Hypogammaglobulinemia, neutropenia, and lymphopenia, and risk for infection and mortality in patients following daratumumab for multiple myeloma

Abstract Daratumumab is an IgG kappa monoclonal antibody targeting CD38 approved for the treatment of multiple myeloma. While lymphopenia and neutropenia have been described, the broader immunologic impact, including hypogammaglobulinemia (IgG ≤600 mg/dL), remains undercharacterized. We performed a retrospective analysis of 614 adults receiving daratumumab for multiple myeloma; evaluating demographics, disease characteristics, hypogammaglobulinemia, lymphopenia, neutropenia, infections, immunoglobulin replacement (IVIG) use, and mortality. Mean IgG levels decreased from 568 mg/dL to 371 mg/dL following daratumumab, and hypogammaglobulinemia prevalence rose from 64.3% to 87.9%, with increasing severity. Lymphopenia and neutropenia prevalence and severity also increased. Hypogammaglobulinemia pre-daratumumab was associated with increased risk for infection (IRR 1.28, 95% CI 1.08–1.51), with severe hypogammaglobulinemia conferring the highest risk (IRR 1.85, 95% CI 1.45–2.35). Lower IgG levels were associated with infection risk. Baseline hypogammaglobulinemia, lymphopenia, and neutropenia were associated with increased mortality. When IVIG exposure was modeled as a time-varying variable, infection risk was significantly higher during periods off of IVIG compared with on IVIG (IRR 2.43, 95% CI 1.70–3.48). These findings support closer monitoring of IgG, ALC, and ANC beginning prior to daratumumab initiation and continued at regular intervals, with earlier consideration of immunoglobulin replacement in patients with hypogammaglobulinemia and infectious complications.