 We know that belantamab mafodotin, or belamaf, is an antibody-drug conjugate. The antibody portion targets BCMA on the surface of plasma cells, and it brings in an immunotoxin known as MMAF [monomethyl auristatin F]. An MMAF is basically a cousin of a vinca alkaloid and has the ability, when directly targeted to the cell and then internalized, to kill the cell through DNA damage–type mechanisms.

The FDA-approved study that led to the approval of belamaf [belantamab mafodotin] was a randomized phase 2 study called DREAMM 2. The DREAMM 2 study evaluated 2 different doses of belantamab mafodotin: 2.5 and 3.4 mg/kg. It should be noted that the 3.4 mg/kg was the recommended phase 2 dose, but there were concerns about some unique adverse events that we’ll talk about in a few moments. The FDA requested that a lower dose be tested as well as part of a randomized trial.

There were close to 200 patients randomized between those 2 doses of belamaf, with a median of 6 to 7 prior lines of therapy. It was noted that while the response rate was similar between the 2 arms—about 30%—and the depth of response was similar with similar rates of VGPR [very good partial response] or better, the DOR [duration of response] among responders appeared to be better with the lower dose, likely associated with less severity of some of the unique ocular adverse events that we’re going to talk about in a moment. That ultimately led to the FDA approval of belamaf [belantamab mafodotin] at 2.5 mg/kg.

The potential importance of this study is that in a group of patients who are triple-class refractory, this offers them significant benefit because there are few, if any, treatments available for triple-class refractory myeloma. More important, this represents an off-the-shelf treatment approach. This is important because it potentially offers the ability to get new treatments, particularly treatments that target BCMA when a patient may be noted to have highly resistant or even refractory multiple myeloma.

As belamaf [belantamab mafodotin] has been used more of late, there are studies beginning to combine it with commonly used agents, such as bortezomib and pomalidomide. In fact, these are beginning to bring the use of belamaf into earlier lines of therapy and are being tested in randomized clinical trials. But whether they’re available for first or second relapse is being studied in a number of studies in the DREAMM series that will help us better evaluate how to best use belamaf [belantamab mafodotin] in the context of relapsed multiple myeloma.

Videos

The rationale for treating relapsed/refractory multiple myeloma with belantamab mafodotin, and studies investigating the drug’s potential in earlier treatment settings.

BCMA-Targeting Belantamab Mafodotin: Role in the Treatment Landscape of RRMM

 program titled “BCMA-Targeting Agents in the Treatment of Multiple Myeloma: Translating Evidence to Clinical Practice.” I’m Sagar Lonial, a professor and the chair of the department of hematology and medical oncology and the chief medical officer of Winship Cancer Institute of Emory University in Atlanta, Georgia. I’m joined by 2 experts who see patients with multiple myeloma. The first is Dr Karen Klugo, a comprehensive ophthalmologist and cataract surgeon at Cincinnati Eye Institute in Cincinnati, Ohio; and Dr Natalie Callander, who is a professor in the department of medicine and the director of the myeloma program at Carbone Cancer Center at the University of Wisconsin in Madison, Wisconsin. Welcome, and thank you both for joining us.

We’re going to discuss recent updates on the role of BCMA-targeting agents in the treatment of multiple myeloma that were presented at key recent conferences. We’ll discuss the data in the context of guidelines, the treatment landscape, and its impact on clinical practice.

Let’s get started with a case. We start with a 57-year-old previously healthy man who’s found to have symptomatic IgG kappa R-ISS [Revised International Staging System] and ISS [International Staging System] stage II multiple myeloma. Laboratory studies demonstrate hypercalcemia and anemia with a normal LDH [lactate dehydrogenase], but on FISH [fluorescence in situ hybridization] analysis the presence of deletion of 17p. PET [positron emission tomography]–CT scan showed diffuse lytic disease throughout the axial skeleton, and the past medical history was unremarkable. The patient was initially treated with daratumumab plus VRd [bortezomib, lenalidomide, dexamethasone] induction followed by high-dose melphalan and autologous stem cell transplant, and then lenalidomide maintenance.

Unfortunately, about 2 years after that, he had evidence of serologic progression as well as new lytic bone disease and was switched over to a pomalidomide-plus-daratumumab–based salvage therapy. However, the response to that was less than 6 months, and he was subsequently switched to carfilzomib as given in the ENDEAVOR trial at 56 mg/m2 twice a week with dexamethasone and a bit of oral cyclophosphamide. The patient tolerated that treatment well, but its response lasted only 3 or 4 months, and this patient basically had triple-class refractory multiple myeloma.

Given that the patient had received 3 prior lines of therapy, including an IMiD [immunomodulatory imide drug], a PI [proteasome inhibitor], and anti-CD38 antibody, his physician recommended starting him on belantamab mafodotin. The patient underwent evaluation by an ophthalmologist prior to initiating belamaf [belantamab mafodotin] and was found to have good eye health. Fourteen months into treatment with belantamab [mafodotin], the patient is tolerating the treatment well and is quite active.

When we begin thinking about how to treat patients with relapsed and refractory multiple myeloma, the first things we look at are what they received at induction, what their genetics are, and how long their remission lasted. We also begin to evaluate patients who received lenalidomide-based induction therapy or PI-based induction therapy and non-CD38–based induction regimens.

This patient unfortunately had received lenalidomide, PI, and CD38-based induction regimens, which are rapidly evolving into a standard of care. However, they’d also received additional lines of therapy that got them into triple-class refractory myeloma, meaning that it’s resistant to PIs, resistant to IMiDs, and resistant to anti-CD38 antibodies. This opens the door to using treatments that aren’t in what we’d consider our big 5 or 6 as induction or salvage therapy approaches. These include agents with new mechanisms of action, specifically potentially targeting things like BCMA. That’s where belantamab mafodotin comes in.

Sagar Lonial, MD, FACP, highlights a novel treatment option available for a 57-year-old man whose disease progresses after 3 prior lines of therapy, including an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody.

Natalie Callander, MD

Articles

BCMA-Targeting Belantamab Mafodotin: Role in the Treatment Landscape of RRMM

Treatment Approach for a 57-Year-Old Man With Triple-Class Refractory MM