Paper Details

ABSTRACT

Introduction: Tec+dara was recently approved for patients with relapsed/refractory multiple myeloma (RRMM) after ≥ 1 prior therapy based on the MajesTEC-3 trial. Because both agents are associated with immune-mediated toxicities, including cytokine release syndrome (CRS), the trial protocol mandated staggered initiation: weekly dara beginning on cycle 1, day 1, tec introduced SUD on days 2 and 4, and combination therapy starting on day 8, with a 3-hour interval between the initial doses. It remains unclear whether these schedules are consistently implemented in real-world clinical practice or how variations in sequencing and timing may affect the incidence and severity of CRS. Therefore, we conducted a multicenter retrospective study to characterize real-world tec+dara administration patterns and evaluate CRS incidence, timing, and other safety outcomes in patients with RRMM.

Methods: Seven US academic medical centers contributed data on patients who received at least 1 full cycle of commercial tec+dara. All patients received premedication per the label while prophylactic tocilizumab (prophy toci) was administered per investigator discretion. SUD was administered in either the inpatient or outpatient (outpt) setting at the discretion of the treating oncologist. CRS/ICANS were graded using the ASTCT criteria. Outcomes included incidence and severity of CRS and neurotoxicity including ICANS, dosing schedule, admission rates, and hospital length of stay (LOS).

Results: Of the 62 patients included, the median age was 73 years (range 34-84), 34% of patients were non-Hispanic Black and 55% of patients were female. The median prior lines of therapy was two (range 1-13). Sixty-five and 68% of patients were refractory to lenalidomide or dara, respectively. Fifteen percent of patients had received prior BCMA-directed therapy, all CAR T. Seventy-seven percent of patients would not have met MajesTEC-3 eligibility criteria, most commonly due to dara refractoriness or receipt of prior BCMA-directed therapy. Twenty-nine (47%) patients received prophy toci day 1 of SUD of which 21 (72%) received all SUD outpt. Five patients initiated SUD as an outpt without prophy toci.

Overall, CRS was observed in 15 (24%) patients, of which all events were grade 1 (19%) or grade 2 (5%). Among the 29 patients who received prophy toci, CRS occurred in 1 (3%) patient, compared with 14 of the 33 (42%) patients who did not. Two patients experienced ICANS (one grade 1, one grade 2). One of the 26 patients who received outpt SUD was admitted for CRS management. Average hospital LOS was 2.1 days in patients who received prophy toci vs 7.3 days in those who did not.

Eight (13%) patients received initial doses of dara day 1 and tec day 2 akin to the MajesTEC-3 protocol. All received SUD in the outpt setting with 6 receiving prophy toci. Tec+dara were administered consecutively on day 8 without a 3-hour interval. No patient experienced CRS, ICANS, or unplanned admission during cycle 1. One patient experienced day 15 dose delay due to respiratory infection.

Eleven (18%) patients received both initial tec+dara doses on cycle 1 day 1 without a 3-hour interval. Ten (91%) received prophy toci and nine (82%) received SUD as an outpt. One patient who was dara naïve and did not receive prophy toci developed grade 2 CRS on day 2. Isolated grade 2 ICANS following the second tec SUD was observed in 1 patient, while another reported injection-site reaction. No dose delays or hospitalization occurred in the outpt SUD group during cycle 1.

The remaining 43 patients initiated dara after tec SUD was complete (median day 15, range 8-35). Fourteen (33%) patients experienced CRS (93% grade 1, 7% grade 2) with 1 experiencing grade 1 ICANS. All 14 experienced CRS during the SUD period and no events occurred with the addition of dara after SUD. Injection site reaction, headache, and pruritic rash were each reported in 1 patient. Four patients had a dose delay during the first cycle. One patient was admitted to the ICU for septic shock and aortic ulcer but was able to safely restart SUD after recovery.

Conclusion: In this largely MajesTEC-3 ineligible real-world population, tec+dara was administered using a variety of patterns that differed from the trial protocol without an apparent increase in immune-mediated toxicities. CRS and ICANS were uncommon and limited to grade 1-2 events. Prophy toci was associated with lower rates of CRS, successful outpt SUD, and shorter LOS.