BCMA-Targeting Agents for Heavily Pretreated MM
An expert in multiple myeloma considers rationale for targeting BCMA and discusses recent FDA approval of belantamab mafodotin based on the DREAMM 2 trial.
Sagar Lonial, MD, FACP: When we think about targeting BCMA, or B-cell maturation antigen, there are a couple of reasons it represents an almost-optimal target in the context of multiple myeloma, either in the relapsed setting or earlier. The first is that its expression seems to be much more limited on a plasma cell than CD38, for instance, which is expressed on a number of B cells and T cells or on a SLAMF7, which is expressed on NK [natural killer] cells as well as plasma cells. The expression of BCMA seems to be much more limited, and if it is on earlier lines, then it is expressed at a much lower level. Additionally, BCMA is not expressed on stem cells or other cells that are high in the hematopoietic chain, which means that myelosuppression may be less of an issue, particularly when partnering with other drugs.
The other thing about BCMA that is important is that BCMA is binding with its natural ligand BAFF or APRIL. It seems to be responsible for many of the things that plasma cells do that cause trouble: proliferation, drug resistance, and binding to the macroenvironment. If you can block BCMA with any number of approaches, then you prevent some of those stimulating factors that cause myeloma cells to be more challenging to eliminate to be blocked as well, and that then makes it easier to treat with other combinations or other agents in addition.
Belantamab mafodotin was approved on the basis of the DREAMM 2 clinical trial. The DREAMM 2 was the study I led, which was a randomized trial of 2 different doses of belantamab mafodotin: 2.5 and 3.4 mg/kg. The 3.4-mg/kg dose was a dose that was achieved in the phase 1 trial of belantamab mafodotin done previously in the DREAMM-1 trial, but there was a question about whether the lower dose might be equally effective and may have a different adverse event profile, so the FDA requested that these 2 different doses were tested.
The patient population enrolled in the DREAMM 2 trial was a heavily pretreated group of patients with a median of 6 to 7 prior lines of therapy, and all of them were triple-class refractory. A large percentage of them were penta-refractory coming into this trial. What the trial demonstrated was that the response rate for the 2.5-mg/kg dose was about 30%, and the response rate for the higher dose was slightly higher.
The progression-free survival was similar between the 2 doses, but the duration of response [DoR], which is the ability of responders to stay on treatment longer, was better with the lower dose. It appears that the severity of the keratopathy, 1 of the main adverse effects of the immunotoxin MMAF, which is part of belantamab mafodotin, was a bit lower in grade and quicker to recover at the lower dose. Based on that efficacy and DoR data, the FDA and the company went forward with the lower dose as the standard FDA-approved dose for belantamab mafodotin: the 2.5 mg/kg dosing.
This is important, and perhaps we will talk more about adverse events and safety profile. But in my mind, that DoR is an amalgamated end point between safety and efficacy. The fact that the DoR was longer with the lower dose speaks to that balance of safety and efficacy and puts it in line with other approved drugs in refractory myeloma, such as daratumumab, carfilzomib, and pomalidomide, which all had similar response rates, progression-free survival rates, and durations of response with a slightly different safety pattern.
Transcript edited for clarity.
