Long-Term Evaluation of Luspatercept in Erythropoiesis‑Stimulating Agent (ESA)-Intolerant/Refractory Patients (pts) with Lower-Risk Myelodysplastic Syndromes (LR-MDS) in the Phase 3 MEDALIST Study

Background: Pts with LR-MDS receiving luspatercept in the phase 3 MEDALIST trial previously reported durable, long-term red blood cell (RBC) transfusion independence (RBC-TI) (Fenaux P, et al. J Clin Oncol 2022;40[suppl 16]. Abstract 7056). MEDALIST pts were eligible to enroll in a follow-up study to evaluate long-term efficacy and safety.

Aims: To report long-term efficacy and safety outcomes in ESA-refractory/intolerant pts with LR-MDS treated with luspatercept in the MEDALIST trial with an additional 26 mo of follow-up from the final MEDALIST data cutoff.

Methods: Eligible pts were ≥ 18 y of age; IPSS-R-defined Very low-, Low-, or Intermediate‑risk MDS with ring sideroblasts; were refractory, intolerant, or unlikely to respond to ESAs, and required regular RBC transfusions. Pts were randomized 2:1 to luspatercept (starting dose 1.0 mg/kg, with titration up to 1.75 mg/kg) or placebo. Efficacy outcomes include RBC-TI ≥ 8 wk and ≥ 16 wk. Cumulative duration of response was determined by Kaplan–Meier (KM) analysis. Rates of longest single and cumulative duration of RBC-TI ≥ 1 y and exposure-adjusted incidence rates (EAIR) of treatment-emergent adverse events (TEAEs) and AEs of special interest (AESIs) were calculated. Rates of high-risk (HR)-MDS and acute myeloid leukemia (AML) progression were calculated from LR-MDS diagnosis to HR-MDS/AML diagnosis, or to last HR-MDS/AML follow-up date for pts who did not progress.

Results: As of January 2, 2023, 11 pts remained on luspatercept treatment; 8 pts randomized to luspatercept and none from placebo continued in post-treatment follow-up. The median (range) follow-up time was 39.9 (2.8–76.0) mo for luspatercept arm pts and 38.7 (1.7–68.6) mo for placebo arm pts. The median (range) duration of treatment was 50.9 (5.9–332.9) wk for luspatercept pts and 24.0 (9.0–103.0) wk for placebo pts. Seventy-five of 153 (49.0%) luspatercept pts achieved RBC-TI ≥ 8 wk during the entire treatment period and 53/75 (70.7%) had ≥ 2 response periods with a median cumulative duration of 110.14 wk (95% confidence interval [CI], 53.71-154.14; Figure A). Overall, 31/75 (41.3%) luspatercept pts had the longest RBC-TI duration ≥ 1 y, and 44/75 (58.7%) had a cumulative RBC-TI duration ≥ 1 y. In total, of the 48/153 (31.4%) pts receiving luspatercept who achieved RBC‑TI ≥ 16 wk during the entire treatment period, 32/48 (66.7%) had ≥ 2 response periods with a median cumulative duration of 129.29 wk (95% CI, 79.86-240.43). Grade 3/4 treatment-related TEAEs were reported in 14/153 (9.2%; EAIR, 5.3 per 100 pt-y [PYs]) and 3/76 (3.9%; EAIR, 6.6 per 100 PYs) luspatercept and placebo pts, respectively; TEAEs of any grade leading to permanent treatment discontinuation were reported in 24/153 (15.7%; EAIR, 8.6 per 100 PYs) luspatercept and 6/76 placebo pts (7.9%; EAIR, 13.0 per 100 PYs). The most common TEAEs of any grade reported in > 5% of luspatercept pts were fatigue (47/153 [30.7%]; EAIR, 22.1 per 100 PYs; vs placebo, 11/76 [14.5%]; EAIR, 27.1 per 100 PYs), diarrhea (47/153 [30.7%]; EAIR, 23.5 per 100 PYs; vs placebo, 8/76 [10.5%]; EAIR, 18.4 per 100 PYs), asthenia (41/153 [26.8%]; EAIR, 18.8 per 100 PYs; vs placebo, 9/76 [11.8%]; EAIR, 21.5 per 100 PYs), peripheral edema (40/153 [26.1%], EAIR, 17.6 per 100 PYs; vs placebo, 13/76 [17.1%]; EAIR, 32.0 per 100 PYs), and back pain (38/154 [24.7%]; EAIR, 16.8 per 100 PYs; vs placebo, 5/76 [6.6%]; EAIR, 11.7 per 100 PYs; Figure B). During the entire treatment period, 26/44 (59.1%), 9/23 (39.1%), and 12/86 (14.0%) pts who received ≤ 1 mg/kg, 1.33 mg/kg, and 1.75 mg/kg luspatercept, respectively, reported fatigue of any grade. No new progression to HR-MDS or AML events have been reported since the last data cutoff (Santini V et al. Blood 2022;140[suppl 1]:4079–4081).

Conclusions: Pts with LR-MDS who received luspatercept for > 2 years longer than in the original MEDALIST study, continued to experience sustained periods of RBC-TI with more than half of pts experiencing cumulative RBC-TI for ≥ 1 year. The long-term safety profile of luspatercept is consistent with previous shorter-term reports, and AEs were mostly lower grade with rates of fatigue decreasing with increasing luspatercept dose. These data demonstrate the long-term efficacy and safety of luspatercept in pts with LR-MDS intolerant/ineligible for ESA treatment.