Cellular Therapies for Multiple Myeloma: A Paradigm Shift

The field of cellular therapy for myeloma is evolving rapidly, and a paradigm shift in treatment is on the horizon, according to Adam D. Cohen, MD, Director of Myeloma Immunotherapy at the Abramson Cancer Center, Philadelphia, Pennsylvania. At the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, held from June 1–5 in Chicago, he delivered an Education Session presentation, “CAR-T and Cellular Therapy in Myeloma,” and contributed a chapter to the ASCO Educational Book, “CAR T Cells and Other Cellular Therapies for Multiple Myeloma: 2018.” Dr. Cohen noted that gene-modified T cells, particularly B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cells, are yielding promising response rates in early studies of patients with highly refractory myeloma.

He said that while there have been significant advances in therapy for myeloma over the past 5 years, the disease is still incurable in most patients. Dr. Cohen said outcomes remain particularly poor for patients who have adverse cytogenetics or disease that is resistant to multiple lines of therapy.

“Despite multiple new drug approvals for myeloma, the majority of patients develop resistance and ultimately succumb to their disease. CAR T cells represent a novel immune-based approach with the potential to overcome drug resistance and other poor prognostic features,” Dr. Cohen told Cancer Network.

Dr. Cohen emphasized that cellular therapies have the potential to overcome drug resistance and induce long-term remissions. He said the two primary approaches that are being studied are non––gene-modified strategies and gene-modified strategies. Non–gene-modified strategies rely on the endogenous antimyeloma T-cell repertoire. Gene-modified strategies employ a new T-cell receptor (TCR) or a CAR to confer novel antigen specificity. So far, CAR T cells have been the first out of the gate to show the greatest activity.

Dr. Cohen said multiple antigen targets are being explored for myeloma. These include BCMA, CD19, CD38, CD138, and SLAMF7. Currently, however, BCMA is showing the most promise. Dr. Cohen said preliminary data from four phase I studies of BCMA CAR T cells have been reported. The four trials have included 90 evaluable patients with relapsed/refractory disease, and each trial employed a different CAR construct.

The data revealed response rates ranging from 60% to 100%, including minimal residual disease at effective doses. However, response durability has been more variable. Dr. Cohen said this variability may be related to differences in CAR T-cell products or in responses to lymphodepleting regimens. He said other problems of variability may be related to patient selection criteria and/or underlying biology/prognostic factors.  

“The biggest pro is the potential to induce durable remissions with a single treatment, which is very different than the current treatment paradigm in myeloma, where continuous drug therapy is the norm. The biggest cons are the logistical challenges in collecting, manufacturing, and administering the CAR T cells, which currently can be done only at specialized centers,” said Dr. Cohen.

Toxicities associated with these treatments include cytokine release syndrome and neurotoxicity. These adverse events can be severe and remain challenging. However, Dr. Cohen said they are reversible in almost all patients and perhaps may be mitigated by earlier use of the immunosuppressive agent tocilizumab.

Multiple BCMA CAR T-cell studies are ongoing, said Dr. Cohen, adding that investigators are now exploring a variety of combinations with immunomodulatory drugs, checkpoint inhibitors, and various gene-edited cellular products.