Belantamab Mafodotin in Combination with Lenalidomide Plus Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma: Safety and Efficacy Analysis of DREAMM-6 Trial Arm-a

Introduction: Belantamab mafodotin (belamaf) is a first-in-class, antibody-drug conjugate that targets B-cell maturation antigen. In the recent ALGONQUIN study, clinical activity associated with belamaf in combination with the immunomodulatory drug pomalidomide were increased in triple-class exposed/refractory multiple myeloma (MM) patients, highlighting the potential for belamaf-based combinations in this population (Trudel, et al. Blood. 2022;140 (Suppl 1):7306–07). Preclinical data indicate that belamaf combined with other immunomodulatory agents, such as lenalidomide (Len) may also provide additional benefit. Arm A of the Phase I/II DREAMM-6 (NCT03544281) study aimed to assess the safety and clinical activity of belamaf doses/schedules in combination with the standard of care (SOC) of Len plus dexamethasone (Dex) in patients with relapsed/refractory MM (RRMM).

Methods: Patients were eligible to participate if they had received ≥1 prior line of therapy (LOT). In Part 1 (dose escalation), up to two dose levels of belamaf (1.9 mg/kg [dose level -1 Q4W]; 2.5 mg/kg Q4W [dose level 1]) and alternative dosing schedules were administered in combination with the fixed SOC dose. In Part 2 (dose expansion), patients received belamaf at the following doses/schedules: 1.9 mg/kg Q8W, 1.9 mg/kg Q4W, 2.5 mg/kg Q4W, or 2.5 mg/kg Q4W split dose (50% on Days 1 and 8 of a given cycle). For this study, Len 25 mg was administered orally (10 mg if estimated glomerular filtration rate <60 mL/min/1.73m²) on days 1–21 and Dex 40 mg was administered (20 mg for patients >75 years old, patients with BMI <18.5, or patients with prior tolerability issues to Dex) on Days 1, 8, 15, and 22 of every 28-day cycle. The primary outcome of Part 1 was the number/percent of subjects with adverse events (AE) or dose-limiting toxicity (as reported previously). The primary outcome of Part 2 was safety profile (AEs and serious AEs) and efficacy (overall response rate [ORR]). Pharmacokinetics (PK) and anti-drug antibodies were secondary outcomes. Duration of response (DOR), progression-free survival (PFS) and overall survival (OS) were exploratory endpoints.

Results: Overall, 45 patients were enrolled across Parts 1 and 2. At the final analysis cutoff date (Feb 28, 2023), the median (range) age was 68 (36–80) years; patients had received a median (range) of 3 (1–10) prior LOTs, and 26/45 (57.8%) patients were Len-exposed (Table). The median (range) follow-up was 23.7 (0.5– 51.3) months. Incidence of AEs resulting in permanent discontinuation and dose reduction/delays of any study treatment were similar across groups; however, interpretation is limited due to the small sample size. The most common drug-related Grade 3+ AEs were keratopathy, visual acuity decline, and neutropenia. Safety and efficacy data are presented in the Table below. The ORR ranged from 58% to 75% across groups. The greatest depth of response (≥very good partial response [VGPR] 56%, ≥complete response 44%) was observed in the 2.5 mg/kg Q4W cohort. Interpretation of DOR, PFS, and OS was limited due to the small sample size in each cohort (Table). PK characteristics of belamaf were consistent with those previously reported for belamaf monotherapy considering baseline patient characteristics. Higher Cycle 1 peak and average concentrations (C_ave) were observed with higher doses, with large overlap among cohorts; lower peak concentrations were seen with the split dosing regimen. Len PK were consistent with historical data. PK data indicated no drug–drug interaction between belamaf and Len. A positive trend was observed between belamaf Cycle 1 C_ave and the probability of achieving PR or better.

Conclusion: Belamaf in combination with SOC (Len/Dex) demonstrated deep and durable responses with a manageable safety profile in patients with RRMM. As anticipated, there was no drug–drug interaction between belamaf and Len. These findings support the use of belamaf in combination with SOC for patients with RRMM.