Efficacy and safety of recombinant adjuvanted zoster vaccine in patients with monoclonal gammopathies: A prospective study Free

Patients with multiple myeloma (MM) are prone to infections due to immunosuppression, whereas they show impaired serological responses to vaccination. Prophylactic valacyclovir is routinely administered to prevent varicella-zoster virus (VZV) infection. The two-dose, recombinant, adjuvanted herpes zoster vaccine (RZV) is approved for immunocompromised patients, but data in patients with monoclonal gammopathies are limited. In this study, we aimed to assess the efficacy of immunological response to RZV in patients with MM or other monoclonal gammopathies.

We conducted a prospective study to evaluate the immunogenicity of RZV in patients with MM, smoldering MM (sMM), Waldenström's macroglobulinemia (WM), and monoclonal gammopathy of undetermined significance (MGUS). VZV–specific IgG antibodies were measured using Human VZV IgG ELISA kits (OriGene) at three time points: before 1^st vaccination, one month (before 2^nd vaccination) and three months after the first dose. Antibody levels were expressed as index values and were categorized as: negative (<0.9), borderline (0.9–1.1), positive (>1.1), and high-positive (>2.0). Serological response was defined as seroconversion from negative or borderline, to positive, whereas boosting of humoral response as a ≥2-fold increase in IgG index values among patients with positive IgG levels.

A total of 89 patients were included in this analysis, 68 with MM, 12 with sMM/MGUS and 9 with WM; median age was 71 years and the 55 (61.8%) were males.

42 (47.2%) patients had a history of prior VZV infection, complicated by neuralgia in 20 (47.6%), keratitis in 3 (7.1%) and encephalitis in 1 (2.4%); all were resolved at the time of vaccination. Patients with MM/WM (n=77) were under treatment at the time of enrollment with monoclonal antibodies (n=39, 43.8%), bispecific antibodies (n=4, 4.5%), small molecule inhibitors (n=13, 12.4%) including Bruton's tyrosine kinase inhibitors (n=7), bcl-2 inhibitors (n=1) and exportin 1 inhibitors (n=3), proteasome inhibitors and/or immunomodulatory drugs (n=23, 25.8%). The 32 (41.6%) of the patients were newly diagnosed, 23 (29.9%) were on maintenance, while 22 (28.6%) were in relapse. Responses at the time of vaccination, were VGPR or better in 65 (84.4%, PR in 6 (7.8%), MR in 1 (1.3%) and SD in 5 (6.5%). Patients with MGUS/sMM received no treatment.

Before vaccination, IgG indices were negative in 42 (47.2%) of patients, borderline in 10 (11.2%) and positive in 37 (41.6%). Among patients with prior VZV infection, 29 (69.1%) were positive at baseline. Out of 52 negative or borderline patients prior to first dose, seroconversion was achieved in 44 (84.6%) after the first and in 51 (98.1%) after both doses. Furthermore, among 37 IgG-positive patients at baseline, boosting of humoral response was observed in 22 (59.5%) after both doses. Boosting rates seemed to be associated with treatment type (p<0.001) and ongoing treatment (p=0.010). After adjustment, treatment type retained its significance (p=0.017). Adverse events due to vaccination included fever (n=32, 36.0%), pain (n=31, 34.8%) and redness (n=28, 31.5%) at the injection site while 4 (4.5%) patients reported none.

A total of 73 patients were receiving VZV prophylaxis with valacyclovir, which continued even after vaccination. Valacyclovir was associated with boosting rates post second dose, compared to baseline and post first dose (p=0.052 and p<0.001, respectively). 4 patients with symptomatic disease did not receive valacyclovir due to intolerance.

Following vaccination, 5 patients developed breakthrough VZV infections at a median time of 6 months from the first dose; 1 with MGUS/sMM (no treatment and no prophylaxis), 3 with MM (1 on PI+IMiD, 2 on Anti-BCMA) and 1 with WM (on BTKi); all on prophylaxis. 2 had seroconverted after vaccination and 3 had positive IgG antibodies after prior infection; 2 of the latter had boosted levels after the second vaccination. All cases presented with localized pain and rash without systemic symptoms, and were managed with oral acyclovir. No cases of disseminated or severe VZV infection were observed.

Two doses of RZV seems to induce humoral responses in the vast majority of patients with monoclonal gammopathies, with minimal toxicity. A minority of patients on anti-myeloma treatment with breakthrough VZV infections had adequate IgG antibody levels, no systemic symptoms, and were successfully managed with oral antiviral therapy.