By Frits van Rhee, M.D., Ph.D.
Novel immune therapies are making a dramatic entry into the options for myeloma therapy and bringing with them a renewed hope to patients. These new treatments include chimeric antigen receptor (CAR) T-cells, antibody drug conjugates and bispecific antibodies. Approvals and clinical trials for these new treatments presently focus on patients with relapsed myeloma.
CAR T-cells, made from the patient’s own T-lymphocytes immune cells, are collected in a process very similar to stem cell collection. However, no prior chemotherapy or administration of growth factor is required. During a four- to five-week manufacturing process, the immune cells are genetically altered in a laboratory to recognize a protein on the surface of myeloma cells known as B-cell maturation antigen (BCMA).
Prior to the infusion of the CAR T-cells, the patient must undergo three days of chemotherapy treatments to empty their immune system and make room for the genetically altered immune cells. When the infused CAR T-cells encounter the myeloma cells, they become highly activated, rapidly multiply and kill the myeloma cells.
Ide-cell (short for idecabtagene vicleucel) (® ABECMA) is the first CAR T-cell product for myeloma, approved by the Federal Drug Administration (FDA) in March 2021. In clinical trial, complete responses were seen in up to 40% of patients at the highest dose of CAR T-cells infused. Equally encouraging or even better results were seen with a second CAR T-cell product called cilta-cel. The FDA is expected to approve it this year.
Side effects of CAR T-cell therapy include cytokine release syndrome with symptoms such as fever, low blood pressure and neurological toxicities such as confusion. In general, most of these side effects are not severe and can be easily managed.
Belantamab mafodotin (® BLENREP) was approved for relapsed myeloma in August 2020. It is an antibody drug conjugate, a type of immune therapy in which an antibody carries a chemotherapy drug directly to the myeloma in a “silver bullet” type of approach.
Like the CAR T-cells, belantamab targets the BCMA protein on the myeloma cells. Overall, approximately one-third of patients respond to therapy with some achieving complete remissions. The principal side effect of belantamab is blurry vision, a result of irritation of the corneas of the eyes. Because of this, patients need to have their eyes evaluated by an ophthalmologist or optometrist before receiving each dose.
Bispecific antibodies, not yet approved by the FDA, recognize both myeloma cells and immune cells, causing the immune cells to become activated and attack the myeloma cells, similar to the CAR T-cell approach. They also have the similar side effects of cytokine release syndrome and neurotoxicity.
Several antibodies are currently in clinical trial, most of which target the BCMA protein, while bispecific antibodies that attack other targets are also being developed. The FDA’s approval of one or more of these antibodies is eagerly awaited and may occur later this year.
These approaches all have their pros and cons. CAR T-cells can induce rapid and deep responses; however, creating them is complex and time-consuming, and the capacity to manufacture them is limited, reducing the number of patients who can receive the treatment. Hopefully, the arrival of cilta-cel will help.
An advantage of antibody therapy is that it is immediately available for infusion and no chemotherapy is needed. The sight-related side effects of the antibody, belantamab, are reversible and can be managed by adjusting the dosing interval and amount.
Bispecific antibodies require hospitalization for the first doses due to the risk of cytokine release syndrome and the treatment’s effectiveness depends on how healthy the patient’s own immune cells are. While bispecific antibodies have not been directly compared to belantamab, initial clinical trial results suggest that bispecific antibodies may be more effective.
These new treatments offer exciting options for patients with relapsed myeloma. It seems likely that in future, these treatments alone or in combination with other treatments, will be used much earlier and eventually may partially or completely replace chemotherapies, such as stem cell transplants. There is the real prospect of treatment approaches with no or only limited chemotherapy, and ultimately a cure for myeloma.