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Abstract Background Elranatamab (ELRA) is a B-cell maturation antigen (BCMA)-CD3 bispecific antibody indicated for the treatment of adult patients (pts) with RRMM. In the phase 2 registrational MagnetisMM-3 (NCT04649359) study, ELRA demonstrated an objective response rate (ORR) of 61.0%, median progression-free survival (PFS) of 17.2 mo, and median overall survival (OS) of 24.6 mo in pts with RRMM and no prior BCMA-directed therapy. Here we report results from a post hoc analysis of the subgroup of pts enrolled in MagnetisMM-3 who had a prolonged ELRA treatment interruption or who permanently discontinued ELRA and maintained the response >6 mo. Methods MagnetisMM-3 evaluated the efficacy and safety of ELRA monotherapy in pts with RRMM. Eligible pts had RRMM with disease refractory to ≥1 immunomodulatory drug, ≥1 proteasome inhibitor, and ≥1 anti-CD38 antibody. Pts were given subcutaneous ELRA as step-up priming doses followed by 76 mg once weekly (QW) for 6 cycles. Pts given QW dosing for ≥6 cycles who achieved partial response (PR) or better lasting ≥2 mo were transitioned to every-2-week (Q2W) dosing, then to every-4-week (Q4W) dosing after ≥6 cycles of Q2W dosing. The primary endpoint was ORR assessed by blinded-independent central review (BICR) per IMWG criteria. Pts who had not received treatment for >6 consecutive mo at any point during the study but who were still being assessed for efficacy (without starting new anticancer therapy) were included. Safety was assessed up to initiation of new anticancer therapy, 90 days after the last dose, or end of study participation, whichever was earlier. Data cutoff was March 10, 2025, ≈38 mo after the last pt was initially dosed. Results Among the 187 pts enrolled in MagnetisMM-3, 28 met the criteria for this post hoc analysis. The median age was 69.0 (range, 52-84) y, 46.4% were female, and 67.9% were White. Pts had a median of 5 (range, 2-14) prior lines of therapy; 100% had triple-class and 35.7% had penta-drug refractory disease. The most common treatment-emergent adverse events (≥10%) leading to prolonged treatment interruption/discontinuation were infections (28.6%), hematologic adverse events (17.9%), fatigue (10.7%), and exacerbation of pre-existing peripheral sensory neuropathy (10.7%). The median duration of treatment before interruption/discontinuation was 12.1 mo (range,1.2-35.1) and the median duration of the treatment-free period was 15.5 mo (range, 6.5-35.4). At the time of the interruption/discontinuation 10.7% had stable disease, 3.6% minimal response, 17.9% PR, 21.4% very good PR (VGPR) and 46.4% complete response or better (≥CR) by BICR; the best overall response (at any time) was PR in 7.1%, VGPR in 25.0%, and ≥CR in 67.9%. As of data cutoff, the median global follow-up and follow-up after the interruption/discontinuation were 39.4 mo (range, 9.9-43.5) and 19.9 mo (range, 7.3-40.6), respectively. Median PFS was not reached (95% CI, 38.5-not estimable [NE]) and the probability of being event-free at 36 mo was 79.4% (95% CI, 57.0-90.9). Median OS was not reached (95% CI, NE-NE) and the probability of being alive at 36 mo was 84.2% (95% CI, 63.0-93.8). Of 28 pts, 6 (21.4%) had an event (3 had progressive disease [PD] and permanently discontinued ELRA at time of PD, 3 died [septic shock, respiratory failure, and deterioration of general condition]) and 22 (78.6%) were censored (7 [25.0%] permanently discontinued follow-up and 15 [53.6%] were ongoing). Among the 3 pts with an event of PD: 2 pts did not have high-risk features, achieved ≥CR, and had PD ≈2 and ≈3 y after the last dose; 1 pt had an ISS disease score of 3, achieved PR and had PD ≈1 y after the last dose. Two pts have restarted elranatamab after interruptions of ≈12 and ≈14 months and are continuing treatment. Both pts had ≥CR at the start of the long interruption and were still in ≥CR as of the data cutoff date. One pt had early signs of relapse (positive immunofixation in serum [SIFE] and urine [UIFE]) and became SIFE and UIFE negative again after treatment resumption. Conclusions In this cohort of pts, despite a prolonged treatment interruption, the majority of pts maintained clinical response, demonstrating the durability of ELRA responses. Furthermore, these data support the feasibility of dose interruptions to manage adverse events and allow for treatment breaks without compromising the efficacy of ELRA. Studies evaluating the possibility of restarting ELRA upon signs of disease progression are warranted.