(PA-090) Deficiencies in Cellular Immunity Associated with Increased Risk of Infection with Bispecific Antibody Therapy in Multiple Myeloma

Multiple myeloma (MM), a disease of clonal plasma cells, leads to immune dysfunction, primarily thought to be humoral in nature. Bispecific antibodies (BiAb) have shown efficacy in engaging T cells to kill tumor cells, inducing deep and durable responses. Despite their efficacy, there is a significant infectious risk, with severe (grade 3 or higher) infections occurring in 7% to 45% of MM patients treated with BiAbs. While significant effort has been made to understand mechanisms of BiAb resistance, more information is needed to better identify patients at high risk of severe infection with BiAbs. We previously described a specific immunophenotype in MM patients with suboptimal responses to COVID vaccination. Based on our preliminary data, we hypothesize that a similar immunophenotype can help identify MM patients at greater risk for infection while on BiAb therapy.

Methods:   

Peripheral blood mononuclear cells from 13 patients on BiAbs with variable infectious rates were characterized using a spectral flow cytometry antibody (Ab) panel to stain for myeloid and lymphoid cell subsets.

Results:   

11 of 13 (84.6%) patients achieved a stringent complete response (sCR) while on therapy. 12 of 13 (92.3%) patients experienced an infection of any grade, 5 of 13 (38%) experienced grade 3/4 infections and 1/13 (7.7%) experienced a grade 5 infection. When stratified into more infections (≥3 infections) or less infections (< 3 infections), differences in immune cell subsets were identified between the groups. In the more infections group a decrease in B cells, subsets of Tfh cells, and mature cytolytic NK cells was seen. Similar percentages of dendritic cells and monocytes were seen between the groups. To further investigate the monocytes, we assessed expression of CD38, a surface glycoprotein on many leukocytes, as its expression indicates activation. We also assessed CD16 expression, an Fc receptor, as it is involved in Ab-dependent cell mediated cytotoxicity. We found in the less infections group that most monocytes were CD38⁺, but in the more infections group there was an additional distinct population of CD38^- cells. Similarly, there was an additional population of CD16^- cells in the more infections group that was not present in the less infections group.  

Conclusions:   

Treatment with BiAbs leads to deficiencies in humoral and cellular immunity. We demonstrate a distinct immunophenotype that is seen in patients who experience more infections, specifically impaired monocytes, B, Tfh, and NK cells. Independent validation of this immunophenotype in larger cohorts is ongoing to determine if it can be used to identify patients at higher infectious risk. Prompt identification of such patients may allow for early intervention, including IVIg, prophylactic antibiotics, or judicious changes in dosing frequency to allow for immune reconstitution. This will hopefully serve to mitigate the infectious toxicity of very effective BiAb treatments and rationally guide therapy selection in individual patients.