Belantamab Mafodotin Triplet Highlights Low Ocular Toxicity in Intermediate-Fit, Frail Newly Diagnosed Myeloma

Belantamab mafodotin plus lenalidomide and dexamethasone yielded a stringent CR of 42.9% in patients with newly diagnosed multiple myeloma.

Belantamab mafodotin-blmf (Blenrep), lenalidomide (Revlimid), and dexamethasone yielded high rates of complete response (CR) and low rates of ocular toxicity in intermediate-fit or frail patients with newly diagnosed multiple myeloma, according to long-term findings from the phase 1/2 BelaRd trial (NCT04808037), which were presented at the 22nd Annual International Myeloma Society Meeting and Exposition.

At a median follow-up of 29 months and a data cutoff date of March 1, 2025, among all patients in the trial who received belantamab mafodotin at 1.9 mg/kg once every 8 weeks in combination with lenalidomide and dexamethasone (n = 42), the rates of stringent CR (sCR), CR, very good partial response (VGPR), and PR were 42.9%, 9.5%, 35.7%, and 9.5%, respectively. Among patients who received the combination with belantamab mafodotin at 2.5 mg/kg (n = 12), these respective rates were 50.0%, 25.0%, 8.3%, and 16.7%. Among those who received the combination with belantamab mafodotin at 1.4 mg/kg (n = 12), these respective rates were 41.7%, 8.3%, 50.0%, and 0%.

“In all dosing schedules investigated in the study, only a few patients had to stop driving or reading due to eyesight[-related adverse] effects,” lead study author Evangelos Terpos, MD, and coauthors wrote in a poster of the data.

Terpos is a professor in the Department of Clinical Therapeutics at the National and Kapodistrian University of Athens School of Medicine in Greece.

What Was the Design of the BelaRd Trial?

BelaRd enrolled patients with documented multiple myeloma who were transplant ineligible. Patients needed to have an ECOG performance score of 0 to 2, be classified as intermediate-fit or frail per the International Myeloma Working Group (IMWG) frailty score, and have adequate organ system function.

In the dose-finding part of the study (part 1), 36 patients were randomly assigned 1:1:1 to receive belantamab mafodotin at 2.5 mg/kg (cohort 1; n = 12), 1.9 mg/kg (cohort 2; n = 12), or 1.4 mg/kg (cohort 3; n = 12) every 8 weeks. Patients also received lenalidomide at 25 mg per day on days 1 through 21 of each 28-day cycle, and dexamethasone at 40 mg per day on days 1, 8, 15, and 22 of each 28-day cycle. Treatment continued until disease progression or unacceptable toxicity. Notably, the recommended phase 2 dose (RP2D) of belantamab mafodotin was identified as 1.9 mg/kg.

In the dose-expansion portion of the study (part 2), 30 patients received belantamab mafodotin at the RP2D plus lenalidomide and dexamethasone at the same doses and schedules as in cohort 2 of part 1. Patients were randomly assigned 1:1 to receive care under the supervision of an ophthalmologist (group A; n = 15), with dose modifications permitted per the Keratopathy Visual Acuity scale; or a hematologist (group B; n = 15), with dose modifications permitted per the novel Visual Rating and Assessment (VRA) tool for belantamab mafodotin–related ocular AEs and grade 3 or higher ocular AEs. Treatment continued until disease progression or unacceptable toxicity.

Regarding baseline characteristics, across all cohorts in both parts, most patients were intermediate-fit vs frail per the IMWG frailty score, and most patients had cataracts. In part 1, the respective rates of treatment discontinuation (including rates of discontinuation due to death, PD, and withdrawal of consent), as well as the median treatment duration, were as follows:

• Cohort 1: 16.7% (16.7%, 0.0%, 0.0%), 40.5 months (range, 2.8-7.5)
• Cohort 2: 25%; 16.7%, 8.3%, 0.0%, 40.1 months (range, 12.5-47.3)
• Cohort 3: 50.0%; 33.3%; 0.0%; 16.7%, 32.9 months (range, 5.4-46.4)

In part 2, the respective rates of treatment discontinuation (including rates of discontinuation due to death, PD, and withdrawal of consent), as well as the median treatment duration, were as follows:

• Group A: 13.3% (13.3%, 0.0%, 0.0%), 21.9 months (range, 2.2-28.3)
• Group B: 40.0% (26.7%, 6.7%, 6.7%), 18.6 months (range, 2.3-29.0)

What Additional Efficacy Findings Were Seen in BelaRd?

When efficacy outcomes were stratified by dose intensity, 76.2% of patients in cohort 2 across parts 1 and 2 who received belantamab mafodotin at a dose intensity below 0.6 mg/kg every 4 weeks achieved a CR or better; none experienced progressive disease (PD). Conversely, 28.6% of patients who received belantamab mafodotin at a dose intensity above 0.6 mg/kg every 4 weeks achieved a CR or better, and 2 experienced PD.

“Patients treated with lower dose intensity had improved efficacy, suggesting an off-target effect of belantamab mafodotin,” the authors wrote.

Notably, VRA score was shown to be a driver for dose modifications. Of 300 and 251 assessments in group A and B, respectively, 10 and 2 did not have substantial time VRA findings. Furthermore, of the 121 dosing cycles in which ophthalmologists interrupted hematologist-driven dosing in group B, there were no dosing cycles showing grade 3 or higher ocular AEs without also showing substantial time VRA findings; this was not applicable in group A.

What Was the Safety Profile of Belantamab Mafodotin Plus Lenalidomide and Dexamethasone in BelaRd?

Almost all patients across all dose levels were able to continue with daily activities like reading and driving. In total, 5.1% and 0.9% of monthly assessments revealed patients who needed to stop these respective activities.

All patients experienced at least 1 serious or non-serious treatment-emergent AE (TEAE). In cohort 1, 50.0% of patients had serious TEAEs that were grade 3 or higher. The most common non-ocular serious or non-serious TEAEs of grade 3 or higher in this cohort were fatigue (66.7%), diarrhea (16.7%), cataracts (16.7%). Grade 3 or higher infections and infestations occurred in 25.0% of these patients and included COVID-19 (16.7%) and pneumonia (8.3%). Two patients had fatal AEs: COVID-19 and pneumonia (n = 1 each). Belantamab mafodotin–related serious or nonserious TEAEs and serious TEAEs of grade 3 or higher occurred in 91.7% and 16.7% of patients, respectively.

In cohort 2, 26.2% of patients had serious TEAEs that were grade 3 or higher. The most common non-ocular serious or non-serious TEAEs of grade 3 or higher in this cohort were fatigue (69.0%), diarrhea (11.9%), cataracts (19.0%). Grade 3 or higher infections and infestations included COVID-19 (7.1%) and pneumonia (7.1%). Eight patients had fatal AEs: pneumonia (n = 3), sudden death (n = 2), COVID-19 (n = 1), cardiac failure (n = 1), and asphyxia (n = 1). Belantamab mafodotin–related serious or nonserious TEAEs and serious TEAEs of grade 3 or higher occurred in 100.0% and 2.4% of patients, respectively. The most common TEAE deemed related to belantamab mafodotin in this cohort was fatigue (9.5%).

In cohort 3, 41.7% patients had serious TEAEs that were grade 3 or higher. The most common non-ocular serious or nonserious TEAEs of grade 3 or higher in this cohort were fatigue (69.0%), diarrhea (25.0%), cataracts (19.0%). Grade 3 or higher infections and infestations occurred in 33.3% of these patients and included COVID-19 (16.7%) and pneumonia (16.7%). Four patients had fatal AEs: COVID-19 (n = 2), sudden death (n = 1), and intracranial hemorrhage (n = 1). Belantamab mafodotin–related serious or nonserious TEAEs occurred in all of patients, none of which were serious and grade 3 or higher. The most common TEAE deemed related to belantamab mafodotin in this cohort was fatigue (16.7%).

No drug administrations, as defined by hematologist ocular assessment, were interrupted by an ophthalmologist due to grade 3 or higher ocular AEs. In part 1, across cohorts, assessments with Best-Corrected Visual Acuity (BCVA) change from baseline were mild (grade 0 to 1), moderate (grade 2), and severe (grade 3 or higher) in patients at these respective rates:

• Cohort 1 (ocular assessments, n = 413): 42.4%, 38.3%, 19.4%
• Cohort 2 (ocular assessments, n = 434): 56.2%, 31.1%, 12.7%
• Cohort 3 (ocular assessments, n = 333): 59.8%, 30.6%, 9.6%

In part 2, similar rates of ocular AEs were reported across both groups. Assessments with BCVA change from baseline were mild, moderate, and severe in patients at these respective rates:

• Group A (ocular assessments, n = 300): 57.7%, 37.0%, 5.3%
• Group B (ocular assessments, n = 251): 79.7%, 18.3%, 2.0%

Additionally, in part 1, assessments with keratopathy findings were mild, moderate, and severe in patients at these respective rates:

• Cohort 1: 85.5%, 11.4%, 3.2%
• Cohort 2: 87.3%, 12.4%, 0.2%
• Cohort 3: 90.1%, 9.6%, 0.3%

In part 2, assessments with keratopathy findings were mild, moderate, and severe in patients at these respective rates:

• Group A: 95.7%, 4.0%, 0.3%
• Group B: 85.7%, 14.4%, 0.0%

“These results support the investigation of the belantamab mafodotin/lenalidomide and dexamethasone combination in a phase 3 trial in this patient population vs the standard of care,” the authors concluded.

Disclosures: Terpos did not report any disclosures.

Reference

Terpos E, Gaviratopoulou M, Ntanasis-Stathopoulos I, et al. Belantamab mafodotin plus lenalidomide/dexamethasone in intermediate-fit or frail newly diagnosed patients with multiple myeloma: long-term efficacy and safety results from the phase 1/2 BelaRd study. Presented at: 22nd Annual International Myeloma Society Meeting and Exposition; September 17-20, 2025; Toronto, Canada. Abstract PA-321.