Although the introduction of proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs) has improved clinical outcome, nearly all multiple myeloma (MM) patients ultimately relapse or become refractory to these drugs. However, knowledge of the biology of MM progression is rapidly accumulating and a large number of novel agents are under investigation. Currently, no treatment can be considered as standard for relapsed/refractory MM, and the appropriate choice of therapy is based on several myeloma- and patient-related factors. The efficacy of bortezomib and lenalidomide has been demonstrated by large prospective trials with long-term follow-up periods, and results from studies evaluating novel PIs (carfilzomib and ixazomib), IMiDs (e.g. pomalidomide), and histone deacetylase inhibitors are becoming available. Data from trials of agents with new mechanisms of action, particularly monoclonal antibodies, are awaited. This review will discuss the management approach to relapsed/refractory MM, focusing on approved therapies and on the most advanced new therapeutic compounds.
Criteria for choosing treatment in relapsed/refractory MM patients
Managing relapsed/refractory MM patients can be compared, at present, with unravelling a skein, if all patient-related and disease-related factors are to be considered in the selection of therapy. Furthermore, knowledge of the biology of MM progression is rapidly increasing, and many agents belonging to new classes are being tested, together with those agents already known to be effective, making for a particularly tangled skein.
The introduction of the IMiDs thalidomide and lenalidomide, and the PI bortezomib, has improved survival in relapsed/refractory MM. However, patients who become resistant to novel agents have poor outcomes, with a median event-free survival (EFS) and a median overall survival (OS) of 5months and 9months, respectively; the median OS is only 4months for patients with International Staging System (ISS) stage 3 disease. Thus, the natural history of MM is not much changed from previousyears and, despite the availability of new effective agents, the duration of response decreases with each additional salvage therapy, suggesting the emergence of increasingly resistant disease[3,4]. However, recent biological data are consistent with subclonal heterogeneity of myeloma ab initio, as demonstrated by array comparative genome hybridization, whole-genome sequencing, and next-generation sequencing approaches[5–7]. MM tumor cell populations were shown to be constituted of multiple subclones with different clinical behaviors and treatment sensitivities, and which alternated their dominance at different stages of disease. An agent given to a patient eradicates sensitive, but not resistant, subclones; the resistant subclones subsequently become dominant, but resistance to a specific agent is not absolute, as a sensitive subclone may later re-emerge making that agent effective again. It is probable that, in the near future, these findings will radically change the management of MM patients and the clonal composition at each stage of disease will guide the choice of treatment.