Haematologica 2003 - Supplements

transcriptional activity of NF-êB; induced phosphorylation,
cytoplasmic sequestration and functional neutralization of proapoptotic
Forkhead transcription factors; and upregulated the
expression of intracellular inhibitors of apoptosis (e.g. survivin).
Furthermore, IGF-stimulation and co-culture with BMSCs
triggered a wide constellation of previously unappreciated
proliferative/anti-apoptotic molecular events, such as
transcriptional activation of genes encoding 26S proteasome
subunits; increase in activity of the proteasome (as evidenced by
20S proteasome chymotryptic activity assays); upregulation of
molecules with key role in MM survival, including molecular
chaperones hsp90, hsp70 and caspase inhibitors (including cIAP-
2 and FLIP); as well as increased expression of DNA synthesis
and repair enzymes (e.g DNA-PK and MSH2) and oncogenes
(e.g. myb, vav). The overlap in molecular sequelae of IGF
stimulation and co-culture of MM cell with BMSCs may be
attributed, at least in part, to the upregulation of IGF secretion by
MM and BMSCs, triggered by their co-culture. Despite the
overlapping patterns of signaling pathways triggered by BMderived
cytokines, important qualitative and quantitative
differences were also noted. Of particular interest is the more
pronounced and sustained biologic sequelae triggered by
stimulation of MM cells with pathophysiologically relevant levels
of IGFs vs. IL-6. Indeed, IGF-1 induced more pronounced and
protracted effects on the activity of NF-êB, Akt, proteasome or
Forkhead transcription factors; and triggered upregulation of a
broader spectrum of intracellular anti-apoptotic molecules (e.g.
IGF-1 upregulated FLIP, XIAP, cIAP2, survivin, while IL-6
upregulated only survivin). These findings may account for the
fact that inhibition of IGF/IGF-1R signaling sensitizes MM cells
against a broader spectrum of anti-MM agents (e.g. Dex,
Doxorubicin, PS-341, Apo2L/TRAIL), in contrast to IL-6
signaling (which cannot protect MM cells from e.g. PS-341- or
Apo2L/TRAIL-induced apoptosis). Furthermore, these findings
are also consistent with the observation that IGF-1R inhibitors
had more potent effect in suppressing the drug-resistance (e.g.
against Dex) conferred to MM cells by adhesion to BMSCs (CS
Mitsiades et al. Blood 2002; 100, 170a).
Importantly, novel biologically-based therapies can counteract
key anti-apoptotic molecular events triggered by MM cell
adhesion to BMSCs; e.g. the proteasome inhibitor PS-341
abrogated the MM-BMSC adhesion-induced upregulation of
survivin and cIAP-2; the upregulation of 20S proteasome activity
could be counteracted either by inhibition of its proteolytic active
site by PS-341, or by agents (e.g. the HDAC inhibitor SAHA or
IGF-1R inhibitors) who target the expression of proteasome
subunits and ubiquitin pathway members. In addition, the
molecular sequelae of adhesion-induced hsp90 upregulation were
abrogated at the level of hsp90 function (by 17-AAG or other
geldanamycin analogs which inhibit the ATPase activity and,
thus, the chaperoning function of hsp90) or at the level of hsp
expression (by SAHA which reduced hsp90 transcription). These
findings are of major pathophysiological and clinical interest,
because they delineate novel roles of the proteasome and heat
shock proteins in mediating survival of MM cells in the BM
milieu, and because they provide mechanistic insight into why
novel therapies targeting the proteasome, the heat shock proteins
(e.g. hsp90) and the IGF/IGF-1R pathway can neutralize the
protective effects of the BM milieu against pro-apoptotic
therapies and yield objective anti-MM responses in vivo.
Furthermore, our GFP-based model of MM-BMSC co-culture
represents a useful tool, not only to delineate the role of the BM
microenvironment in MM, but also to test novel therapies
targeting the BM milieu of MM.
7. New prognostic criteria for
classification and monitoring MM
P7.1
DEVELOPMENT OF AN INTERNATIONAL PROGNOSTIC
INDEX (IPI) FOR MYELOMA: REPORT OF THE
INTERNATIONAL MYELOMA WORKING GROUP
P.R. Greipp, J.F. San Miguel, R Fonseca, H. Avet-Loiseau,
J.L. Jacobson+, E. Rasmussen+, J.J. Crowley+, and
B.G.M. Durie
On behalf of the International Myeloma Working Group* **+(CRAB)
Cancer Research and Biostatistics, Seattle, WA *Supported by the
International Myeloma Foundation - Los Angeles, CA
Background: Proper staging is important for accurate prognosis
and for comparison of data from clinical trials from different
institutions and groups. Investigators have recognized since the
1960’s that variables such as hemoglobin, creatinine and calcium
forecast survival in multiple myeloma (MM) 1,2 . In 1975, Durie
and Salmon developed a staging system (DS) to identify patients
with higher or lower tumor burden that includes measurement of
the level of M-protein in the serum and urine, hemoglobin,
calcium, bone lesions, and creatinine 3 . Attempts to improve on
the widely accepted DS system have stimulated development of
numerous prognostic systems. Acceptance of new systems has
been limited because of inconsistent use of tests at the community
level, lack of agreement on relative merits of the individual
components, and difficulty reaching consensus on how best to
combine variables into a single, easy to use staging system. We
wished to develop an international consensus on a new myeloma
staging system which could be adopted as the myeloma
International Prognostic Index (IPI) for both standard and high
dose therapy. We also wished to analyze the prognostic impact of
karyotype analysis in the subset of patients in which conventional
cytogenetics had been performed.
Methods: Meetings were held in St. Thomas in 2000 and 2002,
and at the American Society of Hematology meetings in 2000,
2001, and 2002. Attendance included an international community
from North and South America, Europe, Asia, and Africa, There
was general acknowledgment of the need to update DS and to
develop a simple, easy to use, reliable myeloma IPI. Solicitations
of support were sent worldwide and data requests were sent to
institutions and groups who agreed to participate. The data was
received and closed to entry by March 1, 2003. CRAB developed
data spread sheets, coordinated data collection,
corrected/evaluated incomplete data and performed the
subsequent data analysis. An executive committee, supervised the
collection and analysis of data, and held a series of
teleconferences.
CRAB and the Executive Committee adopted an overall strategy
to identify 2 or 3 variables that would provide the best separation
of survival and to identify a group at highest risk. Test
availability, relative risk, independent prognostic significance,
reproducibility, biologic relevance, and practicality were
considered in choosing and combining candidate variables. Final
choices for inclusion in the model were data driven and decided
by consensus once the univariate assessment was complete and
several models were tested. In addition to test variables
consideration was given to performance status, age, gender, race
and ethnicity.
Less commonly available data such as plasmablastic morphology,
the plasma cell labeling index, and circulating myeloma cells,
though prognostically very relevant, were not used for the final
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