Hypogammaglobulinemia and Its Implications in Patients Treated with Daratumumab: A Single Institution Experience
Authors: Paul Yonette , Aguirre Luis E. , Basher Fahmin , Miao Feng , Koru-Sengul Tulay , Hoffman James E. 
Published: November 2019

Introduction: Daratumumab is an IgG Kappa monoclonal antibody (mAB) to CD38, a surface glycoprotein expressed on plasma cells. It was approved in 2015 as monotherapy for Multiple Myeloma (MM) patients who failed three prior lines of therapy. Its approval was then expanded to second line and most recently first line. As such, patients are now getting earlier and longer exposure to this mAB. Disease response to daratumumab is monitored by demonstrating a fall in paraprotein levels. It is becoming widely appreciated that hypogammaglobulinemia (HGGE) ie. (IgG<600mg/dl) with risk of infection, is a potential complication for patients on daratumumab. The immune mediated attack by daratumumab on CD38 expressing plasma cells also results in destruction of normal lymphocytes, resulting in impaired production of polyclonal immunoglobulins and diminished immunity. We aim to explore the incidence, severity and clinical significance of HGGE in patients on daratumumab.
Methods: We conducted a retrospective chart review of all patients treated with daratumumab as single agent or in combination (November 2015-June 2019), who had documented baseline and post therapy quantitative IgG levels. Demographics, subtype of plasma cell disease, bone marrow cytogenetics/FISH, serial IgG levels, incidence of significant infections and need for IVIG therapy were collected as part of this exploratory data analysis.
Results:
Among 145 eligible patients, 53% were male, 37% Hispanic, 19% Black/African American and 72% were age<70 at diagnosis. The majority of patients had an IgG paraprotein (56.6%), followed by IgA (18.6%), Free Kappa only (13.1%) and Free Lambda only (9.7%). Hispanics were more likely to have high risk cytogenetics (OR=2.29, p=0.0804). 34.5% of patients had previous autologous stem cell transplant. At baseline 30.3% of all patients had HGGE; 58.1% non-IgG patients and only 9.6% IgG patients. The mean baseline IgG level in IgG patients was 1986.1 mg/dl and for non-IgG patients was 698.1 mg/dl. After being treated with daratumumab, 61.4 % of all patients developed HGGE; 42.2% of IgG patients and 87.1% of non-IgG patients. The mean Nadir IgG level for the IgG subtype cohort was 643.7 mg/dl and for the non-IgG cohort was 355.9 mg/dl. The incidence of significant infection in total group was 23.4% (21.7% in IgG vs 25.8% in non-IgG). Bacterial pneumonia and sepsis were the two most common infections. Despite the relatively high incidence of HGGE in this cohort, only 11 were treated with IVIG. (5 IgG vs 6 non-IgG). Using a univariate logistic regression model, Black/ African Americans and patients with higher baseline IgG were less likely, but non-IgG patients were more likely to develop HGGE (all p<0.05) .
Conclusion: Our study identifies a high incidence of meaningful HGGE in patients on daratumumab. In the non-IgG subtype, the relationship is straightforward, as any drop in IgG reflects a drop in polyclonal immunoglobulins and impaired humoral immunity. In contrast, in the IgG subtype, a fall in IgG levels has two components; a fall in the monoclonal protein (indicative of favorable disease response) as well as a fall in polyclonal IgG.
There was a lower incidence of pre and post treatment HGGE in the IgG cohort compared to the non-IgG cohort( ie.IgA, IgD, Free Kappa and Free Lambda). In contrast the incidence of infection in both cohorts were very similar. This suggests that polyclonal HGGE in IgG subtype plasma cell disorders may be largely undetected and undertreated, due to apparently normal IgG levels caused by pathologic production of monoclonal IgG.
When we attempt to subtract the monoclonal element (m-spike in the serum protein electrophoresis) from the total IgG, the magnitude of hypogammaglobulinemia in the IgG cohort approximates that of the non-IgG group. Given that daratumumab adds a small amount to the measured m-spike, further techniques to quantify true polyclonal IgG levels in the IgG cohort are needed.
The incidence and depth of HGGE associated with daratumumab has not been previously well quantified. Our study demonstrates that the incidence of HGGE doubled after therapy with daratumumab (30.3% vs 61.4%). This data will sensitize physicians and possibly lead to generation of guidelines for closer monitoring of IgG, use of IVIG and other precautions in patients on daratumumab. In our own institution, we anticipate the detection of HGGE and use of IVIG in these patients to increase substantially.

Disclosures
Hoffman: Celgene: Speakers Bureau.