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BCMA-Targeted Bispecific Antibodies in R/R MM
BCMA-Targeted Bispecific Antibodies: A New Approach for Relapsed/Refractory Multiple Myeloma

Released: April 14, 2022

Expiration: April 13, 2023

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In a recent commentary, Nina Shah, MD, discussed currently approved BCMA-targeted therapies for relapsed/refractory (R/R) multiple myeloma (MM). BCMA, or B‑cell maturation antigen, has proven to be an exciting new target for treatment of R/R MM. Currently, 2 CAR T-cell therapies—idecabtagene vicleucel and ciltacabtagene autoleucel—have been approved by the FDA for patients with R/R MM after ≥4 previous lines of therapy, including a proteasome inhibitor, an immunomodulatory drug, and a CD38 monoclonal antibody. In addition, the antibody–drug conjugate belantamab mafodotin received FDA approval for treatment of patients with R/R MM who have received ≥4 previous therapies, including a CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory drug.

In this commentary, we will focus on a novel approach to targeting BCMA—bispecific antibodies and bispecific T-cell engagers.

Introduction to BCMA-Targeted Bispecific Therapy
Bispecific antibodies and bispecific T-cell engagers are new to plasma cell disorders, but this treatment approach has been established in B-cell acute lymphoblastic leukemia. Bispecific agents are similar to an unconjugated antibody, such as daratumumab or elotuzumab, but have important structural differences. Whereas most monoclonal antibodies target only 1 receptor, such as CD38 with daratumumab or SLAMF7 with elotuzumab, bispecific agents target 2 different molecules: a surface molecule on the myeloma cell, in this case BCMA, and CD3 on endogenous T-cells. Functionally, this brings T‑cells in proximity to a myeloma cell expressing BCMA, and that T‑cell is then activated and kills the myeloma cell.

Bispecific Therapies vs CAR T-Cells
Bispecific therapies share elements with both an unconjugated antibody and a CAR T‑cell, in the sense that these agents use a patient’s own T‑cells to target and kill malignant cells. In contrast to unconjugated antibodies, bispecific therapies do not depend on B‑cell–mediated tumor killing. In addition, unlike CAR T-cells, bispecific therapies are “off the shelf” and do not require a multiweek production process that comes with the risk of production failures.

That being said, bispecific therapies and CAR T‑cells can cause both cytokine-release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS). In patients with MM who receive bispecific therapies, CRS severity is generally less than that seen with CAR T‑cells. Most patients experience low-grade CRS with the first or second dose of bispecific therapy, and many trials are now using step‑up dosing to reduce the risk of CRS and neurologic toxicity. Toxicity risk is further mitigated by hospitalizing patients receiving the initial step‑up doses.

One of the concerns that I certainly had about bispecific therapies is that they require T‑cells to be healthy and functional—a challenge in the context of R/R MM. Despite presumably poor T‑cell health in patients with MM refractory to many prior lines of therapy, we see response rates of 60% to 80% with bispecific therapies—slightly lower than those with CAR T-cells. Nonetheless, this suggests that T‑cells may somehow be able to “wake up” with bispecific therapy.

It remains to be determined how durable these responses can be with bispecific therapies, which are given continuously. We also wait to see what potential toxicities and complications can occur with continuous bispecific therapy, given that suppression of BCMA results in profound immunodeficiency. Whereas the half‑life of a CAR T‑cell may be just a few months and there is normalization of B‑cells and plasma cells, a continuously immunosuppressed patient may be at risk for unusual infections.

Current Bispecific Therapies
In MM, numerous BCMA‑directed bispecific therapies that somewhat differ in structure and binding properties are under clinical investigation. These investigational therapies include teclistamab, REGN5458, ABBV-383, and elranatamab. These agents appear to have comparable efficacy and safety, but this is difficult to determine because we are comparing small, early-phase studies. 

There are several important differences in administration among these agents. First, some bispecific agents are IV, whereas others are SC, and we have learned from our experience with daratumumab that patients much prefer SC administration. Second, the frequency of dosing ranges from every week to every 3 weeks. If efficacy and safety are indeed similar, then patient preference and convenience may drive treatment selection.

Sequencing Therapy
Turning to sequencing, the first issue to consider is the development of resistance to BCMA-targeted bispecific therapies. Unlike CD19‑directed therapy, where a major mechanism of resistance is loss of CD19 expression, fewer than 10% of patients experience BCMA loss with progression on BCMA-targeted therapies. BCMA loss may be more likely in those with 17p deletion, which places patients at a higher risk for losing 16p, where BCMA is located.

Data suggest that initial responses to BCMA-targeted CAR T-cells can be partially recaptured with bispecific therapies, depending on the resistance mechanism. If a patient is progressing on CAR T-cells and still expresses BCMA, there is a very high chance that they will respond to a BCMA‑directed bispecific therapy, because the mechanism of resistance may be loss of the CAR rather than loss of BCMA. However, we currently lack data on whether a patient who progressed on a BCMA-targeted bispecific therapy will recapture response if switched to another BCMA-targeted bispecific therapy.

Combination Therapy
By combining anti-MM therapies, we achieve synergistic interactions that have greatly improved survival in patients with MM. Ongoing trials are evaluating bispecific therapies in combination with other anti‑MM therapies, with the goals of improving both efficacy and durability of response. These therapies include daratumumab (NCT05020236), daratumumab or lenalidomide (NCT05137054), and pomalidomide (NCT03287908).

There also is interest in partnering bispecific therapies with CAR T‑cells, perhaps in sequence. For example, patients who have not yet achieved a complete response at 3 months after CAR T-cell therapy administration may need a bispecific therapy to deepen response, or vice versa.

Other Targets
There are bispecific agents targeting novel molecules other than BCMA with encouraging activity in refractory MM, including BCMA-resistant MM. These novel targets are GPRC5D and FCRH5, both of which are almost universally expressed on the surface of plasma cells. Although their expression is more limited in terms of lineage than that seen with BCMA, bispecific therapies targeting GPRC5D or FCRH5 are associated with response rates of 70% to 80%. Their safety profiles are characterized again by CRS and neurotoxicity. Phase I data for GPRC5D-targeted therapy also have reported taste changes, mouth dryness, and skin issues. Research is underway into mitigating these adverse events with dose modifications or holds. We have not observed novel adverse events with FCRH5-targeted therapy.

Your Thoughts?
How would you sequence BCMA-targeted bispecific therapies and CAR T-cells? Please join the conversation by posting a comment in the discussion section and answering the polling question.

Want to know more? Check back on this program page to read an in-depth text module on the use of BCMA-targeted therapy for MM and download the corresponding slides when they are available.

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