Targeting BCMA in Myeloma With Antibody–Drug Conjugates and Bispecific Agents

B-cell maturation antigen (BCMA) is a member of the tumor necrosis factor receptor superfamily, and it is strongly expressed on plasma cells in multiple myeloma (MM). This makes it an excellent target for potential therapeutic approaches in this disease. In a previous commentary, I discussed the use of BCMA-targeted CAR T-cell therapy as a treatment strategy in MM.

Here, I address 2 other approaches to targeting BCMA: antibody–drug conjugates (ADC) and bispecific antibodies and T-cell engagers.

BCMA-Targeting ADCs
Belantamab mafodotin is the first BCMA-targeted ADC to be approved by the FDA and the EMA, indicated for adult patients with relapsed/refractory MM who have received at least 4 previous therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent. Belantamab mafodotin comprises a BCMA-targeted IgG₁ antibody linked to a microtubule inhibitor, auristatin. The molecule is also afucosylated to enhance antibody-dependent cytotoxicity, and it is administered as a 30-minute IV infusion every 3 weeks.

In clinical trials, belantamab mafodotin has been shown to have single-agent activity of approximately 33%, and it was shown to be highly active in combination with bortezomib and dexamethasone, with a response rate of 78% in heavily pretreated patients with relapsed MM. An unusual and common adverse event of this agent is ocular toxicity affecting the cornea, which requires holding or modifying the dose of the drug to resolve the keratopathy. This ADC is a subject of numerous ongoing trials as monotherapy and in multiple drug combinations. Other BCMA ADCs in early stages of development include MEDI2228 and CC-99712, which are being developed in ongoing phase I studies.

Bispecific Antibodies and T-Cell Engagers
Another approach that exploits BCMA targeting is the development of bispecific antibodies and T-cell engagers. These molecules take either the Fc portion of antibody molecules directed against the T-cell antigen CD3 or an entire antibody molecule, and then link these with a similar antibody construct that targets BCMA. The first of these to be presented was AMG 420 in 2018. Although high response rates were noted, the cumbersome 4-week continuous infusion schedule and neurotoxicity will likely limit development of this agent. More promising is the AMG 701 molecule, which can be administered in a short IV infusion. Phase I data from an ongoing trial with the bispecific engager teclistamab was also presented at ASCO 2020, with response rates of 67% in the highest dose level tested. At the 2019 ASH meeting, phase I data involving 30 patients receiving another bispecific engager, CC-93269, demonstrated response rates of 89% in an equally heavily pretreated population. All of these cellular therapies do come with the risk of cytokine-release syndrome, and for this reason, typically the first few doses are given in the hospital. However, after the first few doses, it appears that judicious outpatient administration will be possible.

With the targeting of BCMA in MM, researchers and clinicians now have an increasing number of promising novel therapeutic strategies for patients with heavily pretreated relapsed/refractory MM.

Your Thoughts?
What are your thoughts on BCMA as a target in MM? Please share your thoughts and questions in the discussion box below.