Hypogammaglobulinemia and Daratumumab in Multiple Myeloma: Risk Factors, Infections, Immunoglobulin Replacement, and Mortality

Introduction:

Daratumumab is an IgG kappa monoclonal antibody targeting CD38 that is approved for the treatment of multiple myeloma (MM). CD38 is highly expressed on myeloma cells and also expressed at basal levels on normal plasma cells. Hypogammaglobulinemia, a condition characterized by low serum immunoglobulin (Ig) or antibody levels, is common following daratumumab, with increased risk of infection. This risk may be mitigated by the use of immunoglobulin replacement including intravenous immunoglobulin (IVIG). There is limited data to date on the prevalence and severity of hypogammaglobulinemia following daratumumab, as well as risk and mitigating factors for infection.

Methods:

We performed a retrospective analysis evaluating demographics, disease characteristics, infectious history, immunoglobulin levels and use of IVIG for patients receiving daratumumab for MM at our institution. Hypogammaglobulinemia was evaluated pre- and post-daratumumab, stratified as mild (IgG ≤ 600mg/dL), moderate (<400mg/dL) or severe (<200mg/dL). In patients with IgG subtype MM, a corrected polyclonal IgG value was obtained by subtracting out the quantified monoclonal component, “M-spike.” The change in mean IgG values was compared via paired T-test. Risk factors for hypogammaglobulinemia and infections were calculated using logistic and Poisson regressions, adjusted for age, sex, lymphopenia, and neutropenia. The impact of IVIG on infections was evaluated, from the time of daratumumab initiation (day 0) to the last infusion plus six months. IVIG use during this time was stratified into: “On” IVIG timepoints, which was considered 30 days after any IVIG infusion, or “Off” IVIG, which were intervals without IVIG administration. The effect of hypogammaglobulinemia on survival following daratumumab was evaluated using a Kaplan Meier survival curve.

Results:

We identified 614 patients (58% male, mean age 70.4 years [STD±10]) who received daratumumab for multiple myeloma. Patients were evenly distributed across the MM International Staging System (Stage 1 [36.3%], Stage 2 [28.3%], Stage 3 [35.4%]). The majority of patients had IgG-subtype myeloma (325/614 (53%)), with the non-IgG group (IgA, IgM, IgD, and light chain only subtypes) making up the rest of the cohort (46%). Following daratumumab, 289/614 (47%) patients developed severe infections, 215 of which required hospitalization. In patients with data available in the 100 days pre- and post-daratumumab (n=477), the proportion of patients with severe infections increased post-daratumumab (57 [12.0%] to 79 [16.6%]; p=0.04). Corrected mean IgG levels decreased significantly following daratumumab (532 to 350 mg/dL, p<0.0001). The prevalence of hypogammaglobulinemia increased from 407 (69.3%) to 501 (89.6%) patients. Pre-existing hypogammaglobulinemia was the greatest risk factor for hypogammaglobulinemia post-daratumumab (OR 8.25, 95% CI 4.35-15.64; p<0.0001). The severity of hypogammaglobulinemia increased following daratumumab (moderate: pre-30.8% to post-47.4%, severe: pre-12.4% to post-34.7%). In patients with non-IgG subtype MM, severe hypogammaglobulinemia was associated with significantly higher rates of infection (IRR 3.61, 95% CI 1.15-11.35; p=0.028). Stratifying IVIG use after daratumumab by “On” IVIG vs “Off” IVIG timepoints, we found that patients were at a significantly higher risk for infection when they are “Off” IVIG (IRR 2.37, 95% CI 1.68-3.34; p<0.0001). A Kaplan-Meier survival estimate demonstrated patients who had hypogammaglobulinemia (n=407) had increased mortality when compared to those without hypogammaglobulinemia (n=180) following daratumumab therapy (p=0.0015).

Conclusion:

Daratumumab was associated with increased prevalence and severity of hypogammaglobulinemia. Hypogammaglobulinemia was, in turn, associated with an increased risk for infections and mortality. Patients receiving IVIG had a significantly lower risk of infection while on IVIG. This emphasizes the importance of immunological monitoring for patients on daratumumab, with future studies needed to prospectively validate the immunologic benefit of immunoglobulin replacement.