Efficacy of Antiviral Treatment in Hepatitis C Virus (HCV)-Driven Monoclonal Gammopathies Including Myeloma

Abstract

Multiple myeloma (MM) remains an incurable plasma cell malignancy. While its origin is enigmatic, an association with infectious pathogens including hepatitis C virus (HCV) has been suggested. Here we report nine patients with monoclonal gammopathy of undetermined significance (MGUS) or MM with previous HCV infection, six of whom received antiviral treatment. We studied the evolution of the gammopathy disease, according to anti-HCV treatment and antigen specificity of purified monoclonal immunoglobulin, determined using the INNO-LIA™ HCV Score assay, dot-blot assays, and a multiplex infectious antigen microarray. The monoclonal immunoglobulin from 6/9 patients reacted against HCV. Four of these patients received antiviral treatment and had a better evolution than untreated patients. Following antiviral treatment, one patient with MM in third relapse achieved complete remission with minimal residual disease negativity. For two patients who did not receive antiviral treatment, disease progressed. For the two patients whose monoclonal immunoglobulin did not react against HCV, antiviral treatment was not effective for MGUS or MM disease. Our results suggest a causal relationship between HCV infection and MGUS and MM progression. When HCV was eliminated, chronic antigen-stimulation disappeared, allowing control of clonal plasma cells. This opens new possibilities of treatment for MGUS and myeloma.

Keywords: antiviral; hepatitis (C) virus; infection; monoclonal gammopathies; multiple myeloma.

Figure 1

Stable complete remission and specific recognition of HCV in a patient with MM treated with antiviral drugs. Panel (A) shows the HCV load quantified by reverse-transcriptase quantitative polymerase chain reaction in the patient’s serum. The black horizontal dotted line represents the threshold of virus detection. Panel (B) shows the quantity of monoclonal IgG as determined by serum protein electrophoresis. Panel (C) shows the percentage of plasma cells determined by bone marrow examination (cytology) or next generation 8-color multiparametric flow cytometry, and the percentage of pathological plasma cells as determined by immunophenotyping. (A–D) The blue vertical dotted line indicates the time of antiviral treatment. Panel (D) shows a representative agarose gel electrophoresis of polyclonal Igs in serum before (2014) and after (2017) antiviral treatment – the encircled band corresponds to the patient’s monoclonal Ig. Panel (E) shows the INNO-LIA™ HCV test and immunoblotting assay used to detect reactivity of the patient’s serum IgG and of the purified monoclonal IgG against different HCV proteins. The signal obtained with HCV core for the monoclonal IgG of patient P1 was weak but always reproducible when different preparations of the purified monoclonal IgG were tested. C, positive controls; S, serum; Mc, monoclonal Ig.

Figure 2

Disease evolution and evaluation of HCV-specificity of the monoclonal Ig from patients who were treated with antiviral drugs. Panel (A) shows the HCV load quantified by reverse-transcriptase quantitative polymerase chain reaction in patients’ serum. The black horizontal dotted line represents the threshold of virus detection. Panel (B) shows the quantity of monoclonal Ig as determined by serum protein electrophoresis. (A, B) The blue vertical dotted line indicates the time of antiviral treatment. Panel (C) shows the INNO-LIA™ HCV test to detect reactivity of patients’ serum IgGs and of the purified monoclonal IgG against different HCV proteins. Panel (D) shows the dot-blot assay to detect reactivity of patients’ serum IgAs and of the purified monoclonal IgA against different HCV proteins (IgAs cannot be studied using the INNO-LIA™ HCV test). The monoclonal IgA of patient P4 strongly recognized the HCV NS3 protein, whereas the monoclonal IgA of patient P6 did not recognize any HCV protein of the assay. C, positive controls; S, serum; Mc, monoclonal Ig.

Figure 3

Disease evolution and evaluation of HCV recognition by the monoclonal Ig from patients who were not treated with antiviral drugs. Panel (A) shows the quantity of monoclonal IgG as determined by serum protein electrophoresis. Panel (B) shows the INNO-LIA™ HCV test used to detect reactivity of the serum IgGs and of the purified monoclonal IgG for Patient P7, which strongly recognized the HCV NS3 protein. Panel (C) shows the dot-blot assay used to detect reactivity of serum IgAs and of the purified monoclonal IgA in patient P8, which reacted against HCV NS3 protein. A weaker signal was noted for HCV NS4, possibly due to contaminating polyclonal IgAs. C, positive controls; S, serum; Mc, monoclonal Ig.