The development of multiple myeloma (MM) is a complex multi-step process involving both
early and late genetic changes in the tumor cell as well as selective supportive conditions by the bone
marrow (BM) microenvironment. Based predominantly on our understanding of the functional
importance of the MM BM microenvironment and its interrelation with the MM cell, which triggers
tumor cell homing, seeding, proliferation, and survival, a multitude of new molecular targets have been
identified. The clinical approval of four derived agents, thalidomide, its immunomodulatory derivative
Len, the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin have fundamentally
changed treatment regimens in MM during the last decade. Moreover, based on a pathophysiologic
rationale a multitude of additional agents, most prominently carfilzomib, pomalidomide, vorinostat, and
perifosine have demonstrated promising preclinical and early/ advanced clinical activity indicating the
evolvement of further treatment advancements in near future.
Keywords: Bone marrow microenvironment, thalidomide, bortezomib, ubiquitin-proteasome system
(UPR), salinosporamidine A (NPI-0052), nutilins, aggresomes, signaling pathways, IL-6. VEGF, TNF,
SDF-1, CD40, BAFF/ APRIL, IGF-1, Ras/ MEK/ MAPK, PI3K/ Akt, STAT/ Jak, NFkB, Wnt.