Belantamab Mafodotin Triplet Improves PFS, Responses in R/R Myeloma With High-Risk Cytogenetics

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Combination treatment with belantamab mafodotin (Blenrep), pomalidomide (Pomalyst), and dexamethasone (BPd) improved progression-free survival (PFS) and induced deep responses compared with pomalidomide, bortezomib (Velcade), and dexamethasone (PVd) in patients with relapsed/refractory multiple myeloma who had at least 1 high-risk cytogenetic abnormality, according to results of an updated post hoc analysis from the phase 3 DREAMM-8 trial (NCT04484623).1

Findings presented as a poster during the 2025 ASCO Annual Meeting showed that at a median follow-up of 21.8 months (range, 0.03-39.23), the median PFS in patients with at least 1 high-risk cytogenetic abnormality was 21.1 months (95% CI, 13.5-not reached [NR]) with BPd (n = 68) compared with 9.2 months (95% CI, 6.5-14.8) with PVd (n = 60; HR, 0.58; 95% CI, 0.36-0.95; P = .014).

PFS favored BPd across subgroups of patients with high-risk cytogenetic abnormalities, including amp1q (HR, 0.49; 95% CI, 0.24-1.03), 17p deletion ([del17p] HR, 0.45; 95% CI, 0.22-0.92), t(4;14) [HR, 0.74; 95% CI, 0.31-1.76], and those who had t(4;14), t(14;16), del17p, and amp1q (HR, 0.58; 95% CI, 0.36-0.95). Patients with t(14;16) were not analyzed due to the low number of patients on study (BPd, n = 7; PVd, n = 11).

Additionally, responses were more frequent and deeper with BPd compared with PVd in patients with at least 1 high-risk cytogenetic abnormality.

“In the DREAMM-8 trial, BPd demonstrated PFS benefit and was associated with higher rates of deep responses vs PVd in patients with at least 1 high-risk cytogenetic abnormality,” lead study author Suzanne Trudel, MSc, MD, clinician scientist of the Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre in Toronto, Canada, wrote in a poster presentation during the meeting. “These data support the potential use of BPd as a standard-of-care regimen in this key patient population with a high unmet need.”

Earlier results of DREAMM-8 showed that BPd produced a statistically significant improvement in PFS compared with PVd (HR, 0.52; 95% CI, 0.37-0.73; P <.001) in patients with relapsed/refractory multiple myeloma after at least 1 prior line of therapy, which included lenalidomide (Revlimid).2

Patients with multiple myeloma and high-risk cytogenetic abnormalities, including t(14;4), t(14;16), del17p, and amp1q have poor prognosis.1 As such, investigators presented efficacy outcomes from an updated post hoc analysis of DREAMM-8 of enrolled patients with at least 1 high-risk cytogenetic abnormality.

In the DREAMM-8 trial, 302 patients were randomly assigned to receive BPd, which comprised belantamab mafodotin intravenously (IV) at 2.5 mg/kg (cycle 1) followed by 1.9 mg/kg every 4 weeks from cycle 2 onward, oral pomalidomide at 4 mg on days 1 to 21 in 28-day cycles, and dexamethasone at 40 mg on days 1, 8, 15, and 22; or PVd, which comprised oral pomalidomide at 4 mg on days 1 to 14 in 21-day cycles, subcutaneous bortezomib at 1.3 mg/m2 on days 1, 4, 8, and 11 in cycles 1 to 8, then days 1 and 8 in 21-day cycles, and dexamethasone at 20 mg on the day of and day after bortezomib. Treatment was given until disease progression, unacceptable toxicity, end of study, or withdrawal of consent, and efficacy assessments occurred every 4 weeks.

To be eligible for enrollment, patients with multiple myeloma had to be at least 18 years of age and received at least 1 prior line of therapy, including lenalidomide, documented disease progression during or after their most recent treatment, and no prior treatment with an anti-BCMA–directed agent or pomalidomide. Their disease could not have been refractory to or intolerant of bortezomib.

Stratification factors included prior lines of treatment (1 vs 2 or 3 vs ≥4), prior bortezomib (yes vs no), and prior anti-CD38 therapy (yes vs no).

Patients were recruited between October 2020 to December 2022. The primary end point was PFS, as assessed by an independent review committee per International Myeloma Working Group criteria. Secondary end points included overall survival, minimal residual disease negativity, and duration of response; additional outcome measures included objective response rate (ORR), complete response (CR) rate, very good partial response (VGPR) or higher, time to best response, time to response, time to progression, PFS on second line of therapy, adverse effects, ocular findings, health-related quality of life, and patient-reported outcomes.

Cytogenetic abnormalities were assessed via interphase fluorescence in situ hybridization. High-risk cytogenetic abnormalities were observed in 44% of patients on BPd (n = 68) and 41% of those on PVd (n = 60).

Of all patients with at least 1 high-risk cytogenetic abnormality, the ORR in the BPd arm was 76% (95% CI, 65%-86%), which comprised a CR or higher rate of 43% (95% CI, 31%-55%), a stringent CR (sCR) rate of 15%, a CR rate of 28%, a VGPR or higher rate of 65% (95% CI, 52%-76%), a VGPR rate of 22%, and a partial response (PR) rate of 12%. In the PVd arm, the ORR was 65% (95% CI, 52%-77%), and the CR or higher, sCR, CR, VGPR or higher, VGPR, and PR rates were 15% (95% CI, 7%-27%), 2%, 28%, 13%, and 37%, respectively.

The response rates were consistent across all prespecified subgroups.

In November 2024, the FDA accepted a biologics license application seeking the approval of belantamab mafodotin in combination with bortezomib and dexamethasone, and in combination with pomalidomide and dexamethasone, both for the treatment of patients with multiple myeloma who have received at least 1 prior line of therapy.3 The FDA will decide on the application by July 23, 2025.

References

1. Trudel S, Beksac M, Pour L, et al. DREAMM-8 study of belantamab mafodotin plus pomalidomide and dexamethasone (BPd) vs pomalidomide plus bortezomib and dexamethasone (PVd) in relapsed/refractory multiple myeloma (RRMM): a subgroup analysis in patients with high-risk cytogenetic features. J Clin Oncol. 2025;43(suppl 17):7533. doi:10.1200/JCO.2025.43.16_suppl.7533
2. Dimopoulos M, Beksac M, Pour L, et al. Belantamab mafodotin, pomalidomide, and dexamethasone in multiple myeloma. N Eng J Med. 2024;391(5):408-421. doi:10.1056/NEJMoa2403407
3. Blenrep combinations accepted for review by the US FDA for the treatment of relapsed/refractory multiple myeloma. News release. GSK. November 25, 2024. Accessed June 1, 2025. https://www.gsk.com/en-gb/media/press-releases/blenrep-combinations-accepted-for-review-by-the-us-fda-for-the-treatment-of-relapsedrefractory-multiple-myeloma/