ABSTRACT Multiple myeloma (MM) claims over 80,000 lives globally each year. Although several new therapies have been approved over the past decade, virtually all patients relapse, and the median survival remains at only 5 years. The depth of therapeutic response correlates with time to relapse, and eradicating tumor cells early in the disease process may be necessary to achieve clinical cure. A potentially curative approach is autologous cell therapy with chimeric antigen receptor (CAR) T-cells redirected to a target antigen. For MM, an attractive target antigen is B cell maturation antigen (BCMA), an antigen marker with extremely high sensitivity and specificity for myeloma and plasma cells. Experiments described in this SBIR proposal cover early-stage clinical research (Phase I/II Clinical Trial) of an autologous anti-BCMA CAR T-cell product generated with mRNA (Descartes-11) in order to overcome the toxicities associated with permanently modified CAR T-cells. The goals of the Specific Aims are to 1) determine the safety, tolerability and Maximum Tolerated Dose of Descartes-11 in patients with relapsed/refractory MM; 2) establish preliminary clinical benefit of Descartes-11 at MTD in relapsed/refractory MM; 3) define correlative biomarkers of safety and efficacy in Descartes-11-treated patients. Use of mRNA to generate Descartes-11 enables predictable pharmacokinetics, providing the prospect of controlled CAR T-cell treatment of MM early in the course of the disease.