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Prepublished online as a Blood First Edition Paper on October 3, 2002; DOI 10.1182/blood-2002-06-1675.
Submitted June 6, 2002
Accepted September 15, 2002
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, Michael J Mant, Andrew R Belch, and Linda M Pilarski*
Department of Oncology, University of Alberta & Cross Cancer Institute, Edmonton, AB, Canada
Department of Medicine, University of Alberta, Edmonton, AB, Canada
* Corresponding author; email: lpilarsk{at}gpu.srv.ualberta.ca.
This study analyzed the frequency and clinical significance of t(4;14)(p16;q32) in multiple myeloma (MM) among 208 MM and 52 monoclonal gammopathy of undetermined significance (MGUS) patients collected between 1994 to 2001. Patients with the translocation were identified using RT-PCR to detect hybrid IgH-MMSET transcripts from the der(4) chromosome. We found 31 t(4;14)+ MM patients (14.9%) and one t(4;14)+ MGUS (1.9%). IgH-MMSET hybrid transcripts were detected in bone marrow (BM) and blood. Breakpoint analysis reveals that 67.7% of t(4;14)+ patients express hybrid transcripts potentially encoding full length MMSET while the remainder lack one or more amino terminal exons. Expression of FGFR3, presumptively dysregulated on der(14), was detected by RT-PCR in only 23/31 t(4;14)+ MM patients (74%). 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 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=0.006, median 644 days vs. 1288 days, HR 2.0), even in FGFR3 non-expressors (p=0.003). The presence of t(4;14) is also predictive of poor response to first-line chemotherapy (p=0.05). 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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