FDA Grants Priority Review to Belantamab Mafodotin for Relapsed/Refractory Myeloma

The FDA has granted a priority review designation to a biologics license application (BLA) for belantamab mafodotin as a treatment for patients with relapsed/refractory multiple myeloma who received prior therapy with an immunomodulatory drug (IMiD), a proteasome inhibitor, and an anti-CD38 antibody.¹

The BLA is based on findings from the pivotal DREAMM-2 trial, which showed that belantamab mafodotin elicited an overall response rate (ORR) of 31% (97.5% CI, 20.8-42.6) in patients with relapsed/refractory multiple myeloma who received the treatment at the recommended 2.5 mg/kg dose.² In patients who received belantamab mafodotin at 3.4 mg/kg, the ORR was 34% (97.5% CI; 23.9-46.0); both ORRs were assessed by an independent review committee (IRC).

The priority review designation follows a November 2017 decision by the FDA to grant belantamab mafodotin a breakthrough therapy designation for the treatment of patients with relapsed/refractory multiple myeloma who have failed ≥3 prior lines of therapy, including a CD38-directed antibody, and who are refractory to a proteasome inhibitor and an IMiD.

In the open-label, 2-arm, phase II DREAMM-2 trial, investigators accrued 196 patients with relapsed/refractory myeloma for the intent-to-treat population between June 18, 2018, and January 2, 2019. Patients were randomized 1:1 to receive belantamab mafodotin at either 2.5 mg/kg (n = 97) or 3.4 mg/kg (n = 99) intravenously every 3 weeks until disease progression or unacceptable toxicity.

To be eligible for enrollment, patients had an ECOG performance status of 0 to 2, experienced disease progression on ≥3 lines of therapy, were refractory to a proteasome inhibitor and an IMiD, and were refractory and/or intolerant to a CD38-directed monoclonal antibody.

Patient characteristics were well balanced between the 2 treatment arms. In the 2.5-mg/kg arm, the median age was 65 years (range, 60-70), 53% were male, and 42% had high-risk cytogenetics. Patients had received a median of 7 (range, 3-21) lines of prior treatment, with 84% of patients having received >4 lines of therapy. Prior therapies included bortezomib (Velcade; 98%), carfilzomib (Kyprolis; 76%), lenalidomide (Revlimid; 100%), pomalidomide (Pomalyst; 92%), daratumumab (Darzalex; 100%), and isatuximab (3%). Additionally, 76% of patients were refractory to bortezomib, 65% were refractory to carfilzomib, 90% were refractory to lenalidomide, 87% were refractory to pomalidomide, 100% were refractory to daratumumab, and 3% of patients were refractory to isatuximab.

The median age in the 3.4-mg/kg arm was 67 years (range, 61-72), 57% were male, and 47% had high-risk cytogenetics. Patients had received a median of 6 (range, 3-21) prior lines of therapy, with 83% having received >4 lines. Prior therapies received included bortezomib (98%), carfilzomib (65%), lenalidomide (100%), pomalidomide (85%), daratumumab (97%), and isatuximab (2%). The rate of the overall cohort refractory to each of these therapies was bortezomib, 75%; carfilzomib, 58%; lenalidomide, 89%; pomalidomide, 78%; daratumumab, 92%; and isatuximab, 1%.

Additional results showed that, the 31% ORR in the 2.5-mg/kg cohort included a very good partial response (VGPR) or better in 18 (19%) patients. Of the 34% ORR in the 3.4 mg/kg arm, a ≥VGPR was achieved in 20 (20%) of patients. There were 3 stringent complete responses or complete responses in each cohort.

The median follow-up was 6.3 months and 6.9 months in the 2.5-mg/kg and 3.4-mg/kg cohorts, respectively. Overall, the median duration of response (DOR) was not reached. At the data cutoff date, 18 patients receiving belantamab mafodotin at 2.5 mg/kg and 25 at the 3.4-mg/kg dose had a DOR of ≥4 months; the authors noted that progression-free survival (PFS) follow-up was ongoing and patients were continuing on treatment.

The median PFS was 2.9 months (95% CI, 2.1-3.7) and 4.9 months (95% CI, 2.3-6.2) in the 2.5-mg/kg and 3.4-mg/kg cohorts, respectively. Overall survival data were immature at the time of the analysis.

For the safety analysis, there were 95 patients in the 2.5-mg/kg arm and all 99 patients in the 3.4-mg/kg arm. The most frequently reported grade 3/4 adverse events (AEs) included keratopathy (27% in the 2.5-mg/kg cohort vs 21% in the 3.4-mg/kg cohort), thrombocytopenia (20% vs 33%, respectively) and anemia (20% vs 25%, respectively). Serious AEs occurred in 40% versus 47% of the 2.5-mg/kg and 3.4-mg/kg cohorts, respectively. Investigators reported 2 patient deaths that were potentially related to treatment: 1 case of sepsis in the 2.5-mg/kg cohort and 1 case of hemophagocytic lymphohistiocytosis in the 3.4-mg/kg group.

Dose delays that were related to AEs occurred in 54% of patients on the 2.5-mg/kg cohort compared with 62% of the 3.4-mg/kg cohort. AE-related dose reductions occurred in 29% versus 41% of the 2 cohorts, respectively. Permanent treatment discontinuation due to AEs occurred in 8% and 10% of patients on the 2.5-mg/kg and 3.4-mg/kg arms, respectively.

The authors noted that 2.5 mg/kg was selected as the recommended dose for future studies with belantamab mafodotin, given the similar efficacy and a more favorable safety profile compared with the 3.4-mg/kg dose.

References

1. US Food and Drug Administration (FDA) grants priority review of belantamab mafodotin for patients with relapsed or refractory multiple myeloma [news release]: London, UK. Published January 21, 2020. https://prn.to/2RPCfMf. Accessed January 21, 2020.
2. Lonial S, Lee HC, Badros A, et al. Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomised, open-label, phase 2 study [published online December 16, 2019]. Lancet Oncol. https://doi.org/10.1016/S1470-2045(19)30788-0.