Immune Responses after One Versus Two Influenza A/B Vaccinations in Patients with Multiple Myeloma
Authors: Enssle Julius , Brinkschmidt Tonio , Dürrwald Ralf , Wolf Sebastian , Zurmeyer David , Steffen Björn , Ullrich Evelyn , Serve Hubert , Oellerich Thomas , von Metzler Ivana 
Published: December 2023

Background: Multiple Myeloma (MM) is a hematological cancer affecting plasma cells, suppressing the immune system and increasing the risk of severe Influenza A/B infection. International guidelines recommend Influenza A/B vaccination on an annual basis. Data from the pre-lenalidomide era highlighted poor vaccination responses, with sufficient seroconversion in 39% of patients with MM after single vaccination and an increase to 55% after additional boosting. Lenalidomide is now widely established in different (maintenance) therapy protocols and other novel agents (e.g. anti-CD38-agents) are incorporated into the therapy lines. Hence, it is of high relevance to characterize the sufficient immune response to Influenza A/B vaccination in this context, evaluate the necessity for a prime and boosting approach, and identify patients with high risk of insufficient response and subsequent hazard of severe disease.
Methods: In this retrospective single-center study, we analyzed the serological response from 71 patients with MM treated at our institution who received the annual Influenza A/B vaccination (Influvac Tetra, Mylan, Troisdorf, Germany) in the 2019/20 season. All patients received at least one vaccination with 52 patients receiving a second vaccination. Hemagglutination-inhibition (HI) assay titers for the five most prevalent virus strains were measured before, 21-28 days after the first and 21-28 days after the second vaccination or at observation (42-56 days after first vaccination in case of single vaccination). Peripheral immune cell counts were measured at the initial vaccination event by flow cytometry. Disease, therapy, and patient characteristics were retrieved from the electronical health care system at our institution. Primary endpoint was the sufficient responder status as indicated by ≥1:40 HI titer or an at least four-fold increase in the median HI titers of all strains. All patients declared written informed consent and the study was approved by the local ethics committee.
Results: 71 patients with MM were included in the present study who mostly had IgG MM (46.5%), the minority displayed genetic high-risk MM (25.4%), 64.8% were in their first line of therapy and 69% were in good remission (CR/VGPR). Overall, only 5.6% (n=4) showed sufficient titers before vaccination. 63.3% (n=45) achieved a sufficient serological response after one or two Influenza A/B vaccinations. A strong increase in HI titers against all strains was observed after already the first vaccination. In patients receiving a prime and boost approach, significantly higher titers but no significant increase in responder rates were observed after the boost vaccination. Responders were more frequently without current therapy or under maintenance therapy, showed significantly higher rates of CR/VGPR and significantly less immunoparesis. Interestingly, they trended to lower rates of previous anti-CD38 therapy (24.4% versus 50%, p=0.053). Non-responders displayed significantly lower median CD19 + B-cell counts (20.0/µl versus 79.0/µl p=0.001) and reduced median CD4 + T-cell counts (167.5/µl versus 274.0/µl, p=0.033). Multivariate regression analysis highlighted current CR/VGPR (OR 4.1 [95% CI 1.09-16.57], p=0.04) and no immunoparesis (OR 5.37 [95% CI 1.13-33.21], p=0.046) at timepoint of vaccination as independent predictors for sufficient serological response. Those patients achieving a sufficient responder status only after the boost vaccination among all responders displayed significantly shorter time (5.0 versus 26.5 months, p=0.046) since the last high-dose chemotherapy and autologous stem cell transplantation (autoHSCT).
Conclusions: Together, 63.3% of patients with MM achieved a sufficient serological response after tetravalent Influenza A/B vaccination without a significant general benefit for a prime and boost approach. Current therapy, uncontrolled MM, present immunoparesis and low CD19 + B-cell counts were associated with inferior response rates. Those patients exceptionally benefitting from a boost vaccination were characterized by recent autoHSCT. Hence, annual one-time Influenza A/B vaccination is applicable for patients with MM and patients directly after autoHSCT can be considered for a prime and boost approach. Further studies are warranted to investigate this in a prospective and randomized fashion.