Infections in Patients with Relapsed/Refractory Multiple Myeloma in the United States: A Real-World Analysis
Authors: Ida Fidelia , Ramakrishna Bharat , Nasserinejad Kaz , Radu Adriana , Lawo John-Philip , Zhang Xiang , Gardiner David , Yoon Lara , Dabrowski Elizabeth C. , Shen John , Iyer Monica , Kreisberg Hannah , Espinoza Gabriela , Shahid Zainab , Giralt Sergio A. 
Published: December 2024

Background: Patients (pts) with relapsed/refractory multiple myeloma (RRMM) are at risk of hypogammaglobulinemia (HGG), a secondary immunodeficiency (SID) subtype and herein referred to as SID. SID is defined as low levels (≤7 g/L) of functional serum immunoglobulin (Ig) G, due to the malignancy and/or its treatment (e.g., CAR T therapy or bispecific antibodies). SID can be associated with increased infection risk and management includes prophylactic antibiotics, vaccination, and immunoglobulin replacement therapy (IgRT); however, treatment is not harmonized across the US.

Aims: To investigate the real-world burden of infection in pts with RRMM in the US.

Methods: This retrospective study used the US Optum Market Clarity database (baseline period: 10/2015-4/2016; follow-up period: 4/2016-9/2023). Infection-related outcomes were assessed in pts with RRMM (RRMM defined by ICD-10 diagnosis codes). Pts were excluded if they had history of non-malignant conditions indicated for IgRT (including primary immunodeficiency) prior to MM diagnosis, or &lt;6 months baseline data. Outcomes of interest included frequency, rate, and time to event of infections, serious bacterial infections (SBI; bacteremia/sepsis, bacterial meningitis, osteomyelitis/septic arthritis, bacterial pneumonia, visceral abscess), and other protocol-defined infections; hospitalization due to infection; antibiotic use within 3 days of infection; and death within 45 days of infection. Subgroups were defined based on: IgG level, number of prior infections, neutrophil count, and cancer treatment class.

Results: Overall, 43,793 pts with RRMM were identified. In the baseline period, mean (standard deviation) age was 66.4 (12.0) years old and 44.6% (n=19,533) were male (40.5%, n=17,725 female; 14.9%, n=6,535 unknown). Overall, 10.1% (n=4,409) had history of other heme malignancies, 11.0% (n=4,819) had neutropenia, and 3.6% (n=1,588) had SID. A total of 20.1% (n=8,798) had evidence of baseline IgG lab results. Only 1.2% (n=516) of pts were receiving IgRT, 8.4% (n=3,694) received prophylactic antibiotics, and 30.8% (n=13,497) had been vaccinated.

Outcomes analysis was conducted in the follow-up period for 42,930 pts without prior IgRT. The overall rate of any infection per person year (PY) (95% confidence interval [CI]) was 1.06 (1.04, 1.08), SBI rate was 0.29 (0.28, 0.29). In pts experiencing ≥1 infection, median (interquartile range) time to event for infections was 87 (33, 184) days and for SBI was 100 (40, 197) days. Infection hospitalization rate per PY was 0.18 (0.18, 0.19). Rates of antibiotic use per PY were 0.07 (0.07, 0.08) for IV and 0.12 (0.20, 0.21) for oral antibiotics. Rate of death within 45 days of infection was 0.05 (0.05, 0.06), among 1,663 (3.9%) pts who had an event.

Pts with the lowest IgG levels (&lt;300 mg/dL, n=756) had higher infections rates than those with IgG levels above 600 mg/dL (n=10,008): overall infection rate was 1.47 (1.32, 1.63), with a SBI rate of 0.43 (0.36, 0.50) for the lowest IgG group and SBI rate of 0.28 (0.26, 0.29) for the highest IgG group. Pts with no prior infections (n=31,246) had an infection rate of 0.81 (0.79, 0.82) vs a rate of 2.23 (2.18, 2.28) for pts who had experienced ≥3 infections within 12 months (n=11,039). Across the IgG levels subgroups, infection rates increased with increasing history of previous infections. Neutropenia grade was associated with an increase in infections, Grade 0-2 neutropenia (n=24,195): rate of 1.10 (1.08, 1.12), Grade 4 neutropenia (n=298): rate of 2.94 (2.55, 3.38). The highest infection rate when stratified by anti-cancer treatment was for bispecific antibodies (n=44; rate: 3.60 [2.02, 6.44]), followed by CAR T (n=115; rate: 1.65 [1.21, 2.24]) and alkylating agents (n=6,387, rate: 1.65 [1.58, 1.72]).

Conclusion: These real-world data reveal a high infection burden in pts with RRMM. Only 1 in 5 pts had IgG serum levels tested and overall, only 1 in 100 pts received IgRT, despite guidelines recommending IgRT in pts with SID/HGG. Pts with low IgG levels and those with prior infection history had high rates of infections, as did pts being treated with cancer therapies. These data highlight the urgent need to optimize RRMM infection management. Increasing IgG testing to confirm who has low IgG levels and appropriate use of IgRT may minimize infection burden in pts with RRMM.