Higher Belantamab Mafodotin Dose Intensity Deepens Responses in Transplant-Ineligible NDMM

The final analysis of the phase 3 DREAMM-9 (NCT04091126) trial presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting demonstrated that belantamab mafodotin (bela-maf; Blenrep) plus bortezomib, lenalidomide (Revlimid), and dexamethasone (VRd) demonstrated high response rates across dose levels in patients with newly diagnosed transplant-ineligible multiple myeloma.¹

The phase 1 dose escalation and schedule evaluation trial revealed ORRs of over 83% in 118 patients across dosing cohorts, with higher induction dose intensity associated with deeper responses but higher rates of high-grade ocular toxicity, informing the dosing strategies in use as belantamab mafodotin continues to be studied in other trials.

“Belantamab dosing in the induction phase with the higher dose intensity appears to be optimal in getting to the MRD [minimal residual disease] negativity rate. The longer dosing intervals during maintenance helps improve the tolerability and sustainability of response,” Saad Z. Usmani, MD, MBA, of Memorial Sloan Kettering Cancer Center, stated in his presentation.

Background and Study Design

Bela-maf is a B-cell maturation antigen–directed antibody-drug conjugate with a multimodal mechanism of action comprising payload-mediated cytotoxicity and immune-mediated effects, with the potential to induce an adaptive immune response. It received FDA approval in combination with bortezomib (Velcade) and dexamethasone in patients who had received 2 prior lines of therapy. Prior interim analyses of DREAMM-9 had shown high efficacy and manageable safety in transplant-ineligible newly diagnosed multiple myeloma; the aim of the final analysis was to identify the optimal dose and schedule of bela-maf in this setting.

DREAMM-9 enrolled 118 patients across 8 belantamab mafodotin dosing cohorts spanning 4 induction/maintenance schedules: Q3/Q4 (every 3 weeks until cycle 8, then every 4 weeks), Q6/Q8 (every 6 weeks until cycle 8, then every 8 weeks), Q9/Q12 (every 9 weeks until cycle 8, then every 12 weeks), and Q12W (every 12 weeks with no change after cycle 8). Patients received VRd for the first 8 cycles every 3 weeks, then Rd (lenalidomide and dexamethasone) every 4 weeks thereafter. Bela-maf doses were given at 1.0, 1.4, or 1.9 mg/kg. The primary end point was safety; overall response rate (ORR) or rate of complete response or better (CR+), minimal residual disease (MRD) negativity, and patient-reported outcomes were assessed as secondary objectives.

All patients were ineligible for autologous stem cell transplant and had no prior systemic therapy. The population had a median age of 74.0 years (range, 51-88). Forty-five percent were aged 75 or older, 16% had high-risk cytogenetics, and 13% had extramedullary disease at baseline, a population broadly comparable to other transplant-ineligible newly diagnosed multiple myeloma trials. Median follow-up ranged from 15.9 to 47.1 months across cohorts.

Dose Intensity Drives Depth of Response

Depth of response tracked closely with induction dose intensity: across grouped dosing schedules, the Q6/8W cohorts (n = 24) achieved the highest rates of deep response: ORR of 96%, CR+ of 88%, and MRD negativity in 54%. The Q3/4W cohorts (n = 40) demonstrated ORR of 90%, CR+ of 68%, and MRD negativity in 55%. The Q9/12W and Q12W cohorts (n = 54), with lower planned induction dose intensity, showed ORR of 85%, CR+ of 59%, and MRD negativity in 43%.

Within the Q6/8W group specifically, induction at 1.9 mg/kg produced deeper and faster responses than starting at 1.4 mg/kg. CR+ rates were 92% vs 83% and MRD negativity rates were 67% vs 42%, respectively. Median time to MRD negativity in CR+ patients was 7.9 months with 1.9 mg/kg vs 14.6 months with 1.4 mg/kg, nearly half the time to achieving MRD negativity.

A post-hoc analysis of relative dose intensity revealed that extended dosing schedules were associated with higher relative dose intensity and fewer dose modifications, indicating greater dosing predictability. Maintenance dose intensity was similar across cohorts due to dose modifications in the shorter-interval groups, suggesting that the theoretical advantage of higher-frequency dosing was substantially eroded in practice by the need for schedule adjustments driven by toxicity.

Extended Intervals Reduce Severity of Ocular Toxicity

Ocular events associated with bela-maf were common across all cohorts but were predominantly transient and resolved with adequate follow-up. Across the entire population, 92% of all grade 2 or higher ocular events resolved. Grade 3 or higher ocular event rates followed a pronounced dose-intensity gradient: 74% in the Q3/4W cohorts, 88% in the Q6/8W cohorts, and 35% in the Q9/12W and Q12W cohorts. Resolution rates for first grade 3 or higher events were high across all groups (97%, 86%, and 100%, respectively), though median time to first onset of grade 3 or higher events increased with longer intervals (72, 136, and 193 days for Q3/4W, Q6/8W, and Q9/12W and Q12W, respectively).

Critically, bela-maf discontinuation due to grade 3 or higher ocular events was low overall at 3%, occurring exclusively in 1 patient in each of the 3 Q3/4W cohorts, with no discontinuations in any other schedule group.

Vision-related function (VRF), measured by the Ocular Surface Disease Index (OSDI), was generally maintained in the extended-interval groups throughout both induction and maintenance phases. The Q3/4W interval group exceeded the clinically meaningful deterioration threshold of 12.5 points on the OSDI at multiple timepoints during induction, whereas the Q6/8W and Q9/12W and Q12W groups largely remained below this threshold across most assessments, including during the maintenance phase.

Conclusions and Implications for Phase 3 Development

The DREAMM-9 final analysis defines a practical dosing strategy for bela-maf in the frontline transplant-ineligible setting: a higher induction dose intensity achieves the deepest and fastest responses, whereas transitioning to extended maintenance intervals improves tolerability, preserves vision-related function, and maintains responses without meaningful compromise of efficacy.

The investigators concluded that the data support the selection of 1.9 mg/kg Q8W for 24 weeks followed by Q12W dosing in the ongoing phase 3 DREAMM-10 trial (NCT06679101) of bela-maf plus Rd vs daratumumab (Darzalex) plus Rd in transplant-ineligible newly diagnosed multiple myeloma and PrE1005 trial (NCT07285239) of bela-maf plus VRd vs daratumumab plus VRd in transplant-ineligible newly diagnosed multiple myeloma. The DREAMM-9 findings thus provide the dose-optimization evidence base informing both registrational phase 3 trials in this population, with results from those studies anticipated in the coming years.

When asked which patients are best suited for this regimen, Usmani stressed that it is primarily being investigated in the more frail and older transplant-ineligible population at this time. However, he also noted that “Only about one-fourth of the world’s myeloma population has access to T-cell redirecting therapies, so I think there is room to develop BCMA-directed treatments that are easily accessible for the majority of patients around the world, especially for the older patient population.”

References

Usmani SZ, Mielnik M, Alonso A, et al. DREAMM-9 final analysis: Belantamab mafodotin (belamaf), bortezomib, lenalidomide, and dexamethasone (BVRd) for transplant-ineligible (TI) newly diagnosed multiple myeloma (NDMM). J Clin Oncol. 2026;44(suppl 16):7503. doi:10.1200/JCO.2026.44.16_suppl.7503