Real-World Effectiveness of Immunoglobulin Replacement Therapy on Hypogammaglobulinemia and Infectious Complications in Patients with Multiple Myeloma

Introduction: Hypogammaglobulinemia (HGG), a secondary immune deficiency, can occur in patients with multiple myeloma (MM), due to both the underlying disease and its treatments. Infections are a leading cause of mortality in patients with MM, occurring in 22%-45% of patients, highlighting the need for safe and effective treatments to control infections in patients with MM and HGG. This study assessed the real-world effectiveness of immunoglobulin replacement therapy (IGRT) for treatment of HGG and infections in patients with MM.

Methods: A retrospective, longitudinal study was conducted in adult patients diagnosed with MM on or after January 1, 2010, with ≥3 visits/year and ≥12 months of clinical data, using the Mass General Brigham Research Patient Data Registry. Infections and antimicrobial use were compared 3 months before versus after IGRT initiation. Generalized estimating equation logistic regression models were used to calculate odds ratios (ORs), 95% confidence intervals (CIs), and P values. In patients with available pathology reports, an artificial intelligence-aided program supported the extraction of immunoglobulin G (IgG) data. IgG assessments and determination of HGG (defined as IgG level <500 mg/dL) were compared 3 months before versus after IGRT initiation. Results were reported with descriptive statistics; P values were calculated using McNemar's test for HGG and Wilcoxon signed-rank tests for IgG tests.

Results: Of the 6062 patients with MM who met the eligibility criteria of this study, 3409 (56.2%) were men, and the median age was 65.0 years (interquartile range [IQR]: 58.0, 73.0). Median follow-up was 4.6 years (IQR: 2.4, 7.2).

Within the total population, 471/6062 (7.8%) received ≥1 IGRT administration, and of those, 257/471 (54.6%) received ≥2 IGRT administrations. Among the 214 patients with a single IGRT administration, the median time from MM diagnosis to IGRT initiation was 32.2 months (IQR: 10.2, 58.4). Among patients with ≥2 IGRT administrations (n=257), median time from the first to the second was 3.1 months (IQR: 0.9, 6.5). In patients who received ≥1 IGRT administration and had ≥3 months follow-up before and after IGRT initiation (n=370), significantly lower odds of infections and antimicrobial use were observed in the 3 months after IGRT initiation versus before for: all infections (OR: 0.71; 95% CI: 0.56, 0.89; P=0.004), all severe infections (OR: 0.47; 95% CI: 0.36, 0.62; P<0.0001), infections requiring antimicrobial use (OR: 0.51; 95% CI: 0.39, 0.65; P<0.0001), and severe infections requiring antimicrobial use (OR: 0.43; 95% CI: 0.32, 0.56; P<0.0001).

Among patients with available pathology reports (n=3405), 3231 (94.9%) received ≥1 IgG test, with a median of 18.0 (IQR: 7.0, 40.0) IgG tests per patient during the follow-up period. Most patients (2716/3231, 84.1%) received ≥1 IgG test after their first MM diagnosis, with a median time of 0.5 months (IQR: 0.1, 2.0) from MM diagnosis to first IgG test. HGG was experienced by 2075/3231 (64.2%) patients who had ≥1 IgG test. Among the 227 patients with ≥1 IGRT administration who received ≥1 IgG test 3 months before and after IGRT initiation, median IgG levels were 410.0 mg/dL (IQR: 307.0, 682.0) immediately before IGRT initiation versus 609.0 mg/dL (IQR: 434.0, 855.0) in the 3 months after IGRT initiation; P<0.0001. Of these 227 patients; significantly fewer patients had HGG 3 months after IGRT initiation (n=55, 24.2%) versus 3 months before (n=135, 59.5%); P<0.0001.

Conclusions: To our knowledge, this is the largest real-world cohort study to date of patients with MM treated with IGRT. Significant reductions in infections and infections requiring antimicrobials were observed in the 3 months after IGRT initiation compared with the 3 months after initiation. Moreover, in patients assessed by pathology reports, IGRT use was associated with significant reductions in HGG. While IGRT is currently used for MM treatment, there is potential to optimize its dosing and treatment duration to reduce the morbidity and mortality associated with infections.

O'Donnell:Pfizer: Honoraria; Takeda: Consultancy; Janssen: Honoraria; BMS: Honoraria; Sanofi: Honoraria; Natera: Other: Steering committee; Exact Sciences: Consultancy. Gift:Takeda Pharmaceuticals USA Inc: Current Employment. Yousif:Takeda Pharmaceuticals: Consultancy. Huynh:Apellis: Other: Analysis Group received consulting fees , Research Funding; GSK: Other: Analysis Group received consulting fees , Research Funding; Merck: Other: Analysis Group received consulting fees , Research Funding; Takeda: Other: Analysis Group received consulting fees , Research Funding; Sanofi: Other: Analysis Group received consulting fees , Research Funding; Analysis Group, Inc: Current Employment; Alexion: Other: Analysis Group received consulting fees , Research Funding; Genmab: Other: Analysis Group received consulting fees , Research Funding. Khandelwal:Takeda Pharmaceuticals: Current Employment. Duh:Alexion: Research Funding; Blue Print Medicine: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; GSK: Research Funding; Genmab: Research Funding. Murphy:Mass General Brigham: Current Employment, Other: Shawn Murphy is an employee of Mass General Brigham which received funding from Janssen Scientific Affairs, LLC, to conduct this study. Sanchirico:Takeda Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company.