Impact of viral hepatitis therapy in multiple myeloma and other monoclonal gammopathies linked to hepatitis B or C viruses

Abstract

Subsets of multiple myeloma (MM) and monoclonal gammopathies of undetermined significance (MGUS) present with a monoclonal immunoglobulin specific for hepatitis C virus (HCV), thus are presumably HCV-driven, and antiviral treatment can lead to the disappearance of antigen stimulation and improved control of clonal plasma cells. Here we studied the role of hepatitis B virus (HBV) in the pathogenesis of MGUS and MM in 45 HBV-infected patients with monoclonal gammopathy. We analyzed the specificity of recognition of the monoclonal immunoglobulin of these patients and validated the efficacy of antiviral treatment (AVT). For 18 of 45 (40%) HBV-infected patients, the target of the monoclonal immunoglobulin was identified: the most frequent target was HBV (n=11), followed by other infectious pathogens (n=6) and glucosylsphingosine (n=1). Two patients whose monoclonal immunoglobulin targeted HBV (HBx and HBcAg), implying that their gammopathy was HBV-driven, received AVT and the gammopathy did not progress. AVT efficacy was then investigated in a large cohort of HBV-infected MM patients (n=1367) who received or did not receive anti-HBV treatments and compared to a cohort of HCV-infected MM patients (n=1220). AVT significantly improved patient probability of overall survival (P=0.016 for the HBV-positive cohort, P=0.005 for the HCV-positive cohort). Altogether, MGUS and MM disease can be HBV- or HCV-driven in infected patients, and the study demonstrates the importance of AVT in such patients.

Figure 1.

The effect of antiviral treatment in hepatitis C virus- and hepatitis B virus-infected multiple myeloma cohorts. (A) Study design and flowchart of hepatitis B virus (HBV)⁺ (orange) and hepatitis C virus (HCV)⁺ (blue) cohorts. A total of 1,367 (HBV⁺) or 1,192 (HCV⁺) patients from 49 out of the 73 healthcare organizations (HCO) of the TriNetX network were included in the cohort of patients diagnosed with multiple myeloma (MM) after HBV or HCV infection. Anti-viral treatments (AVT) were tenofovir disoproxil, lamivudine, peginterferon alfa-2a, interferon alfa-2b, tenofovir alafenamide, entecavir. Anti-HCV treatments were elbasvir, grazoprevir, glecaprevir, pibrentasvir, sofosbuvir, velpatasvir, voxilaprevir, or combinations of these drugs. (B) Survival analysis of the HBV⁺ and HCV⁺ cohorts. Number of patients and log-rank test in each cohort, with outcome and survival probability at the end of time window in HBV or HCV cohorts. df: degree of freedom. (C) Kaplan-Meier plots comparing overall survival since the time of MM diagnosis of patients with HBV or HCV infection who received AVT (purple) or not (green). Since no differences in age or sex among groups of AVT treated versus untreated patients were observed, analyses were performed without propensity score matching (HBV⁺ patients: P=0.270; HCV⁺ patients: P=0.466).

Figure 2.

Results of the MIAA and dot blot assays of six hepatitis B virus-specific monoclonal Ig. For each patient (Pt), results obtained in parallel with the unseparated serum IgG (serum, left) and the patient’s purified monoclonal IgG (Mc IgG, right) using the MIAA assay are represented; results are shown as fluorescent intensity (FI). The FI values shown for each pathogen, Ag, protein or lysate, were obtained after subtraction of the fluorescent background (F-B) of each pathogen protein or lysate. Dotted lines show thresholds of specific positivity defined for each viral pathogen or protein: 1,400 for Epstein-Barr virus (EBV), cytomegalovirus (CMV), varicella-zoster virus (VZV), hepatitis B virus (HBV) and B. burgdorferi (blue); 1000 for herpes simplex virus (HSV)-1 and HSV-2 (orange); 500 for hepatitis C virus (HCV) and T. gondii (green). Dots may be superimposed; horizontal bars represent means of results obtained for a pathogen (Ag, lysate). Experiments were performed in triplicate, repeated at least once. Inserts show the results of dot blot assays performed with purified recombinant HBV proteins (HBsAg, HBeAg, HBcAg, HBx) and water as control. The assays showed that the Mc IgG (or IgM, Pt M13) recognized a single HBV protein. Experiments were performed at least twice.

Figure 3.

Results of the MIAA and dot blot assays of monoclonal Ig that target an infectious pathogen other than hepatitis B virus. For each patient (Pt), results obtained in parallel with the unseparated serum IgG (serum, left) and the patient’s purified monoclonal IgG or IgA (Mc IgG or Mc IgA, right) using the MIAA assay are represented; results are shown as fluorescent intensity (FI). The FI values shown for each pathogen, Ag, protein or lysate, were obtained after subtraction of the fluorescent background (F-B) of each pathogen protein or lysate. Dotted lines show thresholds of specific positivity defined for each viral pathogen or protein: 1,400 for Epstein-Barr virus (EBV), cytomegalovirus (CMV), varicella-zoster virus (VZV), hepatitis B virus (HBV) and B. burgdorferi (blue); 1000 for HSV-1 and HSV-2 (orange); 500 for hepatitis C virus (HCV), H. pylori and T. gondii (green). Dots may be superimposed; horizontal bars represent the means of results obtained for a pathogen (Ag, lysate). Experiments were performed in triplicate, repeated at least once. Inserts show the results of dot blot assays performed with either purified recombinant proteins from EBV, herpes simplex virus (HSV)-1 or Enterovirus VP1, and water or PBS used as control. Experiments were performed at least twice.