Immunotherapy for Multiple Myeloma

The use of a patient’s own immune system to fight cancer—referred to as immunotherapy—is an exciting area of multiple myeloma research. For myeloma immunotherapy treatments to work, they must be designed to recognize and kill myeloma cells. This has long been a challenge, because myeloma cells—like all cancer cells—have the ability to hide from the body’s normal immune response. Myeloma cells also have the ability to weaken the body’s immune response to such an extent that they can continue to grow and thrive.

Overcoming myeloma’s ability to hide from or weaken the immune system—that is, immunotherapy—is seen as a promising path to potentially achieving treatment success. There are many types of immunotherapy that can rev up or improve a patient’s immune response against myeloma cells. The first three FDA-approved immunotherapies for patients with multiple myeloma—Darzalex, Sarclisa and Empliciti—all fall into a category called antibody-based immunotherapy. Many other immunotherapies are in clinical development and will soon be available for treatment!

Cell surface proteins as myeloma targets.

The advantage of immunotherapy is that it is designed to seek out and kill myeloma cells in the body. How is immunotherapy able to find the myeloma cells? And how does it distinguish between myeloma cells and healthy cells? The answer to these important questions is that myeloma cells have certain proteins on their surfaces. These proteins—which are referred to as cell surface proteins—act as a flag that marks the myeloma cells and allows them to be more easily found by the body’s immune system.

Using these protein “flags” as targets, researchers have developed several different types of immunotherapy. You may have already heard of two of the proteins used as immunotherapy targets: CD38 and SLAMF7. CD38 and SLAMF7 can be found on both myeloma cells and healthy cells, but myeloma cells tend to have them in higher amounts and thus they are useful flags for myeloma cells. The drugs Darzalex and Sarclisa were designed specifically to latch onto CD38. Similarly, the drug Empliciti was designed to latch onto SLAMF7.

Another myeloma cell surface protein that is being used as a target for many different kinds of immunotherapies is called the B-cell maturation antigen, or BCMA. What is especially exciting about BCMA is that—unlike CD38 and SLAMF7—it is found exclusively on myeloma cells. Several types of immunotherapy are being developed for patients with multiple myeloma (these include bispecific antibodies , antibody–drug conjugates [ADCs] , and CAR T-cell therapy ), and most of them target the BCMA protein. Currently, these agents are in the experimental stage of development.

BCMA-bispecific antibody and T-cell engager in action: T-cells killing myeloma cell.

Produced in a laboratory, monoclonal antibodies are engineered to bind to specific myeloma cell surface proteins. In binding to the surface protein, the monoclonal antibody “marks” the myeloma cell—making it easier for the body’s immune cells to find and destroy it.

Several different types of antibody are used as antibody therapy, one of which is called a bispecific antibody (or, sometimes, a bispecific T-cell engager or BiTE). Bispecific antibodies are made from pieces of two different antibodies that have been fused together, so that one piece binds to myeloma cells and another piece binds to cells of the immune system.

Most bispecific antibodies target BCMA on myeloma cells and bind to a protein called CD3 that is found on an immune cell called a T cell. The T cell, once attached to the myeloma cell, releases a type of poison that kill(s) the myeloma cell.

Bispecific antibody treatment is not yet approved for use in patients with multiple myeloma, but several are being studied—and showing promise—in clinical trials.

BCMA-ADC in action: myeloma cell kiling by drug conjugate and NK cells

Antibody–drug conjugates (ADCs) are antibodies that are combined with a cancer-fighting substance—either a drug or a toxin. The antibody part binds to a myeloma cell and the cancer drug kills the myeloma cell. Most of the antibodies in this class target BCMA.

Not only do ADCs target, bind to, and kill myeloma cells directly; they also activate NK cells, which are a special type of cell in the immune system that, once activated, seeks out and destroys myeloma cells by releasing its own cell-killing toxins.

As with bispecific antibodies, ADC therapy for multiple myeloma is still in development and has not yet been approved for use outside of clinical trials. ADCs that target BCMA and have shown promise in clinical trials include belantamab mafadotin, CC-99712, FOR46, MEDI2228, and STRO 001.

BCMA CAR T cells killing a myeloma cell

Chimeric antigen receptor (CAR) T-cell therapy uses a patient’s own white blood cells—a type of immune cell—to fight myeloma.

Normally, a particular type of white blood cell called a T cell circulates throughout the body. T cells are important in fighting infections and looking for cancer cells. When cancer cells are detected, T cells kill them by grabbing onto and pumping toxins into them. Unfortunately, cancer cells have found ways to “hide” from T cells.

In CAR T-cell therapy, a patient’s white blood cells (including T cells) are collected from their blood, modified in a lab to be more effective in identifying and attacking myeloma cells, and then infused back into the patient—as “supercharged” myeloma fighters. These “supercharged” T cells (from which this type of therapy gets its name) are able to find and kill myeloma cells—even when they’re hiding.

Anti-BCMA CAR T-cells in clinical development include bb2121, bb21217, ALLO-715, Descartes-08/-11, JCARH125, JNJ-4528, NKR-2, P-BCMA-101, and UCARTCS1A.