Risk of Infection Increases with Longer Duration of Bispecific Antibody Therapy in Multiple Myeloma

Findings from a recent case series have highlighted the prolonged hypogammaglobulinemia and increased risk of infectious complications in patients with relapsed/refractory multiple myeloma (RRMM) who are treated with bispecific antibody therapy.

Bispecific antibodies targeting novel antigens are a relatively new class of therapeutics showing promise for RRMM. Although hypogammaglobulinemia is expected due to plasma cell depletion, researchers do not fully understand the degree of humoral immunodeficiency and infectious complications with bispecific antibodies.

In a recent case series, investigators included patients with RRMM who were treated in early phase 1 and 2 clinical trials of bispecific antibodies at their institution between January 1, 2019, and December 31, 2021. Patients self-reported their sex, race, and ethnicity, which were collected due to the high incidence of multiple myeloma among racial and ethnic minority groups.

Serial immunoglobulin levels and infections confirmed by clinical, imaging, microbiologic, or histopathologic evidence were captured retrospectively from the start of therapy until the last follow-up or 3 months after study exit.

Cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome were graded according to the American Society for Transplantation and Cellular Therapy criteria, and antibiotic prophylaxis was prescribed per institutional guidelines.

According to the study results, 42 patients contributing 49 treating periods were included in the analysis because 7 patients were counted twice. This included 25 (51%) men and 24 (49%) women with a median age of 67 years. At a median follow-up of 9.5 months, bispecific antibody therapy continued for 17 of the 42 patients.

Serum immunoglobulin G (IgG) levels were 159 mg/dL at a median of 104 days from initiation of treatment. Serum immunoglobulin A (IgA) and immunoglobulin M (IgM) levels were both less than 5 mg/dL at a median of 23 and 21 days, respectively, from the start of therapy.

Serum IgG levels were below the detectable range in 14 patients (28%) at some point during therapy and serum IgA and IgM levels were below the detectable range in 21 (50%) and 25 (60%) patients, respectively. Intravenous immunoglobulin supplementation was administered in 24 of 49 treatment periods (49%).

Importantly, the investigators found that the overall cumulative risk of infections increased with longer duration of therapy. At 3 months the risk was 41%; at 6 months, 57%; at 9 months, 64%; at 12 months, 67%; and at 15 months, 70%.

The most common infections (54%) were bacterial, followed by viral (41%) and fungal (5%) infections. Respiratory tract infections accounted for 41 of 81 infections (51%). Four deaths were attributed to infections, including 2 patients who died within 90 days of treatment.

In a multivariate analysis, ongoing bispecific antibody therapy, prior infection, low baseline functional IgG levels, and elevated serum M-spike levels were independently associated with risk of infection.

In the current series, 17 patients (40%) received 1 COVID-19 booster and 2 (5%) received 2 boosters. Although 6 of 16 patients (38%) mounted an anti-spike antibody response to the primary COVID-19 immunization series, this increased to 12 (75%) after booster doses. Four patients had breakthrough COVID-19 infection: 2 after the primary series and 2 after a booster dose.

The authors concluded that the risk of infection was associated with the degree of hypogammaglobulinemia and increased further with treatment. They also noted an increasing rate of seroconversion with COVID-19 booster vaccination series.

Although the study had a small sample size, the findings underscore the changing continuum of humoral immunodeficiency and infection risk with the growing use of bispecific antibodies in RRMM.

REFERENCE

Hammons L, Szabo A, Janardan A, et al. Kinetics of Humoral Immunodeficiency With Bispecific Antibody Therapy in Relapsed Refractory Multiple Myeloma. JAMA Netw Open. 2022,5(10):e2238961. Doi:10.1001/jamanetworkopen.2022.38961