Innovative Approaches Augment Sequencing in Prolific Multiple Myeloma Armamentarium

Sarah Nagle, MD

With a number of novel therapeutic regimens on the rise, such as CAR T-cell therapy, in multiple myeloma, researchers in the field are hopeful that an optimal sequencing strategy is in sight, explained Sarah Nagle, MD.

“In the multiple myeloma space, novel therapies are defined as targeted therapies. In other words, they specifically target multiple myeloma cells, rather than universally killing cells throughout the body. Some examples include CAR T-cell therapy and monoclonal antibodies, which target BCMA, and venetoclax (Venclexta), a BTK inhibitor,” Nagle said.

In an interview with OncLive^® during the 2020 Institutional Perspectives in Cancer webinar on Multiple Myeloma, Nagle, who is an assistant professor of medicine in the School of Medicine at Oregon Health & Science University, spotlighted the critical role of targeted therapy in multiple myeloma.

OncLive^®: Could you spotlight some emerging therapies in multiple myeloma that you are excited about?

Nagle: There are several emerging therapies in this space, which we expect to receive regulatory approval [within the] next year. The first is idecabtagene vicleucel (ide-cel; bb2121), which targets BCMA. At this point, we seem to know the most about this agent. 

The second is a product by Janssen [JNJ-4528], that has demonstrated fabulous results. This one also targets BCMA and should be approved at some point next year as well. 

A host of other agents are being studied, such as allogenic CAR T-cell therapies, which are still fairly early in development.

All of the [agents] that we are studying right now are directed towards BCMA. However, there is an increasing interest in targeting other markers. That will start coming out, particularly for people who relapsed after BCMA-directed therapy.

Some are being used [in combination] with backbones, while others are being used alone. It depends on the agent. For instance, some can stand alone, such as CAR T-cell therapy, while therapies, such as venetoclax, may be used in combination.

What are some of the benefits with off-the-shelf allogenic CAR T-cell products?

These products can be given rapidly. The manufacturing time for CAR T-cell therapy is generally 1 month. Oftentimes, patients cannot wait that long, between the collection period and the administration of the therapy. Even if we administer a bridging therapy, we cannot guarantee that it’s going to work. As such, the fact that these products are readily available and can be administered quickly are the main benefits. 

With the number of therapies available in this space, how do you currently approach sequencing? 

It’s been tough. We’re now wondering if we should be using a number of therapies up front or if we should be saving them for later. Once we have this answer, we can better sequence therapies. 

There is also a population of patients who do not respond to novel agents as well; although, they do respond to cytotoxic chemotherapy. If we can identify these patients early-on, we can better direct their therapy. 

Even though this has been a major struggle in the space, it’s a good problem to have. We have so many therapies that we worry about using them appropriately.

What is the latest with monoclonal antibodies and BCL-2 inhibitors? 

Administration has been an important factor. Historically, daratumumab (Darzalex) has a long administration time; however, it gets shorter as the number of infusions increase.

Notably, a subcutaneous version [of daratumumab] is now available; you have to monitor the patient afterwards. This method is easier for patients; thus, I believe it will revolutionize the use of monoclonal antibodies. 

To date, venetoclax and similar agents are primarily used in patients who have high BCL-2 expression or t(11;14). We don't really use [venetoclax] outside of that group of patients.

There is also the question of whether these agents should be used in combination or alone. The utility of this class of agents will play out, but it’s still unclear [at the moment].

What are some of the key combination strategies in myeloma that bode well for future research?

Daratumumab is the best example because this therapy is being added to almost everything. I think of [daratumumab] as the rituximab (Rituxan) of multiple myeloma. 

Since its mechanism of action is unique and it doesn't have many adverse effects, it can be used in combination with other therapies. For instance, daratumumab plus lenalidomide (Revlimid) and dexamethasone or daratumumab added to bortezomib (Velcade), lenalidomide, and dexamethasone [are common regimens]. Ultimately, as we become more comfortable with these agents, their use [in other combinations] will increase.