A Randomized Trial Demonstrates a 3-Shot Flu Vaccine Series Improves Protection over a Single Shot in Multiple Myeloma
Authors: Hofmeister Craig C. , Gupta Vikas A. , Kaufman Jonathan L. , Nooka Ajay K. , Joseph Nisha S. , Lonial Sagar , Dhodapkar Madhav V. 
Published: December 2024

Background: In myeloma patients on treatment, there is a 20% risk of influenza-like illness (PMID 25487843, 29427192) and they have a 10-fold higher risk of viral URIs (PMID 25344526). Increasing the influenza dose (Fluzone) compared to standard-dose influenza vaccination confers more protection against influenza in patients under 65 years of age (Hsiao A et al, NEJM, 2023; PMID 38091531). Vaccine preventable illnesses have not been prevented in myeloma due in part to lack of seroresponse and maintenance of seroprotection with standard dosing algorithms. The SHIVERING trial revealed that myeloma patients lost seroresponse over the influenza season despite 2 high dose injections separated by 30 days (Branagan AR, ...Dhodapkar MV, et al, 2021, PMID 33683337). We hypothesized that THREE high dose vaccinations would improve seroprotection by the end of the flu season.
Design: This randomized controlled trial enrolled patients with a plasma cell disorder into the experimental arm to receive Fluzone HD at the beginning of the flu season and at 2 and 4 months compared to the control arm where they received just one Fluzone vaccination. We hypothesized that the 3-part Fluzone series would maintain hemagglutination inhibition (HAI &gt; 40) in &gt;58% of patients at week 21, a 25% increase in seroprotection against all strains. We excluded patients that had already received seasonal influenza vaccine, history of Guillain-Barré syndrome, or a history of severe allergic reaction to a influenza vaccine.
Results: A total of 165 patients were enrolled - 50 patients Oct-Dec 2019 and 115 patients Sep-Dec 2020. Patient demographics in regards to age, sex, race, and type of plasma cell disorder (90% multiple myeloma) were balanced in the experimental / intense 3-shot arm (80 patients) and the standard / 1-shot arm (85 patients). Twenty percent of patients had undergone a transplant within the last year, 60% after 1 year. Half of the patients were undergoing first line therapy, and approximately 20% were in second line. Overall, 60% in the intense arm were on therapy and 73% in the standard arm were not on treatment. One quarter of all patients were receiving Daratumumab; 62% in the standard arm and 49% in the intense arm had never received Daratumumab. There was one patient in each arm that had received a T-cell engager. Mean IgG at enrollment was 850 mg/dL in the intense arm and 1047 mg/dL in the standard arm.
In an intent to treat analysis, 41% in the intense arm compared to 25% in the standard arm were seroprotected at the end of the flu season (p=0.0412). In an as treated analysis, the mean number of flu vaccines received in the intense arm was 2.49 compared to 0.98 in the standard arm. This led to statistically significant differences in seroprotection by number of flu vaccines received (p=0.0064). Daratumumab exposure decreased the proportion of patients with seroprotection in those that received 1-2 shots (32% to 11%), but seroprotection was maintained despite Daratumumab exposure after 3 shots.
Conclusions: This randomized controlled trial demonstrates that myeloma patients significantly increased their seroprotection at the end of the season by receiving three Fluzone HD vaccinations at 0, 2, and 4 months compared to a single shot. Clinicians should consider this 3-dose vaccine series as the new standard in patients with multiple myeloma. Despite this 3-dose series, seroprotection for all strains was still just over 50% at week 21.