Rare Igh Translocations in Newly Diagnosed Multiple Myeloma (MM) Patients: Cytogenetic Characterization and Relevance on Prognosis
Authors: Marzocchi Giulia , Ameli Gaia , Pezzi Annalisa , Zamagni Elena , Cavallo Federica , Petrucci Maria Teresa , Waage Anders , Di Raimondo Francesco , Patriarca Francesca , Rambaldi Alessandro , Gamberi Barbara , Crippa Claudia , Zweegman Sonja , Montefusco Vittorio , Vincelli Iolanda , Offidani Massimo , Palumbo Antonio , Sonneveld Pieter , Cavo Michele , Testoni Nicoletta 
Published: October 2019

Abstract
INTRODUCTION: Cytogenetic abnormalities (CA) are one of the major factor for risk stratification in Multiple Myeloma (MM). Approximately 50% of MM patients (pts) harbour a translocation involving the Immunoglobulin Heavy chain locus (IgH). Each translocation is associated with deregulation of a D group cyclin, either directly in t(11;14)(q13;q32) and t(6;14)(p21;q32) or indirectly in t(4;14)(p16;q32) and in MAF translocations: t(14;16)(q32;q23) and t(14;20)(q32;q12). Some translocations are recurrent but rare events, occurring in less than 5% of the pts: t(6;14) is considered a standard prognostic feature, whereas t(14;16) and t(14;20) are associated with bad prognosis. As a result of their low incidence, few data support their use of these abnormalities in the risk stratification. Currently, deletion(17)(p13) and gain(1)(q21) are linked with adverse clinical outcome and, recently, also deletion(1p) has been considered adverse prognostic factor. AIM: To assess the type and frequency of these rare IgH translocations and their association with other adverse genetic lesions and with clinical characteristics, in a large series of newly diagnosed MM pts.
METHODS: A total of 682 pts newly diagnosed MM pts, enrolled in several prospective clinical trials of bortezomib-based induction therapy and subsequent autologous stem cell transplantation, including most recent EMN02 clinical trial, were analyzed. Probes for FISH analysis were used to detect t(4;14), t(6;14), t(11,14), t(14;16), t(14;20); deletion of 1p32, 13q14, 17p13; gain of 1q21; trisomy of chromosomes 5/9/15.
RESULTS: On evaluable cases, the frequency of each IgH translocation, as detected by FISH was as follows: t(11;14) in 114/596 (19.1%), t(4;14) in 78/605 (12.9%), t(14;16) in 27/603(4.5%), t(14;20) in 9/591(1.5%) and t(6;14) in 7/587(1.2%). Every rare translocation was associated with deletions flanking the breakpoints, either as unique pattern or with classical translocation. The t(6;14) was closely associated with del(6)(p21)(6/7), del(13q)(4/7) and del(16)(q23)(3/7); additional gain 1q and deletion 17p was observed in a single case. All together, the high-risk (HR) translocations, t(14;16) and t(14;20), were detected in 36 pts: 63.9% were females and 36.1% males. The t(14;16) was frequently occurred with del(13q) (84.6%), gain(1q) (74.1%; 20/27) and del(16)(q23) (74.1%; 20/27), while t(14;20) was associated with del(13q) (88.9%; 8/9), gain(1q) (5/9; 55.6%) and del(20)(q12) (5/9; 55.6%). In selected cases, the presence of these additional abnormalities was shown also by SNPs arrays. Beyond del(13q), gain(1q) was the most frequent additional abnormality (69.4%; 25/36), occurring in 56.4% (44/78) of t(4;14) cases and in 20.2% (23/114) of t(11;14) cases (p<0.001). Del(17p) was present in 16.6% (6/36) of rare HR translocations and in 10.3% (8/78) and 7.9% (9/114) of t(4;14) and t(11;14) cases, respectively (p=0.313). Likewise, the presence of del(1p) was higher in pts with HR translocations (7/36, 19.4%) as compared to pts with t(4;14) and t(11;14) (6/77, 7.8% and 2/114, 1.8% respectively, p=0.001). Rare HR translocations never occurred as in isolation.
Compared with pts without rare HR translocations, pts harbouring t(14;16) or t(14;20) showed a high probability to present with additional characteristics related to poor prognosis, including ISS stage 3 (42% vs 20%, p=0.002), Hb <10.5 g/L (58% vs 38%, p=0.016) and Ptls < 150000/mm3(31% vs 13%, p=0.003). The occurrence of lytic bone lesions was reported in 61% vs 79% of pts with and without HR translocations respectively (p=0.011). Other clinical parameters, such as age, C reactive protein and LDH were similar between the two groups.
CONCLUSION: t(14;16)(q32;q23) and t(14;20)(q32;q12) are rare in newly diagnosed MM pts and are associated with an increased frequency of additional HR abnormalities, including gain(1)(q21), deletion(1)(p32) and deletion(17)(p13). Furthermore, they are related to features of aggressive disease, such as ISS stage 3, lower level of hemoglobin and lower platelet count. A longer follow-up is needed to point out their prognostic relevance of these abnormalities.

Disclosures
Cavallo: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria; Onyx: Honoraria. Petrucci:Bristol Meyer-Sqibb: Honoraria; Sanofi: Honoraria; Janssen-Cilag: Honoraria; Celgene: Honoraria. Palumbo:Amgen: Consultancy, Honoraria; Brystol-Myers Squibb: Consultancy, Honoraria; Array BioPharma: Honoraria; Genmab A/S: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Millenium Pharmaceuticals, Inc.: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Onyx Pharmceuticals: Consultancy, Honoraria; Sanofi Aventis: Honoraria. Sonneveld:Celgene: Research Funding, Speakers Bureau; Millennium-Takeda: Research Funding; Onyx: Research Funding, Speakers Bureau; Janssen: Speakers Bureau. Cavo:Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Millennium Pharm.: Consultancy, Honoraria; Bristol-Myers Squib: Consultancy, Honoraria; Onyx: Honoraria.