Summary

Disease progression in MM is associated with complex biologic pathways and processes, making it difficult to manage the disease successfully, and increasing the probability of relapse. The pathophysiology of MM contributes to the development of resistance to standard therapy. Over the past 2-3 years, there has been a remarkable expansion in drug development for MM that will probably result in a positive impact on survival. This has included development of bortezomib, lenalidomide, and "rediscovering" thalidomide and arsenic trioxide, agents that have shown promise in treatment of relapsed and refractory myeloma.

Novel treatment strategies are further needed to target the underlying pathogenic mechanisms, but they must be safe for a predominantly older patient population. Nontraditional therapeutic agents having novel mechanisms of action are under investigation. The current approach is to target the progression of myeloma at multiple different pathways simultaneously. It is probably time to proceed on two simultaneous developmental tracks: one, the continuation of the current strategy to develop targeted therapy; the other, to properly define the dose, frequency, and combination strategies of the available new agents. Combination of novel agents with established therapy may fill an unmet need in the management of relapsed/refractory MM.

Table 87.2 Novel agents under study in treatment of relapsed/refractory multiple myeloma

Proteasome inhibitor (PS-341, bortezomib) Thalidomide

Immunomodulatory derivatives (ImiDs)

Arsenic trioxide

Heat-shock proteins

Anti-VEGF antibodies

Farnesyltransferase inhibitors

Histone deacetylase inhibitors

Bcl-2 antisense molecules

2-Methoxyestradiol

Bisphosphonates

IGF-1 receptor inhibitors

RANKL antagonist

Lysophosphatidic acid acyltransferase ß inhibitors Vaccines of cyclophosphamide, etoposide, and cisplatin) or DT-PACE, in which thalidomide and doxorubicin are added to DCEP.81

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