Blood, 1 November 2002, Vol. 100, No. 9, pp. 3061-3061
Myeloma therapy: from the bench to the clinic
Despite advances in the understanding of the pathophysiology of
multiple myeloma, the disease continues to be incurable. Chemotherapy, including high-dose therapy, does not result in cure, increase overall survival, and probably does not impact to a significant degree
progression-free survival since the introduction of melphalan and
prednisone (Blade et al, Fermand et al, and Segeren et al, 2001, ASH
43rd Annual Meeting, abstracts 3386, 3387, and 3388, Blood.
2001;98:815a). This is related to the inherited redundant protective mechanisms that allow this immune cell to survive
different insults. To advance therapy in this disease, an agent
or a combination of agents that target and modulate different levels of
the tumor's microenvironment are needed. Hideshima et al (Blood.
2000;96:2943) have shown that one of the potent
immunomodulatory derivatives (IMiDs) of thalidomide, CC-5013, induces
apoptosis in resistant MM cell lines and patient cells and, more
importantly, decreases binding of MM cells to bone marrow stromal
cells. The compromise of this relationship between the myeloma cell and
its microenvironment results in inhibiting the production in the BM
milieu of cytokines (IL-6, VEGF, TNF-
) mediating growth and survival
of MM cells and blocking angiogenesis.
In this phase 1 trial by Richardson et al (page 3063), CC-5013
was investigated in a group of relapsed refractory myeloma patients.
Overall, 71% of the evaluable patients experienced at least 25%
reduction in paraprotein, and 29% of the patients, at least 50%
reduction. Impressively, the common side effects noted with the
parent compound were not appreciated at all dose levels. Grade 3/4
myelosuppression was the dose-limiting toxicity, with the 25 mg/d dose being the maximal tolerated dose. With a broad multilevel activity on the myeloma cell and its microenvironment, the
ability to resensitize the resistant myeloma cell to different chemotherapeutic agents, and the low toxicity profile, this agent holds
major promise not only as a single agent but in combination with
chemotherapeutic drugs that reached their limit some years ago. Further
studies to define schedule and dosing with other agents are under way.
Mohamad A. Hussein
Cleveland Clinic Taussig Cancer
Center
