Current and Future Roles of BCMA-Targeted Therapies for Multiple Myeloma

Rationale for Targeting BCMA in Multiple Myeloma (MM)
BCMA-targeted agents are an exciting new treatment approach for patients with relapsed/refractory (R/R) MM. BCMA stands for B‑cell maturation antigen, which is a protein that is expressed on late-stage B-cells, plasma cells, and plasmablasts. BCMA also is expressed on MM tumor cells and is an important survival mechanism for these malignant plasma cells. It is an ideal antigen to target with antibody–drug conjugates (ADCs), chimeric antigen receptor (CAR) T‑cell therapy, and bispecific T‑cell engagers or bispecific antibodies because it is specific to these B‑cell lines and thus has fewer unwanted off‑target effects. 

Currently Approved BCMA-Targeted Therapies for MM
Currently, 2 BCMA‑directed therapies are approved by the FDA for patients with R/R MM. The first—belantamab mafodotin—is an ADC currently approved for patients who have received at least 4 previous therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory drug. ADCs are designed to include an antibody that is attached to a cytotoxic payload via a linker. Belantamab mafodotin comprises an antibody-targeting BCMA and the cytotoxic agent monomethyl auristatin-F (MMAF). In addition, the first CAR T‑cell therapy against BCMA—idecabtagene vicleucel—was approved for patients who have received at least 4 previous lines of therapy, including an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.

Belantamab mafodotin was approved based on data from the phase II DREAMM-2 trial, which reported an overall response rate of 32% (7% with stringent complete response/complete response and 11% with very good partial response) and a median duration of response of 11 months in patients who received the FDA-recommended dose (2.5 mg/kg IV once every 3 weeks). Ocular toxicity, particularly keratopathy, is the most common adverse event (AE) with belantamab mafodotin, but regular ophthalmologic examinations (at baseline and before each dose) can help detect these events early for easier management, and most patients can recover while receiving treatment.

Idecabtagene vicleucel was approved based on data from the phase II KarMMa study, which showed a 73% overall response rate and an 81% response rate in patients who received the highest target dose. The most common AEs with idecabtagene vicleucel include hematologic AEs, cytokine-release syndrome, and neurotoxicity. Cytokine-release syndrome and neurotoxicity largely were lower grade, and experienced centers can manage and mitigate these AEs through the early use of tocilizumab or corticosteroids.

Using BCMA-Targeted Therapies in Clinical Practice
BCMA‑directed therapy is currently approved for use in later lines of therapy for R/R MM; both belantamab mafodotin after 4 previous therapies and idecabtagene vicleucel in the fifth line or later. Therefore, these therapies are being used very late in the disease course, although the hope is that clinical trials will allow them to be used sooner in a patient’s disease course. For right now, deciding which BCMA-targeted therapy to use for individual patients depends on patient comorbidities and preferences. CAR T-cell therapy is the best option for patients who can tolerate lymphodepleting chemotherapy and wait on the manufacturing of their CAR T-cells, assuming the patient has access to this treatment. Belantamab mafodotin is an option for patients who may not be able to tolerate CAR T-cell therapy, who cannot wait for CAR T-cell manufacturing due to aggressive disease, or who do not want to undergo hospitalization or do not have access to CAR T-cell therapy.

It also is difficult to know how to sequence all of our therapies, but preliminary data suggest that after BCMA has been targeted once, it is possible to subsequently use a different BMCA-targeted modality and still see a response. Ongoing clinical trials with BCMA‑targeting agents include cohorts of patients who have previously received other BCMA‑directed therapy.

The Future of BCMA-Targeted Therapy in MM
We are excited about the new advances in BCMA‑targeted therapy, which include not only additional CAR T‑cell therapies (such as ciltacabtagene autoleucel) but also bispecific T‑cell engagers. These agents are engineered to recognize and engage CD3 on immune effector cells, as well as BCMA on the target cells, to stimulate the patient’s own immune system against the malignant cells. Therapies under investigation include BCMA x CD3 bispecific antibodies such as teclistamab, REGN5458, ABBV-383, and elranatamab. Some of these bispecific antibodies, such as teclistamab and elranatamab, are given subcutaneously, which may be advantageous for patients. As we learn more about these bispecific agents, it will be nice to see whether differences in manufacturing or the structure of each bispecific antibody results in differences in efficacy and/or safety.

In addition, we are excited to see additional data on the use of combination therapy with BCMA-targeted agents, as well as moving these immunotherapies to earlier lines of treatment and not waiting for the last line of therapy when the patient’s immune system may not be as fit. 

Your Thoughts?
Have you incorporated BCMA-targeted therapy for your patients with R/R MM since the FDA approval of belantamab mafodotin and idecabtagene vicleucel? Answer the polling question and join the conversation by posting a comment in the discussion section.

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.