A Prospective Study of t(4;14) Multiple Myeloma.
Authors: Karlin Lionel , Ghez David , Choquet Sylvain , Belhadj Karim , Macro Margaret , Bouscary Didier , Soulier Jean , Porcher Raphael , Malphettes Marion , Asli Bouchra , Brouet Jean-Claude , Fermand Jean-Paul , Arnulf Bertrand 
Published: October 2019

Abstract
The t(4;14)(p16.3;q32) leads to the ectopic expression of two oncogenes, the Multiple Myeloma Set Gene (MMSET) and the Fibroblast Growth Factor 3 (FGFR3). It is found in 15% of patients with multiple myeloma (MM) and indicates a poor prognosis. To identify the clinico-biological features associated with this adverse prognosis, we prospectively studied a series of 79 patients with t(4;14) MM.Between March 2002 and July 2007, a t(4;14) was detected by real time quantitative PCR of the IGH/MMSET and FGFR3 transcripts in 79 patients. The clinico-biological data were analysed at diagnosis and at relapse. Response rate and time to progression (TTP) after successive lines of chemotherapy, and overall survival (OS), according to beta2m and haemoglobin level, and expression of FGFR3, were evaluated. Among the 79 patients (median age:55 years), 18 (22.8%) had a MGUS or smouldering myeloma and 61 (77.2%) had a symptomatic MM. At diagnosis, no clinical or radiological feature was significantly associated. As expected, 15 patients (18%) had a t(4;14) without expression of FGFR3. IgA isotype was found in 41% and del(13) in 90% of patients. Contrasting with previous studies, only 52% of symptomatic MM had elevated beta2m (>3mg/L). Fourty-two patients (53.1%) received autologous stem cell transplantation (ASCT). In those, the overall response (OR) was 90%. Among those responders, 16% had a complete response (CR) and 53% had a very good partial response (VGPR). Median TTP after ASCT was only 12 months. At relapse, aggressive features (plasmocytoma, cytopenias, acute renal failure, circulating plasma cells) were observed in 23% of cases. After 2nd line chemotherapy, response rate was only 49% and TTP was 6.4 months. Noteworthy, there was a trend toward a better TTP in patients treated with bortezomib as compared to thalidomide in 2nd line therapy (p=0.06). Median OS after ASCT was 31 months, independently of FGFR3 expression and isotype. OS was not significantly different in patients with and without high beta2m (>3mg/L) or low hemoglobin (<100 g/L) at diagnosis. Nineteen patients (24%) received conventional chemotherapy. The OR rate was lower than after ASCT (52%). In this subgroup, median TTP and OS were respectively 7,6 and 30 months. Of the 18 patients (22,8%) with MGUS or smoldering MM, 7 (30%) became symptomatic within a median time of 9,2 months. This study shows that t(4;14) MM are characterized by a high response rate after ASCT contrasting with a short TTP and aggressive, chemoresistant relapses. Despite the increased use of novel molecules, the OS of t(4;14) MM remains shorter than other types of MM. However, the use of bortezomib in first relapse seems to be more effective than thalidomide. Classically used prognosis factors such as beta2m and hemoglobin level here had no impact on OS. Interestingly, t(4;14) and FGFR3 expression are significantly detected in MGUS/smoldering MM. A high proportion of those patients progressed into aggressive stage in a short period of time, suggesting an early transforming role of FGFR3 subsequently leading to molecular additional events.