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

Introduction. Currently, no established treatments exist for relapsed/refractory (RR) light chain (AL) amyloidosis especially for daratumumab & bortezomib exposed patients (pts). Belantamab mafodotin (belamaf), a multi-modal antibody-drug conjugate targeting BCMA, has shown efficacy and tolerability in heavily pretreated pts with RR multiple myeloma (MM), including those refractory to daratumumab. Clonal plasma cells in AL and MM are phenotypically similar, expressing BCMA; thus, belamaf could be a novel treatment option in RRAL amyloidosis. This study evaluates the efficacy and safety of belamaf monotherapy in pts with RRAL amyloidosis.

Methods. The ongoing prospective, open-label, multinational, phase 2, EMN27 study (NCT04617925) aims to enroll 36 RRAL amyloidosis pts who require therapy. Pts at Mayo cardiac stage 3B are excluded. Belamaf monotherapy at 2.5 mg/kg is administered every 6 weeks for up to 8 cycles; dosing can be reduced to 1.92 mg/kg for toxicity. Per study design, an interim safety analysis (after 6 pts received ≥1 treatment cycle) and an efficacy analysis (after 13 pts are enrolled) were planned. The safety analysis revealed no new safety signals, and the efficacy analysis was conducted in 13 pts; with at least 3 pts achieving very good partial response (VGPR). Enrolment is continuing to include all planned pts. This descriptive analysis included pts initiating treatment ≥3 months before the cut-off date (31 May 2022).

Results. Seventeen pts were included in this analysis (median age: 65 years [range: 46.0–80.0]; 12 male [70.6%]). At baseline, 5 (29.4%) and 12 (70.6%) pts had New York Heart Association class I and II symptoms respectively; the median N-terminal pro-brain natriuretic peptide, high-sensitivity troponin T, and dFLC were 1,588.0 ng/L (range 190.0–7,270.0), 46.2 ng/L (range 11.0–115.6), and 145 mg/L (range 39-2791), respectively. Except for the heart, commonly involved organs were the peripheral nerves (8 pts, 47.1%), kidneys (4 pts, 23.5%); liver, soft tissue, and gastrointestinal tract involvement was seen in 3 (17.7%) pts, each. Median number of prior lines was 3 (range 1-7). Ten (58.8%) pts had previously received daratumumab treatment and 15 pts (88.2%) had previous bortezomib exposure. At data cut-off, 4 (23.5%) pts were continuing treatment and 13 (76.5%) discontinued due to disease progression (7, 41.2%), adverse event (AE; 3, 17.7%), death (2, 11.8%) and physician decision (1, 5.9%). AEs leading to discontinuation were renal failure (1pt) and keratopathy (2pts).

Median duration of belamaf therapy was 1.5 months (range <0.1–8.8). At a median follow up of 8.4 months (range 3.4–14.5), best hematologic response rate for all pts was 52.9% (9 pts - VGPR: 23.5% [4 pts], partial response [PR]: 29.4% [5 pts]). At 1 and 3 months, the respective best hematologic response rates were 52.9% (9 pts; VGPR: 17.6% [3 pts], PR: 35.3% [6 pts]) and 52.9% (9 pts; VGPR: 23.5% [4 pts], PR: 29.4% [5 pts]). The subgroup of pts previously exposed to daratumumab had a best hematologic response rate of 40.0% (4 pts; VGPR and PR: 20.0% [2 pts] each response) during follow-up. For all pts, median time to first hematologic response was 9.0 days (range 7.0-28.0) and to VGPR or better 22.0 days (range 15.0-85.0); the corresponding median times for pts previously exposed to daratumumab were 15.0 days (range 8.0-28.0) and 22.0 days (range 15.0-29.0). For all pts, any organ response rate at 3 months was 29.4% (5 pts; heart: 17.6% [3 pts], kidney: 11.8% [2 pts]).

All pts on the study experienced >1 treatment-emergent adverse event (TEAE), with 16 pts (94.1%) experiencing eye disorders, 7 pts (41.2%) experienced blood and lymphatic system disorders, and cardiac disorders occurred in 2 (11.8%) pts. Two (11.8%) pts had a fatal SAE, both unrelated to study treatment.

Out of 16 pts with ocular adverse events, 13 pts (76.5%) were reported to have visual acuity reduced, while 11 pts (64.7%) were reported to have keratopathy (all non-serious AEs) and 2 pts (11.8%) with visual impairment, both serious AEs (SAE) (Table 1).

Conclusions. In heavily pretreated RR pts with AL amyloidosis, belamaf monotherapy induced rapid, clinically meaningful responses with a convenient delivery scheme and manageable safety profile. Longer dosing intervals (compared to myeloma) show reduced severity of ocular events. The results suggest that belamaf may represent a valid new treatment option for this difficult to treat patient population.