OA – 57: Results of a phase 1 clinical trial of belantamab mafadotin (BelMaf) combined with carfilzomib, lenalidomide, and dexamethasone (KRd) for multiple myeloma (MM) after one prior line of therapy (LOT)

Introduction:
BelMaf, a novel antibody-drug conjugate targeting BCMA, showed an overall response rate (ORR) of 32% and median duration of response (DOR) of 11 months in patients (pts) with relapsed or refractory MM (RRMM). However, a BelMaf dose of 2.5 mg/kg once every 3 weeks resulted in 27% grade 3 keratopathy.


We hypothesized that BelMaf at lower doses given every 8 weeks in combination with KRd for pts with RRMM would be effective with acceptable safety.



Methods:
Phase 1 included a 3+3 dose escalation design followed by an expansion cohort to better inform the recommended phase II dose (RP2D). The primary objective for phase 1 was to establish the maximum tolerated dose (MTD) of BelMaf- KRd as determined by dose-limiting toxicities (DLTs) in cycle 1. Secondary objectives included ORR, response depth, DOR, progression-free survival, overall survival, and safety. Two doses of BelMaf were tested: 1.4 mg/kg and 1.9 mg/kg IV over 30 – 60 min every 8 weeks + KRd (K 20/56 mg/m2 IV days 1,8,15; R 25 mg po days1-21; and d 20/40 mg po weekly) in 28-day cycles. In the absence of progression or toxicity, pts were treated for 18 cycles followed by R maintenance.



Results: With a data cutoff of April 4, 2024, 26 pts consented to phase 1, and 19 were enrolled; 6 pts at 1.4 mg/kg and 13 at 1.9 mg/kg. The median age was 63. 63% were male, while 42% were black, and 53% had high-risk cytogenetics (HRCGs). 50% of pts with available staging data had stage III MM and 42%, 11%, 26%, and 26% were refractory to lenalidomide, bortezomib, double refractory, and daratumumab, respectively. The median LOT was 1 (range 1-3).

Out of 19 pts, 18 were DLT evaluable. At the 1.4 mg/kg dose level, one DLT of grade 4 thrombocytopenia was reported out of 6 pts. No DLTs were reported among the 12 DLT evaluable pts enrolled at 1.9 mg/kg dose (6 pts in dose escalation and 6 for dose expansion). Most common adverse events were non-specified eye disorders (total; ≥G3) (89.5%; 26.3%), blurred vision (73.7%; 26.3), hypokalemia (52.6%, 10.5%), fatigue (52%,0%), diarrhea (42.1%, 0%), pain (47.4%, 0%), and constipation (26.3%, 0%).

15 pts experienced ≥G2 corneal events per KVA (26 total ≥G2 events), and 15 pts experienced a decline of 2+ lines on Snellen Visual Acuity scale (25 events). Median follow-up (IQR) was 11.8 months (6.5; 19.2). The ORR was 100%. VGPR(+), CR(+), MRD negativity 10^-5 and 10^-6 by flow cytometry rates were 89.5%, 63.2%, 52.6% and 42%, respectively. Responses are expected to further deepen with treatment.


Conclusions: The MTD and RP2D of BelMaf with KRd was 1.9 mg/kg every 8 weeks. KRd-BelMaf demonstrated deep responses in pts with high-risk features, including HRCGs and R refractory disease. Keratopathy was frequent but manageable with dose delays and reductions. Pts with high-risk newly diagnosed MM will be enrolled in the phase 2 portion of this trial.