Belantamab Mafodotin Plus Cyclophosphamide and Dexamethasone for Patients with Relapsed or Refractory Multiple Myeloma: Interim Results from the UK Myeloma Research Alliance Prommise Clinical Trial

Introduction: Belantamab Mafodotin (Belamaf) is a BCMA targeted antibody drug conjugate with a multi-modal mechanism of action including direct MMAF induced cellular cytotoxicity as well as immunogenic cell death. It has demonstrated superior progression free survival compared to standard of care when combined with either bortezomib (DREAMM-7) or pomalidomide (DREAMM-8) for patients with relapsed or refractory multiple myeloma (RRMM). However these trials dose Belamaf at either Q3W or Q4W which may lead to dose delays and interruptions. ProMMise is a platform trial investigating Belamaf combinations for RRMM using an extended dosing schedule of Q8W to improve tolerability. ProMMise B combines Belamaf with oral cyclophosphamide which at low doses may be synergistic through induction of T and NK cell anti myeloma immune responses by T regulatory cell depletion so may augment the single-agent efficacy of Belamaf. Additionally, cyclophosphamide is low cost, widely globally available and commonly used in combination with standard of care agents.

Methods: This was a multi-centre Phase I/II clinical trial for patients with RRMM with 2-4 prior lines. The primary endpoint was to identify the recommended dose of Belamaf in combination with cyclophosphamide and dexamethasone, to estimate the ≥ VGPR rate and assess the safety and toxicity of the combination. Patients received Belamaf 1.9mg/kg (dose level 1) escalating to 2.5mg/kg (dose level 2) Q8W plus cyclophosphamide 500mg orally days 1,8,15 with dexamethasone 40mg weekly Q4W until disease progression/ intolerance. Dose limiting toxicities were evaluated during the dose escalation phases of both levels followed by cohort expansion at the recommended dose. Ocular exams were required at baseline and for at least the first 3 doses of Belamaf. The trial management group included a diversity officer who monitored enrolment monthly according to age, sex and self-identified ethnicity compared to UK cancer registry data.

Results: 26 patients were registered with a median age of 63 years (range: 49-86); male:female 1.6; White (54%), Black (15%), Asian (4%), Unknown (27%). Patients had received a median of 3 prior lines (2-4). 7 patients were treated at dose level 1 and 6 into dose level 2 with1 DLT (G3 thrombocytopenia with bleeding) noted. Belamaf 2.5mg/kg was declared the recommended dose and 13 patients were enrolled into dose level 2 expansion. At the time of reporting, patients had completed a median of 6 (2-24) 28 day cycles (level1: 16, level 2: 5). The overall response rate for all patients was 68% (dose level 1: 88% (95% CI 47-100%); dose level 2: 59% (95% CI 33-82%)). The ≥VGPR rate was: 40% (dose level 1: 75% (95% CI 35-97%); dose level 2: 24% (95% CI 7-50%)). In interpreting response rates, it is relevant that responses were seen to deepen over time and follow-up is currently relatively shorter for dose level 2.

At dose level 2, the most common all grade adverse events (AEs) reported were: thrombocytopenia (65%), fatigue (35%), nausea (29%) and pain (29%). ≥G3 AEs were thrombocytopenia (19%), fever (13%), neutropenia (6%). Serious AEs of infections were reported in 29%. ≥ G3 corneal events were reported in 38% for dose level 1 and 35% for dose level 2, although more cycles were completed for dose level 1 than 2. 63% of cycles were modified or delayed in dose level 1 vs 63% in dose level 2. Within the first 6 cycles, Belamaf was given at 67% of planned for dose level 1 and 60% of planned for dose level 2. Cyclophosphamide was given at 53% of planned dose at dose level 1 and 45% at dose level 2.

Conclusions: Belamaf Q8W in combination with cyclophosphamide and dexamethasone was safe, tolerable and efficacious for patients with RRMM with an ORR of 59-88%. Whilst the initial recommended dose taken for expansion was Belamaf 2.5mg/ kg, the 1.9mg/kg dose has now been chosen for further evaluation due to improved treatment compliance, lower corneal adverse events and similar efficacy.

Funding: GSK provided funding and Belamaf supply. This study was also supported by Myeloma UK through the UKMRA-MUK- concept and access research programme. Trial registration number: ISRCTN19869915