymphocytopenia [8] and neutropenia secondary to bone marrow infiltration [2] further increase the possibility of infection. Cytokines released by myeloma cells, such as interleukin (IL-)6 and IL-10, promote an imbalance in the Th1/Th2 ratio, resulting in a defective Th1 response [9]. Other immune defects include a reduction in the number of circulating dendritic cells [10] and increased levels of IL-10 and transforming growth factor (TGF)-beta, further impairing the T cell response [11].

In addition to specific defects in immunity, some MM-related complications increase the risk of infection. These include primarily renal failure [12], but also respiratory compromise caused by the collapse of thoracic vertebra and analgesic opiates, as well as decubitus ulcers and urinary tract retention secondary to paraparesis if spinal cord compression occurs. Multisystem involvement resulting from myeloma-associated deposition disease (amyloid light-chain [AL-] amyloidosis and light-chain deposit disease) [1] and iron overload also increase the risk of infection; iron overload is common among MM patients even during earlier disease stages [13]. Furthermore, MM affects mostly older adults, a population in whom immunosenescence and organ dysfunction are additional risk factors for infection [14].

Infection in the first months after diagnosis — Despite the introduction of various newer agents in the treatment of MM and the remarkable improvement in survival, a substantial proportion of patients still die in the first few months after diagnosis, before they have the opportunity to benefit from the effects of these agents. Using population-level data, a study conducted in the United States reported 28.6 percent mortality within the first year following diagnosis [15]. Another study analyzing 3107 MM patients entered into the United Kingdom Medical Research Council MM trials between 1980 and 2002 reported a 10 percent death rate within 60 days following diagnosis [16]. The most frequent cause of death was infection (45 percent), with pneumonia accounting for 66 percent of bacterial infections, followed by renal failure (28 percent) and vascular events (myocardial infarction or cerebrovascular accident; 8 percent).

The use of agents for MM that are cleared by the kidneys increases the risk of infection when used in patients with reduced renal function. As an example, a study comparing melphalan plus prednisone with cyclophosphamide plus prednisone in patients with renal impairment showed higher rates of infection and infection-related mortality in the melphalan arm; this was attributed to the poor renal clearance of melphalan [17]. In contrast, cyclophosphamide is not cleared by the kidney.

Irrespective of the chemotherapeutic regimen, tumor burden is another important determinant of the risk of infection, with higher infection rates occurring among patients with active disease as opposed to those in remission or in the plateau phase of the illness [18]. Indeed, a study reported that elevated baseline serum lactic dehydrogenase (which is a marker of tumor burden) was an independent risk factor for infection occurring in the first year post-diagnosis of MM in transplant noneligible patients (incidence rate ratio [IRR] 2.43, 95% CI 1.39-4.26). Smoking was the other risk factor for infection (IRR 2.11, 95% CI 1.12-3.98), while receipt of >6 cycles of therapy was protective (IRR 0.49, 95% CI 0.28-0.88) [19]. In addition to a high tumor burden, other important determinants of the risk of severe infection during this period are poor performance status and high comorbidity scores [20-22]. The predictors of early mortality (within one year from diagnosis) among 542 MM patients receiving novel agents were identified as age-adjusted Charlson comorbidity score (≥4), low body mass index (<20 kg/m²), thrombocytopenia, and renal failure [21]. The risk for early mortality was 4.1, 14.3, and 27.4 percent with no factor, 1 factor, or ≥2 factors, respectively [21]. Additional factors reported to be associated with early mortality from severe infection include hyperglycemia [23], lymphocytopenia, and low serum values of normal (nonmyeloma-associated) immunoglobulins [20].

A risk score model for early (within the first four months) infection in newly diagnosed patients with transplant noneligible MM was developed based on the analysis of 1378 patients and validated with data from three clinical trials [24]. Variables included in the model were serum beta-2 microglobulin ≤3 mg/L (-2 points), Eastern Cooperative Oncology Group (ECOG) performance status 0 (-1 point), hemoglobin ≤11 g/dL (1 point), ECOG performance status ≥2 (1 point), lactate dehydrogenase (LDH) ≥200 units/L (1 point), and serum beta-2 microglobulin ≥6 mg/L (2 points). The incidence of early infection in the high-risk group (2 to 5 points) was 24 percent compared with 7 percent in the low-risk group (-3 to 1 point), with a relative risk of 3.4.

Although the causative pathogens early after diagnosis vary according to local epidemiology, most reports indicate that gram-positive bacteria account for >50 percent of such infections [25,26], with S. pneumoniae and Staphylococcus aureus being the most common pathogens. Among gram-negative bacteria, Enterobacteriaceae (especially Escherichia coli) are the leading pathogens. In addition, with the introduction of bortezomib, herpes zoster became a frequent infection in the first months of therapy. (See 'Proteasome inhibitors' below.)

Cumulative immunosuppression — The increase in survival of MM patients is a result of the ability to salvage patients with relapse with repeated courses of novel agents, often in combination, sometimes given over years. However, these treatments result in a cumulative multifactorial immunosuppression with progressive reduction in CD4+, CD45+, CD19+, and NK cells [2].

Compounding the risk of infection at the advanced disease stage are iron overload, resulting from multiple transfusions [13], and significant tumor burden, causing neutropenia and hypogammaglobulinemia, as well as MM-related comorbidities, particularly renal failure, declining performance status, and increasing age [1]. This immunosuppression results in an increase in the frequency and severity of infections and a broadening of the spectrum of pathogens, including bacteria, fungi, viruses, mycobacteria, and parasites.

As MM progresses, host defenses become severely impaired, with profound T cell immunodeficiency, hypogammaglobulinemia, and neutropenia. As a result, the incidence of infection increases and the list of pathogens broadens, as shown in a cohort study evaluating infectious episodes in 199 MM patients [27]. The first peak of viral infections occurred around 4 to 6 months following diagnosis, while the second peak was not seen until around 52 to 54 months; for bacterial infections, the first peak occurred around 7 to 9 months following diagnosis, while the second peak occurred around 70 to 72 months. The majority of viral infections were herpes zoster (69.3 percent), herpes simplex (23.3 percent), and cytomegalovirus (CMV) reactivation (8.3 percent). Several risk factors for infection were identified during the latter peak of infection: number of prior treatment lines, intensive combination chemotherapy, intravenous cyclophosphamide, and the cumulative dose of glucocorticoids.

In two other studies from the same group, the epidemiology of respiratory viral infections and invasive fungal diseases were characterized. Most respiratory viral infections occurred in the setting of progressive myeloma, and receipt of more than three lines of therapy was the only risk factor identified. The most frequent viral pathogens were picornavirus (34.0 percent), parainfluenza (18.9 percent), respiratory syncytial virus (RSV; 18.9 percent), and influenza (11.3 percent) [28].

Recovery of some respiratory viruses may be common depending on local epidemiology. For example, a study evaluating RSV recovered from respiratory secretions (nasopharyngeal wash or bronchoalveolar lavage) in cancer patients (77 percent with MM) in a one-year period, RSV was identified in 37 percent of patients [29]. However, the rate of serious respiratory complications and death were not significantly different among RSV-positive and RSV-negative patients, suggesting that recovery of RSV may be frequent but does not always result in increased morbidity and mortality in this specific setting. Tracheobronchitis, however, was more common among the RSV-positive group.

Invasive fungal disease (IFD) and CMV infection are uncommon early in the course of treatment of MM. However, during the later phases of the disease, the risk for such infections increases because of cumulative immunosuppression from multiple courses of prior therapy [30,31].

In one study evaluating the epidemiology of IFD at a single center over a three-year period, an overall rate of 2.4 percent was reported but was as high as 15 percent among heavily pretreated patients (≥3 courses of therapy) [31]. IFD developed at a median of 35 months from diagnosis of MM, and molds accounted for the majority of cases [32]. A retrospective study evaluated 248 MM patients treated at a single institution and found an incidence of 5.6 percent of IFD. Invasive aspergillosis was the most frequent IFD [32]. Another study reported 98 episodes of invasive aspergillosis in MM patients [33]. Most patients (83 percent) had active MM, and aspergillosis was diagnosed at a median of 24 months from diagnosis of MM. Half of the patients developed invasive aspergillosis after chemotherapy and half following an autologous HCT. All but two patients were receiving glucocorticoids at a median cumulative prednisone equivalent dose of 1150 mg (range 0 to 7590 mg). The patients were severely immunosuppressed, with median CD4 counts of 189 cells per cubic mm and median serum levels of normal (total nonmyeloma-associated) immunoglobulins of 222 mg/dL [33].

Invasive pulmonary aspergillosis (IPA) in patients with MM may also occur as a result of cumulative immunosuppression, especially high doses of glucocorticoids and neutropenia. In such patients, the clinical manifestations may be mild, and imaging findings may not be typical of more advanced phases of IPA. Instead of macronodules with the halo sign, well-circumscribed infiltrates, air crescent, or a cavity, most patients present with subcentimeter centrilobular micronodules, ground-glass opacities, tree-in-bud infiltrates, and focal bronchiectasis [34]. (See "Epidemiology and clinical manifestations of invasive aspergillosis".)

Most cases of CMV reactivation remain asymptomatic in MM patients [35]. Accordingly, we do not recommend routine CMV viral load monitoring in MM patients. The most frequent setting of CMV reactivation in MM patients is after autologous HCT. Fever alone is the most frequent clinical manifestation of CMV reactivation. Organ invasion is unusual [36].

RISK OF INFECTION BASED ON MM THERAPY — The increased risk of infection in MM patients result from various defects in host defenses caused by the disease and its treatment [37].

Despite improvements in the outcome of patients with MM, a significant proportion of patients still die within the first months after diagnosis [15], and infection remains the leading cause of death [16]. Therefore, a pre-emptive or prophylactic approach management of infection during this period should be very aggressive, taking into consideration the most frequent sites of infection and pathogens. Early initiation of treatment with rapidly active anti-MM agents and immediate control of MM-related complications such as renal failure are paramount because these conditions may increase the risk of infection and death [38].

Conventional chemotherapy — Various chemotherapeutic regimens are used in the treatment of MM. Agents that are used frequently include melphalan (typically in patients who are not eligible for autologous hematopoietic cell transplantation [HCT]), cyclophosphamide, doxorubicin, vincristine, etoposide, cisplatin, and bendamustine [39,40]. These agents impair the immune system either by their toxic effect on the bone marrow, resulting in neutropenia, or by disrupting the mucosal barrier of the gastrointestinal tract. Agents such as cyclophosphamide and bendamustine have a potent suppressive effect on T and B cells [41,42].

In general, the risk of infection following conventional chemotherapy in MM patients is dependent on the degree of myelosuppression, mucositis, and B and T cell immunodeficiency resulting from a particular regimen. The risk is expected to be lower with regimens such as oral melphalan and prednisone and higher with regimens incorporating multiple agents, such as cisplatin, an anthracycline, and etoposide, or high doses of alkylating agents [43-45].

Dexamethasone — Dexamethasone is a key component in the treatment regimen for MM and is given during all phases of treatment. Dexamethasone exerts various inhibitory effects on the cells of the immune system, including T cells, B cells, dendritic cells, macrophages, monocytes, and neutrophils and inhibits the production of various cytokines, such as interleukin (IL-)1 through IL-6, IL-11, IL-16, interferon-gamma, and tumor necrosis factor (TNF)-alpha [46]. The inhibitory effects on cytokines result in an imbalance of Th1 and Th2 responses, reducing the inflammatory response to infection. Dexamethasone-induced hyperglycemia may further increase the risk of infection [47]. (See "Susceptibility to infections in persons with diabetes mellitus", section on 'Risk of infection' and "Glucocorticoid effects on the immune system".)

In general, the higher the cumulative dose of dexamethasone, the higher the risk of infection is. As an example, in a study of patients with newly diagnosed MM receiving lenalidomide with either a high-dose dexamethasone regimen (three cycles of four days each, every month) or a low-dose dexamethasone regimen (once a week), a significantly higher incidence of grade 3 to 4 infection occurred among recipients of the high-dose regimen [48]. In another study, higher disease stage and cumulative dose of dexamethasone were key predictors of severe infections during induction therapy [27]. The hazard ratios were 5.36, 7.67, and 9.38 for cumulative doses of 0 to 800 mg, >800 to 1600 mg, and >1600 mg, respectively [27].

The use of dexamethasone may be even more deleterious in older patients, as shown in a study in which higher rates of severe pyogenic infections were observed among patients 65 to 75 years of age receiving dexamethasone-based regimens compared with patients treated with standard melphalan and prednisone [49].

The use of high doses of dexamethasone is associated with an increased risk of infection overall [27] and a broadening of the spectrum of offending pathogens.

Once dexamethasone is incorporated into chemotherapeutic regimens, infection caused by a depression in T cell immunity is expected, including herpes simplex virus reactivation, herpes zoster, Pneumocystis pneumonia, and mucosal candidiasis [12].

Proteasome inhibitors — The proteasome inhibitors, bortezomib, carfilzomib, and ixazomib, exert various effects on the immune system, including depletion of CD4 T cells, impairment in the cytotoxic effects of CD8+ T cells and antibody-mediated B cell responses, decreases in various proinflammatory cytokines, and impairment in antigen presentation by dendritic cells [50].

Bortezomib increases the risk for reactivation of varicella-zoster virus. In a randomized trial of patients with relapsed or refractory MM, 13 percent of bortezomib recipients developed herpes zoster compared with 5 percent among patients treated with dexamethasone [51]. In another trial of newly diagnosed MM patients comparing melphalan, prednisone, and bortezomib with melphalan and prednisone, the incidence of herpes zoster was 13 and 4 percent, respectively [52]. The rate was reduced to 3 percent after the introduction of routine prophylaxis with acyclovir. The majority of cases of herpes zoster occur during the first three cycles of bortezomib [53].

Patients with MM have a high prevalence of hepatitis B virus (HBV) infection [54]. Patients with serologic evidence of HBV infection are at risk for HBV reactivation mainly if they receive high-dose chemotherapy with HCT and/or high-dose dexamethasone [55]. Whether proteasome inhibitors alone increase the risk of HBV reactivation or disease remains unclear.

The incidence of severe infection seems to be higher in patients receiving bortezomib as part of combination therapy. In a randomized trial comparing bortezomib, thalidomide, and dexamethasone with thalidomide and dexamethasone in relapsed MM, 10.5 percent of bortezomib recipients developed severe infection versus 5.4 percent in the control arm, a difference that was not statistically significant [56]. Lymphocytopenia appears to increase the risk of infection following bortezomib [57].

A study evaluated the frequency of cytomegalovirus (CMV) reactivation among 31 CMV seropositive patients with MM or amyloid light-chain amyloidosis receiving bortezomib-based regimens. Reactivation was detected in 12 patients (39 percent), 10 of which occurred after the first cycle of treatment. All patients were asymptomatic and five received treatment with valganciclovir [58].

While data regarding the risk of infection with the other proteasome inhibitors carfilzomib and ixazomib are limited, a class effect is expected, with a higher incidence of viral infections and impairment in antigen presentation [59]. In a randomized double-blind, placebo-controlled trial of ixazomib as maintenance after autologous HCT in patients with MM, the rate of herpes zoster in patients not on antiviral prophylaxis was 60 percent in the ixazomib arm and 26 percent in the placebo arm. Among patients receiving appropriate antiviral prophylaxis, the rates were 2 and <1 percent in the ixazomib and placebo arms, respectively [60].

A randomized study comparing carfilzomib plus dexamethasone with bortezomib plus dexamethasone in relapsed or refractory MM patients reported similar rates of infection in both arms [61]. In another trial, the rates of infection were similar among MM patients with relapsed disease receiving lenalidomide plus dexamethasone with or without carfilzomib [62]. By contrast, a randomized trial comparing carfilzomib plus dexamethasone maintenance versus observation after salvage autologous HCT reported a higher incidence of bacterial infections in carfilzomib-recipients (41 versus 26 percent) [63]. Finally, a meta-analysis of four randomized clinical trials involving 2985 patients in which carfilzomib was used in relapsed/refractory patients (three studies) and as first-line therapy (one study). Serious infection (defined as infections that were life threatening or resulted in death, inpatient hospitalization, extended hospital stay, or significant incapacity) was significantly more frequent in carfilzomib recipients (relative risk [RR] 1.40, 95% CI 1.17-1.69). Most infections occurred in the lower respiratory tract [64].

Other agents

Immunomodulatory drugs — Lenalidomide, pomalidomide, and, to a lesser extent, thalidomide, possess immunomodulatory effects, including T cell stimulation, resulting in an increase in the production of IL-2 and TNF-alpha, activation of NK cells, and suppression of regulatory T cells [65]. Lenalidomide also enhances CD8 responses to viral antigens [66]. The risk of infection with lenalidomide and pomalidomide is related to neutropenia [67,68].

The immunomodulatory drugs thalidomide, lenalidomide, and pomalidomide usually do not cause immunosuppression except neutropenia, which occurs mostly with lenalidomide and pomalidomide. Infections reported among MM patients treated with immunomodulatory drugs are generally neutropenia related and involve sites similar to those seen in MM patients in general, with a predominance of pneumonia and urinary tract infections [69].

A meta-analysis reviewed the safety data of lenalidomide from seven randomized trials and reported higher rates of neutropenia (RR 4.74, 95% CI 2.96-7.57) and infection (RR 1.98, 95% CI 1.50-2.62) with lenalidomide compared with placebo [70]. Another meta-analysis evaluated the RR of infection in phase II and III studies of immunomodulatory drugs given during different stages of therapy (18 studies with thalidomide, 7 with lenalidomide, and 1 with pomalidomide). The RR of severe infection with immunomodulatory drugs during induction therapy was 1.74 (95% CI 1.43-2.12) in non-HCT-eligible patients compared with 0.76 (95% CI 0.67-0.86) for HCT-eligible patients (thalidomide-only studies). During maintenance therapy and upon relapse, the RR was 1.74 (95% CI 1.34-2.26) and 1.51 (95% CI 1.18-1.93), respectively (four studies with thalidomide and three with lenalidomide) [71]. In a randomized trial comparing two doses of lenalidomide as maintenance therapy (25 mg versus 5 mg daily from day 1 to 21 of a 28-day cycle), grade ≥3 neutropenia was more frequent in the higher-dose arm (34.6, 24.3, and 12.8 percent in the first, second and third year of maintenance, respectively compared with 9 percent in the lower-dose arm). Likewise, the rate of grade ≥3 infections was higher in the 25 mg arm (12.3 versus 5.1 percent in the first year) [72].

Monoclonal antibodies

●Daratumumab – Daratumumab is an anti-CD38 monoclonal antibody. In a randomized trial, compared with patients receiving bortezomib and dexamethasone for relapsed or refractory MM, patients receiving these agents plus daratumumab were more likely to develop neutropenia and lymphocytopenia [73].

Combination therapy with and without daratumumab was evaluated in two phase III trials of patients with relapsed MM: bortezomib and dexamethasone in one [73], and lenalidomide and dexamethasone in the other [70]. When compared with controls, patients treated on the daratumumab arm of both studies had significantly higher rates of grade 3 to 4 neutropenia but not of severe infection [73,74]. A 3 percent rate of herpes zoster was reported [75].

In another study, newly diagnosed patients ineligible for autologous HCT were randomly assigned to receive bortezomib, melphalan, and prednisone with or without daratumumab [76]. The rate of grade 3 or 4 infection was significantly higher in daratumumab recipients (23.1 versus 14.7 percent). Pneumonia was the most frequent infection and its incidence was significantly higher in the daratumumab group (11.3 versus 4.0 percent). In another study, among 23 patients receiving daratumumab as salvage therapy, five developed infection associated with viral reactivation (herpes zoster, CMV, and varicella-zoster), with depletion of NK cells [77]. Another study showed a 340-fold increase in the risk of listeriosis in patients with MM receiving daratumumab [78].

A meta-analysis of five phase III randomized trials of daratumumab in patients with MM (two studies in relapsed/refractory and three in newly diagnosed patients) showed higher rates of infection overall (RR 1.27, 95% CI 1.13-1.44) and pneumonia (RR 1.63, 95% CI 1.08-2.45) in daratumumab recipients [79].

In a study of 100 MM patients treated with a daratumumab-based regimen, the rate of infection requiring hospitalization was significantly higher among patients who developed severe lymphocytopenia, defined as an absolute lymphocyte count <500/mcgL (44 versus 22 percent in patients without severe lymphocytopenia). In addition, Epstein-Barr virus or CMV reactivation and fungal meningitis occurred only in patients with severe lymphocytopenia [80].

●Elotuzumab – Elotuzumab is a humanized IgG1 monoclonal antibody that targets the signalling lymphocyte activation molecule 7 (SLAMF7), a surface glycoprotein highly expressed on the surface of myeloma cells, normal plasma cells, and on NK cells. It stimulates NK cell-mediated antibody-dependent cellular cytotoxicity through CD16.

Information about elotuzumab-associated infections is also scarce. In one study, pretreated MM patients were randomly assigned to receive lenalidomide and dexamethasone with or without elotuzumab [81]. The rates of neutropenia (34 percent in elotuzumab recipients versus 44 percent in the control arm) and infection (81 versus 74 percent) were similar in both arms, although lymphocytopenia (77 versus 49 percent) and herpes zoster (4.1 versus 2.2 episodes per 100 patient-years) were more frequent among elotuzumab-treated patients [81]. By contrast, in a randomized study comparing bortezomib, lenalidomide, and dexamethasone with or without elotuzumab in untreated MM patients, the frequency of grade ≥3 infection was higher in the elotuzumab arm (17 versus 8 percent) [82].

Because elotuzumab is administered with other immunosuppressive agents (eg, dexamethasone plus bortezomib or lenalidomide) to patients who have failed other lines of therapy, the attributable risk of infection is confounded by the coadministration of other immunosuppressive agents in the context of progressive or relapsed disease.

●Isatuximab – Isatuximab is another anti-CD38 monoclonal antibody approved for the treatment of relapsed/refractory MM. In a randomized trial comparing isatuximab plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone, the frequency of grade 3 to 4 neutropenia was 85 percent in the isatuximab arm and 70 percent in the control arm [83]. Likewise, the use of granulocyte colony-stimulating factor and infections in the context of neutropenia were more frequent in the isatuximab arm (69.1 versus 53 percent, and 25 versus 19.5 percent, respectively). The frequency of upper respiratory tract infections was also higher in isatuximab recipients (28 versus 17 percent). In another randomized trial in relapsed/refractory MM patients comparing carfilzomib plus dexamethasone with or without isatuximab, the frequency of grade ≥3 neutropenia and respiratory infections (mainly pneumonia) was higher in the isatuximab arm (19 versus 7 percent and 32 versus 24 percent, respectively) [84]. As with daratumumab, listeriosis may also occur in patients receiving isatuximab [85].

●Belantamab mafodotin – Belantamab mafodotin (withdrawn from United States market) is a monoclonal antibody-drug conjugate that targets B cell maturation antigen (BCMA) and has been approved for the treatment of relapsed/refractory MM. A phase 2 study compared two regimens of belantamab mafodotin in heavily pretreated MM patients. Grade ≥3 neutropenia was observed in 9.5 percent of patients receiving the low dose and 15 percent in recipients of the higher-dose regimen. Grade ≥3 pneumonia occurred in 4 percent in the low dose and in 11 percent in the high-dose cohort, including two fatal cases [86].

●Teclistamab – Teclistamab is a bispecific monoclonal antibody authorized for the treatment of relapsed/refractory MM. It targets BCMA on myeloma cells and CD3 on T cells to recruit and activate T cells to kill BCMA-expressing MM cells. In a phase 1-2 study of 165 patients who had relapsed or refractory MM after at least three therapy lines (including immunomodulatory drugs, proteasome inhibitors and anti-CD38 monoclonal antibodies) a high rate of deep and durable response to teclistamab was observed. The rate of grade ≥3 neutropenia, infection and pneumonia were 64.2 percent, 44.8 percent, and 12.7 percent, respectively [87]. A grade 1-2 cytokine release syndrome, which may be difficult to differentiate from a sepsis syndrome, was observed in 73 percent at a median of two days post-dose (See "Cytokine release syndrome (CRS)".)

The degree of humoral immunodeficiency and infection rates were evaluated in 42 patients with relapsed/refractory MM receiving bispecific antibodies (86 percent of whom received anti-BCMA antibodies). Severe hypogammaglobulinemia was present at baseline in 49 percent of patients. During therapy the serum levels of IgG, IgA, and IgM were very low, with undetectable levels of IgG in 28 percent of patients. The cumulative incidence of infection increased with increasing duration of therapy: 41 percent at 3 months, 57 percent at 6 months, and 67 percent at 12 months. Most infections were of bacterial etiology (54 percent), followed by viral (41 percent) and fungal (5 percent). Most patients were heavily pretreated and were therefore at high risk for severe infections. On multivariate analysis, ongoing bispecific monoclonal antibody therapy, prior infection, low baseline functional IgG levels and elevated serum M-spike levels were independently associated with infection. Notably, an increasing rate of seroconversion with COVID-19 booster vaccination was observed [88].

Deacetylase inhibitors — Panobinostat (withdrawn from the United States market) inhibits histone deacetylation in myeloma cells, promoting apoptosis. The main effect of panobinostat on the immune system is neutropenia [81]. Limited data are available about infectious complications in patients receiving panobinostat.

A randomized trial comparing bortezomib and dexamethasone with either panobinostat or placebo in pretreated MM patients reported higher rates of lymphocytopenia in patients treated with panobinostat (53 versus 40 percent) but similar rates of infection [89]. Pneumonia occurred in 17 percent in the panobinostat arm and 13 percent in the placebo arm [89].

Nuclear export inhibitors — Selinexor targets exportin-1, a nucleo-cytoplasmic transport protein responsible for the nuclear export of tumor suppressor proteins, growth regulators, and oncogenic proteins [90], and has been approved by the US Food and Drug Administration for the treatment of MM patients who have received at least four prior therapies. In a phase II study, grade 3 to 4 neutropenia occurred in 21 percent of patients, leading to treatment interruption in 11 percent. Pneumonia (11 percent) and sepsis (9 percent) were the most frequent serious adverse events [91]. A randomized clinical trial compared bortezomib plus dexamethasone with or without selinexor in relapsed/refractory MM patients. Neutropenia was more frequent in the selinexor arm (15 versus 6 percent for any grade and 9 versus 3 percent grade ≥3 neutropenia, respectively). Infection occurred in 69 and 58 percent in the arms with and without selinexor, respectively. The difference was driven by a higher incidence of upper respiratory and urinary tract infections in selinexor recipients [92]. In a systematic review of seven clinical trials of selinexor, the overall incidence of severe infections was 17.8 percent, with pneumonia and upper respiratory tract infections being the most commonly reported infections [93].

Autologous HCT — Autologous hematopoietic cell transplantation (HCT) is a major component of the treatment approach to MM, and high-dose melphalan is the usual agent used in the conditioning regimen [94]. During the first two weeks following HCT, the primary immune defect is profound neutropenia that typically lasts for about one week, as well as gastrointestinal mucositis [95]. While neutropenia occurs in every MM patient after high-dose melphalan, the rate and severity of mucositis is variable and may be related to genetic susceptibility [96]. After engraftment, T cell immunodeficiency predominates [94], and T cell immune reconstitution is slow and may be affected by the subsequent therapies given to control MM. Patients in whom MM is controlled after autologous HCT and who receive maintenance therapy with lenalidomide may have a more efficient immune reconstitution because of the immune stimulatory effects of lenalidomide [65,66]. However, upon MM relapse, salvage therapies further impair the immune system, including T cell immunity [2].

The conditioning regimen for most MM patients undergoing autologous HCT is melphalan based, and the duration of neutropenia and risk of infectious complications are predictable. With the 140 to 200 mg/m² conditioning regimen, patients become neutropenic on approximately day +4 after transplant and recover around day +10 to 12. During neutropenia, bacteremia is the most frequent infection, and pathogens and susceptibility profiles follow local patterns. In general, however, E. coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa account for the majority of gram-negative bacteremias, while most gram-positive infections are caused by coagulase-negative staphylococci, S. aureus, and viridans group streptococci. Clostridioides difficile infection may be a concern, depending on the local epidemiology and patient's risk factors, such as recent antibiotic use and prior history of C. difficile infection [97]. The occurrence, duration, and severity of mucositis increase the risk of infection among autologous HCT recipients [95,98,99]. In one study, prior exposure to bortezomib may have increased post-HCT infection [100].

After engraftment, herpes zoster is the most frequent infection. While CMV reactivation is not uncommon, CMV disease remains rare [101]. In one study, pretransplant use of bortezomib or immunomodulatory drugs (eg, lenalidomide) was a risk factor for symptomatic CMV reactivation (mostly fever) [35]. No patient developed end-organ CMV disease [35].

In one study evaluating 1906 MM patients who received autologous HCT, infection was the most common cause of nonmyeloma related mortality. Infection-related morality declined significantly over time: the 10-year cumulative incidence of infection-related mortality was 14.9 percent in the period between 1989 and 1999, 10.4 percent between 2000 and 2005, and 6.1 percent between 2006 and 2014. Patients receiving novel agents before transplant were at a lower risk for infection-related mortality [102].

The risk of infection in HCT recipients is discussed in greater detail separately. (See "Overview of infections following hematopoietic cell transplantation".)

Chimeric antigen receptor-T cell therapy — Chimeric antigen receptor (Car)-T cell therapy is increasingly used to treat relapsed/refractory B-cell malignancies including MM, with encouraging results. However, these therapies are associated with serious toxicities, including a cytokine-release syndrome, immune effector cell-associated neurotoxicity syndrome, and infection [103]. Idecabtagene vicleucel BCMA Car-T therapy has been approved in the treatment of patients with MM.

A single-center retrospective study described infectious complications in 55 MM patients treated with BCMA Car-T cell therapy. The median time from diagnosis of MM to Car-T cell therapy was 6.8 years, with a median of six lines of therapy (including HCT in 89 percent of patients). Most patients received antibacterial, antiviral, antifungal, and anti-Pneumocystis prophylaxis after Car-T cell therapy. There were 47 infection events: 25 viral (all caused by respiratory viruses), 19 bacterial (5 bloodstream infections), and 3 fungal (2 aspergilloses). Most infections were mild (13 percent) or moderate (79 percent) and occurred in the first 100 days post-Car-T cell therapy (15 percent in the first 30 days). No specific risk factors were identified. Only one death (aspergillosis) was attributed to infection [104].

Long-term B cell immunodeficiency is frequent in patients with MM receiving BCMA Car-T cell therapy. A cross-sectional study evaluated serum levels of pathogen-specific IgG against 12 vaccine-preventable infections >6 months after Car-T cell therapy in 54 patients receiving CD19-targeted Car-T and 11 MM patients receiving BCMA Car-T. MM patients were less likely to have adequate IgG serum levels [105].

PREVENTION OF INFECTION — Prevention of infection in patients with MM involves the recognition of the likely pathogens according to past medical history, local epidemiology, the status of MM, and the current phase of treatment. The treatment phases in patients eligible for autologous hematopoietic cell transplantation (HCT) are induction, followed by consolidation with autologous HCT, post-consolidation treatment, and maintenance. Patients not eligible for autologous HCT receive an induction phase, followed by maintenance therapy until disease progression. Once the disease progresses, patients receive different salvage regimens to control MM [7]. Antimicrobial prophylaxis is recommended in certain settings.

Antibacterial prophylaxis — As noted above, patients with MM are at significant risk of bacterial infection during the first year of therapy and particularly during the first three months of therapy. In addition, since infection is a major contributor to the 10 percent early mortality in MM [16], antimicrobial prophylaxis is recommended in order to reduce early mortality [38]. (See 'Infection in the first months after diagnosis' above.)

Based on data from randomized trials [106-108], especially the largest randomized trial [108], we recommend antibacterial prophylaxis with levofloxacin (500 mg orally once daily) in the first three months of treatment to all newly diagnosed MM patients (table 1). Following this period, a prophylactic strategy based on an assessment of the individual patient's risk for infection may be warranted. We generally continue antibacterial prophylaxis in patients who fail to respond to 3 to 4 cycles of induction chemotherapy until the disease is under control, with a significant reduction in tumor burden. For those who respond to treatment, we do not recommend prophylaxis routinely unless the patient experiences repeated episodes of bacterial infection.

Antibacterial prophylaxis for patients receiving salvage therapy should be individualized, taking into consideration the degree of cumulative immunosuppression, serum levels of uninvolved immunoglobulins, history of recent bacterial infection, and neutropenia induced by the anti-myeloma regimen (including the conditioning regimen before autologous HCT). For patients with serum IgG <400 mg/dl who experience repeated episodes of infections, we give amoxicillin 500 mg once daily. Likewise, fluoroquinolone prophylaxis (ciprofloxacin 500 or 750 mg twice daily or levofloxacin 500 or 750 mg once daily) should be considered if the patient received a regimen expected to cause prolonged (>7 days) neutropenia. (See "Prevention of infections in hematopoietic cell transplant recipients", section on 'Antibacterial prophylaxis' and "Prophylaxis of infection during chemotherapy-induced neutropenia in high-risk adults", section on 'Antibacterial prophylaxis'.)

Three randomized trials have evaluated the effect of antibacterial prophylaxis in newly diagnosed MM patients. The first trial compared trimethoprim-sulfamethoxazole (TMP-SMX) 160/800 mg every 12 hours daily for two months to no prophylaxis in 54 newly diagnosed MM patients [106]. Bacterial infections occurred in 2 of 28 patients (7 percent) in the TMP-SMX group versus 11 of 26 patients (42 percent) in the control group (a statistically significant difference), with rates of 0.29 episodes per patient-year for TMP-SMX recipients and 2.43 per patient-year for controls.

Another prospective randomized trial that included 212 patients compared ciprofloxacin (500 mg orally twice daily) to either TMP-SMX (160/800 mg twice daily) given for two months or no prophylaxis [107]. Severe infections were observed in 12.5 percent of ciprofloxacin recipients, 6.8 percent of TMP-SMX recipients, and 15.9 percent of placebo recipients; these differences were not statistically significant.

Antibacterial prophylaxis has also been evaluated in a randomized trial that included 977 newly diagnosed patients [108]. Levofloxacin prophylaxis (500 mg orally once daily) during the first 12 weeks of therapy was associated with a lower rate of first febrile episode or death than placebo (19 versus 27 percent; hazard ratio 0.66, 95% CI 0.51-0.86). There were similar acquisition rates in the two groups for carriage of C. difficile, extended-spectrum beta-lactamase-producing gram-negative bacteria, and methicillin-resistant S. aureus. The use of TMP-SMX (three times per week) as prophylaxis for Pneumocystis jirovecii pneumonia was permitted and was given to 159 patients in the levofloxacin group and in 155 in the placebo group. Cox regression analysis showed treatment with levofloxacin was the most important factor in reducing febrile episodes or death and also that receipt of TMP-SMX was associated with a reduction in febrile episodes or death, independent of the use of levofloxacin.

In a retrospective study, the rate of severe infection was 17.5 percent in 80 patients receiving bortezomib-containing regimens (41 as induction therapy) who received levofloxacin prophylaxis compared with 30.9 percent among patients in the historical control group [109].

Pneumocystis prophylaxis — Because pneumonia due to P. jirovecii may be potentially fatal, patients receiving dexamethasone as a second- or subsequent line of therapy for relapsed or refractory MM should receive trimethoprim-sulfamethoxazole (one double-strength tablet daily or three times a week) [110]. The duration of prophylaxis is not established, although prophylaxis should probably be continued in patients with persistent severe T cell immunodeficiency [45] as occurs in patients who do not respond to treatment or present with progressive disease requiring dexamethasone-containing regimens to control the disease. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV".)

Varicella-zoster virus and herpes simplex virus prophylaxis — Varicella-zoster virus (VZV)- and herpes simplex virus (HSV)-seropositive patients receiving a proteasome inhibitor (bortezomib, carfilzomib, ixazomib) are at high risk for herpes zoster and HSV infections and should receive antiviral prophylaxis with acyclovir or valacyclovir before starting treatment with any of these agents (table 1) [111,112]. It has been suggested that antiviral prophylaxis be continued until six weeks after discontinuation of proteasome inhibitors [45]. The duration of prophylaxis should take into account the patient's net state of immunosuppression (cumulative immunosuppression) and whether other agents associated with an increased risk for herpes zoster (including the conditioning regimen given in autologous HCT) are subsequently given.

We also give antiviral prophylaxis to all HSV- or VZV-seropositive patients receiving antimyeloma regimens containing elotuzumab, isatuximab, or daratumumab [113]. The occurrence of herpes zoster seems also to be related to the cumulative immunosuppression that follows various treatment lines, including autologous HCT. In such situations, the decision for anti-VZV prophylaxis should be individualized.

Hepatitis B prophylaxis and pre-emptive therapy — Patients with MM and a history of hepatitis B virus (HBV) infection are at risk for HBV reactivation and a flare up of their HBV disease during immunosuppressive treatment. The degree of risk for HBV reactivation depends on the HBV serostatus and the type and duration of immunosuppressive therapies used [54,55].

We recommend testing for evidence of HBV infection prior to initiating immunosuppressive therapies for MM. Testing consists of HBV surface antigen (HBsAg) and HBV core antibody (anti-HBc) as well as circulating HBV deoxyribonucleic acid (DNA) in HBV-seropositive patients. (See "Hepatitis B virus: Screening and diagnosis in adults".)

Patients with moderate to high risk for HBV reactivation (ie, patients who are HBsAg positive receiving any immunosuppressive therapy, including autologous HCT, high cumulative dexamethasone dose, or conventional cytotoxic chemotherapy) should receive antiviral prophylaxis prior to commencing anti-MM therapy. In patients with HBV reactivation, delaying myeloablative therapy and HCT is strongly recommended, when possible, until the infection has been controlled [114].

Pre-emptive therapy is reserved for patients whose risk for reactivation is lower (ie, those with HBsAg negative and anti-HBc positive receiving any form of immunosuppressive therapy).

Patients with evidence of a low level of circulating HBV DNA may be given antiviral therapy or be closely monitored and treated if evidence of increasing viremia, regardless of the serum level of alanine aminotransferase (ALT). Tenofovir or entecavir are preferred, with the former favored in patients with prior exposure to lamivudine [45,114,115]. Antiviral therapy should be maintained for several months and is best directed by the level of HBV viral load and the continuous therapy with immunosuppressive agents.

A study evaluated 139 patients receiving bortezomib, 27 of whom were positive for HBs antigen [116]. Lamivudine or entecavir was given to 22 patients, starting before chemotherapy until at least six months after completion of chemotherapy or autologous HCT. Reactivation occurred in 6 of these 27 patients (22.2 percent). In five, HBV reactivation occurred at a median of 392 days post-transplant. Four of these five patients had discontinued antiviral prophylaxis at the onset of HBV reactivation, two of whom died of fulminant hepatitis [56]. These data suggest that routine screening for HBV should be performed in patients whose treatment plan includes bortezomib and that anti-HBV agents should be given prophylactically to HBV-infected patients.

Hepatitis B infection in immunocompromised patients is discussed in greater detail separately. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy".)

Antifungal prophylaxis — We do not routinely give prophylaxis for oral thrush in patients receiving dexamethasone because the disease can be treated easily when diagnosed. Likewise, although the risk for invasive fungal infections, particularly invasive aspergillosis, is increased late in the course of MM, we do not routinely give mold-active antifungal prophylaxis in this setting, as the incidence is not high (<1 percent).

Immunoglobulin replacement — As noted above, patients with MM have hypogammaglobulinemia and an increased risk of infection caused by encapsulated bacteria [5]. Offering firm recommendations about the use of intravenous immunoglobulin (IVIG) in MM patients is challenging for several reasons. These include the lack of contemporary data supporting its use, its high cost and limited availability, the protection conferred by newer antimicrobial agents, and the potential for IVIG-related severe complications in MM patients including acute kidney injury [117].

We prefer a targeted approach to IVIG prophylaxis, limiting its use to MM patients whose serum IgG levels are below 400 mg/dL and who suffer severe and recurrent infections caused by encapsulated bacteria (or other infections thought to be due to hypogammaglobulinemia), despite appropriate antimicrobial prophylaxis and immunization. Another potential consideration may be for patients with poor antibody production, especially to pneumococcal vaccines.

The evidence supporting the use of IVIG in MM patients is based on a single study conducted in the early 1990s in which 82 patients with stable MM were randomly assigned to receive monthly IVIG at 0.4 g/kg or placebo for one year [118]. Chemotherapy was only mildly immunosuppressive, and no antibiotic prophylaxis was given. Treatment with IVIG resulted in a significantly lower incidence and recurrence of severe infections. As part of the study, 54 were vaccinated with the 23-valent pneumococcal polysaccharide vaccine (PPSV23) before antineoplastic therapy and had their specific IgG responses measured. Poor pneumococcal IgG antibody response identified the patients who benefited the most from IVIG. On this basis, IVIG was recommended for plateau-phase MM patients with hypogammaglobulinemia and recurrent bacterial infections who fail to respond to pneumococcal immunization. However, this trial was conducted in the early 1990s, before the era of high-dose therapy and autologous HCT and the novel treatments. The spectrum of infections in MM patients has significantly changed since, and more potent antimicrobial agents are now available that are likely to obviate the need for IVIG. Moreover, two studies of prophylactic IVIG in MM patients undergoing HCT failed to show a reduction of infections, when IVIG was given during the peri-transplant [119] or the post-transplant phase [120], suggesting that IVIG may not provide additional protection beyond antimicrobial prophylaxis. An alternative route for Ig replacement is the subcutaneous route [121].

Immunizations — There are very limited data regarding the clinical effectiveness of vaccines in MM patients. Because of the T cell immunodeficiency that these patients have throughout the course of their disease, live attenuated vaccines are generally contraindicated.

On the other hand, inactivated vaccines are safe and likely effective. Hence, these should be given as early as possible, including during very early and stable phases such as monoclonal gammopathy of unknown significance and smoldering myeloma [122]. Response to vaccination may be improved if vaccines are given when MM is well controlled (plateau phase) or upon immune reconstitution [123], especially with the concomitant use of lenalidomide [124,125].

Considering the high mortality rate associated with infections during the first months after diagnosis of MM and the contribution of various comorbidities to the risk of infection, prevention of these complications relies on an aggressive control of noninfectious conditions and the early initiation of treatment for MM [38]. Because S. pneumoniae is a predominant pathogen, particularly during this phase, patients should receive the pneumococcal conjugate and polysaccharide vaccines as early as possible and ideally before initiation of therapy. The schedule for vaccination is summarized in the following tables (table 2 and table 3) and discussed in detail separately. (See "Pneumococcal vaccination in adults", section on 'Approach to individuals at highest risk of pneumococcal disease'.)

MM patients should also receive an influenza vaccine annually (see "Seasonal influenza vaccination in adults"). Response to vaccination may be improved if vaccines are given when MM is well controlled (plateau phase) or upon immune reconstitution [123], especially with the concomitant use of lenalidomide [124,125].

As stated above, herpes zoster is a major complication in MM patients, occurring during different phases of disease. Based on the results of a large trial showing that the recombinant zoster vaccine (RZV) is safe and effective in autologous HCT recipients (53 percent of whom had MM), we favor vaccination of autologous HCT recipients who have MM with RZV according to the schedule used in the trial (first dose given 50 to 70 days following transplant and second dose given one to two months later) [126]. In the trial, two doses of RZV reduced herpes zoster episodes, postherpetic neuralgia, and other herpes zoster-associated complications compared with placebo. These data are discussed in greater detail separately. (See "Immunizations in hematopoietic cell transplant candidates and recipients", section on 'Zoster vaccine'.)

A randomized trial compared the immunogenicity of RZV with placebo in >500 patients with hematologic malignancies, 23 percent of whom had MM [127]. The adjusted geometric mean ratio of vaccine versus placebo was 29.75 (95% CI 21.09-41.96). There were 2 cases of herpes zoster among vaccine recipients and 12 among placebo recipients. RZV was tested in another trial that included 69 MM patients at various stages of treatment (median number of therapy lines 1, ranging from 1 to 7), including prior autologous HCT [128]. Seroconversion from baseline was observed in 81.3 percent and 89.5 percent after one and two doses, respectively. The vaccine was well tolerated, with only one patient reporting skin reaction after the first dose, without subsequent reaction with the second dose. These data suggest that the recombinant zoster vaccine is safe and efficacious in MM patients.

Vaccines that are recommended for immunocompromised patients are summarized in the following figure (figure 1). Immunizations in patients with cancer and HCT candidates and recipients are also discussed in greater detail separately. (See "Immunizations in adults with cancer" and "Immunizations in hematopoietic cell transplant candidates and recipients".)

Immunogenicity of the influenza vaccine may be poor in MM patients. Two doses of the high-dose inactivated trivalent influenza vaccine were given to 51 patients with monoclonal gammopathies (49 had MM) with significant production of antibodies in 49 percent after the first dose and 65 percent following the second dose [129]. We recommend vaccinating all MM patients with seasonal influenza vaccine. Although currently available inactivated influenza vaccines are recommended, the high-dose influenza vaccine (Fluzone High-Dose) appears to give the best protection without an increase in adverse events compared with the other formulations [129]. In addition, vaccination of household contacts and health care workers is important for reducing the risk of influenza in MM patients. (See "Immunizations in adults with cancer", section on 'Influenza vaccine' and "Seasonal influenza vaccination in adults".)

Patients with MM have an impaired immune response to coronavirus disease 2019 (COVID-19) vaccines compared with individuals without MM. A study evaluated the production of neutralizing antibodies after two doses of BNT162b2 or AZD1222 COVID-19 vaccines in 276 patients with plasma cell neoplasms (213 with symptomatic MM, 38 with smoldering MM, and 25 with monoclonal gammopathy of undetermined significance [MGUS]) and 226 controls matched for age and gender. Four weeks after the second dose of vaccine, patients with plasma cell neoplasms had significantly lower antibody titers compared with controls. The immune response was inferior inpatients with MM compared with MGUS. Among patients with MM receiving active treatment, the immune response was most impaired in patients receiving daratumumab or belantamab mafodotin [130]. In another study, response to COVID-19 vaccine was evaluated in 320 MM patients who received one of the two messenger ribonucleic acid (mRNA) vaccines. Significantly lower antibody titers were observed in patients receiving daratumumab and BCMA-targeted therapies [131].

Because MM patients receiving BCMA Car-T cell therapy have prolonged B-cell immunodeficiency, these patients should theoretically benefit from vaccination after Car-T cell therapy. However, studies evaluating the safety and effectiveness of vaccination are lacking.

COVID-19 vaccines and recommendations for vaccination in patients with cancer are discussed in detail separately. (See "COVID-19: Vaccines".)

Because of the significant complications of HBV infections in patients with MM, consideration may be given to pretreatment administration of the recombinant HBV vaccine or the combined inactivated HepA-HepB vaccine to patients and nonimmune family and close contacts who are at increased risk for HBV infection. Settings in which the risk for HBV infection is increased include travel to areas of high endemicity, behavioral/occupational exposure, chronic liver disease, and hemodialysis.

Myeloid growth factors — Myeloid growth factors, such as granulocyte colony-stimulating factors (G-CSF), are indicated in afebrile patients in whom the anticipated risk of fever and neutropenia is ≥20 percent [132]. The use of G-CSF to prevent treatment delays should be decided on an individualized basis. (See "Use of granulocyte colony stimulating factors in adult patients with chemotherapy-induced neutropenia and conditions other than acute leukemia, myelodysplastic syndrome, and hematopoietic cell transplantation".)

Autologous HCT — Patients with MM who undergo autologous hematopoietic cell transplantation (HCT) should receive antimicrobial prophylaxis as recommended for HCT recipients, as discussed separately. (See "Prevention of infections in hematopoietic cell transplant recipients".)

COVID-19 CONSIDERATIONS — Patients with MM are likely at higher risk for severe outcomes associated from COVID-19 based on their immunosuppression and the presence of certain comorbidities (eg, renal disease) [133-135]. Like other immunocompromised patients, the immune response to vaccination is lower and an extended dosing schedule is recommended. Management and vaccination are discussed separately. (See "COVID-19: Considerations in patients with cancer" and "Society guideline links: COVID-19 – Hematology care (including hematologic malignancies and transplantation)" and "COVID-19: Management of adults with acute illness in the outpatient setting" and "COVID-19: Management in hospitalized adults" and "COVID-19: Vaccines".)

EVALUATION FOR INFECTION — Fever in patients with MM should be considered of infectious origin until proven otherwise. Noninfectious causes of fever may occasionally be due to the disease itself or to venous thromboembolism (VTE). Tumor fever is likely to be present in heavily pretreated patients with active MM and is usually accompanied by elevated serum levels of C-reactive protein and lactic dehydrogenase [136,137]. The presence of VTE, including deep vein thrombosis with or without pulmonary thromboembolism, should be considered in patients with fever, especially in those at increased risk including those who received an immunomodulatory drug (eg, lenalidomide) and prophylactic recombinant erythropoietin [138].

A noninfectious fever may also develop during the engraftment syndrome, coinciding with marrow recovery among autologous hematopoietic cell transplant (HCT) recipients [139], as well as with the administration of hematopoietic growth factors and with cytokine release syndrome (eg, teclistamab or CAR-T).

The evaluation for infections in patients with MM should generally focus on the most frequently involved sites in this patient population, typically the lungs, bloodstream, skin and soft tissues, and the urinary tract [27]. Other key considerations include the likely pathogen(s) (which depends on the patient's exposures, comorbidities [particularly renal failure], and local epidemiology) and, most importantly, the patient's net state of immunosuppression. The latter factor is usually related to disease and treatment phase (induction versus HCT consolidation, maintenance or salvage for relapse/refractory disease), the current treatment regimen, and the extent and intensity of prior therapy.

The diagnostic evaluation starts with a detailed medical history, with emphasis on previous infections and local epidemiologic factors. Physical examination should be comprehensive, with careful attention to the airways, skin, and the digestive tract. Blood should be collected for cultures, C-reactive protein, and renal and liver function tests. Also, testing for cytomegalovirus (CMV) reactivation using antigenemia or polymerase chain reaction (PCR) should be considered in heavily pretreated patients or after a second HCT, provided that the patient is CMV seropositive [2,36]. These patients should also be monitored for invasive aspergillosis with serum Aspergillus galactomannan antigen testing [34]. The role of 1,3-beta-D-glucan in this setting is yet to be determined. (See "Overview of diagnostic tests for cytomegalovirus infection" and "Approach to the diagnosis of cytomegalovirus infection" and "Diagnosis of invasive aspergillosis".)

Additional testing depends on the clinical scenario. For patients with respiratory manifestations, chest and sinus high-resolution computerized tomography (CT) scans, nasopharyngeal swab or wash for respiratory viruses (influenza, parainfluenza, respiratory syncytial virus, adenovirus, human metapneumovirus), and direct exam and stains/cultures of sputum or other respiratory secretions may be obtained. The presence of abdominal complaints and diarrhea should prompt stool samples for C. difficile testing and, depending on the setting, cultures and PCR for enteric pathogens, and microscopic and other tests for parasites. Persistent fever of undetermined etiology despite a comprehensive workup should prompt a review of the most recent fludeoxyglucose (FDG) positron emission tomography (PET)-CT scan performed or consideration of an FDG PET-CT scan, which may help identify the location(s) and extent of infected sites [140,141].

Because infection caused by S. pneumoniae may be fatal if not adequately treated, MM patients with fever should receive empiric antimicrobial therapy, which includes empiric coverage against this pathogen [1]. Empiric antibiotic therapy is also essential during episodes of neutropenic fever [132]. (See "Overview of neutropenic fever syndromes" and "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)".)

Reactivation of hepatitis B virus (HBV) may be clinically silent, manifesting as an increase in HBV DNA and serum aminotransferase levels, but patients may also present with nausea and vomiting, which can progress to fulminant hepatic failure and death [55]. Reactivation of HBV can also lead to an interruption of anti-MM therapy, with a potentially negative impact on the underlying disease.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Multiple myeloma" and "Society guideline links: Neutropenic fever in adults with cancer".)

SUMMARY AND RECOMMENDATIONS

●Risk of infection − Infection is a major complication and a leading cause of death in patients with multiple myeloma (MM). The risk of infection is due to a multifactorial immunodeficiency caused by the disease itself and the treatment regimens. Significant progress in the management of MM has occurred, resulting in marked improvement in survival. As a consequence, MM has transformed into a chronic disease, with multiple relapses and salvage therapies. As the disease progresses, patients experience cumulative immunosuppression and the list of possible infections broadens. The recognition of this cumulative immunosuppression is a major factor in the proper management of infectious complications in MM. (See 'Introduction' above.)

●Immune defects − In newly diagnosed MM patients, the primary immune defect is B cell immunodeficiency, manifested by hypogammaglobulinemia and an increased risk of infection caused by encapsulated bacteria, including Streptococcus pneumoniae and Haemophilus influenzae. Lymphocytopenia and neutropenia secondary to bone marrow infiltration further increase the possibility of infection. Also, cytokines released by myeloma cells, such as interleukin (IL-)6 and IL-10, promote an imbalance in the Th1/Th2 ratio, resulting in a defective Th1 response. Other immune defects in MM include a reduction in the number of circulating dendritic cells and increased levels of IL-10 and transforming growth factor (TGF)-beta, further impairing the T cell response. (See 'Untreated patients' above.)

●MM-related complications and risk of infection − In addition to specific defects in immunity, some MM-related complications increase the risk of infection. These include renal failure, respiratory compromise caused by the collapse of thoracic vertebra and analgesic opiates, as well as decubitus ulcers and urinary tract retention secondary to paraparesis if spinal cord compression occurs. Multisystem involvement resulting from myeloma-associated deposition disease (amyloid light-chain [AL-] amyloidosis and light-chain deposit disease) and iron overload also increase the risk of infection. In addition, MM affects mostly older adults, a population in whom immunosenescence and organ dysfunction are additional risk factors for infection. (See 'Untreated patients' above.)

●Types of infections − Viral and bacterial infections predominate in patients with MM, with septicemia, pneumonia, cellulitis, and pyelonephritis being the most common types of bacterial infections and respiratory viral infections including influenza and herpes zoster being the most common types of viral infections. Although the causative pathogens early after diagnosis vary according to local epidemiology, most reports indicate that gram-positive bacteria account for >50 percent of such infections, with S. pneumoniae and Staphylococcus aureus being the most common pathogens. Among gram-negative bacteria, Enterobacteriaceae (especially Escherichia coli) are the leading pathogens. (See 'Epidemiology' above.)

●Infections associated with MM treatment

•Dexamethasone increases the risk for herpes simplex virus (HSV) reactivation, herpes zoster, Pneumocystis pneumonia, and mucosal candidiasis. (See 'Dexamethasone' above.)

•The proteasome inhibitors such as bortezomib increase the risk for herpes zoster and HSV reactivation. (See 'Proteasome inhibitors' above.)

•Infections reported among MM patients treated with the immunomodulatory drugs lenalidomide and pomalidomide are generally neutropenia related and involve sites similar to those seen in MM patients in general, with a predominance of pneumonia and urinary tract infections.

•Infectious complications from other agents, autologous hematopoietic cell transplantation (HCT), and chimeric antigen receptor T cell therapy are discussed above. (See 'Other agents' above and 'Autologous HCT' above and 'Chimeric antigen receptor-T cell therapy' above.)

●Vaccinations − Because S. pneumoniae is a predominant pathogen in MM patients, particularly in newly diagnosed patients, we recommend that patients with MM receive the pneumococcal conjugate and polysaccharide vaccines as early as possible and ideally before initiation of therapy (table 2 and table 3) (Grade 1B). MM patients should also receive an influenza vaccine annually. We suggest vaccination with recombinant zoster vaccine for autologous HCT recipients with MM (Grade 2B). Other vaccines should be given according to the usual schedule for cancer patients or HCT candidates or recipients. (See 'Antibacterial prophylaxis' above and 'Immunizations' above and "Immunizations in adults with cancer" and "Immunizations in hematopoietic cell transplant candidates and recipients".)

●COVID-19 considerations − Patients with MM are likely at higher risk for severe outcomes associated from COVID-19 based on their immunosuppression and the presence of certain comorbidities (eg, renal disease). Like other immunocompromised patients, the immune response to vaccination is lower and an extended dosing schedule is recommended. Management and vaccination are discussed separately. (See "COVID-19: Considerations in patients with cancer" and "Society guideline links: COVID-19 – Hematology care (including hematologic malignancies and transplantation)" and "COVID-19: Management of adults with acute illness in the outpatient setting" and "COVID-19: Management in hospitalized adults" and "COVID-19: Vaccines".)

●Antibacterial prophylaxis − We recommend antibacterial prophylaxis with levofloxacin for all MM patients during the first three months of therapy (Grade 1B). Patients are at highest risk for bacterial infections during the first three months of MM therapy and during therapy for relapsed or refractory disease. (See 'Antibacterial prophylaxis' above.)

●Pneumocystis prophylaxis − For patients receiving dexamethasone as a second- or subsequent line of therapy for relapsed or refractory disease, we recommend Pneumocystis prophylaxis with trimethoprim-sulfamethoxazole (Grade 1B). (See 'Pneumocystis prophylaxis' above.)

●Antiviral prophylaxis − For varicella-zoster virus- and/or herpes simplex virus-seropositive patients receiving a proteasome inhibitor, elotuzumab, isatuximab, or daratumumab, we recommend antiviral prophylaxis with acyclovir or valacyclovir (Grade 1B). (See 'Varicella-zoster virus and herpes simplex virus prophylaxis' above.)

●Dosing of prophylactic agents − Dosing information for each of the agents used for prophylaxis is summarized in the following table (table 1).