Targeting BCMA in Multiple Myeloma: Evidence-Based Guidance for Current and Near Future Clinical Integration

Introduction

In this module, Nina Shah, MD, discusses recent evidence on the use of B‑cell maturation antigen (BCMA)-targeted agents for the treatment of patients with multiple myeloma (MM) and how to integrate these agents into clinical practice.

The key points discussed in this module are illustrated with thumbnails from an accompanying downloadable PowerPoint slideset that can be found here or downloaded by clicking any of the slide thumbnails in this module alongside the expert commentary.

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BCMA in Multiple Myeloma

BCMA is a protein expressed on late-memory B‑cells that are committed to plasma cell differentiation and on plasma cells.¹ It is understood that BCMA plays a role in the survival of long‑lived plasma cells. In addition, BCMA also is expressed on MM tumor cells and is an important survival mechanism for these malignant plasma cells. Finally, an enzyme—γ-secretase—can cleave BCMA from the cell surface, which yields soluble BCMA.

Because BCMA is only expressed on a specific subset of cells, specifically on plasma cells and MM tumor cells, it a perfect target antigen for effective therapies, including CAR T‑cell therapy, bispecific T‑cell engager or antibody therapy, and antibody–drug conjugates (ADCs).

These various treatment modalities provide multiple options for targeting BCMA in MM and it is exciting to see some of these new treatment options available in clinical practice after new FDA approvals.

Mechanism of Action for Novel BCMA Targeted Therapies

This module reviews the various classes of novel BCMA‑targeted therapies, each with a different mechanism of action.^1,2 ADCs are designed to include an antibody targeting a cell-surface molecule that is attached to a cytotoxic payload via a linker. ADCs are internalized when they bind to the cell surface and the cytotoxic payload is subsequently released into the cell, causing cell death. The ADC belantamab mafodotin targets BCMA and uses monomethyl auristatin F (MMAF) as the payload. Belantamab mafodotin received FDA approval for treatment of the treatment of patients with R/R MM who have received ≥4 previous therapies, including a CD38 monoclonal antibody, a PI, and an IMiD.

CAR T‑cells can be engineered to express a protein that targets BCMA, yielding a cytotoxic T-cell response. To do this, T-cells are taken from the patient initially, engineered to express a CAR molecule, expanded in vitro, and then given back to the patient after lymphodepleting chemotherapy, to specifically attack myeloma cells that express BCMA. Two CAR T-cell therapies are currently approved by the FDA for patients with R/R MM after ≥4 previous lines of therapy, including a PI, an IMiD, and a CD38 monoclonal antibody—idecabtagene vicleucel and ciltacabtagene autoleucel.

Bispecific antibodies or T‑cell engagers are engineered proteins that bind to 2 different antigens, in this case both BCMA and CD3 on T-cells, to bring a patient’s inherent nonengineered CD3 T-cells in proximity with BCMA-expressing tumor cells to yield a specific cytotoxic response against the MM cells. These “off-the-shelf” therapies do not require any cell engineering.

Various BCMA-targeted therapies have been developed using these modalities and have shown impressive efficacy for patients with even heavily pretreated MM.