Approval Sought for Belantamab Mafodotin Combos for R/R Multiple Myeloma in Japan

A new drug application (NDA) seeking the approval of belantamab mafodotin (Blenrep) plus bortezomib (Velcade) and dexamethasone or pomalidomide (Pomalyst) and dexamethasone in patients with relapsed or refractory multiple myeloma has been accepted for review by Japan’s Ministry of Health, Labour, and Welfare.1 The government ministry also granted the agent an orphan drug designation.

The NDA is supported by interim findings from the phase 3 DREAMM-7 (NCT04246047) and DREAMM-8 (NCT04484623) studies, which both met their primary end points of providing a progression-free survival (PFS) benefit over standard-of-care regimens in this population. A trend toward an overall survival (OS) was also seen in the trials with the belantamab mafodotin combinations, although the between-arm differences were not determined to be statistically significant at the time of the analyses.

“Blenrep combinations show potential based on the results of the DREAMM-7 and DREAMM-8 trials to redefine the treatment of relapsed/refractory multiple myeloma,” Hesham Abdullah, senior vice president of Global Head Oncology, R&D, at GlaxoSmithKline, stated in a news release. “We are committed to working with health authorities worldwide to advance Blenrep along regulatory pathways so we can bring these additional treatment options to patients as quickly as possible.”

Diving Into DREAMM-7

The study enrolled patients with multiple myeloma who previously received at least 1 line of therapy and documented disease progression during or following their most recent therapy. They could not have had prior exposure to an anti-BCMA agent, and they could not be refractory to or intolerant of daratumumab (Darzalex) or bortezomib.

They were randomly assigned 1:1 to arm A (BVd) or arm B (DVd). Those in arm A were given 2.5 mg/kg of intravenous (IV) belantamab mafodotin every 3 weeks plus 1.3 mg/m2 of subcutaneous (SC) bortezomib on days 1, 4, 8, and 11 of cycles 1 to 8 plus 20 mg of dexamethasone on the day of and day after bortezomib in cycles 1 to 8; for cycles 9 and onward, single-agent belantamab mafodotin was administered at a dose of 2.5 mg/kg every 3 weeks. For arm B, patients were given 16 mg/kg of IV daratumumab weekly for cycles 1 to 3 and every 3 weeks for cycles 4 to 8 paired with the same dose and schedule of bortezomib and dexamethasone as arm A; this was followed by daratumumab monotherapy at 16 mg/kg every 4 weeks for cycles 9 and onward.

Patients were stratified based on prior lines of treatment (1 vs 2 or 3 vs ≥4), Revised International Staging System stage (I vs II/III), and prior bortezomib (yes vs no).

In addition to the primary end point of independent review committee (IRC)–assessed PFS, secondary end points included OS, duration of response (DOR), and minimal residual disease (MRD). Additional end points included complete response rate (CRR), overall response rate (ORR), clinical benefit rate (CBR), time to response (TTR), time to progression (TTP, PFS2, toxicity, ocular findings, and quality of life (QOL).

At a median follow-up of 28.2 months (range, 0.1-40.0), the median PFS in the BVd arm (n = 243) was 36.6 months (95% CI, 28.4-not reached [NR]) vs 13.4 months (95% CI, 11.1-17.5) with 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). At a median follow-up of 28.2 months (range, 0.1-40.0), the median OS was NR in both arms (HR, 0.57; 95% CI, 0.4-0.8; P = .00049); the 18-month OS rates were 84% and 73%, respectively.

In the BVd arm, the ORR was 82.7% (95% CI, 77.4%-87.3%), which included a CR or better rate was 34.6% (95% CI, 28.6%-40.9%) and the MRD negativity rate was 24.7% (95% CI, 19.4%-30.6%). In the DVd arm, the ORR was 71.3% (95% CI, 65.3%-76.8%), which included a CR or better rate of 17.1% (95% CI, 12.7%-22.4%) and a MRD negativity rate of 9.6% (95% CI, 6.2%-13.9%) in this group. The median DOR was 35.6 months (95% CI, 30.5-NR) in the BVd arm (n = 201) vs 17.8 months (95% CI, 13.8-23.6) in the DVd arm (n = 179).

Discoveries From DREAMM-8

Patients with multiple myeloma who received 1 or more prior lines of therapy, including lenalidomide (Revlimid) and documented disease progression during or after their most recent treatment were enrolled to the study.3 If they previously received an anti-BCMA therapy or pomalidomide (Pomalyst), they were excluded. They also could not have been refractory or intolerant to bortezomib.

They were randomly assigned in a 1:1 fashion to BPd or PVd. Those in the BPd arm were given IV belantamab mafodotin at 2.5 mg/kg for cycle 1 and 1.9 mg/kg every 4 weeks from cycle 2 and thereafter plus pomalidomide at 4 mg on days 1 to 21 of 28-day cycles and dexamethasone at 40 mg on days 1, 8, 15, and 22. Those in the PVd arm received bortezomib at 1.3 mg/m2 on days 1, 4, 8, and 11 of cycles 1 to 8 and then days 1 and 8 as part of 21-day cycles with pomalidomide at 4 mg on days 1 to 14 and dexamethasone at 20 mg on the day of and day after bortezomib. They were stratified by prior lines of treatment (1 vs 2 or 3 vs ≥4), prior bortezomib (yes vs no), and prior anti-CD38 therapy (yes vs no).

In addition to PFS by IRC assessment and by International Myeloma Working Group criteria, secondary end points included OS, MRD negativity, and DOR. Investigators also examined ORR, CRR, very good partial response (VGPR) or better rate, time to best response, TTP, PFS2, toxicity, ocular findings, health-related QOL, and patient-reported outcomes.

The median PFS with BPd (n = 155) was NR (95% CI, 20.6-NR) vs 12.7 months (95% CI, 9.1-18.5) with 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). The 12-month PFS rates in the respective arms were 71% and 51%. At the time of the analysis, interim data indicated that the median OS was NR in both arms (HR, 0.77; 95% CI, 0.52-1.14); the 12-month OS rates were 83% and 76%, respectively.

Moreover, the ORR with BPd (n = 155) was 77% (95% CI, 70%-84%), which included a CR or better rate of 40% (95% CI, 32%-48%) and a VGPR or better rate of 64% (95% CI, 56%-71%); with PVd (n = 147), the ORR was 72% (95% CI, 64%-79%), which included a CR or better rate of 16% (95% CI, 11%-23%) and a VGPR or better rate of 38% (95% CI, 30%-46%). MRD negativity rates with BPd in those who achieved CR or better was 24% (95% CI, 17%-31%) and 32% (95% CI, 25%-40%) in those who had VGPR or better; with PVd, these respective rates were 5% (95% CI, 2%-10%) and 5% (95% CI, 2%-10%). The median DOR was NR (95% CI, 24.9-NR) with BPd vs 17.5 months (95% CI, 12.1-26.4) with PVd; the 12-month DOR rates were 79% and 61%, respectively

Next Steps

A Japan expansion cohort is set to further examine the DREAMM-7 and DREAMM-8 protocols in Japanese patients, according to a news release issued by GlaxoSmithKline.1 Data for these participants will be shared at a future scientific meeting.

References

1. Blenrep (belantamab mafodotin) combinations in relapsed/refractory multiple myeloma accepted for regulatory review in Japan. News release. GlaxoSmithKline. September 17, 2024. Accessed September 17, 2024. https://www.gsk.com/en-gb/media/press-releases/blenrep-belantamab-mafodotin-combinations-in-relapsedrefractory-multiple-myeloma-accepted-for-regulatory-review-in-japan/
2. Mateos MV, Robak P, Hus M, et al. DREAMM-7 update: subgroup analyses from a phase 3 trial of belantamab mafodotin + bortezomib and dexamethasone vs daratumumab, bortezomib, and dexamethasone in relapsed/refractory multiple myeloma. J Clin Oncol. 2024;42(suppl 16):7503. doi:10.1200/JCO.2024.42.16_suppl.7503
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 vs pomalidomide plus bortezomib and dexamethasone in relapsed/refractory multiple myeloma. J Clin Oncol. 2024;42(suppl 17):LBA105. doi:10.1200/JCO.2024.42.17_suppl.LBA105