High Rates of Varicella Zoster Virus Antibody Seroconversion and Persistence after Administration of the Adjuvanted, Recombinant Varicella Zoster Vaccine in Multiple Myeloma Patients Undergoing Active Treatment

Multiple myeloma (MM) patients are predisposed to high rate of infectious complications, with viral infections and in particular varicella zoster virus infection having a more than 10-fold increased incidence compared to the general population. This risk increases with use of autologous stem cell transplant (ASCT), multiple lines of therapy for relapsed disease, and proteasome inhibitor (PI) or daratumumab treatment. An adjuvanted, recombinant vaccine, consisting of the varicella-zoster virus glycoprotein E antigen (Shingrix, GlaxoSmithKline; Triangle Park, NC) is now available but studies in MM patients have been limited to the post-ASCT setting. We aimed to analyze the initial seroconversion rates as well as persistence of seropositivity in our MM cohort undergoing active anti-myeloma treatment.

We evaluated 85 MM patients undergoing active anti-myeloma treatment who were tested at baseline for VZV antibody (Ab) status. Nine (10.6%) patients were found to have high risk cytogenetics at diagnosis. The median number of prior lines of therapy was 1 (1-10), with 80 (94.1%) patients receiving a prior or current PI-based regimen, 66 (86.8%) receiving ASCT, and 15 (19.7%) receiving a prior or current daratumumab-based regimen. At the time of first vaccination, 35 (41.1%) patients were receiving post-ASCT immunomodulator (IMiD) maintenance. Seven (8.2%) patients had a prior history of VZV infection. 67 (78.8%) patients were actively receiving antiviral prophylaxis with either acyclovir or valacyclovir.

To determine vaccine immunogenicity, we used an anti-VZV ELISA assay. Using this test, VZV Ab seropositivity was measured at baseline and after each of the 2 vaccinations. In the entire cohort, 41 (48.2%) 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 seropositive status. We identified ISS stage 2 (RR 0.31, 95% CI 0.21-0.61; p<0.001) or 3 (RR 0.52, 95% CI 0.32-0.86); p=0.010) disease and prior/ current daratumumab (RR 0.35, 95% CI 0.13-0.95; p=0.04) as strong predictors of baseline VZV seronegativity; IMiD maintenance (RR 2.15, 95% CI 1.00-4.65; p=0.05) and prior shingles (RR 2.61, 95% CI 1.24-5.51; p=0.011) were associated with VZV seropositivity. Sixty-two (72.9%) patients received one vaccine dose, 49 (57.6%) received 2 doses, and 3 (3.5%) refused the vaccine. The median time between both doses was 84 (53-189) days. Overall rates of seropositivity increased after 1 (87.9%; p=0.0002) and 2 (92.6%; p=0.0001) doses. Seroconversion from a baseline negative to positive test was observed in 16 (76.2%) and 23 (95.8%) patients after 1 and 2 doses, respectively. One patient who received prior cytotoxic chemotherapy failed to seroconvert after 2 doses, and 4 patients lost VZV seropositivity after a median of 348.5 days from the second vaccination dose. In a multivariate model, we observed that progressive disease and daratumumab treatment during time from vaccination to follow up VZV testing predicted for loss of VZV seropositivity. Of 42 patients on acyclovir after receiving both doses, 18 (42.9%) discontinued acyclovir with all patients but one remaining seropositive at most recent follow up.

We report the first real world experience of the use of the adjuvanted, recombinant zoster vaccine in MM patients receiving active treatment. We show a high rate of initial VZV seronegativity and were able to show significant seroconversion after a single vaccine dose. In fact, despite studies showing benefit in patients receiving a total of 4 doses, we observed high seroconversion rates using 2 doses. Finally, we report for the first time strong predictors of baseline VZV seronegativity and maintenance of seropositivity in MM patients, in particular treatment with daratumumab. On the other hand, PI treatment was not associated with baseline seronegativity or loss of seropositivity. This data confirms that post-ASCT vaccination would be the optimal time to vaccinate patients, in particular when patients are immunocompetent while in remission on maintenance. The benefit of administering the vaccine in patients undergoing daratumumab or other treatment for progressive disease was not shown here and continued antiviral treatment rather than vaccination is likely to be the ideal prophylaxis strategy.