Treatment of relapsed or refractory multiple myeloma yielded responses with the antibody-drug conjugate belantamab mafodotin, both as a single agent and in combination with bortezomib and dexamethasone. Two reports from the DREAMM team expanded on these findings at the ASCO20 Virtual Scientific Program.1,2
In the phase I/II DREAMM-6 trial, belantamab mafodotin plus bortezomib/dexamethasone led to responses in 78% of patients, with a median of three prior regimens.1 “This aligns with other triplet combinations using the bortezomib and dexamethasone backbone. Of note, 50% of patients achieved a deep response, rather than a very good partial response, which is encouraging at this point in time,” said lead author Ajay Nooka, MD, MPH, Associate Professor, Division of Bone Marrow Transplant, Winship Cancer Institute of Emory University, Atlanta.
Ajay Nooka, MD, MPH
Belantamab mafodotin is a first-in-class antibody-drug conjugate that targets the B-cell maturation antigen (BCMA) expressed on malignant plasma cells. Its effect is multimodal: Upon binding to the myeloma cell surface via the BCMA receptor, belantamab mafodotin is internalized, and the active microtubule inhibitor is released into the cell, leading to apoptosis. This antibody-drug conjugate exerts tumoricidal effects on myeloma cells through antibody-dependent cellular cytotoxicity and phagocytosis, explained Dr. Nooka.
Also, in an updated analysis of the DREAMM-2 trial,2 which evaluated belantamab mafodotin as a single agent, “clinically meaningful deep responses were sustained,” according to Sagar Lonial, MD, the Anne and Bernard Gray Family Chair in Cancer at Emory and Chief Medical Officer at Winship Cancer Institute. Preliminary results were recently reported in The Lancet Oncology.3
Sagar Lonial, MD
In January 2020, the U.S. Food and Drug Administration granted Priority Review to the biologics license application from GlaxoSmithKline, the manufacturer of belantamab mafodotin.
DREAMM-6: Belantamab Mafodotin in Combination
“Given the promising results of single-agent belantamab mafodotin in DREAMM-2, the DREAMM-6 trial was designed to explore its benefit in combination with the standard-of-care therapies lenalidomide/dexamethasone and bortezomib/dexamethasone,” Dr. Nooka said.
To date, DREAMM-6 has enrolled 59 patients who were previously treated with at least one prior line of therapy. Dr. Nooka reported on the cohort of 18 patients treated with a single dose of belantamab mafodotin, given at 2.5 mg/kg on day 1 of a 21-day cycle, in combination with bortezomib (1.3 mg/m2) and dexamethasone (20 mg), for up to eight cycles, with single-agent belantamab mafodotin continued thereafter. At the time of the presentation, patients had been receiving treatment for a median of 18 weeks.
KEY POINTS
- DREAMM-6 evaluated the antibody-drug conjugate belantamab mafodotin given in combination with bortezomib/dexamethasone for the treatment of relapse or refractory multiple myeloma.
- In 18 patients who received a dose of 2.5 mg/kg, responses were observed in 78%, with half achieving a deep response.
- DREAMM-2, which evaluated belantamab mafodotin as a single agent, was updated at 13 months, showing sustained clinical responses.
- Keratopathy is a known side effect of this drug; most cases resolve without hampering clinical response.
Patients had received a median of three prior lines of therapy. Approximately one-third had high-risk cytogenetic features.
“Clinical responses also look promising, with an overall response rate of 78%, a very good partial response rate of 50%, and a clinical benefit rate of 83% in patients with relapsed or refractory myeloma and a median of three prior lines of therapy,” Dr. Nooka said. “As these data mature, we will learn whether these responses deepen further over time and how durable they are, but this early snapshot is extremely encouraging.”
The study is also exploring single and split doses of belantamab mafodotin at 2.5 mg/kg and 3.4 mg/kg in combination with bortezomib/dexamethasone. With the split dose, patients receive half a dose on day 1 and another half on day 8 of each 21-day cycle. This aim is to determine whether this approach improves safety without negatively impacting efficacy.
Phase II DREAMM-2: Single Agent
The phase II DREAMM-2 study enrolled 196 patients with relapsed or refractory myeloma who had received three or more prior lines. They were assigned to a dose of 2.5 mg/kg or 3.4 mg/kg given on day 1 of a 21-day cycle.
In updated findings, based on an analysis done at 13 months, the overall response rate was 32% with 2.5 mg/kg and 35% with 3.4 mg/kg. A very good partial response or better was achieved by 58% and 66%, respectively. The duration of response was not reached in either dose cohort. The median duration of response was 11.0 months and 6.2 months, respectively, Dr. Lonial reported.
These findings show the utility of the antibody-drug conjugate in a population of patients whose depth and durability of responses to treatment are known to diminish with each line of therapy, Dr. Lonial noted.
Median progression-free survival was 2.8 months with the lower dose and 3.9 months with the higher dose. Median overall survival estimates were 14.9 months and 14.0 months, respectively, with an estimated 1-year survival of 58% in both groups.
Safety and Tolerability
With single-agent belantamab mafodotin, most patients had a treatment-related event of any grade, most commonly thrombocytopenia, anemia, and keratopathy. Keratopathy, observed in 75% of patients treated with the lower dose and 77% of those given the higher dose, was the cause of dose delays in about one-quarter of patients.
“Keratopathy is a change in the corneal epithelium observed on ocular exam, either with or without symptoms. As of this analysis, 77% of patients receiving 2.5 mg/kg and 63% receiving 3.4 mg/kg who developed keratopathy had recovered from their first event, with a median time to resolution of 86.5 days and 85.0 days, respectively,” Dr. Lonial said. Of note, he added, no permanent loss of vision has been reported, and most responders who required extended treatment delays were able to restart belantamab mafodotin. During treatment interruptions, “patients maintained or even deepened their clinical responses,” stated
Dr. Lonial.
“[During treatment interruptions,] patients maintained or even deepened their clinical responses.”— Sagar Lonial, MD
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In DREAMM-6, corneal events—keratopathy, blurry vision, and dry eyes—were reported by all 18 patients and were mostly grade 2 or 3. Further follow-up will be needed to determine the resolution of these events in DREAMM-6, Dr. Nooka said. He added that with single-agent treatment in DREAMM-2, most of these events resolved, and vision returned to baseline.
With the combination therapy, serious adverse events relating to treatment were reported in 28% of patients, and most were manageable with dose reductions and delays. Five patients did, however, experience adverse events that led to permanent discontinuation of study treatment. Infusion-related reactions were seen in 17% of patients, typically single grade 2 events that resolved without dose modifications. Thrombocytopenia occurred in two-thirds of the cohort, typically grade 3 or 4, with resolution in most patients prior to the next dosing.
A phase III trial (ClinicalTrials.gov identifier NCT04162210) is currently recruiting patients. It will evaluate the efficacy of belantamab mafodotin vs pomalidomide plus low-dose dexamethasone in patients with relapsed or refractory myeloma.
DISCLOSURE: The studies were funded by GlaxoSmithKline. Dr. Nooka has served as a consultant or advisor to Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen Oncology, Karyopharm Therapeutics, Oncopeptides, Spectrum Pharmaceuticals, and Takeda; has received institutional research funding from Amgen, Janssen Oncology, and Takeda; and has been reimbursed for travel, accommodations, or other expenses by GlaxoSmithKline. Dr. Lonial holds stock or other ownership interests in TG Therapeutics; has served as a consultant or advisor to AbbVie, Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen Oncology, Juno Therapeutics, Merck, Novartis, and Takeda; has received research funding from Bristol-Myers Squibb, Celgene, and Takeda; and has held other relationships with TG Therapeutics.
REFERENCES
1. Nooka AK, Stockerl-Goldstein K, Quach H, et al: DREAMM-6: Safety and tolerability of belantamab mafodotin in combination with bortezomib/dexamethasone in relapsed/refractory multiple myeloma. ASCO20 Virtual Scientific Program. Abstract 8502.
2. Lonial S, Lee HC, Badros A, et al: Pivotal DREAMM-2 study: Single-agent belantamab mafodotin (GSK2857916) in patients with relapsed/refractory multiple myeloma refractory to proteasome inhibitors, immunomodulatory agents, and refractory and/or intolerant to anti-CD38 monoclonal antibodies. ASCO20 Virtual Scientific Program. Abstract 8536.
3. Lonial S, Lee HC, Badros A, et al: Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): A two-arm, randomised, open-label, phase II study. Lancet Oncol 21:207-221, 2020.
