P1506: TECLISTAMAB REDUCES POLYCLONAL IMMUNOGLOBULIN LEVELS AND IMPAIRS VACCINATION RESPONSES IN HEAVILY PRETREATED MM PATIENTS

Abstract Topic: 30. Infections in hematology (incl. supportive care/therapy)

Background: Teclistamab (TEC) is the first approved BCMA-targeting T-cell redirecting bispecific antibody (BsAb) with pronounced activity in heavily pretreated multiple myeloma (MM; ≥PR in 63.0%). The downside is the high incidence of infections (with median follow-up of 14.1 months: 76.4%; ≥grade 3: 44.8%). This may be explained in part by the long-term exposure to immunosuppressive therapies prior to TEC treatment. However, as BCMA is also expressed on normal plasma cells and a subset of B cells, the effect of BCMA BsAbs on normal immune cells may also play a role.

Aims: To assess the impact of TEC on humoral immunity to provide improved guidance on infectious prophylaxis.

Methods: Patients (pts) were included in the MajesTEC-1 study and treated with TEC. Eligible MM pts were aged ≥18 y, and had received ≥3 prior lines of therapy including a PI, an IMiD, and an anti-CD38 mAb. For pts treated with the RP2D of 1500 μg/kg TEC (n=165), B-cells and T cells were enumerated in peripheral blood by flow cytometry, and polyclonal IgG, IgA, and IgM levels were assessed by nephelometry or immunoturbidimetric assays. Vaccination responses were evaluated in a subset of pts who were treated in Amsterdam UMC and achieved at least PR after day 1 of cycle 3 (n=21), and these were compared to responses in pts with newly diagnosed MM (n=23), daratumumab-naïve relapsed/refractory (RR) MM (n=11) or daratumumab-treated RRMM (n=20). Vaccination responses were assessed according to local guidelines. Data on polyclonal immunoglobulins and vaccination response were collected until pts received intravenous immunoglobulin therapy (IVIG) or another anti-MM therapy.

Results: Ex vivo killing assays showed that TEC depletes BCMA-positive normal plasma cells in bone marrow from healthy donors. TEC treatment also resulted in a rapid decline in circulating B-cells (CD45+CD19+) in pts treated at the RP2D (baseline: median=10.6 x10 6 /L; C2D1: median=0.2 x10 6 /L, p<0.001), which persisted during treatment (C7D1: median=0, p<0.001 [panel A]). In contrast, both CD4 and CD8 T-cells initially decreased but subsequently recovered to baseline levels or higher over time. As expected in these heavily pretreated pts, polyclonal immunoglobulins were suppressed at baseline. After start of TEC therapy, there was a further decrease in polyclonal immunoglobulin levels in sequential peripheral blood serum samples. Notably, a significant reduction in polyclonal IgG was observed (baseline: median=1.4 g/L; C5D1: median=0.8 g/L, p<0.05 [panel B]), as well as decrease in IgA (p<0.001), and IgM (p<0.001). Longitudinal analysis throughout TEC treatment, showed no recovery of polyclonal immunoglobulin levels over time. Vaccination response rates following S. pneumoniae (conjugated PCV-13 [prevenar], followed by the polysaccharide PPV-23 vaccine [pneumovax] 8 weeks later) and H. influenzae vaccination (Act-Hib) was significantly lower in TEC-treated pts (8% and 6%, resp.) versus response in newly diagnosed MM (76% and 88%), daratumumab-naïve RRMM (50% and 78%), or daratumumab-treated RRMM pts (65% and 82%; C and D). Maximum antibody titers were also significantly lower for each individual pneumococcal subtype and for H. influenzae in TEC-treated pts versus the other subgroups. After 3 mRNA vaccinations against COVID-19, none of the pts achieved a protective antibody response. Pts who received IVIG had a lower risk of grade ≥3 infections (16% vs 45% of pts after 6 months, p=0.002).

Summary/Conclusion: TEC reduces the levels of polyclonal immunoglobulins and impairs humoral immune response following vaccination, which is explained by rapid depletion of B-cells and normal plasma cells. We recommend the initiation of IVIG supplementation in pts with polyclonal IgG levels <4 g/L to prevent infections.

Keywords: Vaccination, Bispecific, Myeloma