Cytomegalovirus Reactivation in Patients with Multiple Myeloma Treated with Teclistamab: Risk Factors and Clinical Impact

Introduction: Teclistamab is a bispecific B-cell maturation antigen (BCMA)-CD3 directed T-cell antibody recently FDA approved for treatment of relapsed or refractory multiple myeloma (RRMM). Viral infections have been reported as a common complication of teclistimab. Here we report the incidence, treatment and clinical sequelae of patients with teclistamab-associated Cytomegalovirus (CMV) DNAemia.

Methods: We identified 48 patients who received teclistamab for RRMM between January 2023 and May 2024 at our institution. CMV PCR and serology were tested in 23 patients which were included in this analysis. Cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), hematological, and infective complication rates were analyzed, together with specific variables associated with CMV reactivation.

Results: The median age was 73 (range: 49-83) years, with most patients being male (13/23, 56.5%) and non-Hispanic white (19/23, 82.6%). High-risk chromosomal abnormalities were present in 10/23 (43.5%) of patients. Median number of prior lines of therapy was 6 (range: 4-17), with teclistamab given at a median of 4.8 years from MM diagnosis (range 1.1-16.7 years). All patients received step-up dosing inpatient and no prophylactic tocilizumab was given. 12/23 (52.2%) patients had CRS (max grade 2), and 5/23 (21.7%) patients had ICANS. Tocilizumab was given to 9/23 (39.1%) patients, while steroids were given to 3/23 patients (13.0%). Anemia grade 3 or more occurred in 5/23 patients (21.7%), thrombocytopenia grade 3 or more occurred in 4/23 patients (17.4%), and lymphopenia grade 3 or more occurred in 21/23 patients (91.3%) while on treatment. CMV DNAemia by PCR (>500 copies IU/mL) was detected in 12/23 (52.2%) patients (median: 2295.5, range: 653-165,000 copies IU/mL), with 10 patients having >1,000 copies IU/mL and three patients having >10,000 copies IU/mL. Median number of CMV PCR tests was 9 (range: 1-27), with a median positive CMV PCR of 6.5. Median time to CMV reactivation was 54 days (range: 28-123 days). Median lowest absolute lymphocyte count (ALC) at any point was 195/microL (range: 50-590/ microL), while it was 1280 microL (range: 220-4370/ microL) at time of reactivation, with only 3 patients having ALC <500. Symptoms, including fatigue, liver function abnormalities, fevers, leukopenia, or thrombocytopenia were present in 9/12 (75%) patients. CMV syndrome occurred in 5/12 patients (42%) and one patient (8%) had possible CMV colitis. No differences in terms of race, gender, cytogenetic risk, ISS stage, or number of prior lines of therapy were noted between patients with or without CMV reactivation. Onset of CRS or ICANS and use of tocilizumab was not associated with increased risk of CMV reactivation, while steroids increased the risk but in a non-statistical way (0% versus 25%). Rates of grade 3 anemia, thrombocytopenia, lymphopenias, and hypogammaglobulinemia were similar among the two groups, as well as the use of intravenous immunoglobulin. No differences in terms of C-reactive protein, ferritin, or lowest ALC values were noted among the two groups; IgG seropositivity was borderline significant (p = 0.06). Interestingly patients with CMV reactivation also were more prone to other types of infections (67% versus 27%), indicating an overall alteration of the immune response. The percentage of patients achieving a partial response or better was lower in patients with CMV reactivation but not statistically significant (82% versus 58%, p = 0.37). Progression-free survival was not different, but overall survival was shorter in patients with CMV reactivation (p = 0.046), due to toxicities, disease progression, or infections.

Oral valganciclovir was started in 11/12 patients; a patient with only one CMV PCR test was not treated but also discontinued teclistamab. Median time for clearance was 26 days (range: 21- 43 days). Three patients died before clearing their CMV DNAemia due to disease progression, and one patient had intermittent clearance.

Conclusions: CMV reactivation seems to be common with teclistamab use regardless of the CMV serostatus or symptoms. These CMV reactivations can be clinically relevant, with patients presenting with symptoms ranging from fevers to leukopenia to potential CMV colitis. This has prompted us to implement a prospective CMV surveillance algorithm to assess burden of infection and ensure early intervention as needed.