Refractory Myeloma Responds to Proteasome Inhibitor

Refractory Myeloma Responds to Proteasome Inhibitor

ORLANDO—The proteasome inhibitor MLN341 (formerly known as LDP-341 and
PS-341) shows evidence of safety, biologic activity, and antitumor activity
in the treatment of multiple myeloma, according to preliminary analysis of a
phase II trial, Paul G. Richardson, MD, said at the 43rd Annual Meeting of
the American Society of Hematology (abstract 3223). [The proteasome is an
intracellular enzyme present in the cytoplasm and nucleus.]

MLN341 (Millennium Pharmaceuticals, Cambridge, Massachusetts) is being
tested in a variety of malignancies, but appears "especially
promising" in multiple myeloma, Dr. Richardson said.

The agent has previously been shown to kill tumor cells directly and to
induce complete tumor regression in animals, he said. Possible mechanisms of
action in the treatment of myeloma include induction of apoptosis and
disruption of the interaction of the microenvironment with myeloma cells,
inhibiting binding of a myeloma cell to stromal cells.

As a proteasome inhibitor, MLN341 affects the degradation of a large
variety of intracellular proteins, but is selective and does not inhibit
other enzymes. It reduces intercellular factor (IF)kappaB degradation by the
proteasome, allowing more IFkappaB to bind to nuclear factor (NF)kappaB and so
reducing NFkappaB levels.

NFkB, a transcription factor, drives myeloma cell growth in the
microenvironment by upregulating the expression of key growth factors,
including interleukin-6, vascular epithelial growth factor, and tumor
necrosis factor-alfa.

The agent also inhibits degradation of proteins involved in cell cycle
regulation, including p53 and p21 (CDK inhibitor), and may possibly inhibit
angiogenesis, Dr. Richardson said.

Multicenter, phase II studies of MLN341 in multiple myeloma are ongoing,
and the results so far are encouraging. Dr. Richardson, of the Dana-Farber
Cancer Institute and Harvard Medical School, said that MLN341 was well
tolerated, that studies have shown evidence that myeloma cells are 100 to
1,000 times more sensitive to MLN341 than are normal lymphocytes, and that
patients refractory to other treatment modalities have shown good responses.


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