The team then conducted a study in 3 patients with refractory myeloma, administering 3 doses of the GSI LY3039478 over 5 days. They found that GSI treatment nearly tripled the percentage of myeloma cells with measurable BCMA expression.
To Ola Landgren, MD, PhD, professor of medicine and chief of myeloma service at Memorial Sloan Kettering Cancer Center in New York City, the approach is “logical,” he said. “You give a drug, you upregulate [BCMA], and then you can use that benefit to target [myeloma cells] … it’s nice to see but the question still remains if this truly has a clinically differentiating impact.”
To investigate that question, Dr Cowan and colleagues initiated a phase 1 trial earlier this year to evaluate the safety of combined GSI and anti-BCMA CAR-T therapy (ClinicalTrials.gov Identifier: NCT03502577). Eligible patients are those who have multiple myeloma who relapsed after or are refractory to autologous stem cell transplant or failed to respond to 4 cycles of an immunomodulatory drug and proteasome inhibitor combination.
The trial will also accept patients with prior anti-BCMA CAR-T cells or other BCMA-targeting therapies, Dr Cowan noted. Trial participants will receive the GSI JSMD194 on day zero of CAR-T infusion at 3 doses a week for 3 weeks.
Alfred L. Garfall, MD, MS, assistant professor of medicine at the Hospital of the University of Pennsylvania and oncologist at the Perelman Center for Advanced Medicine, Philadelphia, wondered whether a short course of GSIs will boost efficacy of engineered T-cells over long periods of time. “The question is in terms of long-term outcomes, whether there might still be a group of cells that have low BCMA expression that are able to survive and resist the CAR-T cells,” he said. It may perhaps prove more efficacious to administer the drugs over a longer period of time, but that may elevate the risk of side effects associated with GSIs, which include thrombocytopenia and gastrointestinal symptoms.
Dr Garfall also pointed out that availability of target protein is likely not the only factor that may improve the efficacy of CAR-T therapies, as evidenced by patients with very low BCMA expression who still respond to anti-BCMA CAR-T therapy. “It may not be about modifying just 1 factor, but it may be about optimizing multiple factors to get the best response,” such as the health of a patient’s T cells, he said.