How to incorporate the Newest Agents Combo vs Sequence - in Favor of Sequence

Abstract

Treatment paradigms for multiple myeloma have changed significantly in the past decade due to introduction of new drugs. Alkylators, corticosteroids and anthracyclines remained the cornerstone of myeloma therapy until the introduction of proteasome inhibitors (PI) and immunomodulatory drugs (IMiDs). Over the past decade there has been an explosion of new drugs that are being evaluated in myeloma and other plasma cell disorders. Among these, histone deacetylase inhibitor class has been the latest addition to the armamentarium and monoclonal antibodies are likely to enter the arena in the near future. Along with this, several other classes of drugs are undergoing later stage trials including specific HDAC inhibitors, kinesin spindle protein inhibitors, signal transduction pathway inhibitors, and cyclin dependent kinase inhibitors to name a few. Along with these blessings comes the challenge of positioning these drugs for treatment of myeloma in the most effective manner. A major focus of ongoing debates in the field is the optimal sequencing of the different drugs, particularly multidrug combinations versus single agent with or with out dexamethasone. It is clear that combinations of new drugs can lead to deeper responses in a higher proportion of patients compared with those containing only one of the newer drugs. It is also clear from phase 3 trials that these deeper responses lead to longer progression free survival. However, given that the current treatment approaches have not led to a cure for this disease and we have to eventually face disease relapse, would it be better to use one class of drug at a time in order to maximize their use. The case for combinations and deeper responses would have been clear had these trials demonstrated an improved overall survival when combinations are compared to new drugs used one at a time, suggesting a fundamental alteration in the natural history of the disease. However, this data is lacking at this time. However, it is likely that eventual cure of the disease will come from judicious combination of drugs, but these should be explored in th context of clinical trials.