333ments tailored to a patient’s specifi c form of the disease and also narrow down
areas of the chromosomes in myeloma cells likely to contain undiscovered genetic
aberrations that drive myeloma, and which might turn out to be vulnerable to tar-
geted designer drugs.
Researchers at Mayo Clinic Cancer Center, in cooperation with industry part-
ners, have identifi ed tumor specifi c alterations in the cellular pathway by which the
MM drug bortezomib (Velcade) works and they have identifi ed nine new genetic
mutations in cancer cells that should increase a patient’s chance of responding to the
agent. These fi ndings, may help physicians tailor treatment to patients with
MM. Bortezomib seems to work in about one-third of patients who use it, but up to
now it was not possible to predict which ones. Investigators have identifi ed a group
that will likely respond because these nine mutations seem to be present in at least
25 % of newly diagnosed patients. Multiple genetic mutations in the other NF-κB
pathway, the so-called non-canonical pathway, make the tumor more dependent on
that pathway, and consequently more susceptible to bortezomib treatment.
Identifying these mutations in patients will help the decision as to which patients
should be treated with bortezomib, probably as an initial therapy. A test is in devel-
opment to check for activation of the non-canonical NF-κB pathway in patients.
Now that the mutations have been identifi ed, drug designers may be able to fashion
new therapies that are more specifi c to these genetic alterations and, therefore, less
toxic. These mutations represent good targets for drug development.
Despite overwhelming genomic chaos in multiple myeloma (MM), expression
patterns within tumor samples are remarkably stable and reproducible. Unique
expression patterns associated with recurrent chromosomal translocations and
ploidy changes defi ned molecular classes with differing clinical features and out-
comes. Combined molecular techniques also dissected two distinct, reproducible
forms of hyperdiploid disease and have molecularly defi ned MM with high risk for
poor clinical outcome. Gene-expression profi ling (GEP) is now used to risk-stratify
patients with newly diagnosed MM. Groups with high-risk features are evident in
all GEP-defi ned MM classes, and GEP studies of serial samples showed that risk
increases over time, with relapsed disease showing dramatic GEP shifts toward a
signature of poor outcomes. This suggests a common mechanism of disease evolu-
tion and potentially refl ects preferential expansion of therapy-resistant cells.
Correlating GEP-defi ned disease class and risk with outcomes of therapeutic regi-
mens reveals class-specifi c benefi ts for individual agents, as well as mechanistic
insights into drug sensitivity and resistance (Zhou et al. 2009 ).
Signal Genetics’ scientists have analyzed the expression levels of thousands of
human genes that are considered to be linked to MM. Clustering analysis of these
various genes gave rise to the 70 most relevant myeloma linked genes used to make
up the patient’s gene expression profi le, which is the basis of My Prognostic Risk
Signature™ (MyPRS™) as a diagnostic supplement for MM, which can help to
design a personalized regimen. The median survival rate for MM in the US is 2.5–3
years, but personalized approach can raise the median survival rate to 6–7 years.
Personalized Management of Cancers of Various Organs