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Frits van Rhee, MD, Ph.D.
New Immune Therapies Provide Promising Advances in Myeloma Care
| By Frits van Rhee, MD, Ph.D.
Since the late 1990s, 16 drugs have been approved for the treatment of multiple myeloma, including proteasome inhibitors, such as bortezomib and carfilzomib, and the immunomodulatory class of agents comprising thalidomide, lenalidomide and pomalidomide. Immune therapy with the antibody daratumumab was first approved in 2015. These three classes of drugs are now combined with autologous stem cell transplantation in an approach, now widely adopted in the field, which we initially referred to as “Total Therapy.” Patients receive induction, stem cell transplant (if eligible), consolidation and maintenance.
Much progress has been made, and approximately 30% of patients will be cured with many more having very meaningful prolongation of life with good quality.
Many challenges remain, especially for patients who have multiple relapses or those who have so-called high-risk disease. New hope is offered by the introduction of novel immune therapies, which leverage the patient’s own immune system to attack the myeloma. These new treatments have yielded exciting results — both in clinical trials and in everyday clinical use.
One class of agents, referred to as bispecific antibodies, direct the patient’s own immune cells to attack the myeloma. The first drug approved in this class is teclistamab, which recognizes a protein called BCMA on the surface of myeloma cells. The approval of other bispecific antibodies is anticipated and will likely include antibodies that recognize other targets on myeloma cells. One such antibody, talquetamab, attacks a molecule on myeloma cells called GPRC5D — we have used this antibody with success in clinical trials and FDA-approval may happen this year. An advantage of bispecific antibodies is that they are readily available and can be immediately given to the patient. Side effects include an increased risk of infection and toxicities such as cytokine release syndrome (fevers and low blood pressure) due to the hyper stimulation of the immune cells. Fevers are usually confined to the first few “baby” doses (also referred to as step-up dosing.).
In contrast, chimeric antigen receptor (CAR) T-cells require complex manufacturing off-site, and it takes time for the cells to be ready for infusion. Manufacturing failures are also a possibility in the process. It is sometimes not possible to make CAR T-cells from immune cells that are too “beaten up” by prior treatments. Prior to CAR T-cell infusion, lymphodepleting chemotherapy is needed to suppress existing immune cells in order for CAR T-cells to have room to expand in the patient after infusion. Lymphodepleting chemotherapy, although very tolerable, may suppress normal bone marrow cells and up to 20% of patients require a stem cell boost to restore normal bone marrow function. The cytokine release syndrome after CAR T-cell therapy may be more severe and occurs more frequently than with bispecific antibodies, although it can be managed efficiently. Altogether, CAR T-cell therapy is well tolerated, and patients find it easier than a stem cell transplant.
Many questions remain, which are the subject of current research. Patients can still not respond or relapse after both sets of therapy. In some patients, further mutations may arise in myeloma cells, thus conferring resistance to immune therapy. It is also possible that the immune environment in the bone marrow is instrumental in inactivating CAR T-cells or immune cells activated by bispecific antibodies. Furthermore, both the CAR T-cells and immune cells activated by CAR T-cells therapy may become “tired” and cease to function, a phenomenon called immune exhaustion.
Currently, these new treatments are reserved for patients with advanced disease. Clinical trials are investigating these treatments earlier in therapy when the immune cells of the patients are in better shape, which likely will result in even better results.
It also is not clear in which order to give CAR T-cells and bispecific antibodies. Early results suggest that CAR T-cells given shortly after bispecific antibody therapy are less effective. The challenge is to select the best treatment for a given patient at the best time point. Both bispecific antibodies and CAR T-cells have advantages and disadvantages.
These new immune therapies have heralded in a new era in myeloma care. These therapies will undoubtedly be further approved and may even find their way into the front line of therapy of myeloma. Many more exciting innovations are expected, which will improve treatment options and outcomes for myeloma patients.