Stretched Dosing Schedule of Belantamab Mafodotin Plus VRd Is Active, Safe in Transplant-Ineligible Myeloma

Belantamab mafodotin-blmf (Blenrep) demonstrated comparable antitumor toxicity across three dose levels in combination with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) in patients with transplant-ineligible, newly diagnosed multiple myeloma, according to data from the phase 1 DREAMM-9 trial (NCT04091126) presented at the 22nd Annual International Myeloma Society Meeting and Exposition.1

In the 1.9 mg/kg every 3 to 4 weeks (Q3/4W) cohort (n = 12), the objective response rate (ORR) was 100%, which included a 50% stringent complete response (sCR) rate, 25% CR rate, 17% very good partial response (VGPR) rate, and 8% partial response (PR) rate. The median time to VGPR or better was 2.8 months (range, 0.7-4.2), and the median time to CR or better was 8.3 months (range, 2.1-19.4). The percentages of patients who achieved minimal residual disease (MRD) negativity at any point and after achieving CR or better were 75% and 100%, respectively. The median time to achieving MRD negativity after achieving CR or better was 8.3 months (range, 2.1-17.5).

In the 1.9 mg/kg every 6 to 8 weeks (Q6/8W) cohort (n = 12), the ORR was 100%, which included a 33% sCR rate, 58% CR rate, and 8% VGPR rate. The median time to VGPR or better was 2.9 months (range, 0.8-14.7), and the median time to CR or better was 12.0 months (range, 4.4-22.9). The percentages of patients who achieved MRD negativity at any point and after achieving CR or better were 67% and 73%, respectively. The median time to achieving MRD negativity after achieving CR or better was 7.9 months (range, 4.2-14.7).

In the 1.4 mg/kg Q6/8W cohort (n = 11), the ORR was 100%, which included a 27% sCR rate, 64% CR rate, and 9% VGPR rate. The median time to VGPR or better was 2.1 months (range, 0.8-5.0), and the median time to CR or better was 8.8 months (range, 1.4-18.4). The percentages of patients who achieved MRD negativity at any point and after achieving CR or better were 45% and 50%, respectively. The median time to achieving MRD negativity after achieving CR or better was 14.6 months (range, 2.1-23.1).

“In this study, the 1.9-mg/kg [belantamab mafodotin] dose delivered 100% ORR and deep responses, with [at least] 73% MRD negativity in patients with a CR [or better]. A stretched dosing schedule was associated with lower rates of any grade 3/4 adverse effects [AEs] related to [belantamab mafodotin], highlighting that 1.9 mg/kg Q6/8W may optimize efficacy and improve safety in patients with transplant-ineligible newly diagnosed multiple myeloma,” Saad Z. Usmani, MD, MBA, FACP, FASCO, lead study author and chief of the Myeloma Service at Memorial Sloan Kettering Cancer Center in New York, New York, said during a presentation of the data.

What Is the History of Belantamab Mafodotin in Multiple Myeloma?

Belantamab mafodotin is an antibody-drug conjugate (ADC) that has afucosylated anti-BCMA monoclonal antibody conjugated to a cytotoxic payload, cys-mcMMAF. The ADC works on multiple fronts, resulting in cytotoxic activity, antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and induction of an adaptive immune response.

With respect to the current landscape, deep responses and prolonged disease control are desperately needed for patients with transplant-ineligible, newly diagnosed multiple myeloma, despite the availability of standard triplet and quadruplet regimens.

Belantamab mafodotin had been approved for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least 4 prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory drug.2 In February 2023, the agent’s accelerated approval was withdrawn because the confirmatory phase 3 DREAMM-3 trial (NCT04162210) did not meet its primary end point of improving progression-free survival.

However, subsequent positive data from both the phase 3 DREAMM-7 (NCT04246047) and DREAMM-8 (NCT04484623) trials suggest the ADC may possess enhanced activity worthy of further study when used in combination with bortezomib (Velcade) and dexamethasone.

What Do I Need to Understand About the Ongoing DREAMM-9 Trial?

DREAMM-9 is an ongoing, randomized, phase 1 trial designed to test the activity of belantamab mafodotin in combination with VRd in patients with transplant-ineligible, newly diagnosed multiple myeloma.

To be eligible for inclusion, patients had to have received a multiple myeloma diagnosis per International Myeloma Working Group (IMWG) criteria, an ECOG performance status of 0 to 2, not be a candidate for high-dose therapy and transplant because of frailty and/or significant comorbid conditions, and have measurable disease per IMWG criteria.

Patients were excluded if they had received prior systemic therapy for multiple myeloma or smoldering multiple myeloma, or had current corneal epithelial disease. Ocular AEs were managed by dose modifications or extending the dosing interval.

The primary end point was safety characterized by dose-limiting toxicity and AEs. Secondary end points included efficacy defined by ORR according to IMWG criteria, relative dose intensity of lenalidomide and bortezomib after 4 cycles, cumulative administered dose of belantamab mafodotin after 4 cycles with VRd, the incidence and titers of anti-drug antibodies, and pharmacokinetic parameters. MRD negativity assessed in bone marrow aspirate samples using next-generation sequencing at a sensitivity of 10–5 served as an exploratory end point.

A total of 8 dosing levels were tested: 1.0 mg/kg every 12 weeks (n = 10), 1.4 mg/kg every 9 weeks to 1.0 mg/kg every 12 weeks (n = 15), 1.0 mg/kg Q3/4W (n = 15), 1.9 mg/kg every 9 weeks to 1.4 mg/kg every 12 weeks (n = 19), 1.4 mg/kg Q6/8W (n = 12), 1.4 mg/kg Q3/4W (n = 13), 1.9 mg/kg Q6/8W (n = 12), and 1.9 mg/kg Q3/4W (n = 12). Every third to fourth week represented 1 cycle with standard VRd therapy, which was given for 8 cycles and followed by treatment with Rd alone.

The 1.9 mg/kg Q3/4W, 1.9 mg/kg Q6/8W, and 1.4 mg/kg Q6/8W cohorts were selected as the focus of this presentation based on previously reported safety and efficacy data.

Between December 18, 2019, and March 4, 2024, 108 patients were enrolled across the 8 cohorts, including 12 patients in each of the 3 aforementioned cohorts.

Baseline characteristics of the overall trial population (n = 108) revealed that the median age was 74.0 years (range, 51-88) and most patients were male (54%) and White (86%). Most patients had stage II disease at screening (46%) vs stage I (34%) or III (15%); 5% of patients had unknown stage according to the International Staging System classification system. A total of 15% of patients had high-risk cytogenetics, and 11% had extramedullary disease.

Usmani noted that patient demographics were comparable across cohorts, but the 1.9 mg/kg Q3/4W cohort had a higher rate of high-risk cytogenetics, and the 1.9 mg/kg Q6/8W cohort had more patients with extramedullary disease than the others.

The median durations of follow-up in the 1.9 mg/kg Q3/4W, 1.9 mg/kg Q6/8W, and 1.4 mg/kg Q6/8W cohorts, respectively, were 37.6 months (range, 7-50), 32.3 months (range, 6-38), and 32.4 months (range, 5-37).

How Did the Safety Profile of the Regimen Differ Across the Three Cohorts?

“No new safety signals were observed across the cohorts. Lower rates of grade 3/4 AEs related to belantamab mafodotin were observed in the cohorts with a Q6/8W schedule, and AEs were manageable and reversible in all cohorts with appropriate dose modifications,” Usmani said.

All patients across the three cohorts experienced AEs and grade 3/4 AEs. Grade 3/4 AEs related to belantamab mafodotin occurred in the 1.9 mg/kg Q3/4W, 1.9 mg/kg Q6/8W, and 1.4 mg/kg Q6/8W cohorts at respective rates of 67%, 25%, and 33%. Any serious AE occurred in 92%, 83%, and 83% of patients; fatal serious AEs occurred in 8%, 8%, and 25% of patients, respectively. The only fatal event that was related to any study treatment occurred in the 1.9 mg/kg Q6/8W cohort.

With respect to ocular AEs, all patients experienced an event; grade 3/4 instances occurred in 83%, 92%, and 75% of patients. Only 1 case led to belantamab mafodotin discontinuation in the 1.9 mg/kg Q3/4W cohort.

Infections and infestations occurred in 67%, 92%, and 83% of patients in the 1.9 mg/kg Q3/4W, 1.9 mg/kg Q6/8W, and 1.4 mg/kg Q6/8W cohorts, respectively; grade 3/4 events occurred in 42%, 58%, and 25% of patients.

AEs leading to dose interruption/delay of belantamab mafodotin occurred in 83%, 75%, and 83% of patients in the 1.9 mg/kg Q3/4W, 1.9 mg/kg Q6/8W, and 1.4 mg/kg Q6/8W cohorts, respectively. AEs leading to any drug discontinuation occurred in 50%, 42%, and 50% of patients, respectively. Dose reduction of belantamab mafodotin for any reason was required in 42%, 83%, and 42% of cases, respectively.

What Was the Incidence, Time to Onset, and Time to Resolution of First Bilateral Decrease in BCVA Score From Baseline?

“Median time to onset of first bilateral decrease in BCVA from 20/25 or better to 20/50 or worse was longer in the Q6/8W cohorts, and resolution occurred faster,” Usmani said.

The reductions in bilateral BCVA from 20/25 or better at baseline to 20/50 or worse were 50% across the 3 cohorts. The median times to onset were 76 days (range, 42-439), 246 (range, 106-472), and 264 (range, 92-546), respectively. The median times to resolution were 163 days (range, 36-230), 135 days (range, 29-246), and 70 days (range, 43-421). All but 33% of patients in the 1.4 mg/kg Q6/8W cohort experienced resolution.

Is Belantamab Mafodotin Being Evaluated in a Phase 3 Trial in This Population?

Belantamab mafodotin is being evaluated in combination with lenalidomide and dexamethasone vs Rd alone in patients with transplant-ineligible, newly diagnosed multiple myeloma in the phase 3 DREAMM-10 trial (NCT06679101).

Disclosures: Usmani reported consultancy fees from AbbVie, Amgen, Bristol-Myers Squibb, Bristol-Myers Squibb – Celgene, EdoPharma, Genentech, Gilead, GSK, Gracell Therapeutics, Johnson & Johnson – Janssen, Oncopeptides, Sanofi, Seagen, SecuraBio, Skyline DX, Takeda, and TeneoBio; and research funding from AbbVie, Amgen, Array Biopharma, Bristol-Myers Squibb, Bristol-Myers Squibb – Celgene, GSK, Johnson & Johnson – Janssen, Merck, Pharmacyclics, Sanofi, Seagen, Skyline DX, and Takeda.

References

1. Usmani SZ, Mielnik M, Garg M, et al. Optimizing belantamab mafodotin doses for the treatment of transplant-ineligible newly diagnosed multiple myeloma in the DREAMM-9 study. Presented at: 22nd Annual International Myeloma Society Meeting and Exposition; September 17-20, 2025; Toronto, Canada. Abstract PA-416.
2. FDA granted accelerated approval to belantamab mafodotin-blmf for multiple myeloma. FDA. Updated March 7, 2024. Accessed September 19, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-granted-accelerated-approval-belantamab-mafodotin-blmf-multiple-myelo