Belantamab Mafodotin Induces Deep and Durable Responses in R/R Myeloma

Interim findings from the DREAMM-6 study hint that belantamab mafodotin plus lenalidomide and dexamethasone is effective with tolerable safety in patients with relapsed or refractory multiple myeloma.

Belantamab mafodotin-blmf (Blenrep) combined with lenalidomide (Revlimid) plus dexamethasone displayed encouraging clinical activity in a small population of patients with relapsed or refractory multiple myeloma (RRMM), according to interim analysis findings from arm A of the DREAMM-6 clinical trial (NCT03544281).1

Findings presented by Sagar Lonial, MD, FACP during the 10th Annual Meeting of the Society of Hematologic Oncology also showed that belantamab mafodotin with lenalidomide and dexamethasone was tolerable with no new safety signals.

“The combination of Belimumab with [lenvatinib/dexamethasone] certainly was doable. And in fact, we saw enhanced response rates over what you'd expect with either agent given alone. I think more importantly, we did see changes in the safety profile, which make it interesting to think about moving forward,” Lonial said during his presentation.

Belantamab mafodotin is a B-cell maturation antigen (BCMA)-targeted antibody-drug conjugate (ADC) that eliminates myeloma cells by way of direct cytotoxicity and systemic anti-myeloma tumor immune responses. It is the only ADC monotherapy approved to treat patients with triple-class RRMM.

In a prior phase 2 study (DREAMM-2; NCT03525678), belantamab mafodotin demonstrated deep and durable responses in patients with RRMM. The objective response rate (ORR) shown with the drug in DREAMM-2 was 32% with a 11-month median duration of response (DOR). The median survival shown with belantamab mafodotin in DREAMM-2 was 13.7 months.

The decision to explore belantamab mafodotin with lenalidomide and dexamethasone was based on preclinical data in which belantamab mafodotin demonstrated benefit in multiple combination regimens.

DREAMM-6 is a 2-part, 2-arm, open-label, dosing and scheduling evaluation study being conducted in approximately 221 patients with RRMM across 59 study locations. The 45 patients included in arm A were required to have an ECOG performance status of 0 to 2, have undergone stem cell transplant, if eligible, and progressed on 1 or more previous therapies for myeloma. The coprimary end points being explored in part 1 of the study include the number of patients with dose-limiting toxicities, the proportion of patients with adverse events (AEs) or serious AEs (SAEs), and the number of patients with abnormal vital signs or laboratory results. In part 2, the study will primarily assess ORR, AEs, and SAEs.

The secondary end points of the study include pharmacokinetics (PK), ophthalmic exam findings, changes in ocular symptoms, and health-related quality of life.

During the dose-escalation phase of the study (part 1), patients will receive belantamab mafodotin 2.5 mg/kg with lenalidomide/dexamethasone. If the treatment is not tolerated at this dose, the dose will be lowered to 1.9 mg/kg and 2.5 mg/kg to further determine the efficacy and safety of the agent in combination with lenalidomide and dexamethasone.

The patient population assessed for the interim analysis was larger and made up of males whose ages range from 35 to 80 years. The median age of the population was 68.0 years. Most patients had an ECOG score of 1 at baseline were stage I or II. Immunoglobin at baseline was IgG for most patients.

Thirteen percent of the population had extramedullary disease and 29% had high-risk cytogenetics. The median line of therapy in the population was 3 (range, 1-11). Few patients had been previously exposed to anti-myeloma therapies.

Responses in the study were assessed by study investigators and were evaluated by dose cohort. Among patients treated with belantamab mafodotin 1.9 mg/kg every 8 weeks (Q8W), the ORR was 42% (95% CI, 15.2%-72.3%) with a 17% very good partial response (VGPR) rate (95% CI, 2.1%-48.4%), and no complete response (CRs).

Patients who received 1.9 mg/kg every 4 weeks (Q4W) achieved an ORR of 75% (95% CI, 19.4%-99.4%). The VGPR rate in this cohort was 50% (95% CI, 6.8%-93.2%), and the CR rate was 25% (95% CI, 0.6%-80.6%).

In patients treated with 2.5 mg/kg every 4 weeks, the ORR observed was 63% (95% CI, 35.4%-84.8%) with a VGPR of 50% (95% CI, 24.7%-75.3%), and a CR rate of 38% (95% CI, 15.2%-64.6%). Patients who received a split dose of belantamab mafodotin 2.5 mg/kg achieved an ORR of 69% (95% CI, 38.6%-90.9%). The VGPR in this population was 38% (95% CI, 13.9%-68.4%) with a CR rate of 19% (95% CI, 1.9%-45.4%).

The time-to-treatment analysis showed that the median DOR was not reached (NR) in all but 1 cohort. Among the 4 patients treated with 1.9 mg/kg Q4W with lenalidomide and dexamethasone, the media DOR was 11.1 months (3.7-NR). The median time to response ranged from 1 month to 1.9 months across the cohorts.

In terms of progression-free survival (PFS), the median PFS was 8.6 months (95% CI, 1.0-NR) in patients who received the 1.9 mg/kg Q4W dose and 9.0 months (95% CI, 3.2-NR) in the 2.5mg/kg Q4W split group.

Any-grade AEs occurred in 100% of patients in every cohort. The most common AEs in the study were keratopathy, reduced visual acuity, decreased platelet count, decreased neutrophil count, insomnia, neutropenia, and thrombocytopenia.

SAEs occurred in 42% of patients who received 1.9 mg/kg Q8W, 50% of patients who had a 1.9 mg/kg Q4W dose, 56% pf those who received the 2.5 mg/kg Q4W dose, and 40% of those who received the 2.5 mg/kg Q4W split dose. Treatment-related SAEs occurred in 17%, 0%, 19%, and 23%, respectively. Fatal SAEs were observed in the 2.5 mg/kg Q4W cohort in 13% of patients, and the 2.5 mg/kg Q4W split cohort in 8% of patients.

The trial also assessed ocular events and showed no trend of best-corrected visual acuity in patients treated with belantamab mafodotin. Grade 2 and 3 blurred vision was observed at both the 1.9-mg/kg and 2.5-mg/kg cohorts.

“What I think is really interesting is looking a little bit at the safety data. And we've seen this data now, not just for the combination with lenalidomide, but the combination with pomalidomide [Pomalyst], and the combination with the GSI inhibitor nirogacestat. You can actually give lower doses or less frequent administration of [belantamab mafodotin], and perhaps get equivalent or superior response rates. And at the same time, [you can] reduce the incidence of grade 3/ 4 keratopathy, or ocular toxicity,” Lonial explained.

In terms of PK, the profile of belantamab mafodotin was similar to what has been observed with other drugs in RRMM.

Further research is underway to bring more understanding of the clinical benefit and safety of belantamab mafodotin.

REFERENCES:

Quach H, Gironella M, Lee C, et al. Safety and clinical activity of belantamab mafodotin with lenalidomide plus dexamethasone in patients with relapsed/refractory multiple myeloma: DREAMM-6 arm-A interim analysis. Presented at: 10th Annual Meeting of the Society of Hematologic Oncology.