The emerging therapeutic landscape of relapsed/refractory multiple myeloma

From a historic lens, treatment for patients with relapsed/refractory multiple myeloma (R/R MM) has advanced significantly since the advent of immunomodulatory agents (IMiDs) in the 1990s, proteasome inhibitors in the 2000s, monoclonal antibodies in the 2010s, and CAR-T treatments in the 2020s. However, the availability of multiple new therapies has also created significant ambiguity regarding therapy selection and sequencing, as consensus guidelines are limited, and cross-trial comparisons of the novel agents are challenging. In this focused review, we discuss the novel Food & Drug Administration (FDA)-approved medications for R/R MM, including the recently approved first-in-class BCMA-directed bispecific antibody teclistamab. We highlight the seminal clinical trials data and discuss optimal sequencing considerations based on the goal of treatment, with an emphasis on the two novel CAR-T cell products. We consider the limited tolerability of certain agents, prospects for our aging population, and financial aspects of these therapies. Finally, we spotlight ongoing trials involving promising agents making their way through the pharmacologic pipeline including the BCMA-directed bispecific antibody elranatamab and the GPRC5D-directed bispecific antibody talquetamab. We summarize our recommendations based on the best available evidence as we enter 2023.