Invasive fungal infections in patients with multiple myeloma: a possible growing problem in hematology and infectious diseases

Abstract

Multiple myeloma is among the most common hematological malignancies and is characterized by a strong susceptibility to infections primarily bacterial and viral and, to a much lesser extent, fungal. There appears to be a slightly increasing frequency of invasive fungal infections. This is attributed to the use of different combinations of newer drugs and patients’ exposure to increasing therapeutic lines, and thus to risk factors for invasive fungal infections, especially severe and long-term neutropenia. Novel immunotherapy modalities including bispecific antibodies and chimeric antigen receptor T-cell therapy are being introduced for the treatment of relapsing-refractory forms of the disease. Consequently, in the near future, it can be expected that myeloma patients will exhibit a significantly increased frequency of invasive fungal infections. Therefore, we must carefully monitor all epidemiological trends related to invasive fungal infections in patients with multiple myeloma, both in clinical studies and in real life. This will help us learn to prevent fungal infections, as well as quickly recognize and treat them to reduce their impact on patients’ morbidity and mortality. In this review article, we describe in detail the epidemiological characteristics of invasive fungal infections in myeloma patients, the risk factors for these infections, and the treatment and prevention options.

Multiple myeloma and infections

Multiple myeloma (MM) is one of the most common, incurable, malignant hematological neoplasms. It arises from the malignant transformation of plasma cells and is characterized by monoclonal protein production and damage to target organs. An important clinical feature of this disease is marked immunosuppression, and consequent susceptibility to infections, which are a common cause of death in patients with MM. A large population study demonstrated that patients with MM have a 7-fold higher risk of bacterial infections and a 10-fold higher risk of viral infections, compared to the corresponding control group. ¹ Infections with gram-positive and gram-negative pathogens occur with a similar frequency. ² The most common causative agents are gram-negative bacteria from the Enterobacteriaceae family and gram-positive bacteria from the Streptococcus spp. and Staphylococcus spp., while the most common viral causative agents are the varicella-zoster virus (VZV) and the influenza virus.^1,2 The causes of immunosuppression are numerous, as this disease affects nearly every compartment of the immune system (Table 1). Patients with MM often exhibit reduced production of normal immunoglobulins due to a lack of healthy plasma cells, as well as reduced numbers and/or function of neutrophils, B and T lymphocytes, NK cells, dendritic cells, and macrophages. ³ These immune disorders are caused by the disease itself, that is, due to bone marrow infiltration by malignant plasma cells and multicausal suppression of healthy hematopoiesis and immunopoiesis but also by the drugs used for MM treatment, all of which can impair normal immune system functioning in different ways.^4,5

Table 1.

The causes of immunodeficiency in patients with multiple myeloma.

Immunodeficiency in multiple myeloma: caused by the disease itself and different drugs
Hypogammaglobulinemia (immunoparesis)
Decreased number and function of B cells
Decreased number and function of T cells
Decreased number and function of NK cells
Decreased number and function of dendritic cells
Neutropenia

Patients’ susceptibility to infection is greatest when the tumor burden is large (i.e. when MM is not well-controlled by therapy) meaning that the infection risk is highest a few months after the discovery of the disease, when antitumor therapy has just been started, and during disease relapse, when the tumor mass is again large.^6,7 During remission and maintenance therapy, the infection risk is significantly lower, but it is always present and poses a lifelong threat to patients. Another time when patients are particularly susceptible to infections is when patients receive autologous transplantation of hematopoietic stem cells, before the recovery of hematopoiesis. Numerous risk factors for infection have been identified. Our group found that the most important factors affecting infections in patients with MM included advanced disease stage, kidney failure, elevated serum ferritin, neutropenia, poor general condition, and the presence of a catheter. ² Other authors have identified additional risk factors for infection, including elevated lactate dehydrogenase, anemia, and decreased numbers of lymphocytes or CD56⁺ cells in peripheral blood.^6–11

The current treatment for MM involves combinations of different groups of drugs – primarilyproteasome inhibitors (PIs) (e.g. bortezomib, carfilzomib, or ixazomib); immunomodulatory drugs (IMIDs) (e.g. thalidomide, lenalidomide, or pomalidomide); monoclonal antibodies (MABs) (e.g. daratumumab, isatuximab, or elotuzumab); and glucocorticoids (dexamethasone), which are a component of almost every treatment regimen. Therapeutic regimens increasingly also include different types of immunotherapy (e.g. bispecific antibodies). Chimeric antigen receptor (CAR) T-cell therapy has yielded very promising results and will likely become an important treatment modality in the near future, especially for relapsing-refractory disease. PIs and glucocorticoids have substantial immunosuppressive effects, leading to decreased numbers and functions of T and NK cells, which increases the risk of different infections, especially those caused by viral agents, such as the VZV virus. ⁴ Furthermore, in their meta-analysis, Wongsaengsak et al. ¹² showed that carfilzomib-based protocols are associated with a significantly increased risk of infections, especially in the respiratory tract. When using protocols based on bortezomib and carfilzomib, the reported frequency of severe infections is up to 20%, while the risk of severe infections appears to be somewhat lower with ixazomib treatment.^5,12–15 Several meta-analyses show that IMIDs increase the risk of serious infections, although it is not yet clear what mechanism causes this susceptibility to infections, apart from neutropenia. In most clinical studies that used protocols based on thalidomide and lenalidomide, the percentage of serious infections ranged from 7% to 23%, and with the use of pomalidomide up to 30%.^5,16–18

When using regimens involving MABs (mainly anti-CD38 monoclonal antibodies), the frequency of severe infections ranges from 11% to 31%, depending on the combination of drugs applied, and whether other treatments have been previously administered. Anti-CD38 antibodies deplete not only tumor plasma cells but also healthy ones that produce immunoglobulins, as well as NK cells and cytotoxic T lymphocytes, which all contribute to lymphopenia, a risk factor for infections.^19,20 Monoclonal antibodies mainly increase the likelihood of developing respiratory tract infections and pneumonia, as well as viral infections, such as VZV reactivations/infections.^21–24 Little et al. published an overview of invasive fungal infections (IFI) and targeted therapies in hematological malignancies. For some targeted drugs, such as BTK inhibitors and PI3K inhibitors, that are used to treat hematological tumors (chronic lymphocytic leukemia and lymphomas), there are strong signals that they can increase the risk of IFI. On the other hand, there are currently no such warning data for monoclonal antibodies used for MM treatment (e.g. daratumumab and elotuzumab). ²⁵ In clinical studies, treatment with bispecific antibodies and CAR T-cell therapy is associated with high infection rates, which is a consequence of these drugs’ immunosuppressive effects on immunocompetent cells, as well as the neutropenia they cause. However, in clinical studies involving these drugs, the high incidence of infections is also caused by significant previous overtreatment of the patients involved. For example, among overtreated relapsed-refractory myeloma patients treated with teclistamab, the frequency of all infections was 76.4%, and the frequency of grade 3–4 infections was 44.8%. ²⁶

Risk factors for IFI in hematological neoplasms

Although bacterial and viral infections are the most common causes of death in patients with hematological neoplasms and infections, IFI are also of great medical importance due to their frequency and mortality. ²⁷ Among the causative agents of IFI in immunocompromised patients, the most common are yeasts (mainly Candida spp.) and molds (mainly Aspergillus spp.), while other fungal pathogens (e.g. Zygomycetes, Mucorales, Fusarium spp., Cryptococcus spp., and others) occur much less frequently. ²⁷ In patients with hematological neoplasms, the most common causative agent of IFI is Aspergillus spp., which results in significant mortality. ²⁸ Fungi are opportunistic agents of infection, which can cause IFI in humans (especially in those who are immunocompromised) in the presence of certain risk factors that facilitate the onset of infection. Risk factors for IFI can be best investigated in acute leukemia and hematopoietic stem cell transplantation, where fungal infections are the most common. The known risk factors are related to the applied therapy, patient characteristics, and environmental factors, and they somewhat differ for molds versus yeasts, as well as among various hematological malignancies. ²⁹

The most important risk factor for IFI is neutropenia (its severity and duration) because neutrophils are crucial for the initiation of an acute inflammatory response against fungal agents and for the resorption of the inflammatory infiltrate itself. IFI risk is significantly higher if severe neutropenia (<0.5 × 10⁹/L) lasts longer than 10 days, if the long-lasting neutropenia is extremely severe (<0.1 × 10⁹/L), and if the patient does not receive antifungal prophylaxis. ³⁰ Neutropenia is most often caused by chemotherapy and other antitumor therapies that have a myelosuppressive effect, although it can also be caused or worsened by bone marrow infiltration of the disease itself. In addition to neutropenia, other treatment-related risk factors for IFI include long-lasting monocytopenia (monocytes ⩽ 0.1 × 10⁹/L) and lymphopenia (lymphocytes ⩽ 0.1 × 10⁹/L).^31–34 Long-term use of glucocorticoids at high doses which is often used for the treatment of hematological tumors, especially lymphoproliferative, as well as in transplant patients with graft-versus-host disease damages cell-mediated immunity by suppressing the functions of lymphocytes, macrophages, and neutrophils.^32–35 Various monoclonal antibodies (e.g. anti-CD20 or anti-CD52 antibodies), bendamustine, and purine analogs also lead to long-term lymphocyte depletion, increasing the risk of IFI.^36,37 Iron is of utmost importance for fungal pathogen virulence and IFI pathogenesis, supporting fungal pathogen growth and survival in various ways. ³⁸ Therefore, iron overload (most often caused by frequent blood transfusions) is also an important risk factor for IFI in hematological patients, especially those who have undergone allogeneic hematopoietic stem cell transplantation.^39–43 Finally, another substantial treatment-associated risk factor for IFI (especially caused by Candida spp.) is mucositis of the oral cavity and intestines, which can be caused by chemotherapy-induced damage to epithelial cells, especially if it is severe and long-lasting.^34,44

Other IFI risk factors are related to patient characteristics including age >65 years, poorer performance status, high comorbidity index (especially the burden of chronic lung diseases and diabetes), and active cigarette smoking. Active flared disease and disease with multiple relapses are also risk factors in some hematological neoplasms.^31,44 Evidence also suggests that genetic factors may influence IFI susceptibility. Seo et al. ⁴⁴ reported a ninefold lower risk of invasive aspergillosis among people with the ACC haplotype, which is associated with reduced production of interleukin-10 (a cytokine involved in the immune response), and a higher incidence of infections in people with the ATA haplotype, which is associated with increased interleukin-10 production. Likewise, Sainz et al. ⁴⁵ showed that variations in TNFa production (which is highly genetically determined) play a significant role in the propensity to develop pulmonary aspergillosis, among patients with hematological diseases.

Environmental factors are the last group of IFI risk factors in hematological patients, especially in patients with acute leukemias and those who underwent transplantation, who exhibit the highest incidence of fungal infections. Known environmental risk factors for IFI include construction and reconstruction work performed near where the patient stays; lack of high-efficiency particulate air filters in the patient’s rooms; patient’s occupational history (e.g. construction work, farming or gardening, or direct contact with pets or potted plants and flowers); history of previous aspergillosis or colonization with Aspergillus spp.; and previous multisystemic colonization with Candida spp.^32,44

IFI in multiple myeloma

In patients with MM, IFIs occur with a low incidence, generally less than 5%. Earlier studies reported IFIs in less than 1% of patients with MM^28,46; however, it seems that the use of newer generations of IMIDs and PIs has led to a slightly increased incidence. Teng et al. ⁴⁷ reported that invasive fungal disease occurred in 2.8% of patients with plasma cell neoplasms. Teh et al. ⁴⁸ observed an IFI rate of 2.4%, including an 0.8% rate of invasive mold infection. In another study, Lim and colleagues found IFI in 3.4% of patients with MM treated with combinations of newer drugs, including monoclonal antibodies (daratumumab, isatuximab, and elotuzumab), PIs, and IMIDs of newer generations (carfilzomib and pomalidomide). ⁴⁹ More specifically, Lim et al. ⁴⁹ reported a 2.3% incidence of IFI in patients treated with new-generation PIs and IMIDs, and a 7% incidence of IFI among patients with MM treated with therapies including monoclonal antibodies, which can likely be primarily explained by more frequent and deeper neutropenia but also by lymphopenia due to monoclonal antibodies. It appears that the IFI incidence does not significantly differ when using PIs and IMIDs of the first generation versus newer generations of these drugs.^46,50,51

No data are yet available regarding the IFI frequency in MM patients treated with bispecific antibodies or CAR T-cell therapy. Yang et al. ⁵² demonstrated that an increased risk of breakthrough IFI within 60 days after CAR T infusion was associated with ventilation (low-flow nasal cannula oxygenation, high-flow nasal cannula or mask oxygenation, and mechanical-assisted ventilation), high-grade cytokine release syndrome, and prolonged lymphocyte deficiency among patients with hematologic malignancies (including MM). The IFI incidence may further increase in this group of patients treated with new immunotherapy modalities, considering that these drugs have a strong immunosuppressive effect, causing neutropenia and lymphopenia and that they are mainly used in extremely overtreated patients.

Regarding the causative agents of IFI in patients with MM, Candida spp. and Aspergillus spp. are predominant (as expected in hematological tumors), while other fungal agents are less common. In a series of patients with MM in Taiwan, Tsai et al. found that the most common causes of IFI were yeasts (68.2%), including a high predominance of Candida spp., while the causative agents were molds in 31.8% of patients, with a predominance of Aspergillus spp. ⁵³ Among 2960 patients with MM treated with newer drugs, Baneman et al. ⁵⁴ reported 9 proven and 21 probable IFIs (including 19 invasive aspergillosis, 5 candidemia, 3 cryptococcosis, 1 talaromycosis, 1 mucormycosis, and 2 other IFIs). However, the spectrum of fungal pathogens is changing significantly in all immunocompromised patients, including those with MM.

With regards to yeast, non-albicans Candida spp. infections are becoming more common. In a cohort of transplant and cancer patients, Oto et al. reported that Candida bloodstream infections were most commonly caused by the following non-albicans Candida spp.: Candida glabrata (38%), followed by C. parapsilosis (19.2%), C. tropicalis (12.6%), C. krusei (10.7%), C. lusitaniae (5.7%), and C. guilliermondii (4.4%). They also reported a 30-day mortality rate of 40% and found that 4.5% of patients had additional non-albicans Candida spp. isolates. ⁵⁵ The multicenter retrospective observational Epidemiological Surveillance of Infections in Hematological Diseases (SEIFEM) study analyzed 133 candidemia episodes among patients with hematological tumors, between 2011 and 2015. The results showed a predominance of species other than C. albicans (66.9%) with C. parapsilosis identified in 26.3% of episodes, C. glabrata in 12.0%, C. krusei in 10.5%, C. tropicalis in 9.8%, and uncommon species in 8.3% of episodes while C. albicans accounted for the remaining 33.1% of episodes. ⁵⁶ In addition, C. kefyr is an emerging pathogen among patients with hematologic malignancies, which shows prominent summer seasonality. ⁵⁷ In a study of Kuwait hospitals, Khan et al. ⁵⁸ reported a 1.2% prevalence of C. dubliniensis among bloodstream Candida spp. isolates, supporting a global trend of the epidemiology of candidemia shifting in favor of non-albicans Candida spp. The results of an earlier study demonstrated that hematological neoplasms and prior exposure to antifungal drugs are independent predisposing factors for uncommon yeast species infections. ⁵⁹ In the above-mentioned studies, the most common infection localizations are the lungs, blood, and paranasal sinuses, and disseminated diseases.^49,53

In terms of IFI-related mortality, Tsai et al. ⁵³ showed that MM patients with IFI had poorer overall survival compared to patients without IFI and that mortality did not significantly differ according to whether the fungal infection was caused by yeasts or molds. Older studies have shown very high mortality (up to 60%) in cases of IFI, especially aspergillosis, among patients with MM. ⁶⁰ Importantly, more recent studies including patients treated with newer drugs have still found high mortality rates from systemic fungal infections. Teh et al. ⁴⁸ reported a 30-day all-cause mortality rate of 44% in their patient cohort, while Liu et al. ⁵⁰ found an 11.7% mortality rate among Chinese patients with MM and probable or possible IFI.

The risk factors for IFI in MM patients correspond, in principle, to those identified in cases of other hematological tumors. The confirmed risk factors in myeloma patients include severe and long-lasting neutropenia (<0.5 × 10⁹/L neutrophils for over 10 days), active and aggressive disease, numerous previous lines of therapy (three or more), previous IFI, treatment with bortezomib, and high glucocorticoid doses (⩾0.5 mg/kg/day of prednisolone or equivalent over 4 weeks).^43,48,50,61 Tsai et al. ⁵³ reported that albumin of <3.5 g/L, hemoglobin of <80 g/L, light chain disease, and allogeneic hematopoietic stem cell transplantation are also significant risk factors for IFI in patients with MM. Liu et al. ⁵⁰ studied MM patients, and univariate analysis showed that greater IFI risk was significantly associated with prior history of IFI, deep vein thrombosis, catheterization, broad-spectrum antibiotic use for >7 days, hepatic dysfunction, decreased serum albumin, and the absence of antifungal prophylaxis; however, only a prior history of IFI retained prognostic significance in their multivariate analysis. Figure 1 presents risk factors for IFI in various hematological tumors. It could be expected that autologous hematopoietic stem cell transplantation would be a risk factor for IFI in MM because it is associated with temporary neutropenia. However, previous analyses have not supported this possible association, likely due to the widespread prophylactic use of fluconazole during this type of treatment and because the period of severe neutropenia is not much longer than 2 weeks in most patients.^49,53

Figure 1.

Described risk factors for invasive fungal infections in hematological tumors and multiple myeloma.

Diagnosis, treatment, and prophylaxis of IFI in MM

The diagnostic approach and treatment for myeloma patients with IFI do not differ from those in other malignant hematological diseases. There remain several unsolved problems regarding IFI diagnosis in patients with malignant hematological diseases, including MM. One issue is the small number of infections that are proven based on evidence of a fungal pathogen in a tissue biopsy. Such evidence can be difficult to obtain in hematological patients, due to an inaccessible localization of the fungal focus, the patient’s poor general condition, or an increased risk of bleeding due to refractory thrombocytopenia. High-resolution computed tomography is a generally accepted imaging method for diagnosing fungal pneumonia (most often caused by Aspergillus spp., much less often by Mucorales). However, such diagnosis is based on evidence of nodular lesions, air-crescent signs, and cavitary lesions, and thus this method lacks specificity because IFIs can also present with alveolar consolidations, nonspecific infiltrates, or ground-glass opacities. ⁶² Moreover, the proof of a positive biochemical fungal marker can also be doubtful in MM, as confirmed by Ko et al., ⁶³ who found that up to 25.5% of patients with MM had a false-positive galactomannan test. Another serum marker, 1-3-beta-d-glucan (BDG), can be detected in most cases of IFIs (except Mucorales, Blastomyces, and most Cryptococci), with lower sensitivity in invasive aspergillosis compared to candidiasis. ⁶⁴ However, BDG is not specific for any fungal pathogen and thus must be used in combination with other diagnostics [radiology, polymerase chain reaction (PCR), culture-based tests, and non-culture-based tests] and clinical presentation. Among hematological patients, the specificity of BDG can be increased by obtaining two consecutive positive assays and by avoiding testing if there are factors that lead to false-positive results, for example, prior treatment with immunoglobulins, albumins, beta-lactam antibiotics, pegylated asparaginase, or hemodialysis; concomitant bacterial infections with Pseudomonas spp., Nocardia spp., or Streptococcus pneumoniae Type 37; chronic renal disease; end-stage liver disease or severe mucositis. ⁶⁴ False-negative results can be caused by prior antifungal prophylaxis and treatment, hyperbilirubinemia, C. parapsilosis and C. auris infections, or infection of poorly vascularized sites. ⁶⁴ Sterile fluids (e.g. cerebrospinal fluid) are suitable for BDG testing if there is suspicion of central nervous system involvement but, unfortunately, bronchoalveolar lavage is not suitable material for BDG testing. ⁶⁴ Finally, although PCR is a very promising method for diagnostic confirmation of IFI from various samples (especially bronchoalveolar lavage), it is not yet sufficiently standardized in terms of protocols for DNA extraction and PCR assays. ⁶⁵

Several types of antifungal drugs (such as polyenes, azoles, echinocandins) are now available for use in clinical practice to treat infections caused by molds and yeasts. It is critically important to suspect, detect, and start treating fungal infections as soon as possible, thereby preventing the growth and spread of the fungal focus. Despite the growing number of systemic antifungal drugs, resistant fungal strains, and breakthrough infections are rising problems, prompting a great need to discover new groups of drugs. A large prospective epidemiological study established the occurrence of triazole-resistant Aspergillus fumigatus in many European countries. The prevalence ranged from 0% to 26% among different centers, with an overall triazole resistance rate of 3.2%. ⁶⁶ Resistance can develop as a result of azole application during patient treatment (patient route), or after environmental exposure of A. fumigatus to fungicides (environmental route). Mutations responsible for resistance are most often in Cyp51A genes, although other mechanisms of resistance have been described. ⁶⁷

Data from the United States showed that 7% of all Candida blood samples tested at the Centers for Disease Control and Prevention were resistant to fluconazole, and 1.6% were resistant to echinocandins. Resistance was a relatively rare phenomenon in C. albicans and was much more common in other species, particularly C. auris, C. glabrata, and C. parapsilosis. ⁶⁸ Posteraro et al. reported that 42.1% of patients with hematological malignancies and single-species candidemia episodes developed breakthrough candidemia, even though most of these patients were administered prophylaxis based on azoles, especially fluconazole and posaconazole. C. krusei has most commonly shown resistance to fluconazole. ⁵⁶ Puerta-Alcalde et al. analyzed 121 episodes of breakthrough IFI (41 proven, 53 probable, and 27 possible) among patients with malignant hematological diseases and who underwent hematopoietic stem cell transplantation. They reported that invasive aspergillosis (predominantly caused by non-fumigatus Aspergillus spp.) was the most frequent breakthrough IFI (45.5% of all episodes), followed by candidemia (19%), mucormycosis (5.8%), other molds (5%), and other yeasts (4.1%). ⁶⁹ Azole resistance/non-susceptibility was commonly found, and the previously used antifungal drug was most often changed to liposomal amphotericin-B. The overall 100-day mortality rate was 47.1%. ⁶⁹ Furthermore, a study of 197 adult patients with hematological tumors, who were prophylactically treated with isavuconazole, demonstrated a significant frequency of breakthrough IFI (8.3%), predominantly caused by Aspergillus spp. but also by other pathogens (Candida spp. and Mucor). ⁷⁰

One particularly worrying pathogen is C. auris, a potentially multidrug-resistant yeast showing resistance to fluconazole (less often to echinocandins and amphotericin B). Some isolates of this yeast, which harbor several specific mutations, reportedly cause high mortality in immunocompromised patients, including those with MM. ⁷¹ Another cause of concern is Magnusiomyces-associated breakthrough infections in patients with hematological malignancies, which lead to high mortality, and occur during prophylaxis with posaconazole and echinocandins. ⁷²

The potential for treatment-resistant IFIs means that the most prominent IFI risk factor, neutropenia, should be consistently prevented and treated with granulocyte growth factor. In addition, severe hypogammaglobulinemia should be managed with immunoglobulin, although there is currently no evidence that immunoglobulin can prevent IFI in patients with MM. Patients should be advised to avoid staying in houses that are undergoing construction work or in areas near construction sites, to avoid spending too much time in gardens and forests, and to not engage in agricultural work. IFI prophylaxis is not routinely recommended in patients with MM who are in some phase of treatment. However, in patients with MM and long-term and severe neutropenia, the prophylactic use of drugs directed against Aspergillus spp. (e.g. posaconazole) should be considered, always with consideration of possible drug interactions. The recommendations from the most recent international guidelines can be summarized as follows: posaconazole remains the drug of choice for mold-active prophylaxis in high-risk hematological patients; voriconazole is an alternative agent; isavuconazole is not recommended as a first-line prophylactic drug but can be considered if other azoles are contraindicated (e.g. due to QTc prolongation); and micafungin can be considered if azole use is not suitable (contraindicated) or there are concerns about drug absorption.^73,74 Finally, patients treated with autologous hematopoietic stem cell transplantation, in whom short-term severe neutropenia is expected, can receive prophylactic fluconazole until hematological recovery, especially if mucositis develops.

Conclusion

MM involves great immune damage at all levels, caused both by the disease itself and by the applied therapies. While bacterial and viral infections are a frequent and serious threat to patients with MM, the frequency and clinical importance of IFIs in this hematological neoplasm are less pronounced compared to some other hematological diseases. Notably, it seems that the most important risk factor for IFI severe and prolonged neutropenia is not as common among patients with MM, compared to patients with acute leukemias, myelodysplastic syndrome, or who receive allogeneic stem cell transplantation. Although neutropenia is often encountered in patients with MM, it is usually not severe or long-lasting.

However, the treatment of MM is dynamically changing such that the average patient lives longer and is subjected to a greater lifetime number of therapeutic lines than was previously the case. Now, the key treatment is becoming immunotherapy such as with CAR T-cell therapy and bispecific antibodies (as monotherapy or in combination with conventional drugs). Importantly, the most common side effects of these treatments include neutropenia and lymphopenia. Along with a greater number of previous lines of treatment (which also cause myelosuppression), increased use of immunotherapy will certainly increase the frequency of IFI among patients with MM. Therefore, it is critical to carefully monitor the epidemiological data and frequency of IFI among patients with MM treated with new therapeutic options, both in clinical studies and in real life. Such analyses will improve our ability to recognize trends and respond to them in time, especially with antifungal prophylaxis, given that IFIs still carry a significant mortality risk.