Infectious Complications of Bispecific Antibody Therapy in Patients with Multiple Myeloma

Introduction Infection is a leading contributor to morbidity in heavily treated patients with multiple myeloma (MM) with severe infection rates of up to 30% reported (Lim et. al. Clin Lymphoma Myeloma Leuk 2021). Bispecific antibody (BsAb) therapy is increasingly used in the treatment of multiple myeloma (MM) patients, but the infectious risks and optimal antimicrobial prophylaxis are not well-characterised. A retrospective observational study was conducted to describe the epidemiology, infectious complications, and outcomes to better guide antimicrobial prophylaxis and empiric treatment in this cohort.

Methods All MM patients who received BsAb therapy at the Peter MacCallum Cancer Centre between 1^st January 2018 to 30^th May 2022 were included. Retrospective chart review of patients was conducted, and demographic, clinical, and microbiological data related to disease and infection episodes were collected. Complications of BsAb therapy such as cytokine release syndrome (CRS) were defined according to published criteria. Episodes of infection were graded by CTCAE criteria, and categorised as microbiologically-defined (MDI), clinically-defined (CDI) or fever of unknown focus (FUO) as defined by presence of fever and the absence of compatible microbiology or focal symptoms. Patients were followed up for 6 months post last BsAb dose, until next line of treatment, or death. Descriptive statistics were utilised to summarise clinical data and univariate and multivariate logistic regression performed to identify factors associated with MDI. Statistical analysis was conducted on Rstudio with p<0.05 considered statistically significant.

Results: Overall, 39 patients were included. Patients were predominantly male (24, 62%), with a mean age of 62 (range: 27-78). The majority (67%) had IgG type myeloma, 28% had an International Staging System (ISS) score of 3 and had a median of 6 (IQR 4-7) lines of therapy prior to BsAb.

Patients received a median of 5 (IQR 2-11) cycles of therapy and CRS occurred in 28 (72%) patients. Median duration of neutropenia and lymphopenia <1.0x10⁹/L was 1 (IQR 0-3) and 22 (13-61) days respectively. Baseline characteristics are presented in Table 1.

Of the 39 patients, 35 (90%) had at least 1 episode of infection (MDI, CDI, FUO), 15 (38%) had an MDI, and 16 (41%) had a grade 3 or higher infection episode. There was a total of 111 infection episodes and prior valaciclovir prophylaxis was administered in 104 (94%), trimethoprim/sulfamethoxazole in 104 (94%) and antifungals in 38 (34%) episodes. Cumulative prednisone-equivalent dose in the preceding 30 days was median of 266.7mg (IQR 106.7-266.7).

Of these 111 episodes, 33 (30%) were MDI, 43 (39%) were CDI, and 35 (32%) were FUO (Table 2). Respiratory system was the commonest site of infection (46, 41%). Of the MDI, viral infections were commonest (22, 67%), particularly rhinovirus/enterovirus (8, 36%), followed by cytomegalovirus (4, 18%) and adenovirus (4, 18%). Bacterial infections were Gram negative in 12 (80%) and Gram positive in 3 (20%). There were no episodes of invasive fungal disease. Majority of FUO were likely CRS (31, 89%). Episodes occurred during a median of 2 (IQR 1-7) cycles of therapy.

Hospital admission was associated with 63 (57%) episodes with a median (IQR) length of stay of 4 (3-6) days. Intensive care admission was required in 4 (4%) episodes and all-cause mortality was 3%.

Baseline clinical variables age, functional status (ECOG), international staging system stage, lines of therapy, CRS, and its treatment were not found to be associated with increased risk for MDI on univariate or multivariate logistic regression.

Conclusions: Infection remains a clinically significant burden in heavily-treated MM patients on BsAb therapy. Clinically diagnosed, respiratory tract infections were most frequently diagnosed. Viral infections were the most common type of MDI identified, facilitating targeting of prevention and surveillance measures. Future larger studies are required to define associated risks for infection.

Er:Peter MacCallum Cancer Centre and Royal Melbourne Hospital: Current Employment; Roche: Honoraria. Harrison:Celgene/BMS, GSK, Janssen Cilag, Haemalogix: Research Funding; Abbvie, Amgen, Celgene/BMS, GSK, Janssen Cilag, Novartis, Roche Genentech, Haemalogix, Eusa, Terumo BCT: Honoraria; Abbvie, Amgen, Celgene/BMS, GSK, Janssen Cilag, Novartis, Roche Genentech, Eusa: Speakers Bureau; Haemalogix: Membership on an entity's Board of Directors or advisory committees; Abbvie, Amgen, Celgene/BMS, GSK, Janssen Cilag, Novartis, Roche Genentech, Haemalogix, Eusa, Terumo BCT: Consultancy. Slavin:Takeda: Consultancy; Pfizer: Consultancy, Speakers Bureau; F2G: Research Funding, Speakers Bureau; Gilead: Consultancy; Merck: Consultancy, Research Funding, Speakers Bureau; NHMRC: Research Funding. Teh:MSD, Seqirus and Sanofi: Research Funding; CSL-Behring, Takeda and Moderna: Other: Advisory board; Gilead, Pfizer, Alexxion: Other: Speaker fees - paid to institution.