EMA Accepts MAA for Belantamab Mafodotin Combos in R/R Multiple Myeloma

The European Medicines Agency has accepted a marketing authorization application (MAA) seeking the approval of belantamab mafodotin (Blenrep) paired with bortezomib (Velcade) and dexamethasone (BVd) or with pomalidomide (Pomalyst) and dexamethasone (BPd) for the treatment of patients with relapsed or refractory multiple myeloma.¹

The application is supported by interim data from the phase 3 DREAMM-7 (NCT04246047) and DREAMM-8 (NCT04484623) trials, which both met their primary end points of significant improvements in progression-free survival with belantamab mafodotin regimens over standard-of-care (SOC) combinations.

Specifically, data from DREAMM-7 indicated that treatment with BVd (n = 243) led to a median PFS of 36.6 months (95% CI, 28.4-not reached [NR]) vs 13.4 months (95% CI, 11.1-17.5) with daratumumab (Darzalex) plus Vd (DVd; n = 251), translating to a 59% reduction in the risk of disease progression or death (HR, 0.41; 95% CI, 0.31-0.53; P < .00001).2 Additionally, DREAMM-8 findings showed that BPd (n = 155) led to a median PFS that was NR (95% CI, 20.6-NR) vs 12.7 months (95% CI, 9.1-18.5) with pomalidomide plus Vd (PVd; n = 147), translating to a 48% reduction in the risk of disease progression or death (HR, 0.52; 95% CI, 0.37-0.73; P < .001).3 PFS benefit consistently favored the belantamab mafodotin regimens over the SOC regimens across all prespecified subgroups in both trials.^2,3

“Today’s milestone reinforces the potential for Blenrep to redefine outcomes for patients with multiple myeloma at or after first relapse,” Hesham Abdullah, senior vice president and global head oncology, R&D, at GlaxoSmithKline, stated in a news release.¹ “We are working to bring Blenrep to patients as quickly as possible given the high unmet need and the clinically robust effects of the Blenrep combinations in the DREAMM-7 and DREAMM-8 phase III head-to-head trials.”

Diving Into DREAMM-7: Design, Treatment, Objectives, and More

The study enrolled patients with multiple myeloma who had received at least 1 prior line of therapy and experienced disease progression during or after their most recent therapy. They could not have previously received BCMA-directed therapy or be refractory to or intolerant of daratumumab or bortezomib.²

Participants were randomly assigned 1:1 to receive 1.3 mg/m2 of subcutaneous bortezomib on days 1, 4, 8, and 11 of cycles 1 to 8 plus 20 mg of dexamethasone on the day of and after bortezomib in cycles 1 to 8 with 2.5 mg/kg of intravenous belantamab mafodotin (arm A) or 16 mg/kg of intravenous daratumumab weekly in cycles 1 to 3 and every 3 weeks in cycles 4 to 8 (arm B). Those in arm A went on to receive single-agent belantamab mafodotin at 2.5 mg/kg every 3 weeks for cycles 9 and on whereas those in arm B went on to receive daratumumab monotherapy at 16 mg/kg every 4 weeks.

The study’s primary end point was PFS, and key secondary end points included overall survival (OS), duration of response (DOR), and minimal residual disease (MRD). Additional secondary end points comprised complete response rate (CRR), clinical benefit rate, overall response rate (ORR), time to response (TTR), time to progression (TTP), PFS2, adverse effects (AEs), ocular assessment, and quality of life (QOL).

The ORRs experienced with BVd and DVd were 82.7% (95% CI, 77.4%-87.3%) and 71.3% (95% CI, 65.3%-76.8%), respectively; the CR and better rates in these arms were 34.6% (95% CI, 28.6%-40.9%) and 17.1% (95% CI, 12.7%-22.4%), respectively. The MRD negativity rate in those who achieved CR or better in the BVd and DVd arms were 24.7% (95% CI, 19.4%-30.6%) and 9.6% (95% CI, 6.2%-13.9%), respectively; the MRD negativity rates in those who experienced a very good partial response (VGPR) or better rate in these respective arms were 38.7% (95% CI, 32.5%-45.1%) and 17.1% (95% CI, 12.7%-22.4%). An early OS trend favored BVd over DVd (HR, 0.57; 95% CI, 0.40-0.80; P = .00049); follow-up is ongoing.

The toxicity profile of BVd aligned with what has previously been observed with the individual drugs. All patients in this arm experienced AEs; these effects were grade 3 or 4 in 95% of patients. Toxicities led to discontinuation of any study treatment in 31% of patients in the arm. AEs led to dose interruptions or reductions for 94% and 75% of patients, respectively. Half of patients experienced serious AEs (SAEs) and 10% experienced SAEs that proved fatal.

DREAMM-8: Delving into Study Design, Key End Points, and Additional Data

To enroll to the trial, patients with multiple myeloma were required to have received at least 1 previous line of therapy for their disease, including lenalidomide, and have documented disease progression during or following their most recent therapy.³ They could not have prior exposure to an anti-BCMA therapy or pomalidomide and they could not be refractory or intolerant to bortezomib.

Patients were randomized 1:1 to receive belantamab mafodotin at 2.5 mg/kg for cycle 1 followed by 1.9 mg/kg every 4 weeks from cycle 2 and thereafter plus 4 mg of oral pomalidomide on days 1 to 21 and 40 mg of dexamethasone on days 1, 8, 15, and 22; or bortezomib at 1.3 mg/m2 on days 1, 4, 8, and 11 of cycles 1 to 8 then days 1 and 8 of 21-day cycles plus 4 mg of pomalidomide on days 1 to 14 and 20 mg of dexamethasone on the day of and day after bortezomib.

In addition to the primary end point of PFS, important secondary end points included OS, MRD negativity, and DOR. Additional secondary end points included ORR, CRR, VGPR or better rate, time to best response, TTR, TTP, PFS2, AEs, ocular data, health-related QOL, and patient-reported outcomes.

Additional data indicated BPd elicited an ORR of 77% (95% CI, 70%-84%) vs 72% (95% CI, 64%-79%) with PVd; the respective CR or better rates were 40% (95% CI, 32%-48%) and 16% (95% CI, 11%-23%), and the respective VGPR or better rates were 64% (95% CI, 56%-71%) and 38% (95% CI, 30%-46%). Higher MRD negativity rates were also reported with BPd vs PVd. The MRD negativity rates in those who achieved a CR or better in the BPd and PVd arms were 24% (95% CI, 17%-31%) and 5% (95% CI, 2%-10%), respectively; the MRD negativity rates in those who achieved a VGPR or better in these respective arms were 32% (95% CI, 25%-40%) and 5% (95% CI, 2%-10%). The median DOR with BPd was NR (95% CI, 24.9-NR) vs 17.5 months (95% CI, 12.1-26.4) with PVd.

Moreover, a longer time to PFS2 was reported with BPd vs PVd (HR, 0.61; 95% CI, 0.43-0.86), and a positive OS trend favored the belantamab mafodotin regimen over the SOC regimen (HR, 0.77; 95% CI, 0.53-1.14).

Regarding safety, almost all patients in the BPd arm experienced AEs, and these effects were grade 3 or 4 for 91% of patients. AEs led to dose interruptions and reductions for 91% and 61% of patients, respectively. Toxicities led t discontinuation of study treatment for 15% of those in the BPd arm. Sixty-three percent of patients experienced SAEs and they proved fatal for 11% of patients.

References

1. Blenrep (belantamab mafodotin) combinations in multiple myeloma application accepted for review by the European Medicines Agency. News release. GlaxoSmithKline. July 19, 2024. Accessed July 19, 2024. https://www.gsk.com/en-gb/media/press-releases/blenrep-belantamab-mafodotin-combinations-in-multiple-myeloma-application-accepted-for-review-by-the-european-medicines-agency/
2. Mateos M-V, Robak P, Hus M, et al. Results from the randomized phase III DREAMM-7 study of belantamab mafodotin (belamaf) + bortezomib, and dexamethasone (BVd) vs daratumumab, bortezomib, and dexamethasone (DVd) in relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2024;42(suppl 36):439572. doi:10.1200/JCO.2024.42.36_suppl.439572
3. Trudel S, Beksac M, Pour L, et al. Results from the randomized phase 3 DREAMM-8 study of belantamab mafodotin plus pomalidomide and dexamethasone (BPd) vs pomalidomide plus bortezomib and dexamethasone (PVd) in relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2024;42(suppl 17):LBA105. doi:10.1200/JCO.2024.42.17_suppl.LBA105