INTRODUCTION
Multiple myeloma (MM) patients are at an increased risk of infection from diagnosis due to the immunosuppressive nature of the disease itself and the host factors (older age at diagnosis, compromised renal function). 1 Ensuing treatment based on immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs) and anti-CD38 antibody aggravates the risk of infection as IMiDs are associated with neutropenia while PIs and anti-CD38 antibody are associated with certain viral reactivations. 2
Now we have a new class of immunotherapeutic agents: the bispecific antibodies (BsAbs). BsAbs form an immune synapse between T-cells via surface marker CD3 and malignant cell markers including B-cell maturation antigen (BCMA), G protein-coupled receptor (GPRC5D) and Fc Receptor-Like 5 (FcRH5). 3 Although this new class of drug is associated with good disease control, they are also associated with increased risk of cytopenia, hypogammaglobulinemia, and infectious complications. 4 , 5 , 6
Since seroprevalence of latent viruses or epidemiology of community-acquired and nosocomial infections vary across the globe, it is important to comprehensively understand the similarities and differences amongst patients undergoing the same treatment. Recognizing the lack of East Asian representation in recent studies reporting the infection risk associated with BsAbs, 7 , 8 we conducted this study.
METHODS
Patients and event definitions
All MM patients who received BsAb therapy between January 2021 and January 2024 at Seoul National University Hospital were included. Patients receiving BsAb therapy through a range of clinical trials were also included. We collected clinical data retrospectively, including patient characteristics, clinical features, laboratory findings, bone marrow examination results, immunophenotype findings, molecular analyses, treatment, treatment outcomes, and any events associated with the treatments.
Triple refractory MM is defined as disease refractory to 3 previous therapies including IMiDs and PIs. Penta refractory MM is defined as disease refractory to 5 previous therapies including 2 IMIDs, 2 PIs and monoclonal antibodies (daratumumab).
Infections were categorized as microbiologically defined infection (MDI), clinically defined infection (CDI), or fever of unknown focus (FUF) 7 , 8 and severity graded according to published criteria. 9 The MDI was defined as a laboratory isolated pathogen with a compatible clinical syndrome, CDI was defined by a compatible clinical syndrome without an isolated pathogen, and FUF was defined as the presence of fever and the absence of compatible microbiology or focal symptoms. Systemic infection included bacteremia, viremia, fungemia and infections affecting multiple organs. Complications of BsAb therapy such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were defined according to published criteria. 10
CMV reactivation was defined as the detection of CMV replication in blood (or other sites) among CMV-seropositive patients. 11 Clinically significant CMV infection was defined as CMV disease or CMV viremia leading to preemptive treatment. 12 CMV disease was defined as the presence of attributable clinical symptoms and/or signs with the documentation of CMV in tissue from the relevant organ by histopathology, virus isolation, rapid culture, immunohistochemistry, or DNA hybridization. 13
At our institution, valaciclovir 500 mg once daily is routinely used for herpes simplex virus (HSV) and varicella zoster virus (VZV) prophylaxis. Trimethoprim/sulfamethoxazole 80 mg/400 mg once daily is also routinely given as Pneumocystis jirovecii pneumonia (PJP) prophylaxis. Antibacterial and antifungal prophylaxis is guided by an individualized risk-based approach. We generally used prophylactic antifungal agents when the patient has the past medical history of fungal infection, and used prophylactic antibacterial agents when the patient has the past medical history of systemic bacterial infection or showed prolonged neutropenia of any grade. We used granulocyte-colony stimulating factor for all grade 3–4 neutropenic patients.
Hypogammaglobulinemia is assessed every 4 to 6 weeks by subtracting out the monoclonal immunoglobulin (Ig) and defined as IgG < 400 mg/dL. Intravenous immunoglobulin (IVIG) is routinely replaced for hypogammaglobulinemia.
Statistical analysis
Differences between groups were assessed using a Student’s t -test or one-way analysis of variance for continuous variables, and Pearson χ 2 test for categorical variables, as indicated. Data available up to 30 April 2024 were used. P values of < 0.05 were considered statistically significant.
Infectious events were analyzed with time-dependent cumulative incidence using the Fine-Gray competing risk model with death or progression as a competing risk event. These data were analyzed using the Statistical Package for the Social Sciences software (IBM ® SPSS ® Statistics, version 22.0; IBM Corp., Armonk, NY, USA) and R language (version 4.2.1 or higher; R Foundation for Statistical Computing, Vienna, Austria).
Ethics statement
This study was conducted according to the Declaration of Helsinki and was approved by the Institutional Review Board at Seoul National University Hospital (H-2404-110-1532). The requirement for informed consent was waived by the board.
RESULTS
Patient characteristics
Table 1 shows the baseline characteristics of the enrolled patients. We identified 61 patients who underwent BsAb therapy at our center with median follow-up of 34 weeks (95% confidence interval [CI], 25.85–55.85). Thirty-three patients (54%) received BCMA-targeting BsAb, and 30 (49%) received combination therapy (CD38 targeting monoclonal antibody + BsAb or dual BsAb). The median age at BsAb therapy was 63 years (range 33–81), with a median of 4 prior lines of treatment exposure. CRS occurred in 37 (60.7%) and ICANS in 0 patients.
Table 1
Baseline disease characteristics
Values are presented as median (range) or number (%). BsAb = bispecific antibody, Tx = treatment, ISS = International Staging System, Ig = immunoglobulin, HSCT = hematopoietic stem cell transplantation, CRS = cytokine release syndrome, ICANS = immune effector cell-associated neurotoxicity syndrome, CMV = cytomegalovirus, IVIG = intravenous immunoglobulin.
| Characteristics | Values | ||
| No. of patients | 61 | ||
| Age at BsAb tx, yr | 63 (33–81) | ||
| Sex, male | 42 (68.9) | ||
| Duration of BsAb tx, mon | 9 (1–30) | ||
| BCMA-targeting BsAb | 33 (54.1) | ||
| Combination therapy | 30 (49.2) | ||
| ISS | |||
| I | 37 (60.7) | ||
| II | 15 (24.6) | ||
| III | 9 (14.8) | ||
| Immunochemical subtype | |||
| IgG | 30 (49.2) | ||
| IgA | 9 (14.8) | ||
| IgM | 1 (1.6) | ||
| IgD | 1 (1.6) | ||
| Light chain | 20 (32.8) | ||
| Prior treatment | |||
| Triple refractory | 37 (60.7) | ||
| Penta refractory | 23 (37.7) | ||
| Prior lines | 4 (1–12) | ||
| Prior HSCT | 44 (72.1) | ||
| All grade CRS | 37 (60.7) | ||
| Grade 1 | 30 (81.1) | ||
| Grade 2 | 7 (18.9) | ||
| Corticosteroids | 9 (24.3) | ||
| Tocilizumab | 16 (43.2) | ||
| Both | 7 (18.9) | ||
| All grade ICANS | 0 | ||
| Other neurotoxicity | 5 (8.2) | ||
| Neutropenia | |||
| Any grade | 37 (60.7) | ||
| Grade 3–4 | 29 (47.5) | ||
| CMV status | |||
| Seropositivity | 58 (95.1) | ||
| Viremia | 0 | ||
| Antigenemia | 0 | ||
| IVIG administration | 20 (32.8) |
Incidence and characteristics of infection
Of the 61 patients, 40 (66%) had at least one episode of infection (MDI, CDI or FUF). A total of 69 infections affecting patient management occurred during the study period, of which 63 (91%) were MDI, 4 (6%) were CDI and 2 (3%) were FUF. As shown in Table 2 14 , 15 the predominant localization was the lower respiratory tract infection (n = 32/69, 46%), followed by systemic infection (n = 21/69, 30%).
Table 2
Incidence and characteristics of infectious complications
Values are presented as number (%). CNS = central nervous system, CMV = cytomegalovirus, HSV = herpes simplex virus, VZV = varicella zoster virus, HBV = hepatitis B virus, SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2, JC = John Cunningham. a Includes influenza/parainfluenza virus (n = 2), respiratory syncytial virus (n = 1), and SARS-CoV-2 (n = 13).
| Characteristics | Total | ||
| Site of infection, all | 69 events | ||
| Systemic | 21 (30) | ||
| Upper respiratory tract | 3 (4) | ||
| Lower respiratory tract | 32 (46) | ||
| Gastrointestinal tract | 2 (3) | ||
| Genitourinary tract | 1 (1) | ||
| Skin and soft tissue | 8 (12) | ||
| CNS and ocular | 2 (3) | ||
| Viral infections | 46 (67) | ||
| CMV, clinically significant 14 | 15 | ||
| HSV | 6 | ||
| VZV | 6 | ||
| HBV | 2 | ||
| Respiratory viruses a | 16 | ||
| Severe SARS-CoV-2 15 requiring oxygen | 12 | ||
| JC virus | 1 | ||
| Fungal infections | 9 (13) | ||
| Aspergillus spp. | 2 | ||
| Pneumocystis jirovecii | 7 | ||
| Bacterial infection | 7 (10) | ||
| Tuberculosis | 1 (1) |
Hospitalization was required in 54 (88%) infectious episodes, and intensive care unit admission was required in 7 (10%) episodes. There was a total of 5 (8%) deaths attributed to infection during the study period. As shown in Table 3 , in 69 infection events, 2 (3%) episodes were grade 1 infection, 5 (8%) were grade 2, 44 (72%) were grade 3, 5 (8%) were grade 4 and 5 (8%) were grade 5.
Table 3
Comparison with previous studies involving patients receiving bispecific antibodies therapy
Values are presented as median (range) or number (%). BCMA = B-cell maturation antigen, MDI = microbiologically defined infection, CDI = clinically defined infection, FUF = fever of unknown focus, CMV = cytomegalovirus.
| Characteristics | Current study | Australia 7 | France 8 | |
| No. of patients | 61 | 39 | 229 | |
| BCMA vs. non-BCMA | 33 (54) vs. 28 (46) | 12 (31) vs. 27 (69) | 200 vs. 29 | |
| Prior lines of therapy | 4 (1–12) | 6 (4–7) | 4 (0–15) | |
| Infection episodes | 69 | 111 | 234 | |
| Infection category | ||||
| MDI | 63 (91) | 33 (30) | 165 (71) | |
| CDI | 4 (6) | 43 (39) | 62 (26) | |
| FUF | 2 (3) | 35 (32) | 7 (3.0) | |
| Bacterial, % | 10 | 39 | 56 | |
| Viral, % | 67 | 58 | 38 | |
| CMV (CMV events/total viral events) | 15/46 (33) | 4/22 (18) | 8/63 (13) | |
| Fungal, % | 13 | 0 | 5 | |
| Tuberculosis, % | 1 | 3 | 0 | |
| Grade of infections | ||||
| 1 | 2 (3) | 37 (33) | 12 (5) | |
| 2 | 5 (8) | 50 (45) | 98 (41) | |
| 3 | 44 (72) | 22 (20) | 75 (32) | |
| 4 | 5 (8) | 0 | 28 (12) | |
| 5 | 5 (8) | 2 (2) | 20 (9) |
Etiology wise, viral infections were most common ( Table 2 ), followed by fungal infections and bacterial infections. For fungal infections, there were 2 cases of invasive pulmonary aspergillosis and 7 cases of PJP. For bacterial infections there were 3 cases of bacteremia, 1 streptococcal bacteremia, 1 Escherichia coli bacteremia and 1 Pseudomonas aeruginosa bacteremia. The last patient with Pseudomonas bacteremia demised due to infection while in complete remission after 4 cycles of treatment. There was one case of pulmonary tuberculosis (TB) in a 47-year-old male without previous history of TB.
Global cumulative incidence of first infection was 76.9% (95% CI, 63.1–90.7%), with specific rates of 13.5% at 30 days (95% CI, 4.1–22.8%), 36.5% at 90 days (95% CI, 23.3–49.5%), and 63.5% at 180 days (95% CI, 49.7–77.3%) ( Fig. 1 ).
Viral infections
There were 46 (67%) episodes of viral infections. Respiratory viruses were most common with 16/46 (35%) events, mostly attributed to SARS-CoV-2 infection. There were 2 deaths associated with severe SARS-CoV2 infection. One patient was in very good partial response after 1 cycle of therapy, while the other patient showed stable disease after 2 cycles of therapy. Global cumulative incidence of viral infection was 77.6% (95% CI, 64.5–90.6%), with specific rates of 12.1% at 30 days (95% CI, 3.6–20.5%), 27.6% at 90 days (95% CI, 16.0–39.2%), and 51.7% at 180 days (95% CI, 38.7–64.8%) ( Fig. 1 ).
Cytomegalovirus (CMV) infection was next in line with 15/46 (33%) events. To be specific ( Table 4 ), CMV reactivation 11 was seen in 49% of the patients (30/61). Global cumulative incidence of CMV reactivation was 66.0% (95% CI, 51.4–80.5%), with specific rates of 10.6% at 30 days (95% CI, 1.7–19.6%), 42.6% at 90 days (95% CI, 28.2–56.9%), and 55.3% at 180 days (95% CI, 40.8–69.9%) ( Fig. 1 ). Among them, 15 were clinically significant 12 requiring intervention. There were 4 cases of CMV disease: 3 CMV pneumonia and 1 CMV retinitis. Two of the 3 patients with CMV pneumonia demised due to infection. Both were in very good partial response at the time of death.
Table 4
CMV specifics
Values are presented as number (%). CMV = cytomegalovirus, BCMA = B-cell maturation antigen. a BCMA group vs. non-BCMA group; b Single immunotherapy group vs. combination therapy group.
| Characteristics | Total (N = 61) | BCMA (n = 33) | Non-BCMA (n = 28) | P value a | Single immunotherapy (n = 31) | Combination therapy (n = 30) | P value b |
| Reactivation 11 | 30 (49.2) | 22 (66.7) | 8 (28.6) | 0.005 | 9 (29.0) | 21 (70.0) | 0.002 |
| Median time to reactivation, days | 58 | 58 | 58.5 | 0.307 | 43 | 65 | 0.287 |
| Clinically significant CMV infection | 15 (24.6) | 13 (39.4) | 2 (7.1) | 0.006 | 5 (16.1) | 10 (33.3) | 0.119 |
| CMV disease | 4 | 3 (9.1) | 1 (3.6) | 0.385 | 1 (3.2) | 3 (10.0) | 0.354 |
| Lung | 3 | 3 | 0 | 0 | 3 | ||
| Retinitis | 1 | 0 | 1 | 1 | 0 |
Interestingly, patients receiving BCMA-targeting agents showed higher incidence of CMV reactivation as shown in Table 4 ( P = 0.005). The incidence of clinically significant CMV infection was also higher in BCMA group ( P = 0.006). Not surprisingly, CMV reactivation was associated with combination therapy. Fortunately, there were no significant differences in clinically significant CMV infections among patients receiving single immunotherapy vs. combination therapy.
DISCUSSION
As newer immunotherapies including BsAbs prolong survivals of MM patients, supportive care is becoming increasingly important to ensure good quality of life and sustain treatment response. Infection control constitutes a major pillar of such supportive care, not only because MM disease itself is associated with B-cell depletion and T-cell dysfunction, 16 but also because of the susceptibility and the frailty of the patients from undergoing multiple prior lines of therapy ( Tables 5 and 6 ). When dealing with infections varying prevalence and determinants of opportunistic infections per region should also be taken into consideration. We thought the first step to optimizing preventative and therapeutic strategies was determining the nature of infectious disease dynamics.
Table 5
Baseline characteristics with BsAb target
Values are presented as median (range) or number (%). BsAb = bispecific antibody, BCMA = B-cell maturation antigen, Tx = treatment, ISS = International Staging System, Ig = immunoglobulin, HSCT = hematopoietic stem cell transplantation, CRS = cytokine release syndrome, ICANS = immune effector cell-associated neurotoxicity syndrome, IVIG = intravenous immunoglobulin.
| Characteristics | BCMA | Non-BCMA | ||
| No. of patients | 33 | 28 | ||
| Age at BsAb tx, yr | 63 (33–76) | 62 (43–81) | ||
| Sex, male | 26 (78.8) | 16 (57.1) | ||
| BsAb tx duration, mon | 8 (1–24) | 13 (1–30) | ||
| ISS | ||||
| I | 20 (60.6) | 17 (60.7) | ||
| II | 8 (24.2) | 7 (25.0) | ||
| III | 5 (15.2) | 4 (14.3) | ||
| Immunochemical subtype | ||||
| IgG | 19 (57.6) | 11 (39.3) | ||
| IgA | 2 (6.1) | 7 (25.0) | ||
| IgM | 1 (3.0) | 0 | ||
| IgD | 1 (3.0) | 0 | ||
| Light chain | 10 (30.3) | 10 (35.7) | ||
| Prior treatment | ||||
| Triple refractory | 20 (60.6) | 17 (60.7) | ||
| Penta refractory | 13 (39.4) | 10 (35.7) | ||
| Prior lines | 4 (1–8) | 4 (1–12) | ||
| Prior HSCT | 26 (78.8) | 16 (64.3) | ||
| All grade CRS | 19 (57.6) | 18 (64.3) | ||
| Grade 1 | 17 (89.5) | 13 (72.2) | ||
| Grade 2 | 2 (10.5) | 5 (27.8) | ||
| Corticosteroids | 5 (26.3) | 4 (22.2) | ||
| Tocilizumab | 6 (31.6) | 10 (55.6) | ||
| All grade ICANS | 0 | 0 | ||
| Other neurotoxicity | 2 (6.1) | 3 (10.7) | ||
| Neutropenia | ||||
| Any grade | 23 (69.7) | 14 (50.0) | ||
| Grade 3–4 | 19 (57.6) | 10 (35.7) | ||
| IVIG administration | 17 (51.5) | 3 (10.7) | ||
| Any infection | 26 (78.8) | 14 (50.0) |
Table 6
Baseline characteristics with single or combination therapy
Values are presented as median (range) or number (%). BsAb = bispecific antibody, Tx = treatment, ISS = International Staging System, Ig = immunoglobulin, HSCT = hematopoietic stem cell transplantation, CRS = cytokine release syndrome, ICANS = immune effector cell-associated neurotoxicity syndrome, IVIG = intravenous immunoglobulin.
| Characteristics | Single | Combination | ||
| No. of patients | 31 | 30 | ||
| Age at BsAb tx, yr | 63 (43–81) | 60 (33–75) | ||
| Sex, male | 18 (58.1) | 14 (46.7) | ||
| BsAb tx duration, mon | 11 (1–30) | 11 (1–26) | ||
| ISS | ||||
| I | 16 (51.6) | 21 (70.0) | ||
| II | 9 (29.0) | 6 (20.0) | ||
| III | 6 (19.4) | 3 (10.0) | ||
| Immunochemical subtype | ||||
| IgG | 11 (35.5) | 19 (63.3) | ||
| IgA | 7 (22.6) | 2 (6.7) | ||
| IgM | 0 | 1 (3.3) | ||
| IgD | 1 (3.2) | 0 | ||
| Light chain | 12 (38.7) | 8 (26.7) | ||
| Prior treatment | ||||
| Triple refractory | 24 (77.4) | 13 (43.3) | ||
| Penta refractory | 14 (45.2) | 9 (30.0) | ||
| Prior lines | 5 (1–12) | 4 (1–7) | ||
| Prior HSCT | 21 (67.7) | 21 (70.0) | ||
| All grade CRS | 18 (58.1) | 19 (63.3) | ||
| Grade 1 | 13 (72.2) | 17 (89.5) | ||
| Grade 2 | 5 (27.8) | 2 (10.5) | ||
| Corticosteroids | 7 (38.9) | 2 (10.5) | ||
| Tocilizumab | 8 (44.4) | 8 (42.1) | ||
| All grade ICANS | 0 | 0 | ||
| Other neurotoxicity | 1 (3.2) | 4 (13.3) | ||
| Neutropenia | ||||
| Any grade | 19 (61.3) | 18 (60.0) | ||
| Grade 3–4 | 11 (35.5) | 18 (60.0) | ||
| IVIG administration | 7 (22.6) | 13 (43.3) | ||
| Any infection | 15 (48.4) | 25 (83.3) |
As results, we found that more than half of the patients (64%) treated with BsAbs experience infectious complications. This percentage is comparable to previous reports, 4 , 6 , 7 , 8 but we had more cases of grade 3 or higher infections ( Table 3 ). Due to the retrospective nature of the study and the different patterns of healthcare utilization, we cannot draw any definitive conclusions. However, considering the generally lower proportion of chemotherapy tolerable patients in Asian population, 17 , 18 caution is warranted. Spacing out the BsAbs delivery schedule after achieving adequate MM disease control might be an option in frail patients, though further study is required.
The higher proportion of viral infections in our patients, with special regards to CMV, also deserves attention. We saw higher rates of viral infections (67%) compared to Australia (58%) 7 or France (38%). 8 More specifically, 49.2% of the patients had CMV reactivation within 58 days of BsAbs treatment and 24.6% had clinically significant CMV infection ( Table 4 ). The high level of CMV seropositivity in Korea 19 , 20 , 21 and Asia countries 22 is a well-documented phenomenon. Recent guideline by Raje et al. 5 strongly endorses use of IVIG for hypogammaglobulinemia and antiviral prophylaxis against HSV and VZV in all patients, but monitoring of CMV is only recommended in high-risk patients. Based on our experience, we consider all our MM patients undergoing BsAbs high-risk and actively monitor quantitative CMV DNA PCR on regular basis. We consider targeted preemptive therapy at a viral load of ≥ 500 copies/mL. 23 More systematic evidence-based prophylactic regimen, such as use of fixed duration letermovir, 14 should be assessed in further prospective study.
Lastly, it seems that patients undergoing BCMA-directed BsAbs requires more vigilance compared to those receiving non-BCMA agents ( Table 7 ). BCMA is a cell surface marker which is expressed on both malignant and normal plasma cells, though the expression level is much increased in malignant plasma cells. 24 It is easily assumed that BCMA-targeting BsAbs may decrease the normal mature B cell count, 25 followed by the higher risk of infections for patients treated with BCMA-targeting agents than non-BCMA-targeting agents. 4 , 6 , 25 In our study, patients with BCMA-targeting agents showed higher incidence of CMV reactivation ( P = 0.005, Table 4 ) and clinically significant CMV infection ( P = 0.006, Table 4 ) despite the similar baseline patient/disease characteristics ( Tables 5 and 6 ). Likewise, in patients receiving combination therapy, more comprehensive plasma cell aplasia would be induced than patients with BsAb monotherapy. With the combination therapy, higher all-grade and grade ≥ 3 infections were observed than monotherapy in other studies. 6 Similarly, our study showed significant difference in CMV reactivation between patients treated with combination therapy and BsAb monotherapy as shown in Table 4 ( P = 0.002).
Table 7
Incidence and characteristics of infectious complications with subgroups
Values are presented as number (%). BCMA = B-cell maturation antigen, CNS = central nervous system, CMV = cytomegalovirus, HSV = herpes simplex virus, VZV = varicella zoster virus, HBV = hepatitis B virus, SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2, JC = John Cunningham. a Includes influenza/parainfluenza virus (n = 2), respiratory syncytial virus (n = 1), and SARS-CoV-2 (n = 13).
| Characteristics | BCMA | Non-BCMA | Single | Combination | |
| Site of infection, all | 52 events | 17 events | 24 events | 45 events | |
| Systemic | 17 (33) | 4 (24) | 5 (21) | 16 (36) | |
| Upper respiratory tract | 2 (4) | 1 (6) | 1 (4) | 2 (4) | |
| Lower respiratory tract | 25 (48) | 7 (41) | 11 (46) | 21 (47) | |
| Gastrointestinal tract | 2 (3) | 0 | 0 | 2 (4) | |
| Genitourinary tract | 1 (2) | 0 | 1 (4) | 0 | |
| Skin and soft tissue | 4 (8) | 4 (24) | 5 (21) | 3 (7) | |
| CNS and ocular | 1 (2) | 1 (6) | 1 (4) | 1 (2) | |
| Viral infections | 35 (67) | 11 (65) | 16 (67) | 30 (67) | |
| CMV, clinically significant 14 | 13 | 2 | 5 | 10 | |
| HSV | 3 | 3 | 3 | 3 | |
| VZV | 3 | 3 | 4 | 2 | |
| HBV | 2 | 0 | 0 | 2 | |
| Respiratory viruses a | 13 | 3 | 4 | 12 | |
| Severe SARS-CoV-2 15 requiring oxygen | 10 | 2 | 1 | 11 | |
| JC virus | 1 | 0 | 0 | 1 | |
| Fungal infections | 7 (13) | 2 (12) | 3 (13) | 6 (13) | |
| Aspergillus spp. | 0 | 2 | 1 | 1 | |
| Pneumocystis jirovecii | 7 | 0 | 2 | 5 | |
| Bacterial infection | 4 (8) | 3 (18) | 4 (17) | 3 (7) | |
| Tuberculosis | 1 (2) | 0 | 0 | 1 (2) |
All in all, we provide the first set of infectious complication data from homogenous East Asian MM patients treated with BsAbs. Our study has several limitations, including the retrospective nature of the study in single institution, reliance on descriptive analysis, and the absence of a standardized treatment protocol. However, newer therapeutic agents including BsAbs are already very expensive, thus dealing with complications secondary to these types of treatment will ultimately tantamount to significant financial burden in any given healthcare system. Therefore, implementing risk adaptive prophylactic measures and establishing active monitoring know-hows will become even more important for fair allocation of limited medical resources. We believe our data will bridge the gap in knowledge regarding novel therapy in MM and more importantly sets ground for region-specific adaptations of current guidelines on infection risk mitigation and subsequently treatment optimization.
ACKNOWLEDGMENTS
We would like to thank all the hematology staff at Seoul National University Hospital for their devotion and unwavering support.
Footnotes
Disclosure: The authors have no potential conflicts of interest to disclose.
Data Availability Statement: The data that support the findings of this study are available on reasonable request from the corresponding author.
Author Contributions: Conceptualization: Kang CK, Byun JM. Data curation: Park T, Jang S, Koh Y, Shin DY, Yoon SS, Lee CM, Jo HJ, Choe PG, Park WB, Kim NJ, Kang CK, Byun JM. Formal analysis: Park T, Kang CK, Byun JM. Investigation: Park T, Jang S, Koh Y, Shin DY, Yoon SS, Lee CM, Jo HJ, Choe PG, Park WB, Kim NJ, Kang CK, Byun JM. Writing - original draft: Park T, Kang CK, Byun JM. Writing - review & editing: Park T, Jang S, Koh Y, Shin DY, Yoon SS, Lee CM, Jo HJ, Choe PG, Park WB, Kim NJ, Kang CK, Byun JM.
References
1. Balmaceda N, Aziz M, Chandrasekar VT, McClune B, Kambhampati S, Shune L, et al. Infection risks in multiple myeloma: a systematic review and meta-analysis of randomized trials from 2015 to 2019. BMC Cancer. 2021;21(1):730. doi: 10.1186/s12885-021-08451-x.
2. Raje NS, Anaissie E, Kumar SK, Lonial S, Martin T, Gertz MA, et al. Consensus guidelines and recommendations for infection prevention in multiple myeloma: a report from the International Myeloma Working Group. Lancet Haematol. 2022;9(2):e143–e161. doi: 10.1016/S2352-3026(21)00283-0.
3. Ochi T, Konishi T, Takenaka K. Bispecific antibodies for multiple myeloma: past, present and future. Int J Hematol. 2024;120(1):23–33. doi: 10.1007/s12185-024-03766-4.
4. Mazahreh F, Mazahreh L, Schinke C, Thanendrarajan S, Zangari M, Shaughnessy JD, Jr, et al. Risk of infections associated with the use of bispecific antibodies in multiple myeloma: a pooled analysis. Blood Adv. 2023;7(13):3069–3074. doi: 10.1182/bloodadvances.2022009435.
5. Raje N, Anderson K, Einsele H, Efebera Y, Gay F, Hammond SP, et al. Monitoring, prophylaxis, and treatment of infections in patients with MM receiving bispecific antibody therapy: consensus recommendations from an expert panel. Blood Cancer J. 2023;13(1):116. doi: 10.1038/s41408-023-00879-7.
6. Reynolds G, Cliff ERS, Mohyuddin GR, Popat R, Midha S, Liet Hing MN, et al. Infections following bispecific antibodies in myeloma: a systematic review and meta-analysis. Blood Adv. 2023;7(19):5898–5903. doi: 10.1182/bloodadvances.2023010539.
7. Sim BZ, Longhitano A, Er J, Harrison SJ, Slavin MA, Teh BW. Infectious complications of bispecific antibody therapy in patients with multiple myeloma. Blood Cancer J. 2023;13(1):34. doi: 10.1038/s41408-023-00808-8.
8. Jourdes A, Cellerin E, Touzeau C, Harel S, Denis B, Escure G, et al. Characteristics and incidence of infections in patients with multiple myeloma treated by bispecific antibodies: a national retrospective study on the behalf of G2I and Intergroupe Francophone du Myelome. Clin Microbiol Infect. 2024;30(6):764–771. doi: 10.1016/j.cmi.2024.02.023.
9. Pizzo PA, Armstrong D, Bodey G, Pauw B, Feld R, Glauser M, et al. From the Immunocompromised Host Society. The design, analysis, and reporting of clinical trials on the empirical antibiotic management of the neutropenic patient. Report of a consensus panel. J Infect Dis. 1990;161(3):397–401. doi: 10.1093/infdis/161.3.397.
10. Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant. 2019;25(4):625–638. doi: 10.1016/j.bbmt.2018.12.758.
11. Imlay H, Limaye AP. Current understanding of cytomegalovirus reactivation in critical illness. J Infect Dis. 2020;221:S94–S102. doi: 10.1093/infdis/jiz638.
12. Chemaly RF, Ullmann AJ, Stoelben S, Richard MP, Bornhäuser M, Groth C, et al. Letermovir for cytomegalovirus prophylaxis in hematopoietic-cell transplantation. N Engl J Med. 2014;370(19):1781–1789. doi: 10.1056/NEJMoa1309533.
13. Ljungman P, Boeckh M, Hirsch HH, Josephson F, Lundgren J, Nichols G, et al. Definitions of cytomegalovirus infection and disease in transplant patients for use in clinical trials. Clin Infect Dis. 2017;64(1):87–91. doi: 10.1093/cid/ciw668.
14. Marty FM, Ljungman P, Chemaly RF, Maertens J, Dadwal SS, Duarte RF, et al. Letermovir prophylaxis for cytomegalovirus in hematopoietic-cell transplantation. N Engl J Med. 2017;377(25):2433–2444. doi: 10.1056/NEJMoa1706640.
15. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. JAMA. 2020;323(13):1239–1242. doi: 10.1001/jama.2020.2648.
16. Murakami H, Ogawara H, Hiroshi H. Th1/Th2 cells in patients with multiple myeloma. Hematology. 2004;9(1):41–45. doi: 10.1080/10245330310001652437.
17. Hasegawa Y, Kawaguchi T, Kubo A, Ando M, Shiraishi J, Isa S, et al. Ethnic difference in hematological toxicity in patients with non-small cell lung cancer treated with chemotherapy: a pooled analysis on Asian versus non-Asian in phase II and III clinical trials. J Thorac Oncol. 2011;6(11):1881–1888. doi: 10.1097/JTO.0b013e31822722b6.
18. Pathak S, Zajac KK, Annaji M, Govindarajulu M, Nadar RM, Bowen D, et al. Clinical outcomes of chemotherapy in cancer patients with different ethnicities. Cancer Rep (Hoboken) 2023;6(Suppl 1):e1830. doi: 10.1002/cnr2.1830.
19. Sohn YM, Park KI, Lee C, Han DG, Lee WY. Congenital cytomegalovirus infection in Korean population with very high prevalence of maternal immunity. J Korean Med Sci. 1992;7(1):47–51. doi: 10.3346/jkms.1992.7.1.47.
20. La Y, Kwon DE, Yoo SG, Lee KH, Han SH, Song YG. Human cytomegalovirus seroprevalence and titres in solid organ transplant recipients and transplant donors in Seoul, South Korea. BMC Infect Dis. 2019;19(1):948. doi: 10.1186/s12879-019-4607-x.
21. Choi SR, Kim KR, Kim DS, Kang JM, Kim SJ, Kim JM, et al. Changes in cytomegalovirus seroprevalence in Korea for 21 years: a single center study. Pediatr Infect Vaccine. 2018;25(3):123–131.
22. Fowler K, Mucha J, Neumann M, Lewandowski W, Kaczanowska M, Grys M, et al. A systematic literature review of the global seroprevalence of cytomegalovirus: possible implications for treatment, screening, and vaccine development. BMC Public Health. 2022;22(1):1659. doi: 10.1186/s12889-022-13971-7.
23. Green ML, Leisenring W, Stachel D, Pergam SA, Sandmaier BM, Wald A, et al. Efficacy of a viral load-based, risk-adapted, preemptive treatment strategy for prevention of cytomegalovirus disease after hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2012;18(11):1687–1699. doi: 10.1016/j.bbmt.2012.05.015.
24. O’Connor BP, Raman VS, Erickson LD, Cook WJ, Weaver LK, Ahonen C, et al. BCMA is essential for the survival of long-lived bone marrow plasma cells. J Exp Med. 2004;199(1):91–98. doi: 10.1084/jem.20031330.
25. Frerichs KA, Verkleij CPM, Mateos MV, Martin TG, Rodriguez C, Nooka A, et al. Teclistamab impairs humoral immunity in patients with heavily pretreated myeloma: importance of immunoglobulin supplementation. Blood Adv. 2024;8(1):194–206. doi: 10.1182/bloodadvances.2023011658.