Improving outcomes with immune therapies for multiple myeloma
Sham Mailankody
MBBSMemorial Sloan Kettering Cancer Center
Project Term: July 1, 2024 - June 30, 2029
The primary focus of research is to better understand mechanisms of resistance to immunotherapies and design treatment approaches to improve outcomes. I hope to accomplish this by conducting clinical trials that concurrently target both BCMA and GPRC5D in patients with advanced multiple myeloma and by studying antigen expression, tumor genetics, and T cell characteristics to better understand mechanisms of resistance. The goal is to develop more effective immune treatments for myeloma.
Multiple myeloma is the second most prevalent blood cancer in adults, affecting 140,000 people in the US with a 5-year survival rate of 54%. While treatments for multiple myeloma and overall patient survival rates have improved substantially in the last two decades, patient relapse or development of refractory disease is common and limited treatment options exist for advanced disease. Cell therapy strategies targeting a particular cell surface protein called the B cell maturation antigen (BCMA) have shown promising outcomes in relapsed and refractory myeloma; such strategies have been based largely on chimeric antigen receptor (CAR) T cell therapies, a promising new way to get immune cells called T cells (a type of white blood cell) to fight cancer. Based on this, two BCMA CAR T therapies for multiple myeloma have been approved by the Food and Drug Administration. However, despite significant responses in treated patients, relapse remains common there are currently no established standard therapies for patients with progressive disease after receiving these therapies. Another cell surface protein called the orphan G protein coupled receptor, class C group 5 member D (GPRC5D) has also been recently identified as a potential therapeutic target for multiple myeloma patients. We recently published results from the first-in-human phase I trial of a GPRC5D-targeted CAR T cell in patients with relapsed and refractory multiple myeloma. Like BCMA CAR T cells, GPRC5D CAR T cells also have promising efficacy, but relapses are common. We are currently planning genomic and immunologic studies to understand mechanisms of resistance in patients treated on this trial. We are also evaluating targeting both BCMA and GPRC5D in ongoing clinical trials: (1) A first-in-human trial of concurrent administration of CAR T cells targeting these receptors; and (2) A phase II trial of talquetamab (GPRC5D bispecific antibody) as follow-up therapy in patients treated with BCMA CAR T cells. The anticipated outcome of these studies will be the development of new, much needed therapies, as well as significant improvement in overall prognosis and survival rates for multiple myeloma patients.