Sequencing BCMA-Directed Therapies Expands Multiple Myeloma Treatment Horizons

Sikander Ailawadhi, MD

In an interview with OncLive^®, Sikander Ailawadhi, MD, an oncologist in the Department of Hematology at Mayo Clinic in Jacksonville, Florida, discussed key points from a presentation he gave during an OncLive® Institutional Perspectives in Cancer webinar on myeloma and hematology, which he chaired. Ailawadhi spotlighted the characteristics of multiple myeloma that drive the decision to use teclistamab-cqyv (Tecvayli), elranatamab-bcmm (Elrexfio), or talquetamab-tgvs (Talvey).

He also explained how the efficacy of BCMA-directed targeted agents compares with that of CAR T-cell therapy in patients who have previously received BCMA-directed therapy and noted ongoing trials that are seeking to compare standard-of-care (SOC) multiple myeloma regimens and explore novel treatment options for patients in this population. Additionally, Ailawadhi provided further insights from his colleagues’ presentations in another interview.

OncLive: What patient and disease characteristics guide your decisions between available bispecific antibodies?

Ailawadhi: Three bispecific antibodies are currently available [for patients with multiple myeloma]. Two of them, teclistamab and elranatamab, go after the same target, BCMA. The third drug, talquetamab, goes against a different target, GPRC5D.

When we are trying to decide between these 3 agents, the 2 targeting BCMA, teclistamab and elranatamab, don’t have many differences [regarding efficacy] or adverse effects. One of the [considerations] we offer to patients is that at least the way they are currently FDA approved, elranatamab can be given every other week after [week 24], as long as the patient is responding; conversely, teclistamab has to be given weekly [following step-up dosing] for as long as it works. Sometimes patients find out this information and [decide that] if there’s a possibility of spacing out [treatments] down the road, then they would like to have that opportunity because it makes [treatment] a little easier.

On the other hand, talquetamab, which is the third drug in this category, has a completely different target. Talquetamab could come either before one of the other 2, or it could come after one of the other 2. [Our goal with talquetamab] is about sequencing [it with the other available bispecific antibodies].

What data may inform the potential sequencing of BCMA-directed therapies in multiple myeloma?

One of the hot topics in myeloma care is how to sequence these BCMA-targeting agents. Should we sequence them or does the patient get only one shot at them? Data have been presented on all these drugs before and after each other in the setting of patients who are previously untreated with BCMA-directed [therapy] and in the setting of patients who have been previously treated with a BCMA-directed drug. These drugs work in those settings.

However, taking the example of CAR T cells, if CAR T-cell therapy is used in patients who have never had a BCMA-targeting agent their outcomes are good. When we use CAR T cells in patients who have had previous treatment with BCMA-directed agents, the benefit decreases a little. They still work, but [they do not provide] as much of a benefit. If a patient is considered a CAR T-cell therapy candidate, we would like them to have CAR T-cell therapy as their first BCMA-directed approach, because [that is how they will receive the most] benefit. From the standpoint of bispecific antibodies, [those agents] work well. The drop off in response [to bispecific antibodies] is smaller [than the drop off in response to CAR T-cell therapy] when the patient has been previously treated with BCMA-directed therapy.

What ongoing hematology clinical trials is Mayo Clinic involved in?

We have quite a few hematology clinical trials. The areas of focus for me are multiple myeloma, Waldenström macroglobulinemia, and chronic lymphocytic leukemia [CLL]. We are heavily involved with the development of BCL2 inhibitors, which are targeted drugs. We have trials with a specific agent called lisaftoclax [APG-2575]. We [are investigating] lisaftoclax in multiple myeloma, a phase 1 Waldenström macroglobulinemia [trial NCT04260217], a phase 1 CLL [trial NCT04215809], and in an early therapeutic or phase 1 trial in multiple different malignancies with different regimens [NCT03537482].

Another important question for our patients is always: When multiple agents or regimens are available in a setting, which might be the best? In that realm, we’re leading a national trial investigating treatment options for patients with newly diagnosed multiple myeloma, especially those who are frail, elderly, or cannot undergo transplant. We are comparing 2 popular regimens, daratumumab [Darzalex] plus lenalidomide [Revlimid] and dexamethasone or bortezomib [Velcade] plus lenalidomide and dexamethasone, head-to-head. [This is] a national trial supported by the National Cancer Institute, and we are leading it. We’re excited about that. Another part of that trial is a specific focus on health care disparities. The trial has been modified to be more patient friendly and has the potential to accrue more African American patients.

In some earlier trials, we are bringing in CAR natural killer cells [and other] exciting newer treatment options, including some newer bispecific antibodies, such as cevostamab [RG 6160], which goes against yet another new target, FcRH5. Those advanced early-phase treatments are also exciting because they help us improve our current SOC.