Growth in the Multiple Myeloma Treatment Armamentarium Diversifies Treatment Strategies

Rahul Banerjee MD, FACP

The increasing number of agents entering the multiple myeloma treatment paradigm both complicates and informs treatment decision-making, according to Rahul Banerjee MD, FACP, who noted the absence of definitive biomarkers to assist when deciding between bispecific antibodies and CAR T-cell therapy.

Additionally, Banerjee, who serves as a physician-researcher and an assistant professor in the Clinical Research Division of Fred Hutchinson Cancer Center, as well as an assistant professor in the Division of Hematology and Oncology at the University of Washington in Seattle, noted in an interview with OncLive® that the lengthy wait times for CAR T-cell therapy are weighed in the decision-making process, making bispecific antibodies a better treatment option in some cases, specifically for patients with rapidly progressing disease.

Banerjee shared additional insights on the utility of bispecific antibodies, CAR T-cell antibodies, and ongoing investigations in multiple myeloma in another article.

OncLive: What criteria do you use to decide between bispecific antibodies and CAR T-cell therapy for patients with multiple myeloma?

Banerjee: We don't have a good answer. However, [instead of] one-point biomarkers, dynamic biomarkers can be helpful for us, [including in the] traditional tests we already have access to. For example, if a patient has rapidly proliferating disease where the biomarkers are rising, they may not be the best candidate for the autologous CAR T-cell products that are currently FDA approved. The vein-to-vein time between [leukapheresis] and administering CAR T-cells is approximately 1 to 2 months for both idecabtagene vicleucel [Abecma] and ciltacabtagene autoleucel [Carvykti; cilta-cel], though it can be slightly longer for cilta-cel.

‘Brain-to-vein time’ is [a term used to describe the time it takes for a patient to receive CAR T-cell therapy after their hematologist has decided they need it]. That interval can often be closer to approximately 6 months because we have to find [appointment times in the CAR T-cell center] for them to come in to get their T cells collected, and there’s often a waitlist for that. Once patients get their T cells collected, [the cells need] to be sent out to a lab, [which requires] shipping time back and forth. Once [the cells are] ready, [they need to be] tested, [then the patient needs to be] brought back [to the CAR T-cell center]. Overall, this is a long interval.

Before bispecific antibodies were around, we were desperate to get patients to CAR T-cell therapy by any means necessary, [such as with the use of] high-dose chemotherapy. That causes a lot of problems. For patients [with rapid disease progression], a bispecific antibody is a far better tool [than CAR T-cell therapy], because the brain-to-vein time [with bispecific antibodies] is closer to approximately 2 weeks, including obtaining insurance approval and getting the logistics in place. That’s a dynamic biomarker.

What patient and disease characteristics inform your decision to use a bispecific antibody instead of CAR T-cell therapy?

Most centers in the United States are still administering inpatient bispecific antibodies. At Fred Hutchinson Cancer Center, we are moving to [administering these agents in the] outpatient setting, and other centers have already moved to outpatient dosing. There, biomarkers are helpful.

[Theoretically], if you can estimate a patient’s disease burden, be it by their M spike, bone marrow biopsy, plasma cell burden, or how quickly the kappa lambda is rising, it stands to reason that patients with higher disease burden are more likely to have immunotherapy-related toxicities [from treatment with bispecific antibodies], for example, cytokine release syndrome [CRS] from T cells being re-engaged and attacking more myeloma cells; the more myeloma cells [they attack], the more cytokines [are also affected].

In real life though, [outpatient administration of bispecific antibodies is] much trickier than that, because patients need to have fit T cells to be able to [receive these agents in the outpatient setting]. A lot of my patients with high disease burden have been receiving chemotherapy before [bispecific antibodies] to control their high disease burden, so their T cells are less functional. Therefore, we expect them to have CRS, but nothing happens. Sometimes they don’t even respond or they have a low response. Overall, I wouldn’t use any biomarker to choose between BCMA-directed bispecific antibodies as of now.

Is it possible to use soluble BCMA to decide between bispecific antibodies or determine whether a patient should receive GPRC5D-directed therapy?

A paper from the Memorial Sloan Kettering Cancer Center [in New York, New York] sought to answer this question. BCMA is shed at a steady state from plasma cells, good and bad, into the blood by a protein called gamma-secretase. If a patient has downregulated BCMA from their myeloma cells, you should also see a decrease in soluble BCMA levels. If a patient has no soluble BCMA in their blood, they are probably not the best candidate for a BCMA-directed bispecific antibody. This is a tricky decision because we don’t have validated assays or sequencing techniques for soluble BCMA. We also don’t have a validated cutoff for positive vs negative [BCMA levels].

[The choice of] BCMA-directed therapy depend [on the patient]. We simplistically say that we shouldn’t give one BCMA-directed agent before another. That’s because we don’t know how to tell the epitopes apart. In real life, every BCMA-directed therapy binds the protein slightly differently. [Research has shown] that for some patients for whom 1 BCMA-directed therapy has stopped working, we would probably say not to administer another BCMA-directed therapy right away. That’s what I would tell a patient today. However, [this research has also shown that upon] sequencing the BCMA protein and examining the cells one by one, some mutations [developed] after prior BCMA therapy against which another BCMA-directed approach worked immediately, with no questions and no issues.

Five years from now, I would love to have those types of biomarkers, some type of an ex vivo drug sensitivity assay, to guide us through how to sequence therapies, because that’s where things get tricky. Right now, we don’t have that, so we are not ready to say that a biomarker, or any sort of test, is available to help us guide our decision-making at this point. However, that’ll change.