Efficacy and Safety of Belantamab Mafodotin Monotherapy in Patients with Relapsed or Refractory Light Chain Amyloidosis: An Updated Analysis of a Phase 2 Study By the European Myeloma Network

INTRODUCTION Belantamab mafodotin (belamaf), an antibody-drug conjugate targeting the B-cell maturation antigen, demonstrated substantial clinical activity with a manageable safety profile in patients (pts) with relapsed/refractory (RR) multiple myeloma (MM). Since clonal plasma cells in AL amyloidosis and MM are phenotypically similar, belamaf could be a much-needed treatment option in AL amyloidosis. Herein, we present updated safety and efficacy data from the EMN27 study, assessing belamaf monotherapy in pts with RR AL amyloidosis. METHODS The ongoing, prospective, open-label, multinational, phase 2 EMN27 study (NCT04617925) aimed to enroll 36 adult pts with Mayo cardiac stage 1-3A RR AL amyloidosis and symptomatic organ involvement. Belamaf monotherapy at 2.5 mg/kg is administered by intravenous infusion every 6 weeks (Q6W) for up to 8 cycles; dosing can be reduced to 1.92 mg/kg for toxicity. Per the study design, the outcomes of an interim safety analysis (after 6 pts received ≥1 treatment cycle) and an efficacy analysis (after 13 pts were enrolled) were favorable, and study enrolment continued. Data are descriptively analyzed. RESULTS Enrolment closed with 35 pts enrolled in the study. By the cut-off date of this analysis (31/05/2024), one patient (2.9%) continues treatment and 34 (97.1%) have discontinued. Reasons for discontinuation were disease progression: 9 [25.7%]; inadequate response: 5 [14.3%]; adverse events [AE]: 8 [22.9%]; death: 4 [11.4%]; investigator's decision: 2 [5.7%]; consent withdrawal: 1 [2.9%]), while 5 (14.3%) pts completed the 8-cycle treatment. At baseline, 29 pts had cardiac involvement (82.9%), 20 pts had renal involvement (57.1%), while involvement of peripheral nerve was seen in 25.7% and liver in 14.3% of them. Most pts were at Mayo 2 and 3a cardiac stages (54.3% and 31.4%, respectively), and most of them (77.1%) were classified in New York Heart Association class II. The median (range) number of prior treatment lines was 3 (1-10), while 26 (74.3%) and 30 (85.7%) pts had previously received daratumumab (dara) and bortezomib, respectively. At a median follow-up of 14.3 months (range 3.5 - 30.5), the overall hematologic response (≥partial response [PR]) and ≥very good partial response (VGPR) rates were 51.4% (18 pts) and 31.4% (11 pts), respectively. One patient achieved complete response (CR). The respective rates for pts previously treated with dara were 50% (13 pts) and 34.6% (9 pts). The median (range) time to first ≥PR and ≥VGPR were 15 (7-148) and 44 (15-274) days, respectively. Four (11.4%) pts achieved a cardiac response at 3 months. Median (95% Confidence Interval) OS and MOD-PFS were 21.54 (14.23 - NR) and 9.99 (5.72-12.16) months, respectively. Among 130 belamaf doses, 86 (66.2%) were at 2.5 mg/kg, 37 (28.5%) at 1.92 mg/kg and 7 (5.3%) at 1.25 mg/kg. The median (range) number of belamaf administrations was 3 (1-8). Sixteen (45.7%) pts had 35 belamaf dose holds due to Adverse Events (AEs) or Serious AEs, with a median (range) delay of 21 (7-128) days from planned belamaf administration. Ocular AEs were observed in 34 (97.1%) pts, with 24 pts (68.6%) manifesting a Gr≥2 Best Corrective Visual Acuity (BCVA) change from baseline and 15 pts (42.9%) a Gr≥2 keratopathy. The median (range) time to resolution for BCVA change from baseline was 1.4 (0.3-6.9) months. Twenty-two (62.9%) pts experienced at least one Gr≥ 3 AE, while 15 (42.9%) pts manifested at least one Gr≥3 ocular AE. Four (11.4%) pts experienced fatal events (GI neoplasms: 2 [5.7%]; pneumonia: 1 [2.9%]; ischemic stroke: 1 [2.9%]), all considered unrelated to belamaf. SUMMARY/CONCLUSION In patients with RR AL amyloidosis, belamaf monotherapy, administered at an extended dosing interval, has shown significant efficacy. Ocular AEs were the most common Gr≥3 safety finding observed, while BCVA drops from baseline resolved in a consistent with previous reports way. These findings underscore the potential of belamaf as a promising treatment option for this difficult-to-treat population. Further studies evaluating belamaf in combination with other active agents may allow for longer dosing intervals (e.g. 8-12 weeks), while maintaining or even enhancing its efficacy.