Nina Shah, MD, associate professor of medicine at the University of California, San Francisco Helen Diller Comprehensive Cancer Center, discusses challenges with chimeric antigen receptor (CAR) T-cell therapy in multiple myeloma.

The biggest concern 1 year ago was cytokine release syndrome (CRS), says Shah. Although CRS is still commonly seen in approximately 63% of patients, it is relatively well-controlled. Physicians have more experience now—they know when to administer dexamethasone and other agents&mdash;and as such, are more comfortable with dealing with it, explains Shah. Concerns over safety have now been replaced with efficacy and durability concerns, she adds.

Another challenge with implementing this therapy into practice has been financial. Physicians are still unsure how much each product is going to cost, who will reimburse it, and who will be eligible to receive reimbursement. Those questions will need to be addressed before research is taken any further, as they play an important role in the accessibility and the applicability of this therapy, concludes Shah.

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Dr. Shah Discusses Challenges With CAR T-Cell Therapy in Myeloma

Nina Shah, MD, associate professor of medicine at the University of California, San Francisco Helen Diller Comprehensive Cancer Center, discusses the potential of bb21217 in the treatment of patients with multiple myeloma.

In a study presented at the 2018 ASH Annual Meeting, the anti—BCMA chimeric antigen receptor (CAR) T-cell therapy bb21217 was tested in patients with relapsed/refractory multiple myeloma who were treated with at least 3 prior lines of therapy. Participants had to have been previously exposed to an immunomodulatory agent and a proteasome inhibitor, while expressing at least 50% BCMA in their bone marrow plasma. Shah notes that this is a particularly difficult-to-treat patient population.

The toxicity profile associated with bb21217 was comparable to what it is typically seen with CAR T cells, Shah says. Two-thirds of patients had cytokine release syndrome (CRS), and most of these were grade 1 or 2 events; however 1 patient had a grade 3 event, Shah reports. Three patients had neurotoxicity, 2 of which were grade 1 or 2, but 1 patient had a grade 4 event with encephalopathy in the setting of a grade 3 CRS.

The grade 4 event, explains Shah, required her team to expand the dose level. Another 6 patients ended up receiving treatment at this dose level in order to determine if high versus low tumor burden could contribute to the safety signal. They found that the rest of the patients did not experience any dose-limiting toxicities, so they concluded the grade 4 event to be an isolated one.

Objective response rate was 83.3%, with a very good partial response or better rate of 75% in the 12-patient cohort. The complete remission (CR) or stringent CR rate was 25%, with a minimal residual disease negativity rate of 100% in this group. Greater follow up is needed to understand the full efficacy of the treatment, Shah notes.

Dr. Shah Discusses Potential of bb21217 in Multiple Myeloma

Nina Shah, MD, associate professor of medicine at the University of California, San Francisco Helen Diller Comprehensive Cancer Center, discusses initial results from a phase I clinical trial of bb21217, a next-generation anti-BCMA CAR T-cell therapy, in patients with multiple myeloma during the 2018 ASH Annual Meeting.

Dr. Shah on Initial Results for bb21217 in Multiple Myeloma

Nina Shah, MD, associate professor, Department of Medicine, University of California, San Francisco Helen Diller Comprehensive Cancer Center, discusses the current state of chimeric antigen receptor (CAR) T-cell therapy in multiple myeloma.

Right now, most of the literature regarding CAR T-cell therapy is preliminary, Shah says, and the information available has only been presented at large oncology conferences. Data presented at the 2018 ASCO Annual Meeting showed that the CAR T-cell therapy bb2121 had a median progression-free survival (PFS) of 11.8 months and a median duration of response of 10.8 months for patients with relapsed/refractory heavily pretreated myeloma. Although, the median PFS for patients who achieved minimal residual disease negativity was over 17 months.

Shah says that these data demonstrate areas that can be improved. For example, the timing of CAR T-cell therapy could be earlier, so patients do not need to undergo 7 lines of therapy first. It could also be combined with different agents. Preclinical data have shown that CAR T cells in combination with immunomodulatory agents may make the T cells last longer.

Nina Shah, MD, associate professor, Department of Medicine, University of California, San Francisco Helen Diller Comprehensive Cancer Center, discusses the current state of CAR T-cell therapy in multiple myeloma.
 

Dr. Shah on the Current State of CAR T-Cell Therapy in Myeloma

Nina Shah, MD, associate professor, Department of Medicine, University of California, San Francisco (UCSF) Helen Diller Comprehensive Cancer Center, discusses the potential of chimeric antigen receptor (CAR) T-cell therapy in myeloma.

There are many existing cellular therapies, specifically engineered T-cell receptors that target NY-ESO-1. There are several clinical trials exploring this, one of which UCSF will be participating in. In addition, the updated results of CAR T-cell therapy, presented at the 2017 ASH Annual Meeting, showed response rates of 94% in those who were evaluable. Similarly, 9 out of 10 patients had minimal residual disease (MRD) negativity.

There is much excitement that patients who have been heavily pretreated, specifically a median of 7 lines of treatment, can reach MRD negativity. UCSF will soon open several respective trials to further explore the use of CAR T cells in myeloma.

Nina Shah, MD, associate professor, Department of Medicine, University of California, San Francisco (UCSF) Helen Diller Comprehensive Cancer Center, discusses the potential of chimeric antigen receptor T-cell therapy in myeloma.

Dr. Shah on Cellular Therapies for Patients With Myeloma

Nina Shah, MD, associate professor, Department of Medicine, University of California, San Francisco Helen Diller Comprehensive Cancer Center, classifies two antibody-type treatments for patients with myeloma.

Shah distinguishes between antibody-drug conjugates and bispecific therapies. Though both therapies target specific myeloma cells—in which a toxic drug linked to a specific antibody is carried to the corresponding myeloma cell&mdash;antibodies in bispecific therapies are also coded to their T cells. This approach uses the patient’s own T cells and antibodies with the intent of killing the myeloma cell and potentially even having some T-cell membrane, which is one of the goals of that therapy.

As advances continue to be made in this landscape, clinical trials will soon determine where to sequence these drugs and whether or not they can be administered earlier.

Nina Shah, MD

Articles

Dr. Shah Discusses Challenges With CAR T-Cell Therapy in Myeloma

Dr. Shah Discusses Potential of bb21217 in Multiple Myeloma

Dr. Shah on Initial Results for bb21217 in Multiple Myeloma

Dr. Shah on the Current State of CAR T-Cell Therapy in Myeloma

Dr. Shah on Cellular Therapies for Patients With Myeloma

Dr. Shah on Novel Antibodies for Patients With Myeloma