Use of Baseline Inflammatory Markers to Predict Toxicities Among Relapsed/Refractory Multiple Myeloma Patients Receiving Ambulatory Teclistamab and Talquetamab

Background

Teclistamab (tec) is the first B-Cell Maturation antigen (BCMA) x CD3 bispecific antibody to receive FDA approval for treatment of relapsed or refractory multiple myeloma (RRMM). Similarly, talquetamab (tal) is the first G protein-coupled receptor, class C group 5 member D (GPRC5D) x CD3 bispecific antibody approved by the FDA for the treatment of (RRMM) in patients who have received ≥4 prior lines of therapy. The MajesTec-1 and MonumenTAL-1 studies raised similar concerns for cytokine release syndrome (CRS)/immune effector cell-associated neurotoxicity syndrome (ICANS) during initiation of these novel treatments. We report our institutional experience with ambulatory tec and tal administration and use of baseline biomarkers to predict incidence of CRS and ICANS.

Methods

This was a retrospective study of patients treated in our institution's inpatient/outpatient (IPOP) hybrid nursing unit. This unit is staffed with specialized nurses, advanced practice providers, and attending physicians. Patients were treated with the recommended step-up dosing schedule. For patients receiving tal, ramp-up dosing was performed with plan for biweekly dosing. CRS grading and ICE scoring were performed daily. Both CRS and ICANS were graded according to the ASTCT grading systems. We collected toxicities until the second full treatment dose of tec or first treatment dose (0.8mg/kg) of tal. Baseline inflammatory labs, including ferritin, CRP, and fibrinogen, were collected within 1 week of initiation of treatment. Statistical analysis was performed using Fisher's Exact Test with significance set at P < 0.05.

Results:

In total, 33 patients were treated with tec and 10 patients were treated with tal between January 2023 to June 2024. The median age of patients treated with tec and tal was 67 years old (range 45-89). Thirty patients (69.8%)) were Caucasian, 11 (25.6%) patients were African American, 1 (2.3%) patient was Asian and 1 (2.3%) was native Hawaiian/pacific islander. Patients had received a median of 6 prior lines of therapy. One patient was dialysis dependent prior to starting tec. All patients were triple class refractory. Eighteen (55%) patients received bone marrow transplant prior to tec, and 6 (60%) patients received bone marrow transplant prior to tal. One (4%) patient receiving tec had received prior anti-BCMA CAR-T therapy. Five (50%) patients treated with tal had prior T-cell redirection therapies (2 BCMA bispecific antibodies, 2 BCMA CAR-T, 1 received both).

Twenty-one (64%) tec patients required admission for CRS or ICANS during ramp up. Eight (80%) tal patients required admission during the tal ramp up period for CRS or ICANS. CRS was mostly grade 1/2. However, 2 patients had grade 3 CRS and 1 patient had grade 4 CRS. ICANS was reported in 9 (27%) patients who received tec and 2 (20%) patients treated with tal. Two of those tec patients developed Grade 3/4 ICANS. No tal patients had higher than grade 2 ICANS.

Patients who developed CRS after the first dose of bispecific antibody did not have higher baseline ferritin (cutoff >350 ng/mL, 83.3% versus 50.0%), CRP (cutoff > 1.0 mg/dL ng/mL, 57.1% versus 24.0%) or fibrinogen (cutoff > 400 mg/dL, 42.9% versus 32.0%). Baseline inflammatory markers were also not significantly associated with anytime development of CRS or ICANS or more severe grade II-IV CRS or grade II-IV ICANS.

Conclusions

Tec and tal administration through an inpatient/outpatient hybrid model is safe and feasible. CRS was common but low grade. Higher grade CRS and ICANS as seen in our patients is confounded by infections, rapidly progressive disease/plasma cell leukemia, and the presence of CNS disease. Baseline elevations in inflammatory markers may help identify risk for early CRS, but in this small study did not significantly predict incidence or severity of subsequent CRS and ICANS with the use of these bispecific antibodies. Future larger multi-institution studies are needed to identify patients who are higher risk for CRS and ICANS during ramp-up treatment. Interval testing of inflammatory markers before each ramp up dose, combined with assessment of disease burden, pro-inflammatory cytokines, and soluble BCMA, may allow better identification of these high-risk patients and implementation of prophylactic interventions with the ultimate goal of moving toward complete outpatient administration of these bispecific antibodies.

Singel:Janssen: Consultancy. Mooney:Kite Pharma: Speakers Bureau; Johnson&Johnson: Consultancy, Membership on an entity's Board of Directors or advisory committees. Huff:Legend Biotechnologies: Honoraria; Janssen: Honoraria; Sanofi: Honoraria. Ali:Pfizer/IMF: Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Research Funding. Imus:Janssen: Research Funding.