Is there a suggested sequence for the use of CAR T cells and bispecific antibodies?
There are two main challenges with finding the most appropriate sequence of CAR T cell therapy and bispecific antibodies. First, treatment sequencing has not been clinically addressed adequately and second, patients may not always receive the exact same sequence. Many clinicians will opt to offer CAR T cell therapy first for their relapsed/refractory patients due to the impressive response rates and duration of response. Furthermore, since CAR T cells are a “one-and-done” treatment, the time that patients get to experience off therapy allows their bodies and immune system to recover. However, CAR T-cell therapy can take several weeks to prepare which makes a patient’s disease biology an important factor to consider when deciding between a CAR T cell or a bispecific antibody. For example, patients for whom waiting a few weeks is not possible because their myeloma is aggressive (that is, fast-growing) might be better candidates for a bispecific antibody than a CAR T cell. But if the myeloma is slow-growing and there is a CAR T slot available, CAR T cell therapy would be the best choice.
However, patients shouldn’t get discouraged if they receive a bispecific antibody before CAR T cell therapy. Clinical trial data suggests that patients with relapsed/refractory multiple myeloma who are treated with CAR T therapy after bispecific antibodies can have an effective response. Furthermore, there are other types of CAR T cells under investigation that have different targets. Ultimately, bispecific antibodies are good options.
Do bispecific antibodies work in patients with high-risk multiple myeloma?
About half the patients in clinical studies of CAR T cells and bispecifics are considered high risk based on standard cytogenetic definitions like chromosomal translocation 4;14 or chromosome 17p deletion, among others. And in spite of having these cytogenetic abnormalities, patients are responding to these treatments; therefore, having high risk cytogenetics may not impact outcome as much with these types of treatments. However, most of these observations have come from single-arm studies and only a randomized, phase 3 study will help to discern whether any treatment is preferentially benefitting a high-risk subgroup of patients (for example, a large group of patients that are randomized to treatment A versus treatment B, and standard-risk and high-risk patients in each group are compared).
One type of high-risk myeloma patient that tends not to do well on bispecific antibody therapy, based on clinical study data, are those with extramedullary disease (EMD; that is, myeloma cells that are growing outside of the bone marrow). Patients with EMD do respond to treatment, but their response rate is not as high and not as long-lasting as in patients without EMD. Other strategies, such as combination therapies, are needed for these patients.