Part 1 Results of a Dose Finding Study of Belantamab Mafodotin (GSK2857916) in Combination with Pomalidomide (POM) and Dexamethasone (DEX) for the Treatment of Relapsed/Refractory Multiple Myeloma (RRMM)

Background: Belantamab mafodotin (Belamaf), a first-in-class immunoconjugate targeting B-cell maturation antigen (BMCA), showed clinically meaningful activity and a manageable safety profile in patients (pts) with RRMM. Pomalidomide (POM) is an immunomodulatory drug (IMiD), that auguments T-cell and natural killer cell-mediated immunity. The ability of IMiDS to enhance immune responses including antibody-dependent cellular cytotoxic (ADCC) forms the basis for combining belamaf with POM.

Methods: A phase 1, 2-part multicenter, dose-escalation study evaluated the maximum tolerated does (MTD), recommended phase 2 dose (RP2D), safety, tolerability and efficacy of belamaf in combination with POM and dexamethasone (DEX) (B-Pd) in pts with RRMM. Eligible pts had received > 2 prior lines of treatment, were exposed to lenalidomide (LEN) and a proteasome inhibitor (PI) and were refractory to their last line of therapy. POM was administered at 4 mg days 1-21, DEX 40 mg (20 mg age > 75 years) weekly in conjunction with IV belamaf SINGLE (1.95 or 2.5 mg/kg, day 1) or belamaf SPLIT (2.5 or 3.4 mg/kg, split equally on days 1 and 8) Q4W. In addition, the protocol allowed for exploration of alternative schedules at the 2.5 mg/kg dose, including a 2.5 mg/kg LOADING dose followed by 1.92 mg/kg Q4W from cycle 2 onwards and 2.5 mg/kg dosed Q8W or Q12W. Dose escalation was accomplished using a standard 3+3 dose escalation design. Responses were assessed by International Myeloma Working Group (IMWG) criteria and adverse events (AEs) were graded by CTCAE criteria except for corneal findings which were also graded by the pre-specified keratopathy and visual acuity (KVA) scale. To better inform the RP2D for the expansion cohort in Part 2, up to 12 pts could be enrolled at dose levels not exceeding the MTD.

Results: As of July 13, 2020, 35 pts were enrolled after providing informed consent and completed the 28-day dose limiting toxicity (DLT) observation period. Pts were enrolled at the following dose levels and schedules: 1.92 Single (n=12), 2.5 Single (n=7), 2.5 Loading (n=5), 2.5 Split (n=6), 3.4 Split (n=5). Median age was 64 years (range 36-78) and median number of prior regimens was 3 (range 2-5). Prior therapies included stem cell transplant (68.6%), PI (100%, 80% refractory), LEN (100%, 88.6% refractory) and daratumamb (DARA) (45.7%, 100% refractory). 71.4% were refractory to LEN and a PI and 37.1% were refractory to LEN, PI and DARA. Of 19 pts with available cytogenetics, 8 (42.1%) were high risk, defined as del17p13, t(4;14), t(14;16) or 1q gain. All patients experienced at least 1 AE. The most frequent treatment emergent AEs (TEAEs) reported in >30% across all cohorts were keratopathy/microcyst-like epithelial changes (MEC) (65.7%) that was associated with an objective decrease in visual acuity (VA; 51.4%) or blurred vision (40%), fatigue (48.6%), neutropenia (48.6%), thrombocytopenia (48.6%) and fever (31.4%). Grade (G) 3/4 TEAEs reported in > 10% of pts were keratopathy/MEC (40.0%), neutropenia (37.1%), thrombocytopenia (34.3%), decreased VA (22.9%), lung infection (11.4%), and dyspnea (11.4%). Serious AEs were reported in 16 (45.7%) pts. AEs leading to dose holds of belamaf per treatment cycle were more frequent in the 2.5 SINGLE compared to the 1.92 SINGLE dosing cohorts (57.9% vs 22.9%, respectively). Three DLTs were observed, all were ocular events, 1 occurring in the 2.5 SINGLE (G3 keratopathy) and 2 in the 3.4 SPLIT cohorts (1 with G3 decreased VA + G3 keratopathy, 1 with G4 decreased VA +G3 keratopathy). Thus, the MTD was established as 2.5 mg/kg SINGLE and 2.5 mg/kg SPLIT in combination with standard dosing of POM/DEX.

At a median follow up 6 months, 29 pts are evaluable for response. Across all cohorts, the ORR was 86.2% (6 PR, 15 VGPR and 4 sCR). The median number of cycles administered was 6 (range 1-20). To date, 8 pts discontinued treatment due to progressive disease (PD) (n=5), patient decision (n=2) and adverse event of G4 decreased VA (n=1); 27 pts are ongoing. The mPFS has not been reached in any of the treatment groups. Table 1 summarizes efficacy data per dosing cohort.

Conclusions: The results show promising efficacy. The TEAEs were acceptable and consistent with the known safety profiles for belamaf and POM. However, the high rate of dose holds at the 2.5 mg/kg dose has prompted exploration of alternative dosing schedules that are enrolling and will be presented. The RP2D selection is pending completion of the current cohorts.