Dexamethasone for management of cytokine release syndrome (CRS) associated with talquetamab in patients with Relapsed/Refractory multiple myeloma

Abstract

Abstract Introduction: Talquetamab (tal), a GPRC5D-targeting bispecific antibody (bsAb), is approved for treatment of relapsed/refractory multiple myeloma (RRMM). CRS is commonly associated with tal, occurring in up to 80% of patients in the MonumenTAL-1 study. According to IMWG guidelines, tocilizumab (toci) is recommended for treatment of grade 1 and 2 CRS prior to the use of dexamethasone (dex). We conducted a multicenter retrospective study to evaluate the safety and efficacy of dex for CRS management in patients receiving tal. Methods: Seven academic medical centers contributed data on 211 patients with RRMM receiving commercial tal. Patients received pre-medication and step-up dosing (SUD) per package insert. Toxicity management and supportive care followed institutional protocols. CRS and ICANS were graded per ASTCT criteria. Toci was dosed at 8 mg/kg (max 800 mg) and individual dex doses varied by institution (range 4-20 mg). Responses were assessed using IMWG criteria. Outcomes included incidence and severity of CRS events, CRS recurrence, need for additional intervention, treatment delay, and overall response rate (ORR). Results: Among the 211 patients included, median age was 66 years (range 34-87), 18% were Black, and 55% were male. The median number of prior lines of therapy was 6 (range 2-14). Eighty-seven percent were triple-class refractory and 47% were penta-refractory. One hundred twenty-six patients (60%) received prior BCMA-directed therapy with 76 (36%) receiving a prior bsAb. Tal was used as bridging therapy in 53 patients (35%). Most patients (91%) received biweekly tal after SUD and 27 (13%) received prophylactic toci. CRS occurred in 129 (61%) patients, with 43% experiencing grade 1 and 16% grade 2. Two and one patients experienced grade 3 or 4 CRS, respectively. CRS occurred after the first (17%), second (27%), third (29%), and first full dose (7%). Fifty-three patients (25%) experienced a SUD delay due to CRS (median 1 day, range: 0.5-15) and 39 (18%) experienced recurrent CRS after a subsequent SUD. The median duration of CRS was 1 day (range 0-8). ICANS occurred in 29 patients (14%). Of the 129 patients who experienced CRS, dex was the first intervention in 46 patients (36%), toci in 42 (33%), and supportive care (antipyretics, hydration, oxygen) in 37 (29%). Four (3%) received dex + toci simultaneously. Among those receiving dex first, 11 patients experienced concurrent ICANS. The median dose of initial dex was 10 mg. Among 27 patients who received prophylactic toci, CRS occurred in 14 (52%) of patients, primarily grade 1. Within the dex treatment first group, 33 patients (72%) had grade 1 CRS and 11 (24%) had grade 2 CRS. In the toci-first group, 21 patients (50%) had grade 1 and 20 (48%) had grade 2 CRS. Among those who received dex-first, CRS resolved following a single dex dose in 21 patients (46%), with repeat dex doses in 10 patients (22%), a subsequent toci dose in 12 patients (26%), and multiple toci doses in 2 patients (4%). One patient with grade 1 CRS in the dex-first group died after SUD 2 due to respiratory failure vs PE. Of those who received toci treatment first, CRS resolved following a single toci dose in 30 patients (71%), repeat toci doses in 5 (12%), a single dex dose in 2 (5%), and repeat dex doses in 5 (12%). Median duration of SUD delay (1 day, p=0.96) and incidence of delay were similar (48% vs 35%, p=0.28) in the toci and dex groups, respectively. While CRS recurrence after a subsequent SUD was more common in the dex-first group (50% vs. 14%, p=<0.005), repeat events were all grade 1 or 2 and resolved with repeated dex and/or the addition of toci. At a median follow-up of 9.2 months, the ORR of all patients was 77%, with 50% of patients achieving a very good partial response (VGPR) or better. Median PFS and OS were 7.6 and 17.7 months in the entire group and 6.1 and 16.4 months when excluding patients who received tal as bridging prior to CAR T. Best ORR was similar (86% vs 90%, p=0.74) between dex and toci groups and overall population of 77%. Conclusion: Although more patients in the dex-first group experienced recurrent CRS, recurrent CRS was low grade and manageable. When compared to the toci group, the dex group had similar efficacy outcomes. Considering potential advantages of utilizing dex over toci with respect to availability and cost, this study highlights the feasibility of dex for the management of grade 1 or 2 CRS in patients receiving tal.