Our study was the effects of intravenous immunoglobulin supplementation on infections in recipients of teclistamab and BCMA-directed bispecific therapy for multiple myeloma.
What was the study design?
Very basically, B-cell maturation or BCMA-directed bispecific antibodies have been very effective in patients who have relapsed or refractory disease. Bispecific antibodies are molecules that can target two different antigens, like proteins or cells, and bring them together to do something new. In this case, the bispecific antibodies bind to the cancer cells and the T-cells that kill them. One issue with these drugs, though, is that they are associated with a higher risk of serious infections and related mortality.
Several consensus papers have been published but they have varying recommendations about how to protect against infection for patients on these bispecific antibodies. That ranges from giving IVIg before any infections start or giving it in response to low IgG or infection triggers. So the rationale for our study is that giving primary IVIg is useful because almost all patients have profoundly low IgG but there’s limited data supporting the effectiveness. So the main objective of this study was to understand the effect of primary IVIg replacement on clinical outcomes in patients who got BCMA-directed bispecific antibodies.
Patients in this study had relapsed and/or refractory multiple myeloma and they were treated with at least one dose of either teclistamab or standard of care or alternative investigational BCMA-directed bispecific antibodies. For this analysis primary IVIg prophylaxis was defined as giving IVIg after starting bispecific antibodies but before any documented infection. Then secondary prophylaxis was giving IVIg after a documented infection.
A little about study design is we included 225 patients in this study of which 59% did not receive primary IVIg, whereas 41% did. Interestingly, patients who got primary IVIg were actually on bispecific antibodies for a longer time but they had fewer doses per month and longer intervals between doses. Then of the patients who weren’t on primary IVIg, almost a third of them ended up starting it after their first infection.
What are the key results?
We observed 288 infections in 136 patients with a median time to infection of 97 days from the start of therapy. The most common infections were respiratory tract infections and COVID accounted for 11% of those cases. The majority of patients did end up being hospitalised in-patient for infectious complications.
One thing we saw was that 10 out of the 11 most serious infection events were in the group that did not receive primary IVIg prophylaxis. Then some other significant results I want to highlight: median infection free survival for all grade and high grade infections was significantly higher in patients who got primary IVIg prophylaxis. They went 4.7 months longer for all-grade and 6.5 months longer for high-grade infections, meaning they had that much time before they got any infection. Then we saw that secondary IVIg prophylaxis was significantly protective against all-grade and high-grade infections. Then for bacterial infections specifically, both primary and secondary IVIg were protective.
Another thing is that patients who got primary IVIg prophylaxis had significantly longer of a time before their disease progressed. So a median progression free survival was 15 months in the group that had primary IVIg versus only 8 months without it. Then, lastly, for overall survival, primary IVIG prophylaxis was significantly protective, with an 18 month longer survival.
For some conclusions, basically, firstly, primary IVIg prophylaxis was associated with a statistically significant reduction in all-grade and high-grade infection free survival. Administration of tocilizumab for cytokine release syndrome was associated with increased risk of all-grade, high-grade, bacterial and viral infections. Lastly, the use of primary IVIg prophylaxis was independently associated with improved overall survival in patients treated with BCMA-directed bispecific antibody therapy.
What is the clinical significance of these results?
If I had to take one take-away from this study it would be that we should be starting IVIg within about 30 days. At our institution our standard of care practice is to start it within about the first two cycles, so that ended up being around 39 days in our study. But that is the main thing here, that giving IVIg, we have shown, improves your chances of having a longer time before infections set in, a longer time before disease progresses and then just overall survival improves.
