Time for a paradigm shift in immunotherapy-based BCMA/CD3 bispecific drug development in multiple myeloma

Abstract

Drug development is deemed successful for patients not only on the basis of regulatory approval, but when the optimal, and ideally the minimal effective dose and schedule is determined [1]. This allows us to offer patients new approved treatments safely, and with the most optimized balance of risk and benefit. In clinical practice, many drugs in oncology are often given to patients at a dose and schedule that is considerably different from the one used in the pivotal trials to secure drug approval from regulators. These major changes in dose and schedule in clinical practice is usually the result of physicians encountering excess toxicity at approved doses, and reducing dose and dose intensity to improve tolerance and safety. In myeloma, for example, we use several drugs including bortezomib, carfilzomib, dexamethasone, thalidomide, pomalidomide at lower doses and or dose intensity than the doses used in initial pivotal trials. These post approval changes in dosing raises questions on the robustness and safety of the initial drug development processes used to secure approval of anticancer drugs which often carry high risks of toxicity compared to drugs used to treat other diseases.

Drug development in oncology has indeed evolved over the years from the concept of maximal tolerated dose (MTD) to a goal of determining the minimal effective dose (MED) to “minimize unnecessary drug exposure that will not lead to additional benefit to the patient but may increase the risk or severity of adverse events” [1]. However, with the advent of new immunotherapy options, we feel that MED may be difficult to establish and may not be a sufficient target. These new drugs are highly potent and may produce the best overall clinical benefit at doses and dosing intensity below MTD, and even what is initially perceived as the MED. As discussed below, longer-term results show that even the apparent MED may overestimate the required dose and dosing schedule leading to excess and unnecessary toxicity.