High Rates of Varicella Zoster Virus Antibody Seroconversion after Administration of the Adjuvanted, Recombinant Varicella Zoster Vaccine in Multiple Myeloma Patients Undergoing Active Treatment
Authors: Sweiss Karen , Calip Gregory Sampang , Galvin John P , Rondelli Damiano , Patel Pritesh 
Published: November 2019

Multiple myeloma (MM) patients are at higher risk for infectious complications, with viral infections having a 10-fold increased incidence compared to the general population. In particular, the risk of varicella zoster virus (VZV) reactivation increases with use of autologous stem cell transplant (ASCT), multiple lines of therapy for relapsed/refractory disease, and proteasome inhibitors (PI) or daratumumab. Since VZV reactivation can lead to significant morbidity and mortality, prophylactic strategies including vaccination are warranted. Until recently, the only available vaccination was a live attenuated vaccine with limited efficacy and generally contraindicated in these patients. An adjuvanted, recombinant vaccine, consisting of the varicella-zoster virus glycoprotein E antigen (Shingrix, GlaxoSmithKline; Triangle Park, NC) is now available. Since the use of this vaccination in MM bas been limited to the post-ASCT setting, we sought to analyze the seroconversion rates and safety of this vaccine in our MM cohort undergoing active anti-myeloma treatment.
We evaluated 69 MM patients undergoing active anti-myeloma treatment who were tested at baseline for VZV antibody (Ab) status. The median age was 64 (36-92) years and most patients were female (n=37; 53.6%), African American (n=44; 63.8%), IgG subtype (n=41; 59.4%), and ISS stage 2 (n=27; 39.1%). Six (8.7%) patients were found to have high risk cytogenetics at diagnosis. The median number of prior lines of therapy was 1 (1-7), with 64 (92.8%) patients receiving a PI-based regimen, 54 (78.3%) receiving ASCT, and 7 (10.1%) receiving a daratumumab-based regimen. At the time of vaccination, 30 (43.5%) patients were receiving post-ASCT immunomodulator (IMiD) maintenance, 14 (20.3%) were receiving a PI-based regimen, and 5 (7.2%) were receiving a daratumumab-containing regimen. Five (7.2%) patients had a prior history of VZV infection, 1 (1.4%) patient was previously vaccinated, and 52 (75.4%) patients were actively receiving antiviral prophylaxis with either acyclovir or valacyclovir.
To determine vaccine immunogenicity, we used a commercially available anti-VZV ELISA assay which assesses humoral immunity to multiple VZV glycoproteins. Using this test, VZV Ab seropositivity was measured at baseline and after each of the 2 vaccinations. In the entire cohort, 35 (50.7%) patients were found to be VZV Ab negative at baseline. Multivariate modified Poisson regression models with adjustment for prognostic and clinical factors were used to estimate relative risk (RR) and 95% confidence intervals for baseline VZV Ab serostatus. We identified ISS stage 3 (RR 0.43, 95% CI 0.25-0.75; p=0.0003) and prior or current daratumumab-based treatment (RR 0.12, 95% CI 0.03-0.42; p=0.001) as strong predictors of baseline VZV seronegativity; prior shingles (RR 5.03, 95% CI 1.41-17.85; p=0.013) was associated with VZV seropositivity. Forty-four (63.8%) patients received one vaccine dose, 28 (40.6%) received 2 doses, and only 2 (2.9%) refused the vaccine. The median time between both doses was 72 (54-117) days. Rates of seropositivity increased significantly from baseline, both after 1 (n=29, 87.9%; p=0.0002) and 2 (n=25, 92.6%; p=0.0001) doses. Seroconversion from baseline was observed in 13 (81.3%) and 17 (89.5%) patients after 1 and 2 doses, respectively. Two patients failed to seroconvert after 2 doses, one receiving cytotoxic chemotherapy and one receiving a daratumumab. Overall the vaccine was found to be well tolerated, with one patient reporting a grade 1 skin reaction after the first dose, without subsequent reaction with the second dose.
We report the first ever experience of the use of the adjuvanted, recombinant zoster vaccine in MM patients receiving active treatment. Given the high rate of initial VZV seronegativity in this population, we were able to show high rates of seroconversion after a single vaccine dose using a commercially available assay. We also demonstrate a high vaccine uptake rate, with minimal adverse events. Finally, we report for the first time strong predictors of baseline VZV seronegativity in MM patients, in particular current or prior use of daratumumab. Complete data on seroconversion, persistence of humoral immunity, and the occurrence of VZV infection after withdrawal of antiviral prophylaxis will be updated at the meeting.

Disclosures
Galvin: Incyte: Consultancy. Patel:Janssen: Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Celgene: Speakers Bureau.