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. Author manuscript; available in PMC: 2024 Dec 1.
Published in final edited form as: Br J Haematol. 2023 Jun 7;203(5):736–746. doi: 10.1111/bjh.18909

Recommendations on Prevention of Infections during Chimeric Antigen Receptor T-Cell and Bispecific Antibody Therapy in Multiple Myeloma

Meera Mohan 1, Rajshekhar Chakraborty 2, Susan Bal 3, Anoma Nellore 4, Muhamed Baljevic 5, Anita D’Souza 1, Peter G Pappas 4, Jesus G Berdeja 6, Natalie Callander 7, Luciano J Costa 3
PMCID: PMC10700672  NIHMSID: NIHMS1918566  PMID: 37287117

Abstract

Chimeric antigen receptor T (CAR T) cell and bispecific antibody therapies (BsAb) have shown unprecedented efficacy in heavily pretreated patients with multiple myeloma (MM). However, their use is associated with a significant risk of severe infections, which can be attributed to various factors such as hypogammaglobulinemia, neutropenia, lymphopenia, T-cell exhaustion, cytokine-release syndrome (CRS), and immune-effector cell-associated neurotoxicity syndrome (ICANS). As these therapies have been recently approved by regulatory agencies, it is crucial to establish practical guidelines for infection monitoring and prevention until robust data from prospective clinical trials become available. To address this issue, a panel of experienced investigators from the Academic Consortium to Overcome Multiple Myeloma through Innovative Trials (COMMIT) developed consensus recommendations for mitigating infections associated with CAR T-cell and bispecific antibody therapies in MM patients.

Graphical abstract

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Introduction

T-cell redirecting immunotherapies have revolutionized the treatment of relapsed/refractory multiple myeloma (MM), the 3 most promising targets thus far being B-cell maturation antigen (BMCA) (Bahlis, et al 2022, Berdeja, et al 2021, Hansen, et al, Mi, et al 2023, Moreau, et al 2022, Munshi, et al 2021, Raje, et al 2019, Rodriguez-Otero, et al 2023, Wong, et al 2022, Zhang, et al 2023, Zonder, et al 2021), G protein–coupled receptor, family C, group 5, member D (GPRC5D) (Carlo-Stella, et al 2022, Chari, et al 2022, Mailankody, et al 2022) and Fc receptor-homolog 5 (FcRH5) (Li, et al 2017, Trudel, et al 2021). So far, the most effective drug classes targeting these cell surface antigens are bispecific T-cell engaging antibodies (BsAbs) and chimeric antigen receptor T (CAR T)-cell therapy. While the unprecedented efficacy of BsAb and CAR T-cell therapy in heavily pre-treated MM is encouraging, a signal for high risk of severe infections as well as infection-related deaths have emerged in clinical trials and real-world studies (Berdeja, et al 2021, Chari, et al 2022, D’Souza, et al 2022, Mohan, et al 2022, Moreau, et al 2022, Munshi, et al 2021). The underlying mechanism leading to the increased risk of infections appears to be multifactorial and includes profound hypogammaglobulinemia due to plasma cell aplasia, cytopenias (neutropenia and lymphopenia), and T-cell exhaustion (Fenwick, et al 2019, Philipp, et al 2022). These elements are a consequence of such therapies, as well as immunosuppression produced by the underlying disease and previous therapies (Blimark, et al 2015). A fundamental difference between BsAb and CAR T-cell therapy is the duration of treatment, with the former being prolonged or continuous therapy and the latter being a one-time therapy, typically given without maintenance treatment.

Following the regulatory approval of these agents, we anticipate there will soon be an increase in the uptake of these novel agents globally. High risk of infectious complications with CAR-T cell and BsAb therapies are well recognized (Fishman, et al 2019), and we are in dire need of practical recommendations while robust data based on prospective clinical trials can be generated. In the current article, we review the literature, identify the knowledge gap and provide an expert consensus on infection monitoring and prophylaxis strategies in the context of novel CAR T-cell and BsAb therapy. The main scope of this draft is to supplement current clinical practices informed by prospective studies.

Data Collection and consensus development

We conveyed a panel of experienced investigators from the Academic Consortium to Overcome Multiple Myeloma through Innovative Trials (COMMIT) to review the literature and formulate recommendations for the mitigation of infections associated with CAR T-cell and BsAb in MM. Four investigators searched reported data from clinical trials of CAR T-cell and BsAb since 2017 utilizing PubMed. This search was supplemented by review of abstracts presented at the American Society of Hematology, American Society of Clinical Oncology and European Hematology Association annual meetings for the last 5 years. Retrieved manuscripts and abstracts were further triaged to identify non-redundant primary report of clinical trials (N=17). Next, we summarized the incidence of characteristics of infection complications in these studies and drafted mitigating recommendations. Summary of data and proposed recommendations were reviewed by a series of teleconferences. Once consensus was developed, the final draft was reviewed by 2 infectious disease experts (A.N. and P.G.P) who provided additional edits and endorsed the final document. Due to the scarceness of high-level evidence, the recommendations were intentionally not graded and should be interpreted as expert opinion.

Mechanisms of Immunosuppression

Hypogammaglobulinemia, an on-target off-tumor toxicity of BsAb and CAR T-cell therapies in MM, is an important driver of increased infection risk. The antigens, BCMA (Shah, et al 2020), GPRC5D (Smith, et al 2019) and FCRH5 (Li, et al 2017) are expressed on almost all normal plasma cells, which makes it extremely difficult to avoid hypogammaglobulinemia when using highly effective therapies that target one or more of these antigens. Additionally, BCMA is essential for survival of long-lived plasma cells, further explaining profound plasma cell aplasia seen with BCMA-targeted therapies (O’Connor, et al 2004). Notably, both BsAb and CAR T-cell therapy led to profound and prolonged hypogammaglobulinemia (Hammons, et al 2022, Wang, et al 2021b). In the pivotal KarMMa trial (Idecabtagene vicleucel / ide-cell, CAR T-cell), any-grade hypogammaglobulinemia was reported in 5% of patients at ≤ 8 weeks, 16% of patients at >8 weeks and ≤6 months, and 2% of patients at >6 months (Munshi, et al 2021). In the MajecTEC-1 study, 75% of the patients who received treatment with teclistamab exhibited hypogammaglobulinemia, which is probably a consequence of prolonged plasma cell aplasia resulting from continuous therapy (Moreau, et al 2022). The inclusion criteria of many T-cell directing therapy trials, which necessitate prior exposure to anti-CD38 monoclonal antibodies, is another contributing factor to the compromised production of normal immunoglobulins. Such agents are also associated with prolonged hypogammaglobulinemia and increased infection risk (Johnsrud, et al 2019, Vitkon, et al 2021). Depletion of IgG2 subclass is associated with a higher risk of bacterial infection, whereas that of IgG1/IgG3 subclass confer a higher risk of viral infections (Longhitano, et al 2021).

Prolonged cytopenias are an important driver of infection with CAR T-cell therapy, with persistent grade 3 neutropenia seen in 60% of patients lasting over 30 days in a real-world ide-cel study (Hansen, et al). Pre CAR-T lymphodepletion (LD) chemotherapy (typically with cyclophosphamide and fludarabine) is likely a major contributor of cytopenias but does not fully explain it. In the setting of ide-cel for relapsed/refractory MM, high pre-CAR T tumor burden (BMPC≥50%), circulating plasma cells prior to LD, and grade ≥3 anemia prior to LD were associated with grade 3 or higher cytopenias on day 30 and day 90 post-infusion (Logue, et al 2022).

While grade 3 neutropenia and lymphopenia are seen in a substantial proportion of patients treated with BsAbs, as exemplified in the MajesTEC-1 study (approximately 60% and 30% respectively) (Moreau, et al 2022), the kinetics of cytopenia and the proportion of patients who experience prolonged myelosuppression are yet to be established.

Cytokine release syndrome (CRS), which is a unique complication of BsAb and CAR T-cell, can also lead to immune paralysis due to massive cytokine release and predispose patients to infection (Shimabukuro-Vornhagen, et al 2018). Furthermore, the treatment of CRS or immune effector cell-associated neurotoxicity syndrome (ICANS) can further contribute to immunosuppression and the risk of infection. In the context of CD19-directed CAR T-cell therapy, severity of CRS was significantly correlated with the risk of infection between day 0 and 90 post-infusion (Hill, et al 2018). However, in a real-world study of Ide-cel, the use of tocilizumab, anakinra, or corticosteroids did not demonstrate an elevated incidence of infection. (Logue, et al 2022).

There are emerging data on T-cell exhaustion as an important cause of immunosuppression in the context of BsAb therapies (Logue, et al 2022). In BsAb therapy for B-cell acute lymphoblastic leukemia, in vitro studies have demonstrated a decrease in T cell function with continuous exposure to BsAb that can be potentially reversed with treatment-free intervals (Philipp, et al 2022). Given the current recommendation for continuous treatment in the context of BsAb therapies in MM, T cell exhaustion may be the potential driver of atypical infections such as Pneumocystis jirovecii pneumonia (PJP), Cytomegalovirus (CMV) or Aspergillus species, which are otherwise rare and can be associated with significant mortality (Raje, et al 2022, Teh, et al 2015).

Incidence and characteristics of infections associated with CAR T-cell and bispecific antibody therapy.

We summarize in Table 1 and Table 2 the infectious complications from published or presented clinical trials of CAR T-cell and BsAb therapy in MM. We note significant variability in infection reporting such as site, pathogen, diagnostic methods, prophylactic, and treatment strategies in various clinical trials. We observe a changing spectrum of infections including varying rates of opportunistic infections, viral reactivation, and fungal infections with CAR T-cell and bsAb therapy in MM.

Table 1.

Incidence And Characteristics of Infection Complications Among Patients Undergoing Chimeric Antigen Receptor T Cell Therapy in published clinical trials

Agent /Study Target Phase, N Neutropenia Lymphopenia Hypogammaglobulinemia Infections Bacterial Viral Fungal IVIG administration
(All grades/≥grade 3) (All grades/≥grade 3) (All grades/≥grade 3)
N (%) N (%) N (%) N (%) N (%) N (%) N (%) N (%)
Idecabtagene Vicleucel (Ide-cel) BCMA
CRB-401 (Raje, et al 2019) I, N=33 28 (85)/ 6 (18)/ NA 14 (42)/ NA NA NA NA
28 (85) 6 (18) 2 (6)
KarMMa (Munshi, et al 2021) II, N=128 117 (91)/ 35 (27)/ 52 (41) 88 (69)/ 19 (15) 35 (27) 10 (8) 79 (61)
114 (89) 34 (27) 28 (22)
KarMMa-3 (Rodriguez-Otero, et al 2023) III, N=250 195 (78)/ 73 (29)/ NA 146 (58)/ NA NA NA NA
189 (76) 70 (28) 61 (24)
Ciltacabtagene Autoleucel (cilta-cel) BCMA
CARTITUDE 1 (Berdeja, et al 2021) Ib/II, N=97 93 (96)/ 51 (54)/ 91 (94) 57 (59)/ 1 (1) 7 (7)* 1(1) 37 (38)
92 (95) 48 (51) 22 (23)
CARTIFAN-1 (Mi, et al 2023) II, N=48 47 (98)/ 46 (96) 34 (70) 41 (85) NA NA NA NA
47 (98) 44 (92) 28 (38)
MCARH109 (Mailankody, et al 2022) GPRC5D I, N=17 17(100)/ 17(100)/ NA 3(18)/ 1 (6) 1 (6)* NA NA
17(100) 17(100) 2(12)
OriCAR-017/POLARIS (Zhang, et al 2023) GPRC5D I, N=10 10 (100)/ 3 (30)/ NA NA NA NA NA NA
10 (100) 2 (20)
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BCMA: B cell maturation antigen; GPRC5D: G protein–coupled receptor class C group 5 member D; NA: not available; IVIG: Intravenous Immunoglobulin

*

Indicates ≥grade 3 viral infections.

Table 2.

Rates of Infection Complications in Bispecific Antibody Trials for Relapsed/Refractory Multiple Myeloma

Agent Target Phase, N Neutropenia Lymphopenia Hypogammaglobulinemia Infections IVIG administration
(All grades/≥grade 3) (All grades/≥grade 3) (All grades/≥grade 3)
N (%) N (%) N (%) N (%) N (%)
Teclistamab (Moreau, et al 2022) BCMA I-II, N=165 117 (71)/ 57 (34)/ 123 (75) 99* (60) / 65 (39)
106 (64) 54 (33) 41* (25)
ABBV-383 (D’Souza, et al 2022) BCMA I, N=124 46 (37) / 19 (15) / 17 (14) 51 (42) / 29 (23)
42 (34) 16 (13) 29 (23)
Alnuctamab (Wong, et al 2022) BCMA I, N=68 25 (37)/ NA NA 23 (34)/
22 (32) 6 (9)
Elranatamab (Bahlis, et al 2022) BCMA II, N=123 59 (48)/ 32 (26) 76 (75) 82 (67)/ 50 (41)
59 (48) 30 (24) 43(35)
REGN5458 (Zonder, et al 2021) BCMA I, N=167 48 (29)/ 87 (52) NA
47 (28) 37 (22)
Cevostamab (Trudel, et al 2021) FcRH5 I, N=160 28 (18)/ NA NA 68 (43)/ NA
26 (16) 30 (19)
Forimtamig (Carlo-Stella, et al 2022) GPRC5D I, N=51 (IV) 12(24)/ NA NA 31 (61)/ NA
6 (12) 11 (22)
I, N=54 (SC) 9 (17)/ NA NA 26 (46)/ NA
8 (15) 15 (26)
Talquetamab (Chari, et al 2022) GPRC5D I, N=130 67 (52) / 42 (32) / 31–26 (71–87) • 14–15(47–34)‡/ NA
59 (45) 42 (32) 2–3(7–7)•
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BCMA - B cell maturation antigen; GPRC5D - G protein–coupled receptor, family C, group 5, member D; N : number; FcRH5 - Fc receptor-homolog 5

*

Cumulative incidence of pneumonia, COVID-19, bronchitis, and upper respiratory tract infections

Pneumonia, sepsis, COVID-19 disease, and urinary tract infections

°

Two each of pneumonia, influenza, and sepsis

‡

Two adenovirus and one disseminated varicella zoster, one esophageal candidiasis

•

Represent rates across the dose levels of 405-μg dose and 800-μg.

⸸

Represent infection rates in % across dose levels of 405-μg and 800-μg.

Infection rates in clinical trials of autologous BCMA CAR-T cell therapy ranges from 42–69%. Specifically, grade ≥ 3 infections were reported in 22% and 23% of study subjects treated in the registrational studies of ide-cel and ciltacabtagene autoleucel (cilta-cel), respectively (Table 1). In an recent real-world report infections were observed in 34% of patients treated with ide-cel, the most common being bacterial (20%), followed by viral (16%) and fungal (1%) infections (Hansen, et al). GPRC5D CAR T-cell therapy was also associated with an overall infection rate of 18%, with 12% of these being ≥ grade 3 infections (Mailankody, et al 2021).

In a recent report of a phase I/II study of teclistamab therapy, infections occurred in 77% of patients with about half of these being grade 3 or 4 infections. Of note, 2 patients discontinued teclistamab due to grade 3 adenoviral pneumonia and grade 4 progressive multifocal leukoencephalopathy. Granular data on infections are still lacking but the rates of PJP and COVID19 infections in this study were 4% and 14%, respectively. In this study, the incidence of fatal infection was high (n=14) including deaths due to COVID19 (n=12), progressive multifocal leukoencephalopathy secondary to JC virus (n=1) and Streptococcus pneumonia (n=1) (Moreau, et al 2022). In a phase 1 study of ABBV-383, another BCMA BsAb, 41% of study subjects developed infectious complications and a quarter were serious adverse events. In this study, 6% of deaths were attributed to infection, all related to COVID19 infection (D’Souza, et al 2022). Collectively, BCMA BsAb clinical trials have reported infection rates of 41–77% with 25–23% grade 3 / 4 infections. It should be noted that deaths due to infectious complications have ranged from 6% to 12% in the BCMA BsAb trials. The phase I study of GPRC5D BsAb talquetamab, reported infection (all grades) rates of 34–47% with about 7% of these being grade 3 or 4. Opportunistic infections such as adenovirus infection (n=2), esophageal candidiasis (n = 2), disseminated varicella zoster (n=1) and ophthalmic herpes (n = 1) were observed in 5% of study subjects. In this study, there were no deaths attributed to infectious complications (Chari, et al 2022). Several ongoing studies are investigating combination therapy of BsAb with other MM agents, such as CD38 monoclonal antibodies, immunomodulatory drugs, and proteasome inhibitors, raising concern for even higher rate and severity of infections (Searle, et al 2022).

Prolonged use of BsAbs may trigger the appearance of unusual infections. In a study of 49 patients with heavily pretreated MM patients who enrolled in BsAb clinical trials, the cumulative risk of infections increased from 41% at 3 months to 67% at 15 months highlighting the increasing rate of infection with ongoing therapy. On multivariable analysis, baseline hypogammaglobulinemia, prior infection, ongoing BsAb therapy, and elevated serum M-spike level were significantly associated with risk of infection in this study. The most common infections were bacterial (54%), followed by viral (41%), and fungal (5%) (Hammons, et al 2022). In addition, bacteremias with rare pathogens such as Rhizobium radiobacter and Ochrobactrum anthropi have been described with BsAb therapy (Mohan, et al 2022).

The data presented highlights the unique challenges associated with this new class of drugs. With the initial indication of elevated morbidity and mortality due to infectious complications, we suggest implementing a comprehensive approach to monitor and prevent infections, as detailed below.

Infection prevention strategies

Ideally, infection prevention begins with a risk-adapted selection of antimyeloma therapy considering tumor and host-related factors, with particular emphasis on disease- and age-related organ dysfunction. As data evolves, we proposed a practical approach to infection management in patients receiving CAR T-cell or BsAb therapy (Table 3).

Table 3.

Summary of Recommendations to prevent infectious complications in MM patients treated with CAR-T cell therapy or Bispecific antibodies

Pathogen Intervention Indication/ Duration
Bacterial Levofloxacin 500 mg PO daily. Consider alternate agents such as Cefdinir 300mg PO twice a day, or Augmentin 875 mg PO twice a day in the event of allergy or intolerance to fluoroquinolone CAR-T cell therapy - Start when ANC < 500 or per MD discretion and continue until neutrophil recovery
BsAb- Start with onset of therapy and administer during the first month
Bacterial Immunoglobulin replacement: suggested 400 mg/kg once every 4 weeks CAR T-cell: Day +30 through 1 year. After one year continue until serum IgG > 400 mg/dL#
BsAb: Start at second month of therapy and continue until end of therapy or serum IgG> 400 mg/dL# (whichever is longer)
Bacterial Pneumococcus conjugated vaccine (PCV) Revaccination can begin 3–6 months after CAR T-cell therapy. CDC reccomends administration of 1 dose of PCV20 or 1 dose of PCV15 followed by 1 dose of PPSV23 atleast 1 year later. Update vaccination status prior to starting BsAb.
Herpes Simplex Virus/Varicella Zoster Virus Acyclovir 400–800mg PO twice a day or Valacyclovir 500 mg PO once or twice a day Universal and indefinite prophylaxis, irrespective of vaccination status
Cytomegalovirus (CMV) Pharmacological prophylaxis not recommended Routine monitoring not recommended. Monitoring of viral load by PCR and CMV-directed therapy recommended in patients with suspected CMV-related disease (colitis, pneumonitis, hepatitis) or otherwise unexplained fever and/or cytopenias or in high-risk patients*
COVID19 Immunization Follow health autorities recommendations for immunossupressed patients. Revaccination 3–6 months after CAR-T therapy
Influenza Immunization Seasonal
Hepatitis B virus Entecavir or Tenofovir CAR T-cell or BsAb: patients HBs Ag-positive or HBs Ag-negative, HBc Ab- IgG positive
Yeast and Mold Fluconazole 400 mg PO daily Start when ANC < 500 and continue until neutrophil recovery, consider ongoing prophylaxis with anti-mold azole in high-risk patients*
Pneumocystis jirovecii Trimethoprim 80 mg/sulfamethoxazole 400 mg daily or 160/800 mg 3 times a week (Preferred) or Dapsone 100mg PO daily, or Atovaquone suspension 750mg/5 ml – 1500mg = 10 ml PO daily, or Pentamidine 300 mg by inhalation via nebulizer every 4 weeks CAR T-cell: Start on Day +30 through six months, or until CD4 ≥200/mm3 (whichever is longer)
BsAb: Start with therapy and continue for its duration or until CD4 ≥200/μL (whichever is longer)
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*

High risk candidate such as recipients of >1 dose of tocilizumab, use of second line agents such as anakinra or siltuximab for management of CRS and ICANS, prolonged and or high dose steroid use ( requiring >3 days of ≥ 10 mg dexamethasone per day with a 7-day period or receiving ≥ doses of methylprednisolone ≥ 1 g per day ) should be considered for a more intensive azole based anti-mold prophylaxis.#Discount monoclonal component that may be responsible for IgG elevation

Bacterial infections

Bacterial infections are among the most common infections seen in patients with MM treated with CAR T-cell and BsAb therapy. Pneumonia was the most common grade 3 / 4 infectious event reported in 8% of subjects treated with BCMA CAR T-cell therapy (Berdeja, et al 2021). Early report suggests an ongoing risk of infection (2–4%) that extends up to 24 months after CAR T-cell therapy (Munshi, et al 2021). Pneumonia was also reported in 18% of patients treated with teclistamab with 12.7% grade 3 / 4 and one case of grade 5 event related to Streptococcal pneumonia (Moreau, et al 2022). Plasma cell aplasia and incident hypogammaglobinemia can also compound the risk of sino-pulmonary tract infection with encapsulated bacteria such as Streptococcus pneumoniae, and Haemophilus influenzae in addition to attenuated pre-existing humoral immunity due to depletion of memory or long-lived plasma cells. The effectiveness of prophylactic antibacterial agents in mitigating the risk of serious bacterial infections with this novel class of drugs is a topic of debate. A recent phase 3, randomized, placebo-control study examined the use of levofloxacin prophylaxis in non-neutropenic, newly diagnosed MM and showed a statistically significant improvement in composite end point of time of first febrile episode or death at 12 weeks. However, there was a higher proportion of death secondary to disease progression in levofloxacin group raising concerns of antibiotic mediated alteration in the gut microbiome and impaired response to treatment (Drayson, et al 2019).In another study, exposure to antibiotics 4 weeks before CD19 CAR T-cells conferred higher toxicity and inferior survival in patients with B -cell acute lymphoblastic leukemia and non-Hodgkin’s lymphoma (Smith, et al 2022). Therefore, the role of prophylactic antibacterial agents in non-neutropenic patients remains controversial (Drayson, et al 2019). The nature of immune impairment and the resulting risk and severity of bacterial infections in the context of T-cell directing therapy sets it apart from other settings where antibacterial agents have been used as prophylaxis. Given the lack of prospective evidence in this unique setting, it is reasonable to consider using prophylaxis against bacterial infections for limited periods of time when the risk of infection is highest.

Profound and prolong hypogammaglobinemia is another challenge with this class of drugs. A significant proportion (76%) of patients have hypogammaglobinemia after BCMA CAR T-cell therapy and a third of patients remain on IVIG supplements at 9 -12 months after CAR T-cell infusion (Kambhampati, et al 2022). With BCMA BsAb therapy, nearly every responding patient develop hypogammaglobinemia, and this is compounded by the continuous nature of therapy with BsAb (Hammons, et al 2022, Lancman, et al 2022). Additionally, 50% of relapsed refractory MM patients have baseline hypogammaglobulinemia at the time of initiation of these therapies.

Early studies reported discordant results on the benefits of intravenous immune globulin (IVIG) replacement with no discernable clinical benefits in newly diagnosed MM treated primarily with chemotherapy (Salmon, et al 1967). A double-blind, placebo-controlled study of IVIG or albumin in patients with stable MM showed fewer life-threatening, severe and recurrent infections with IVIG use, and, specifically, patients with a poor response to the pneumococcal vaccine derived the maximum benefit (Chapel, et al 1994). Similarly, IVIG use did not reduce the incidence of infections after autologous stem cell transplant. There were no differences in infectious complications when the cohort was analyzed with respect to pretransplant therapy or documented pretransplant hypogammaglobulinemia (Blombery, et al 2011, Howell, et al 2012, Park, et al 2015). One of the caveats of these studies is the possible lack of applicability of these data in the context of newer therapies, such as BsAb or CAR T-cell therapies with a shifting spectrum of infection. The tempo of profound and prolonged hypogammaglobinemia observed with these agents are uniquely challenging and there is an urgent need to prospectively study the role of IVIG in this context. Other areas of uncertainty include identification of high-risk patients, high risk period, optimal timing, schedule and frequency of IVIG supplementation. In the interim, we believe its prophylactic use is justifiable in many contexts.

Recommendations:

  • Antibacterial pharmacological prophylaxis is recommended for recipients of CAR T-cell therapy while absolute neutrophil count < 500/mm3 and continued for the period of neutropenia (Raje, et al 2022, Taplitz, et al 2018).

  • Recipients of BsAb are recommended to receive antibacterial pharmacological prophylaxis starting at the onset of therapy and continuing for the first month (when neutropenia is more commonly unpredictable). It should be resumed every time the absolute neutrophil count falls below 500/mm3. The decision-making process should consider local antimicrobial resistance patterns and the emergence of multi-drug resistant bacteria prior to considering the use of prophylaxis. It is important to note that in regions with high rates of fluoroquinolone resistant bacteria, prophylaxis is unlikely to be effective.

  • Repeated doses of priority vaccines such as pneumococcal conjugated vaccinations should be administered 3–6 months post CAR T-cell therapy. Update pneumococcal vaccination status prior to starting BsAb therapy.

  • IVIG replacement every 4 weeks is recommended in recipients of CAR T-cell therapy starting approximately 30 days after treatment and continuing until 1 year or serum IgG > 400 mg/dL (whichever is longer).

  • It is reasonable to recommend IVIG replacement every 4 weeks in recipients of BsAb starting the second month of therapy (preventing possible confusion between BsAb-induced CRS and IVIG infusion reaction) and continuing until the end of therapy or until serum IgG levels reach > 400 mg/dL, whichever is longer. Prospective studies are needed to further clarify the optimal duration and dosing of IVIG replacement in this patient population.

  • The concern that myeloid growth factors might worsen CRS has made their use for treatment of prolonged neutropenia controversial. However, no study has conclusively showed harm, and several have suggested benefit, such as reducing incidence of neutropenic fever (Galli, et al 2020, Liévin, et al 2022). For CAR T-cell recipients with neutropenia beyond 14 days after CAR T-cell infusion we recommend use of filgrastim.

Viral infections

The true incidence of viral infection and reactivation is largely unknown due to the lack of uniform testing and short follow-up in various clinical trials (Hammons, et al 2022, Lancman, et al 2022, Mohan, et al 2022). In an early report of 61 MM patients treated with BCMA CAR T-cell therapy, there were 18 events of viral infection or reactivation of latent viruses such as Epstein-Barr virus (EBV) and CMV mainly at 100 days after CAR T-cell therapy (Wang, et al 2021a). A case of grade 5 progressive multifocal leukoencephalopathy secondary to JC virus, another rare viral infection, was observed with teclistamab therapy (Moreau, et al 2022). In a single center report of 37 patients treated with BCMA BsAb, there were 6 unusual opportunistic infections including 22% cases of CMV reactivation with 2 cases of CMV esophagitis (Kambhampati, et al 2022, Lancman, et al 2022). Additionally, a recent meta-analysis, reported CMV infection and/or reactivation rate of 8% in clinical trials of BsAb (Mazahreh, et al 2022).

The global COVID19 pandemic appears to be transitioning to an endemic state and current variants present in the US seem less virulent, but COVID19 will likely remain a serious threat to cancer patients. In addition to the lack of universal uptake of COVID19 vaccination, suboptimal vaccines response has been demonstrated in recipients of CAR T-cell and BsAb therapy (Abid, et al 2022, Hammons, et al 2022). Additionally, COVID19 remains a significant concern to patients with MM with mortality as high as 14% in recipients of BCMA directed T-cell therapy (Hultcrantz, et al 2020, Martínez-López, et al 2023, Spiliopoulou, et al 2023). Given the high rate of US COVID19 infection, and reasonable uptake of vaccination in some geographical areas, high titers of COVID19 neutralizing antibodies are now reported in IVIG products. It is therefore possible that IVIG, as above recommended, could also provide protection against severe COVID19 infection in these patients (Karbiener, et al 2021, Volk, et al 2022).

Recommendations:

  • We recommend a targeted baseline serologic/molecular screening for EBV, CMV, hepatitis B/C virus (HBV / HCV) and human immunodeficiency virus (HIV). This screening aims to identify patients with active hepatitis or HIV infections, those who are at risk of reactivation of HBV, HCV, or CMV, and complications related to EBV. When dealing with clinical scenarios like hypogammaglobinemia, where there are concerns of a false negative serological result, it is recommended to consider polymerase chain reaction (PCR) for HBV and HCV, preferably in collaboration with specialist input.

  • We recommend universal and prolonged prophylaxis for HSV/VZV infection/reactivation with acyclovir or valacyclovir.

  • In the absence of high-quality data, we advise against using pharmacological prophylaxis or generalized monitoring of CMV by PCR, given the unknown value, risk of over-treatment, and the relatively low risk of CMV-related disease.

  • CMV monitoring by whole blood PCR is recommended in the investigation of otherwise unexplained clinical entity where CMV is part of the differential (pneumonitis, hepatitis, colitis), or otherwise unexplained fever or cytopenias, particularly in patients considered at high-risk for CMV-related complications [CMV seropositive recipients of CAR T-cell or BsAb therapy receiving >1 dose of tocilizumab, second line anti-CRS/ICANS agents such as anakinra or siltuximab, prolonged and/or high dose steroid use (>3 days and ≥ 10 mg dexamethasone per day in a 7-day period or receiving methylprednisolone ≥ 1 g per day] (Hill and Seo 2020).

  • Carriers of HBV (HBs Ag-positive) or patients with a previous history of HBV infection (HBsAg negative, anti-HBc Ab IgG positive), should receive prophylaxis with close monitoring of HBV titers and liver function (Raje, et al 2022). Currently, entecavir or tenofovir is recommended for the duration of therapy and continued for 6 to 12 months after the end of treatment. Long-term treatment should be considered from case to case to avoid the risk of viral reactivation (Baden, et al 2016, Strati, et al 2019).

  • Although it is anticipated that patients with MM who have undergone CAR-T or BsAb therapy may have lower response rates to vaccination (Van Oekelen, et al 2021), it is still recommended that they receive updates for their influenza and COVID-19 vaccination series. Repeated vaccinations can be initiated 3–6 months post CAR T-cell therapy.

Fungal Infections

Invasive fungal infections in patients with MM range from 2.4–15%, with an incremental risk with cumulative exposure to treatment and disease burden. These infections represent a significant cause of morbidity and mortality (Lortholary, et al 2000, Teh, et al 2015). In fact, aspergillus infection was observed in 4% of patients treated with BCMA CAR T-cell therapy (Kambhampati, et al 2022). Early reports suggest that PJP infections were also observed in 4% of patients treated with BsAb therapy(Mazahreh, et al 2022).

Recommendations:

  • Fungal prophylaxis is only routinely recommended for patients with expected prolonged (>7 days) and severe neutropenia (< 500/mm3) (Raje, et al 2022). Drawing on the data from CD19 CAR T-cell therapy, it is justifiable to contemplate mold-active azole prophylaxis for individuals at high risk who are receiving BCMA CAR T-cell therapy, particularly those with prolonged and severe neutropenia, who have been given more than one dose of tocilizumab, second-line agents such as anakinra or siltuximab, or prolonged and/or high-dose steroids (i.e. more than 3 days and 10 mg dexamethasone or receiving methylprednisolone at a dose of 1 g per day) for the management of CRS or ICANS (Hill and Seo 2020).

  • We recommend PJP prophylaxis preferably with trimethoprim - sulfamethoxazole in recipients of CAR-T cell therapy starting 30 days after treatment and continuing for 6 months or until CD4>200/mm3, whichever is longer. For recipients of BsAb, we recommend starting PJP prophylaxis with onset of therapy and continue for the duration of therapy or until CD4>200/mm3, whichever is longer (Baden, et al 2016, Raje, et al 2022). In the absence of conclusive evidence, it is recommended to assess the potential advantages of extended PJP prophylaxis after completion of therapy or CD4 count recovery in comparison to the risk of myelosuppression with trimethoprim-sulfamethoxazole. Furthermore, alternative regimens such as dapsone, atovaquone, and inhalation pentamidine may also be more expensive, making the cost a significant factor to consider.

Practical points

Fever can be a manifestation of both CRS and infection. Both conditions can cause rapid clinical deterioration when not properly addressed. Moreover, they may occur concomitantly. Broad spectrum antibiotics should be initiated with fever, particularly in neutropenic patients and then such therapy can be modified based on culture and imaging results.

While opportunistic and rare infections are possible in recipients of CAR-T or BsAb, most infections are caused by common pathogens such as respiratory viruses, bacteria such as Streptococcus pneumoniae, etc. Proper empirical antibiotics should be employed in common clinical syndromes such as suspected pneumonia or urinary tract infection accompanied by conventional work-up including blood, urine and sputum culture, and molecular viral respiratory panels, among others. Patients without clinical improvement and without identification of pathogen should be investigated for atypical, opportunistic infections. Proper management of T-cell redirecting therapy recipients with suspected infection requires the combined expertise of hematologists and infectious disease specialists.

In conclusion, CAR T-cell and BsAb therapy in relapsed refractory MM have undoubtedly established a higher bar with very impressive clinical efficacy. However, infectious complications remain a substantial cause of morbidity and mortality. The general principles and expert recommendations in the current manuscript provide an easy to adopt template aiming at safe administration of these highly potent agents as we wait for more robust prospective data.

Funding sources:

This work was supported in part by the Advancing a Healthier Wisconsin Endowment-CTSI KL2 Award (MM)

Footnotes

Conflict of interest disclosure: M.M received Institutional Research funding from GlaxoSmithKline plc, Takeda Pharmaceutical Company, Ionis Pharmaceuticals, Bristol-Myers Squibb Company, Celgene Corporation and Amgen Inc.; Advisory board : Sanofi S.A.; Honoraria: Sanofi S.A. and MJH life sciences; Research Grant funding : MCW CTSI, AHW KL2 Award; J.G.B. received research support from Celgene, Takeda, BMS, Amgen, Janssen, Novarties, AbbVie, Bluebird Bio, Teva, Genetech/Roche, Poseida Therapeutics, Sanofi, Acetyon Pharmaceuticals, Lilly, Celularity, CRISPR Therapeutics, EMD Serono, Ichnos Sciences, GlaxoSmithKline, Incyte; honoraria from Takeda, BMS, CRISPR Therapeutics, Celgene, Kite, Janssen, Legend Biotech, Secura Bio and Bluebird Bio. L.J.C. received research support from BMS, Amgen and Janssen; honoraria from BMS, Janssen, Janssen, Sanofi, AbbVie, Adaptive biotechnologies. The remaining authors have no relevant conflict of interest to disclose.

Research support for the study: None

Ethics approval statement: NA

Patient consent statement: NA

Permission to reproduce material from other sources: NA.

Clinical trial registration (including trial number): NA.

Data availability statement:

NA

References

  1. Abid MB, Rubin M, Ledeboer N, Szabo A, Longo W, Mohan M, Shah NN, Fenske TS, Abedin S, Runaas L, D’Souza A, Chhabra S, Dhakal B & Hamadani M (2022) Efficacy of a third SARS-CoV-2 mRNA vaccine dose among hematopoietic cell transplantation, CAR T cell, and BiTE recipients. Cancer Cell, 40, 340–342. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Baden LR, Swaminathan S, Angarone M, Blouin G, Camins BC, Casper C, Cooper B, Dubberke ER, Engemann AM, Freifeld AG, Greene JN, Ito JI, Kaul DR, Lustberg ME, Montoya JG, Rolston K, Satyanarayana G, Segal B, Seo SK, Shoham S, Taplitz R, Topal J, Wilson JW, Hoffmann KG & Smith C (2016) Prevention and Treatment of Cancer-Related Infections, Version 2.2016, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw, 14, 882–913. [DOI] [PubMed] [Google Scholar]
  3. Bahlis NJ, Tomasson MH, Mohty M, Niesvizky R, Nooka AK, Manier S, Maisel C, Jethava Y, Martinez-Lopez J, Prince HM, Arnulf B, Rodriguez Otero P, Koehne G, Touzeau C, Raje N, Iida S, Raab M-S, Leip E, Sullivan S, Conte U, Viqueira A & Lesokhin AM (2022) Efficacy and Safety of Elranatamab in Patients with Relapsed/Refractory Multiple Myeloma Naïve to B-Cell Maturation Antigen (BCMA)-Directed Therapies: Results from Cohort a of the Magnetismm-3 Study. Blood, 140, 391–393. [Google Scholar]
  4. Berdeja JG, Madduri D, Usmani SZ, Jakubowiak A, Agha M, Cohen AD, Stewart AK, Hari P, Htut M, Lesokhin A, Deol A, Munshi NC, O’Donnell E, Avigan D, Singh I, Zudaire E, Yeh TM, Allred AJ, Olyslager Y, Banerjee A, Jackson CC, Goldberg JD, Schecter JM, Deraedt W, Zhuang SH, Infante J, Geng D, Wu X, Carrasco-Alfonso MJ, Akram M, Hossain F, Rizvi S, Fan F, Lin Y, Martin T & Jagannath S (2021) Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. Lancet, 398, 314–324. [DOI] [PubMed] [Google Scholar]
  5. Blimark C, Holmberg E, Mellqvist UH, Landgren O, Björkholm M, Hultcrantz M, Kjellander C, Turesson I & Kristinsson SY (2015) Multiple myeloma and infections: a population-based study on 9253 multiple myeloma patients. Haematologica, 100, 107–113. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Blombery P, Prince HM, Worth LJ, Main J, Yang M, Wood EM & Westerman DA (2011) Prophylactic intravenous immunoglobulin during autologous haemopoietic stem cell transplantation for multiple myeloma is not associated with reduced infectious complications. Annals of Hematology, 90, 1167–1172. [DOI] [PubMed] [Google Scholar]
  7. Carlo-Stella C, Mazza R, Manier S, Facon T, Yoon S-S, Koh Y, Harrison SJ, Er J, Pinto A, Volzone F, Perrone G, Corradini P, Cazaubiel T, Hulin C, Touzeau C, Moreau P, Ocio EM, Montes Gaisan CM, Popat R, Leong S, Offner F, Rodriguez Otero P, Alfonso-Pierola A, Bröske A-ME, Dekhtiarenko I, Helms H-J, Belli S, Rossmann E, Fauti T, Eckmann J, Moore T, Schneider M, Jacob W, Weisser M, Hutchings M & Riley CH (2022) RG6234, a GPRC5DxCD3 T-Cell Engaging Bispecific Antibody, Is Highly Active in Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM): Updated Intravenous (IV) and First Subcutaneous (SC) Results from a Phase I Dose-Escalation Study. Blood, 140, 397–399. [Google Scholar]
  8. Chapel HM, Lee M, Hargreaves R, Pamphilon DH & Prentice AG (1994) Randomised trial of intravenous immunoglobulin as prophylaxis against infection in plateau-phase multiple myeloma. The UK Group for Immunoglobulin Replacement Therapy in Multiple Myeloma. Lancet, 343, 1059–1063. [DOI] [PubMed] [Google Scholar]
  9. Chari A, Minnema MC, Berdeja JG, Oriol A, van de Donk N, Rodríguez-Otero P, Askari E, Mateos MV, Costa LJ, Caers J, Verona R, Girgis S, Yang S, Goldsmith RB, Yao X, Pillarisetti K, Hilder BW, Russell J, Goldberg JD & Krishnan A (2022) Talquetamab, a T-Cell-Redirecting GPRC5D Bispecific Antibody for Multiple Myeloma. N Engl J Med, 387, 2232–2244. [DOI] [PubMed] [Google Scholar]
  10. D’Souza A, Shah N, Rodriguez C, Voorhees PM, Weisel K, Bueno OF, Pothacamury RK, Freise KJ, Yue S, Ross JA, Polepally AR, Talati C, Lee S, Jin Z, Buelow B, Vij R & Kumar S (2022) A Phase I First-in-Human Study of ABBV-383, a B-Cell Maturation Antigen × CD3 Bispecific T-Cell Redirecting Antibody, in Patients With Relapsed/Refractory Multiple Myeloma. J Clin Oncol, 40, 3576–3586. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Drayson MT, Bowcock S, Planche T, Iqbal G, Pratt G, Yong K, Wood J, Raynes K, Higgins H, Dawkins B, Meads D, Hulme CT, Monahan I, Karunanithi K, Dignum H, Belsham E, Neilson J, Harrison B, Lokare A, Campbell G, Hamblin M, Hawkey P, Whittaker AC, Low E & Dunn JA (2019) Levofloxacin prophylaxis in patients with newly diagnosed myeloma (TEAMM): a multicentre, double-blind, placebo-controlled, randomised, phase 3 trial. The Lancet Oncology, 20, 1760–1772. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Fenwick C, Joo V, Jacquier P, Noto A, Banga R, Perreau M & Pantaleo G (2019) T-cell exhaustion in HIV infection. Immunol Rev, 292, 149–163. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Fishman JA, Hogan JI & Maus MV (2019) Inflammatory and Infectious Syndromes Associated With Cancer Immunotherapies. Clin Infect Dis, 69, 909–920. [DOI] [PubMed] [Google Scholar]
  14. Galli E, Allain V, Di Blasi R, Bernard S, Vercellino L, Morin F, Moatti H, Caillat-Zucman S, Chevret S & Thieblemont C (2020) G-CSF does not worsen toxicities and efficacy of CAR-T cells in refractory/relapsed B-cell lymphoma. Bone Marrow Transplant, 55, 2347–2349. [DOI] [PubMed] [Google Scholar]
  15. Hammons LR, Szabo A, Janardan A, Dhakal B, Chhabra S, D’Souza A & Mohan M (2022) Kinetics of Humoral Immunodeficiency With Bispecific Antibody Therapy in Relapsed Refractory Multiple Myeloma. JAMA Network Open, 5, e2238961–e2238961. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hansen DK, Sidana S, Peres LC, Leitzinger CC, Shune L, Shrewsbury A, Gonzalez R, Sborov DW, Wagner C, Dima D, Hashmi H, Kocoglu MH, Atrash S, Simmons G, Kalariya N, Ferreri C, Afrough A, Kansagra A, Voorhees P, Baz R, Khouri J, Alsina M, McGuirk J, Locke FL & Patel KK Idecabtagene Vicleucel for Relapsed/Refractory Multiple Myeloma: Real-World Experience From the Myeloma CAR T Consortium. Journal of Clinical Oncology, 0, JCO.22.01365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hill JA, Li D, Hay KA, Green ML, Cherian S, Chen X, Riddell SR, Maloney DG, Boeckh M & Turtle CJ (2018) Infectious complications of CD19-targeted chimeric antigen receptor-modified T-cell immunotherapy. Blood, 131, 121–130. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hill JA & Seo SK (2020) How I prevent infections in patients receiving CD19-targeted chimeric antigen receptor T cells for B-cell malignancies. Blood, 136, 925–935. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Howell JE, Gulbis AM, Champlin RE & Qazilbash MH (2012) Retrospective analysis of weekly intravenous immunoglobulin prophylaxis versus intravenous immunoglobulin by IgG level monitoring in hematopoietic stem cell transplant recipients. American Journal of Hematology, 87, 172–174. [DOI] [PubMed] [Google Scholar]
  20. Hultcrantz M, Richter J, Rosenbaum C, Patel D, Smith E, Korde N, Lu S, Mailankody S, Shah U, Lesokhin A, Hassoun H, Tan C, Maura F, Derkach A, Diamond B, Rossi A, Pearse RN, Madduri D, Chari A, Kaminetzky D, Braunstein M, Gordillo C, Davies F, Jagannath S, Niesvizky R, Lentzsch S, Morgan G & Landgren O (2020) COVID-19 infections and outcomes in patients with multiple myeloma in New York City: a cohort study from five academic centers. medRxiv. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Johnsrud AJ, Johnsrud JJ, Susanibar SA, Kamimoto JJ, Kothari A, Burgess M, Van Rhee F & Rico JC (2019) Infectious and immunological sequelae of daratumumab in multiple myeloma. British Journal of Haematology, 185, 187–189. [DOI] [PubMed] [Google Scholar]
  22. Kambhampati S, Sheng Y, Huang C-Y, Bylsma S, Lo M, Kennedy V, Natsuhara K, Martin T, Wolf J, Shah N & Wong SW (2022) Infectious complications in patients with relapsed refractory multiple myeloma after BCMA CAR T-cell therapy. Blood Advances, 6, 2045–2054. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Karbiener M, Farcet MR, Schwaiger J, Powers N, Lenart J, Stewart JM, Tallman H & Kreil TR (2021) Highly Potent SARS-CoV-2 Neutralization by Intravenous Immunoglobulins manufactured from Post-COVID-19 and COVID-19-Vaccinated Plasma Donations. J Infect Dis, 224, 1707–1711. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Lancman G, Parsa K, Rodriguez C, Richter J, Cho HJ, Parekh S, Richard S, Rossi A, Sanchez L, Thibaud S, Jagannath S & Chari A (2022) Infections and Severe Hypogammaglobulinemia in Multiple Myeloma Patients Treated with Anti-BCMA Bispecific Antibodies. Blood, 140, 10073–10074. [Google Scholar]
  25. Li J, Stagg NJ, Johnston J, Harris MJ, Menzies SA, DiCara D, Clark V, Hristopoulos M, Cook R, Slaga D, Nakamura R, McCarty L, Sukumaran S, Luis E, Ye Z, Wu TD, Sumiyoshi T, Danilenko D, Lee GY, Totpal K, Ellerman D, Hotzel I, James JR & Junttila TT (2017) Membrane-Proximal Epitope Facilitates Efficient T Cell Synapse Formation by Anti-FcRH5/CD3 and Is a Requirement for Myeloma Cell Killing. Cancer Cell, 31, 383–395. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Liévin R, Di Blasi R, Morin F, Galli E, Allain V, De Jorna R, Vercellino L, Parquet N, Mebarki M, Larghero J, de Kerviler E, Madelaine I, Caillat-Zucman S, Chevret S & Thieblemont C (2022) Effect of early granulocyte-colony-stimulating factor administration in the prevention of febrile neutropenia and impact on toxicity and efficacy of anti-CD19 CAR-T in patients with relapsed/refractory B-cell lymphoma. Bone Marrow Transplantation, 57, 431–439. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Logue JM, Peres LC, Hashmi H, Colin-Leitzinger CM, Shrewsbury AM, Hosoya H, Gonzalez RM, Copponex C, Kottra KH, Hovanky V, Sahaf B, Patil S, Lazaryan A, Jain MD, Baluch A, Klinkova OV, Bejanyan N, Faramand RG, Elmariah H, Khimani F, Davila ML, Mishra A, Blue BJ, Grajales-Cruz AF, Castaneda Puglianini OA, Liu HD, Nishihori T, Freeman CL, Brayer JB, Shain KH, Baz RC, Locke FL, Alsina M, Sidana S & Hansen DK (2022) Early cytopenias and infections after standard of care idecabtagene vicleucel in relapsed or refractory multiple myeloma. Blood Adv, 6, 6109–6119. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Longhitano AP, Slavin MA, Harrison SJ & Teh BW (2021) Bispecific antibody therapy, its use and risks for infection: Bridging the knowledge gap. Blood Rev, 49, 100810. [DOI] [PubMed] [Google Scholar]
  29. Lortholary O, Ascioglu S, Moreau P, Herbrecht R, Marinus A, Casassus P, De Pauw B & Denning DW (2000) Invasive aspergillosis as an opportunistic infection in nonallografted patients with multiple myeloma: a European Organization for Research and Treatment of Cancer/ Invasive Fungal Infections Cooperative Group and the Intergroupe Français du Myélome. Clin Infect Dis, 30, 41–46. [DOI] [PubMed] [Google Scholar]
  30. Mailankody S, Devlin SM, Landa J, Nath K, Diamonte C, Carstens EJ, Russo D, Auclair R, Fitzgerald L, Cadzin B, Wang X, Sikder D, Senechal B, Bermudez VP, Purdon TJ, Hosszu K, McAvoy DP, Farzana T, Mead E, Wilcox JA, Santomasso BD, Shah GL, Shah UA, Korde N, Lesokhin A, Tan CR, Hultcrantz M, Hassoun H, Roshal M, Sen F, Dogan A, Landgren O, Giralt SA, Park JH, Usmani SZ, Rivière I, Brentjens RJ & Smith EL (2022) GPRC5D-Targeted CAR T Cells for Myeloma. N Engl J Med, 387, 1196–1206. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Mailankody S, Diamonte C, Fitzgerald L, Kane P, Wang X, Sikder DS, Senechal B, Bermudez VP, Frias D, Morgan J, Grant P, Purdon TJ, Hosszu K, Devlin SM, Shah UA, Landa J, Lesokhin A, Korde N, Hassoun H, Tan C, Hultcrantz M, Shah GL, Landau HJ, Chung DJ, Scordo M, Roshal M, Landgren O, Dogan A, Giralt SA, Park JH, Rivière I, Brentjens RJ & Smith EL (2021) Phase I First-in-Class Trial of MCARH109, a G Protein Coupled Receptor Class C Group 5 Member D (GPRC5D) Targeted CAR T Cell Therapy in Patients with Relapsed or Refractory Multiple Myeloma. Blood, 138, 827–827.34075408 [Google Scholar]
  32. Martínez-López J, De la Cruz J, Gil-Manso R, Alegre A, Ortiz J, Llamas P, Martínez Y, Hernández-Rivas J, González-Gascón I, Benavente C, Estival Monteliu P, Jiménez-Yuste V, Canales M, Bastos M, Kwon M, Valenciano S, Callejas-Charavia M, López-Jiménez J, Herrera P, Duarte R, Núñez Martín-Buitrago L, Sanchez Godoy P, Jacome Yerovi C, Martínez-Barranco P, García Roa M, Escolano Escobar C, Matilla A, Rosado Sierra B, Aláez-Usón MC, Quiroz-Cervantes K, Martínez-Chamorro C, Pérez-Oteyza J, Martos-Martinez R, Herráez R, González-Santillana C, Del Campo JF, Alonso A, de la Fuente A, Pascual A, Bustelos-Rodriguez R, Sebrango A, Ruiz E, Marcheco-Pupo EA, Grande C, Cedillo Á, Lumbreras C, Arroyo Barea A, Casas-Rojo JM, Calbacho M, Diez-Martín JL & García-Suárez J (2023) COVID-19 Severity and Survival over Time in Patients with Hematologic Malignancies: A Population-Based Registry Study. Cancers (Basel), 15. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Mazahreh F, Mazahreh L, Schinke C, Thanendrarajan S, Zangari M, Shaughnessy JD Jr., Zhan F, van Rhee F & Al Hadidi S (2022) Risk of Infections Associated with the Use of Bispecific Antibodies in Multiple Myeloma: A Pooled Analysis. Blood, 140, 4378–4378. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Mi JQ, Zhao W, Jing H, Fu W, Hu J, Chen L, Zhang Y, Yao D, Chen D, Schecter JM, Yang F, Tian X, Sun H, Zhuang SH, Ren J, Fan X, Jin J, Niu T & Chen SJ (2023) Phase II, Open-Label Study of Ciltacabtagene Autoleucel, an Anti-B-Cell Maturation Antigen Chimeric Antigen Receptor-T-Cell Therapy, in Chinese Patients With Relapsed/Refractory Multiple Myeloma (CARTIFAN-1). J Clin Oncol, 41, 1275–1284. [DOI] [PubMed] [Google Scholar]
  35. Mohan M, Nagavally S, Dhakal B, Radhakrishnan SV, Chhabra S, D’Souza A & Hari P (2022) Risk of infections with B-cell maturation antigen-directed immunotherapy in multiple myeloma. Blood Advances, 6, 2466–2470. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Moreau P, Garfall AL, van de Donk N, Nahi H, San-Miguel JF, Oriol A, Nooka AK, Martin T, Rosinol L, Chari A, Karlin L, Benboubker L, Mateos MV, Bahlis N, Popat R, Besemer B, Martinez-Lopez J, Sidana S, Delforge M, Pei L, Trancucci D, Verona R, Girgis S, Lin SXW, Olyslager Y, Jaffe M, Uhlar C, Stephenson T, Van Rampelbergh R, Banerjee A, Goldberg JD, Kobos R, Krishnan A & Usmani SZ (2022) Teclistamab in Relapsed or Refractory Multiple Myeloma. N Engl J Med, 387, 495–505. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Munshi NC, Anderson LD Jr., Shah N, Madduri D, Berdeja J, Lonial S, Raje N, Lin Y, Siegel D, Oriol A, Moreau P, Yakoub-Agha I, Delforge M, Cavo M, Einsele H, Goldschmidt H, Weisel K, Rambaldi A, Reece D, Petrocca F, Massaro M, Connarn JN, Kaiser S, Patel P, Huang L, Campbell TB, Hege K & San-Miguel J (2021) Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma. N Engl J Med, 384, 705–716. [DOI] [PubMed] [Google Scholar]
  38. O’Connor BP, Raman VS, Erickson LD, Cook WJ, Weaver LK, Ahonen C, Lin LL, Mantchev GT, Bram RJ & Noelle RJ (2004) BCMA is essential for the survival of long-lived bone marrow plasma cells. J Exp Med, 199, 91–98. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Park S, Jung CW, Jang JH, Kim SJ, Kim WS & Kim K (2015) Incidence of infection according to intravenous immunoglobulin use in autologous hematopoietic stem cell transplant recipients with multiple myeloma. Transplant Infectious Disease, 17, 679–687. [DOI] [PubMed] [Google Scholar]
  40. Philipp N, Kazerani M, Nicholls A, Vick B, Wulf J, Straub T, Scheurer M, Muth A, Hänel G, Nixdorf D, Sponheimer M, Ohlmeyer M, Lacher SM, Brauchle B, Marcinek A, Rohrbacher L, Leutbecher A, Rejeski K, Weigert O, von Bergwelt-Baildon M, Theurich S, Kischel R, Jeremias I, Bücklein V & Subklewe M (2022) T-cell exhaustion induced by continuous bispecific molecule exposure is ameliorated by treatment-free intervals. Blood, 140, 1104–1118. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Raje N, Berdeja J, Lin Y, Siegel D, Jagannath S, Madduri D, Liedtke M, Rosenblatt J, Maus MV, Turka A, Lam LP, Morgan RA, Friedman K, Massaro M, Wang J, Russotti G, Yang Z, Campbell T, Hege K, Petrocca F, Quigley MT, Munshi N & Kochenderfer JN (2019) Anti-BCMA CAR T-Cell Therapy bb2121 in Relapsed or Refractory Multiple Myeloma. N Engl J Med, 380, 1726–1737. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Raje NS, Anaissie E, Kumar SK, Lonial S, Martin T, Gertz MA, Krishnan A, Hari P, Ludwig H, O’Donnell E, Yee A, Kaufman JL, Cohen AD, Garderet L, Wechalekar AF, Terpos E, Khatry N, Niesvizky R, Yi Q, Joshua DE, Saikia T, Leung N, Engelhardt M, Mothy M, Branagan A, Chari A, Reiman AJ, Lipe B, Richter J, Rajkumar SV, Miguel JS, Anderson KC, Stadtmauer EA, Prabhala RH, McCarthy PL & Munshi NC (2022) Consensus guidelines and recommendations for infection prevention in multiple myeloma: a report from the International Myeloma Working Group. Lancet Haematol, 9, e143–e161. [DOI] [PubMed] [Google Scholar]
  43. Rodriguez-Otero P, Ailawadhi S, Arnulf B, Patel K, Cavo M, Nooka AK, Manier S, Callander N, Costa LJ, Vij R, Bahlis NJ, Moreau P, Solomon SR, Delforge M, Berdeja J, Truppel-Hartmann A, Yang Z, Favre-Kontula L, Wu F, Piasecki J, Cook M & Giralt S (2023) Ide-cel or Standard Regimens in Relapsed and Refractory Multiple Myeloma. N Engl J Med. [DOI] [PubMed] [Google Scholar]
  44. Salmon SE, Samal BA, Hayes DM, Hosley H, Miller SP & Schilling A (1967) Role of gamma globulin for immunoprophylaxis in multiple myeloma. N Engl J Med, 277, 1336–1340. [DOI] [PubMed] [Google Scholar]
  45. Searle E, Quach H, Wong SW, Costa LJ, Hulin C, Janowski W, Berdeja J, Anguille S, Matous JV, Touzeau C, Michallet A-S, Husnik M, Vishwamitra D, Niu Z, Larsen J, Chen L, Goldberg JD, Popat R & Spencer A (2022) Teclistamab in Combination with Subcutaneous Daratumumab and Lenalidomide in Patients with Multiple Myeloma: Results from One Cohort of MajesTEC-2, a Phase1b, Multicohort Study. Blood, 140, 394–396. [Google Scholar]
  46. Shah N, Chari A, Scott E, Mezzi K & Usmani SZ (2020) B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches. Leukemia, 34, 985–1005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Shimabukuro-Vornhagen A, Gödel P, Subklewe M, Stemmler HJ, Schlößer HA, Schlaak M, Kochanek M, Böll B & von Bergwelt-Baildon MS (2018) Cytokine release syndrome. J Immunother Cancer, 6, 56. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Smith EL, Harrington K, Staehr M, Masakayan R, Jones J, Long TJ, Ng KY, Ghoddusi M, Purdon TJ, Wang X, Do T, Pham MT, Brown JM, De Larrea CF, Olson E, Peguero E, Wang P, Liu H, Xu Y, Garrett-Thomson SC, Almo SC, Wendel HG, Riviere I, Liu C, Sather B & Brentjens RJ (2019) GPRC5D is a target for the immunotherapy of multiple myeloma with rationally designed CAR T cells. Sci Transl Med, 11. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Smith M, Dai A, Ghilardi G, Amelsberg KV, Devlin SM, Pajarillo R, Slingerland JB, Beghi S, Herrera PS, Giardina P, Clurman A, Dwomoh E, Armijo G, Gomes ALC, Littmann ER, Schluter J, Fontana E, Taur Y, Park JH, Palomba ML, Halton E, Ruiz J, Jain T, Pennisi M, Afuye AO, Perales MA, Freyer CW, Garfall A, Gier S, Nasta S, Landsburg D, Gerson J, Svoboda J, Cross J, Chong EA, Giralt S, Gill SI, Riviere I, Porter DL, Schuster SJ, Sadelain M, Frey N, Brentjens RJ, June CH, Pamer EG, Peled JU, Facciabene A, van den Brink MRM & Ruella M (2022) Gut microbiome correlates of response and toxicity following anti-CD19 CAR T cell therapy. Nat Med, 28, 713–723. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Spiliopoulou V, Ntanasis-Stathopoulos I, Malandrakis P, Gavriatopoulou M, Theodorakakou F, Fotiou D, Migkou M, Roussou M, Eleutherakis-Papaiakovou E, Kastritis E, Dimopoulos MA & Terpos E (2023) Use of Oral Antivirals Ritonavir-Nirmatrelvir and Molnupiravir in Patients with Multiple Myeloma Is Associated with Low Rates of Severe COVID-19: A Single-Center, Prospective Study. Viruses, 15. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Strati P, Nastoupil LJ, Fayad LE, Samaniego F, Adkins S & Neelapu SS (2019) Safety of CAR T-cell therapy in patients with B-cell lymphoma and chronic hepatitis B or C virus infection. Blood, 133, 2800–2802. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Taplitz RA, Kennedy EB, Bow EJ, Crews J, Gleason C, Hawley DK, Langston AA, Nastoupil LJ, Rajotte M, Rolston KV, Strasfeld L & Flowers CR (2018) Antimicrobial Prophylaxis for Adult Patients With Cancer-Related Immunosuppression: ASCO and IDSA Clinical Practice Guideline Update. J Clin Oncol, 36, 3043–3054. [DOI] [PubMed] [Google Scholar]
  53. Teh BW, Teng JC, Urbancic K, Grigg A, Harrison SJ, Worth LJ, Slavin MA & Thursky KA (2015) Invasive fungal infections in patients with multiple myeloma: a multi-center study in the era of novel myeloma therapies. Haematologica, 100, e28–31. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Trudel S, Cohen AD, Krishnan AY, Fonseca R, Spencer A, Berdeja JG, Lesokhin A, Forsberg PA, Laubach JP, Costa LJ, Rodriguez-Otero P, Kaedbey R, Richter J, Mateos M-V, Thomas SK, Wong C, Li M, Choeurng V, Vaze A, Samineni D, Sumiyoshi T, Cooper J & Harrison SJ (2021) Cevostamab Monotherapy Continues to Show Clinically Meaningful Activity and Manageable Safety in Patients with Heavily Pre-Treated Relapsed/Refractory Multiple Myeloma (RRMM): Updated Results from an Ongoing Phase I Study. Blood, 138, 157–157. [Google Scholar]
  55. Van Oekelen O, Gleason CR, Agte S, Srivastava K, Beach KF, Aleman A, Kappes K, Mouhieddine TH, Wang B, Chari A, Cordon-Cardo C, Krammer F, Jagannath S, Simon V, Wajnberg A & Parekh S (2021) Highly variable SARS-CoV-2 spike antibody responses to two doses of COVID-19 RNA vaccination in patients with multiple myeloma. Cancer Cell. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Vitkon R, Netanely D, Levi S, Ziv-Baran T, Ben-Yzak R, Katz BZ, Benyamini N, Trestman S, Mittelman M, Cohen Y & Avivi I (2021) Daratumumab in combination with proteasome inhibitors, rapidly decreases polyclonal immunoglobulins and increases infection risk among relapsed multiple myeloma patients: a single center retrospective study. Ther Adv Hematol, 12, 20406207211035272. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Volk A, Covini-Souris C, Kuehnel D, De Mey C, Romisch J & Schmidt T (2022) SARS-CoV-2 Neutralization in Convalescent Plasma and Commercial Lots of Plasma-Derived Immunoglobulin. BioDrugs, 36, 41–53. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Wang D, Mao X, Que Y, Xu M, Cheng Y, Huang L, Wang J, Xiao Y, Wang W, Hu G, Zhang S, Zhang T, Li C & Zhou J (2021a) Viral infection/reactivation during long-term follow-up in multiple myeloma patients with anti-BCMA CAR therapy. Blood Cancer Journal, 11, 168. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Wang Y, Li C, Xia J, Li P, Cao J, Pan B, Tan X, Li H, Qi K, Wang X, Shi M, Jing G, Yan Z, Cheng H, Zhu F, Sun H, Sang W, Li D, Zhang X, Li Z, Zheng J, Liang A, Zhou J & Xu K (2021b) Humoral immune reconstitution after anti-BCMA CAR T-cell therapy in relapsed/refractory multiple myeloma. Blood Advances, 5, 5290–5299. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Wong SW, Bar N, Paris L, Hofmeister CC, Hansson M, Santoro A, Mateos M-V, Rodríguez-Otero P, Lund J, Encinas C, Yee AJ, Oriol A, Cerchione C, de la Rubia J, Ferstl B, Carlson K, Ribas P, Bermúdez A, Boss IW, Gaudy A, Li S, Hsu K, Godwin CD, Burgess MR, San-Miguel J & Costa LJ (2022) Alnuctamab (ALNUC; BMS-986349; CC-93269), a B-Cell Maturation Antigen (BCMA) x CD3 T-Cell Engager (TCE), in Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM): Results from a Phase 1 First-in-Human Clinical Study. Blood, 140, 400–402. [Google Scholar]
  61. Zhang M, Wei G, Zhou L, Zhou J, Chen S, Zhang W, Wang D, Luo X, Cui J, Huang S, Fu S, Zhou X, Tang Y, Ding X, Kuang J, He XP, Hu Y & Huang H (2023) GPRC5D CAR T cells (OriCAR-017) in patients with relapsed or refractory multiple myeloma (POLARIS): a first-in-human, single-centre, single-arm, phase 1 trial. Lancet Haematol, 10, e107–e116. [DOI] [PubMed] [Google Scholar]
  62. Zonder JA, Richter J, Bumma N, Brayer J, Hoffman JE, Bensinger WI, Wu KL, Xu L, Chokshi D, Boyapati A, Sharma M, Rodriguez Lorenc K, Kroog GS, Dhodapkar MV, Lentzsch S, Cooper D & Jagannath S (2021) Early, Deep, and Durable Responses, and Low Rates of Cytokine Release Syndrome with REGN5458, a BCMAxCD3 Bispecific Monoclonal Antibody, in a Phase 1/2 First-in-Human Study in Patients with Relapsed/Refractory Multiple Myeloma (RRMM). Blood, 138, 160–160.33831168 [Google Scholar]

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