Stadtmauer Spotlights the Explosion of BCMA-Directed Therapies in Multiple Myeloma

A number of agents have received regulatory approval in multiple myeloma, with the most recent to generate excitement being B-cell maturation antigen (BCMA)- directed therapies, such as antibody-drug conjugates (ADCs) and chimeric antigen receptor (CAR) T-cell therapies, according to Edward A. Stadtmauer, MD.

“BCMA, as a target, is a major development that has truly exploded over the past couple of years. It [has gone beyond] naked antibodies,” said Stadtmauer. “We now have ADCs. Our first FDA-approved BCMA-directed immunotherapy was belantamab mafodotin-blmf [Blenrep], which has been very active with low toxicity, except for ocular [effects]. Moreover, a host of BCMA-directed agents, such as the bispecific antibody teclistamab [JNJ-7957], and CAR T-cell products [have also emerged].”

In an interview with OncLive® during a 2020 Institutional Perspectives in Cancer webinar on hematologic malignancies, Stadtmauer highlighted recent developments with immunotherapy in the multiple myeloma treatment paradigm. He is section chief of hematologic malignancies as well as the Roseman, Tart, Harrow, and Shaffer Families’ President’s Distinguished Professor at the University of Pennsylvania.

OncLive®: What is so exciting about immunotherapy in multiple myeloma?

Stadtmauer: Over the past 5 years, immunotherapy has become one of the most exciting areas in multiple myeloma treatment. The original immunotherapy [approaches] in this space were the immunomodulating agents like lenalidomide [Revlimid] and pomalidomide [Pomalyst], as well as iberdomide [CC-220], which is an investigational next-generation therapy. All these [agents appear] to modulate the immune microenvironment.

In addition, the development of monoclonal antibodies has been particularly exciting, such as the CD38-directed monoclonal antibody daratumumab [Darzalex] and the SLAMF7 monoclonal antibody elotuzumab [Empliciti]; these have become up-front approaches. Notably, daratumumab is similar to rituximab [Rituxan] in that it improves every [regimen] that it’s added to.

What is the impact of the subcutaneous (SC) formulation of daratumumab on the treatment paradigm? Does it present any challenges?

Daratumumab is very active, but toxicity could be experienced after receiving the first dose, such as allergic reactions, fevers, shaking, and chills. As a result, this requires premedication and slow infusions that can occasionally take up to 8 hours. In addition, the first dose is often split into 2 days. With subsequent dosing, you can usually administer the therapy faster, but, traditionally, about 90 minutes is the fastest that it can be infused.

The SC use of daratumumab has truly been a medical breakthrough in that it’s utilized with an enzyme that allows the agent to infuse safely and quickly into the SC tissue. Although it’s a 5-minute infusion, it’s still much faster than the intravenous [IV] infusions. Great studies have shown no difference with regard to efficacy between the SC and IV formulations. Moreover, we discovered that there is much less toxicity with the SC infusion. As such, the SC formulation has advantages in terms of convenience and toxicity without any loss of efficacy.

You mentioned that BCMA is a very important target in myeloma. What other emerging targets are under investigation?

One area of interest is the Fc-directed bispecific antibodies, which was another big headline at the 2020 American Society of Hematology (ASH) Annual Meeting and Exposition. This is a bispecific antibody with a different target, where CD3 activates the T cells. High activity was observed [with this kind of agent] in a phase 1 trial; about 60% of patients responded to treatment.

Although we are seeing great activity with agents that target CD38 and BCMA, even in heavily pretreated patients, they still don’t appear to be curative. Therefore, when patients relapse, having other targets to go after will be beneficial. The FcR target is a very active and preliminary reasonable target for that group of patients.

Belantamab mafodotin has been an important addition to the treatment arsenal. What are some of the nuances associated with this agent?

This has really been a next-generation agent. When this drug is administered to heavily pretreated patients, about one-third of patients will experience nice responses. Those who respond seem to have long-term responses, which makes the agent unique. Moreover, what makes this option very convenient is that it is given in an every-3-week dosing infusion, which averages to about every 6 weeks. However, the drug does have unique toxicity, which is keratopathy. As such, this therapy requires an extra step in that an ophthalmologist needs to examine the eyes prior to each dose of treatment. This was done during the clinical trials.

Notably, if you do that and notice grade 2 or higher keratopathy and hold the dose [for 3 weeks], the toxicity can be reversible in the majority of patients. In addition, the responses to therapy are not lost due to the delay. As such, I believe this is a great addition to the multiple myeloma [treatment arsenal]. Ongoing clinical trials are now trying to determine what the safety profile and efficacy look like when other agents are added to this agent.

BCMA-directed CAR T-cell therapy is another important focus of research. What is some of the work being done right now with this approach in myeloma?

Many BCMA-directed CAR T-cell agents are currently being explored in clinical trials and were presented during the 2020 ASH Annual Meeting and Exposition. From my initial review of phase 2 data that are beginning to mature, the story about the efficacy and toxicity between these products seems to be similar. There are nuances but, in general, the patients are heavily pretreated. In relapsed, refractory, triple-class refractory, and 5-drug-exposed patients, BCMA-directed CAR T cells have been shown to have an 80% to 100% response rate. The responses that we’re seeing in these very heavily treated patients are remarkable.

The toxicities were what you would expect with a CAR T-cell treatment, such as cytokine release syndrome [CRS], which was experienced by most patients. This was typically low grade, but about 20% of patients had a high-grade case. Over the years, we have become very comfortable with the treatment of CRS, and the vast majority of patients recover with minimal treatment required and low toxicities, as long as they’re monitored closely. Moreover, a lower incidence, but a real incidence, of neurotoxicity [is also observed]. Again, high-grade neurotoxicity is very infrequent, and the vast majority of patients were able to recover. Cytopenias are also noted; this is usually from the lymphodepleting chemotherapy that the patients received prior to CAR T-cell therapy.

The response rates are remarkable. The great news is that [some] patients are still responding to CAR T cells after 2 to 3 years. However, the durability of response remains an issue with these products. When conglomerating these studies, the average patient responds for about 1 year or so with a single infusion. More importantly, when compared with non-Hodgkin lymphoma and acute lymphocytic leukemia data, there does not seem to be a plateau in the curve. There seems to be a continued progression in myeloma BCMA-directed CAR T cells.

Most of the work that we’re doing now is focused on determining how we can improve on this even further. A few questions remain. Should we do this procedure earlier in the course of the disease rather than waiting for a patient’s disease to become very resistant? Should we do it earlier so that we have healthier and more potent T cells? Should we combine the CAR T cells with other therapies that will enhance their persistence?