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Prepublished online as a Blood First Edition Paper on October 3, 2002; DOI 10.1182/blood-2002-06-1675.
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Blood, 15 February 2003, Vol. 101, No. 4, pp. 1520-1529
NEOPLASIA
In multiple myeloma, t(4;14)(p16;q32) is an adverse prognostic
factor irrespective of FGFR3 expression
Jonathan J. Keats,
Tony Reiman,
Christopher A. Maxwell,
Brian J. Taylor,
Loree M. Larratt,
Michael J. Mant,
Andrew R. Belch, and
Linda M. Pilarski
From the Departments of Oncology and Medicine,
University of Alberta and Cross Cancer Institute, Edmonton, Alberta,
Canada.
This study analyzed the frequency and clinical significance of
t(4;14)(p16;q32) in multiple myeloma (MM) among 208 patients with MM
and 52 patients with monoclonal gammopathy of undetermined significance
(MGUS); diagnosed between 1994 and 2001. Patients with the
translocation were identified using reverse transcription-polymerase chain reaction (RT-PCR) to detect hybrid immunoglobulin heavy chain
(IgH)-MMSET transcripts from the der(4) chromosome. We found 31 (14.9%) t(4;14)+ MM patients and 1 (1.9%)
t(4;14)+ MGUS patient. IgH-MMSET hybrid transcripts were
detected in bone marrow (BM) and blood. Breakpoint analysis revealed
that 67.7% of t(4;14)+ patients expressed hybrid
transcripts potentially encoding full-length MMSET, whereas the
remainder lacked one or more amino terminal exons. Expression of
fibroblast growth factor receptor 3 (FGFR3), presumptively dysregulated
on der(14), was detected by RT-PCR in only 23 of 31 (74%) patients
with t(4;14)+ MM. Patients lacking FGFR3 expression also
lacked detectable der(14) products. Longitudinal analysis of 53 MM
patients with multiple BM and blood samples showed that, over time, BM
from t(4;14)+ patients remained positive and that
t(4;14) patients did not acquire the translocation.
IgH-MMSET hybrid transcripts and FGFR3 transcripts disappeared from
blood during response to therapy. No correlation was observed between
the occurrence of t(4;14) and known prognostic indicators. However, we
find the t(4;14) translocation predicts for poor survival
(P = .006; median, 644 days vs 1288 days; hazard ratio
[HR], 2.0), even in FGFR3 nonexpressors (P = .003). The
presence of t(4;14) is also predictive of poor response to first-line
chemotherapy (P = .05). These results indicate a
significant clinical impact of the t(4;14) translocation in MM that is
independent of FGFR3 expression.
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