Final Results of Phase 1 Clinical Trial of Belantamab Mafodotin Combined with Carfilzomib, Lenalidomide, and Dexamethasone for Multiple Myeloma after One to Three Prior Lines of Therapy

Introduction/Background:

In the pivotal DREAMM-2 study, belantamab mafodotin (Belamaf), an antibody-drug conjugate targeting BCMA, achieved an overall response rate (ORR) of 32% with a median response duration (DOR) of 11 months in relapsed or refractory multiple myeloma (RRMM). In the DREAMM-7 study, Belamaf showed superior efficacy outcomes compared to daratumumab when combined with bortezomib and dexamethasone. Moreover, in the DREAMM-8 trial, Belamaf outperformed bortezomib in combination with pomalidomide and dexamethasone.

We, therefore, aimed to evaluate the safety and preliminary efficacy of adding Belamaf to carfilzomib, lenalidomide, and dexamethasone (KRd) for patients with RRMM who have received 1 – 3 prior lines of therapy. When Belamaf was administered at a dose of 2.5 mg/kg once every 3 weeks, it resulted in a 27% incidence of grade 3 keratopathy. We theorized that using lower doses of Belamaf every 8 weeks would improve tolerability without compromising efficacy. Here, we present the findings of the phase 1 portion of the trial.

Methods:

Pts with RRMM after 1-3 prior lines of therapy (LOT) were enrolled in the phase 1 component of the trial with a 3+3 dose escalation design followed by an expansion cohort to better inform the recommended phase II dose (RP2D). The primary objective for the phase 1 portion was to establish the maximum tolerated dose (MTD) of Belamaf when given with KRd as determined by dose-limiting toxicities (DLTs) in cycle 1 of therapy. Secondary objectives included ORR, response depth, DOR, progression-free survival, overall survival, and safety. Two doses of Belamaf were tested: 1.4 mg/kg and 1.9 mg/kg given intravenously over 30 – 60 minutes every 8 weeks with KRd (K 20/56 mg/m² 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 disease progression or the emergence of unacceptable toxicity, pts were treated for up to 18 cycles followed by lenalidomide maintenance.

Results:

With a data cutoff of June 10, 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 (6 DLT evaluable pts in 1.4 mg/kg cohort and 12 DLT evaluable pts in the 1.9 mg/kg cohort). Median age was 63. Most pts were males 63%, 42% were black, and 53% had high-risk cytogenetics, including 1q gain and 1p deletion. 50% of pts with available ISS staging data at diagnosis had stage III, 42% were refractory to lenalidomide, 11% were bortezomib refractory, 26% were double refractory, and 26% were daratumumab refractory. The median lines of prior therapy was 1 (range 1- 3).

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 the 1.9 mg/kg dose level (6 pts as part of the dose escalation portion and 6 pts for dose expansion).

The most common adverse events were non-specified eye disorders (total; ≥G3) (94.7%; 31.6%), blurred vision (89.5%; 36.8%), fatigue (57.9%; 0%), hypokalemia (52.6%; 10.5%), cough (47.4%; 0%), diarrhea (47.4%; 0%), and pain (47.4%; 0%).

15 pts experienced G2(+) corneal events per KVA (26 total G2(+) events), and 15 pts experienced a decline of 2 or more lines on the Snellen Visual Acuity scale (25 events). After a median follow-up (IQR) of 16.1 months (11.4; 24.1), 3 pts progressed. The total and median number of cycles of belantamab were 73 and 5 cycles, respectively. All pts achieved a best response of at least a PR, the VGPR(+) rate was 73.7%, and the CR(+) rate was 52.6%, including 52.6% and 36.8% with MRD negativity 10^-5 and 10^-6 by flow cytometry, respectively. Out of 7 pts with R-ISS-III, 57.1% achieved VGPR(+). Out of 8 pts with IMWG high risk cytogenetics, 5 pts (62.5%) achieved a VGPR or better. Responses are expected to deepen with further follow-up. In total, 9 pts achieved sCR, which exceeds the protocol-directed criterion to proceed to Phase 2 at the RPD2 dose. 13 pts are off treatment due to consent withdrawal (n=4), investigator decision post 18 cycles (n=4), participant non-compliance (n=1), and toxicity (n=1).

Conclusions:

This phase 1 trial established the MTD of belantamab of 1.9 mg/kg every 8 weeks in combination with KRd. KRd-B is effective even in pts with high-risk MM. Despite the dosing schedule of every 8 week Belamaf dosing, clinically significant keratopathy was common. Pts with high-risk newly diagnosed MM will be enrolled in the phase 2 portion of this trial.