Sustained remission following limited duration of bispecific antibody therapy in patients with relapsed/refractory multiple myeloma

Abstract Introduction: While bispecific/multispecific antibodies (bsAb) have revolutionized the treatment of relapsed/refractory multiple myeloma (MM), their ongoing use until disease progression can cause T-cell exhaustion, increase infection risk, and require significant resources. Therefore, data on fixed-duration strategies are urgently needed. Here, we report outcomes of patients who received a limited-duration bsAb therapy for MM. Methods: In this multinational study, we identified patients who received bsAb either in early-phase clinical trials or as standard of care, discontinued treatment for reasons other than disease progression or death, and remained alive in remission for at least 3 months after stopping treatment. Baseline demographics and clinical efficacy data points, such as IMWG responses at both treatment discontinuation and last follow-up, data on infections, IgG levels (normal levels assumed to be >700 mg/dL for this analysis), and use of intravenous immunoglobulin replacement (IVIG) off therapy, were retrospectively collected. High-risk cytogenetics was defined as the presence of del(1p), Iq21 gain or amplification, del(17p), and any of these translocations: t(4;14), t(14;16), or t(14;20), as per the last disease assessment prior to the start of treatment bsAb. Relapse-free survival (RFS), and factors predictive of RFS off therapy were computed. The kinetics of humoral immunity recovery were measured by serial IgG levels following treatment discontinuation. IgG measurements for each patient were averaged within 30-day windows and labeled by the midpoint day (e.g., Day 0 for D–14 to D15, Day 30 for D16 to D45) and changes were modelled over time. Results: After screening 720 consecutive patients, 78 were included, with 72% receiving a BCMA-targeted bsAb, 19% receiving a GPRC5D-targeted bsAb, and 9% receiving a multi-specific antibody (BCMA + GPRC5D). The median age was 70 years (range 26-86), 55% were females, and 18% were Black. 47% (n=35) had ≥1 high-risk cytogenetic abnormality, and 8% had extramedullary disease (EMD). The median number of prior lines of therapy was 4 (range, 1-9), and 71% of patients received a prior autologous stem cell transplant (ASCT). The median duration of bsAb prior to discontinuation was 7 months (range, 1-40), with 80% in complete response (CR) at discontinuation. The most common cause for treatment discontinuation was infections (n=34; 44%), followed by ectodermal toxicities (n=12; 15%). At a median follow-up of 17 months from treatment discontinuation, the RFS at 2 years was 67% (95% CI, 55%, 80%). Notably, the 2-year RFS in patients with ≥6 prior lines of therapy was 48%, compared to 79% and 78% respectively, in those with 1-3 and 4-5 prior lines. On multivariable analysis for RFS, the following baseline factors were independently associated with inferior RFS: EMD (HR [hazard ratio] = 7.88; 95% CI 1.95, 31.8; p = 0.004), number of prior lines of therapy (HR = 1.79; 95% CI 1.32, 2.43; p = <0.001), and partial remission (PR) at the time of treatment discontinuation (HR = 28.3; 95% CI 2.06, 3.9; p = 0.012). The cumulative incidence of grade 3 or higher infections post-discontinuation was 22% at 1 year, 32% at 2 years, and 38% at 3 years, with a decrease in cause-specific hazard of first grade ≥3 infection as patients moved further away from treatment. During the first 180 days after stopping treatment, most patients (61% to 86%) had low IgG levels. Between 210 and 450 days after stopping treatment, 46% to 77% had low IgG levels, and beyond 480 days, these numbers improved to 0% to 33%. A similar trend of decreased IVIG replacement was observed with increasing time off therapy. Notably, among the two patients who resumed the same bsAb (both BCMA-targeting) at disease progression, one achieved CR and one did not respond. Conclusion: Our data demonstrate that a substantial proportion of patients can sustain disease remission after discontinuation of bsAb in relapsed/refractory MM, with 2-year RFS in patients with up to 5 prior lines of therapy approaching ~80%. We also observe humoral immune reconstitution, along with a decrease in the incidence of infections, over extended follow-up periods after treatment discontinuation.