MB4-2 breakpoint in MMSET combined with del(17p) defines a subset of t(4;14) multiple myeloma with very poor prognosis

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Published Ahead of Print on July 23, 2015, as doi:10.3324/haematol.2015.127001. Copyright 2015 Ferrata Storti Foundation.

1 Published Ahead of Print on July 23, 2015, as doi: /haematol Copyright 2015 Ferrata Storti Foundation. MB4-2 breakpoint in MMSET combined with del(17p) defines a subset of t(4;14) multiple myeloma with very poor prognosis by Anne Lazareth, Xiu-Yi Song, Aurelie Coquin, Stephanie Harel, Lionel Karlin, Karim Belhadj, Damien Roosweil, Laurent Frenzel, Jerôme Tamburini, Margaret Macro, Sylvie Chevret, Herve' Avet-Loiseau, Stephane Minvielle, Jean Paul Fermand, Jean Soulier, Jean Christophe Bories, and Bertrand Arnulf Haematologica 2015 [Epub ahead of print] Citation: Lazareth A, Song XY, Coquin A, Harel S, Karlin L, Belhadj K, Roosweil D, Frenzel L, Tamburini J, Macro M, Chevret S, Avet-Loiseau H, Minvielle S, Fermand JP, Soulier J, Bories JC, and Arnulf B. MB4-2 breakpoint in MMSET combined with del(17p) defines a subset of t(4;14) multiple myeloma with very poor prognosis. Haematologica. 2015; 100:xxx doi: /haematol Publisher's Disclaimer. E-publishing ahead of print is increasingly important for the rapid dissemination of science. Haematologica is, therefore, E-publishing PDF files of an early version of manuscripts that have completed a regular peer review and have been accepted for publication. E-publishing of this PDF file has been approved by the authors. After having E-published Ahead of Print, manuscripts will then undergo technical and English editing, typesetting, proof correction and be presented for the authors' final approval; the final version of the manuscript will then appear in print on a regular issue of the journal. All legal disclaimers that apply to the journal also pertain to this production process.

2 Ž ƒ Š Ž ˆ ƒ ˆ Ž Ž Ž ƒ Š ƒœƒ Š Ž Šƒ ƒ Ž Žƒ Ž ƒ ŽŠƒ Œ ƒ Ž ƒ œ Ž Ø ƒ ƒ ƒ ƒ Ž Š ± ƒ Šƒ ŽŽ ƒƒ Ž ƒ ƒ Ž ƒš Š ƒ ƒ Žˆ ƒ Ž ƒ Š ƒ ˆƒ ƒ Š Ž ƒšƒ ƒš Š ƒ ƒ ƒ ƒ ˆ ƒ Š Š Š ƒ ƒ Š Ž Ž ƒ Š Ž ˆ Š Š Ž ƒ ƒ Ž ƒ ƒž ƒ ƒ ± ƒ ƒ ± ƒ ƒ ±ƒ Ž ƒ ƒ Ž ƒž ƒ Ž ƒ ƒžƒ ƒ ƒ Ž ƒž ƒ ƒ Ž ƒž ƒ ƒ Ž ƒž Ž ƒ ƒ Ž ƒž ƒž ƒ ƒ ƒ Ž ƒž ƒ ƒ ƒ Ž Š ƒž ƒ ƒ ƒ Ž ƒ ƒž ƒ ƒ ƒ ƒ ƒž ƒ ƒ Ž ƒž ƒ Ž ƒ ƒž Ž ƒ ƒžƒ ƒ Š ƒ ŽˆŠ ƒ Ž Žƒ ŽŽ ˆƒ š ƒ ƒžƒ ƒ Ž ƒš ƒ Ž ƒ ƒ Žˆ Ž ƒ Š ˆ

3 Ž Ž Ž ƒ ƒ Ž ƒž Žƒ ƒ ŽŽ Š Š ƒ ƒ Ž Š ƒ Ž ƒ ˆ ƒ Š ƒ ƒ ƒ Š ƒ Šƒ œ ƒ ŽŽ ƒ ƒ ƒš ƒ ŠŠ Š ƒ ƒ ƒ Š ƒ Ž ƒ ƒž Ž ƒ ƒ Ž ƒž ƒ ƒ Š ˆ ˆ ƒ Ž ƒ ƒ Ž ˆ Š Ž ˆ Š ˆˆ ˆ ˆ Ž ƒž ƒ ƒ Š ƒ Ž Žƒ Š ƒ Ž ƒ Žƒ ƒž ƒ Šƒ Š Šƒ š Š Š Ž ƒ ˆ Šƒ ˆ ƒ ƒ ƒ ƒž Š Š Š š ƒžž ˆ ƒš Š Ž ƒ ˆ ƒ Š Š Ž ƒ ƒ Ž Š ƒœ ƒ Š Š ˆƒ Šƒ ƒ Š ƒ Š ƒ š ƒ ˆ ˆ ƒ Š Ž ƒˆ ŽŽŽ Š ƒ ˆˆ ƒ Š ƒ ˆ Š ƒ Žƒ ˆ Š ˆ ƒ ˆ ƒ Š ƒ ƒžƒ Š ˆ ƒ ƒ Š ƒ ƒ ƒž ƒ Š ˆ ƒ Š Ž ƒž ƒ ƒ Š Ž ƒ ƒ ƒ ƒ ƒ ƒ ƒž Žƒ ˆ ƒ ƒ ƒ ƒ ƒ Š ƒ ƒ Ž ƒžƒ ƒ ˆƒ ƒ ƒ ƒ ƒžž ƒ ƒ ƒ ƒ ƒ ˆ ˆ ˆ

4 ƒ Žƒ ƒ ŽŽ ƒ ƒ ƒƒž š ˆ ƒ Š ˆ ƒ Ž ˆ Š ˆˆ ƒ ƒ ƒ Ž Š ƒ ƒ ƒ ƒ ƒž ƒ ˆ ƒž ƒƒ ƒ ƒˆ ŽŽ ƒ ˆ Š ƒƒž ˆ Š ˆˆ ˆ ƒ ƒž ƒž ƒ ˆ Š ƒ Š Š ƒ ƒ Ž ƒ ƒ Š ƒ ƒ š ˆ ƒ ƒ ƒ ˆ ƒ ˆ Ž Š Š ƒ ƒ Ž Ž Ž ƒž ƒ ƒ Š Š Ž ˆ ƒ Ž ˆ ƒ ƒ Ž Šƒ ƒ ˆ ƒ Š ƒ Ž š Žƒ ƒžž ƒ ƒ ƒ Ž ƒ Š ƒ ˆ ƒ ƒ œ ƒ ˆ Ž Š ƒ ƒ ˆ ƒ Šƒ ƒ ƒ Ž ŽŽ ƒ Žƒ ƒ Ž ƒ ƒƒˆ Žƒ Žƒ œ ƒ ˆ Ž ƒ ƒ ƒ (p=0.026) ƒ ƒ (p=0.0014) ƒžž ƒ Š ˆ Ž Š ƒ ƒ ƒ ƒ Š ƒ Ž Ž ˆ ƒ ƒ Š ƒ ƒ ƒž ƒ ƒ ƒ ˆ ƒ Šƒ Š ƒ ƒ ƒ ƒ Šƒ ƒž ˆ Š ˆ

5 Ž ƒ Ž ƒ ƒ Ž ˆ ƒ ˆ ˆ Ž œ ƒ Š ƒ ˆ ƒ Š ƒ ƒ ƒƒž ƒ ƒ ˆ ƒž ƒžž ƒž ƒž ƒˆ Š ˆ Žƒ ƒ Žƒ ƒƒž Š Šƒ ƒˆ ŽŽ ˆ Š Š ƒ Šƒ ˆ Š ˆˆ ƒ ˆ ƒ Š Š ƒ ƒ Š Šƒ Šƒ ƒ Š Š Š ƒ Ž ƒžƒˆ ˆ Žƒ ƒ Š ƒ Š Š Ž ƒ ƒ ƒƒž ƒ Š Ž Ž Ž ƒž ƒ ƒ Ž Ž Ž Ž ƒ ƒ ƒž ƒ ƒ ƒ ƒ ˆƒ ˆ ƒž ƒž Š Š ƒž ƒ Š ƒ Š Š ƒ ƒ ˆ Ž Š ƒ Ž Š ƒ Žƒ ƒ Šƒ ƒ ˆ Š ƒ Š ƒ ˆ ƒ Š ˆ ƒ Ž ˆ Š ƒ Ž Š Š ƒ ƒ ŠŠ Š ƒ ƒƒž œ ƒ ƒ ƒ ˆ Š Š Žƒ ƒ ŽŽ ƒ ƒ Žƒ Ž ƒžž Ž ƒ ˆ ƒ Ž ƒ ƒ Šƒ ƒ Ž Ž Šƒ ˆ Žƒ ƒ ŽŽ Š ˆ Ž ƒ ƒ ƒ Šƒ ƒž ƒ ƒž Š ƒ ƒ Š Š Ž ƒ ƒ ƒžž ˆ Ž ˆ ŽŽ Š ƒ ƒ ƒ ƒ ˆ ƒ ƒ Žƒ

6 ƒ Žƒ ƒ ŽŽ Š ƒ Š ˆ Ž Š ƒ ƒ Žƒ Š Ž ƒ ƒ Ž ƒ ƒ Š Ž Š Š Šƒ Š ƒ Žƒ ƒ Š Šƒ Š Š Š ƒ Šƒ ƒ ˆ Š ƒ ƒ Šƒ ƒ Š ƒ ˆ Ž Ž ƒ ƒ ƒƒž ˆ ƒ ˆ Š Š Ž ƒ ƒ ƒ ƒ ƒ ˆ ƒž Š Ž ƒ Šƒ ƒ Š Ž ƒ Š ƒ ƒ ˆ Š Š ƒ Šƒ Ž ƒ Š Š ˆ ƒ ƒž Š Šˆ ƒ Žƒ ƒžž ƒž Š ˆˆ Šƒ ƒžƒƒž ƒ ˆ ƒ ƒžž ˆ ƒ ƒ Š ƒž ƒƒž ƒ ƒ Š Š Ž ƒ ƒ Š ƒ Ž ƒˆ ŽŽŽ Š ƒ ƒ Ž ƒ ƒ ƒ Šƒ ƒ Š ˆ ƒž ˆ Š ƒ Š Ž Žƒ ƒ ˆ Š ƒ Žƒ Ž ƒ ƒ Š Š ƒ Ž ƒ Šƒ Š Šƒ š ˆ ƒ ƒ ˆ Š Žƒ ƒ ƒ ƒ Š Žƒ ƒ ƒ ˆ ƒ ƒ Ž Š Žƒ Ž ƒ š ƒ Ž ƒ Š Ž Šƒ Š Š Š Ž Ž ˆ Ž ˆ š ˆƒ ƒ Ž

7 Žƒ ƒ ŽŽ ˆ Ž Š ƒ Ž ƒžž Š ˆ Š ƒ Ž Šƒ Ž Š ƒ ƒž Šƒ ƒž Ž ƒ Š ŽŽ Žƒ ƒƒ Š Š Š Š Ž ƒ ˆ ƒ ƒ Š ˆ Š Š Š Žƒ ˆ Š Š Šˆƒ Ž ƒ Š ˆƒ Ž ƒ ƒ ƒ Š ˆ Š ƒž ˆ ƒ ˆ Š Š ˆ Šƒ ƒ Ž ƒ Š ˆ ƒ Ž ƒ Ž Š Š ƒ ˆ ƒ ˆˆ ƒž ˆˆ ƒƒ ƒ Ž Ž ƒ ˆ Š ˆˆ Ž ƒž ˆ Š ƒ ƒžž ƒ ˆˆ ƒ Ž Žƒ Š ˆ Š ƒ Žƒ Š ƒ Ž ƒ Š Ž Š ƒ Ž ƒ ƒ ƒ Žƒ Š ƒ Š š ˆ ƒ ƒ ˆ Š ƒ ŽŽ ƒ Š Š Š ƒ Ž ƒ Š ˆˆ ƒ ƒ š ˆˆ ƒ Š ƒ Š ˆ ƒ ƒ ƒš Šˆ ˆ Ž ƒ Žƒ ƒ ŽŽ š Š ƒ ˆ ˆ Š ƒ ˆ Š ƒ ƒž Ž ƒ ƒ Š Ž ƒ ˆ ƒžž Ž ƒ ƒ Š Ž ƒ Š Š Šƒ ƒ Žƒ ˆ ƒ ƒ ƒ Š Ž ƒž ƒ Š ˆˆ ƒ ƒ Š

8 ƒ ƒ ƒ Š Ž ƒ ˆ Ž ƒ Ž Š Ž ƒ Šƒ Š ƒ Š Š Ž ƒ š Žƒ ƒ Š Š ˆ ƒ ƒ Š Š ƒ ƒ ˆ ƒ ˆ Š ƒ ƒž Š Š ˆ ƒ Ž ƒ ˆ Ž Š ƒƒ ˆ ƒ Š ƒ ƒ ƒ Š ƒ ˆ ˆ Š ƒ ƒ ƒ

9 ˆ ƒ Ž Ž ƒž œ Ž šƒ Šƒ ˆ ƒ Š Ž ƒ ˆ ƒ Š Ž Ž Ž ƒ ƒ Ž ƒž ƒ Ž ƒ Š ˆ Ž Ž Ž ƒ ƒžž ƒ Š Š ƒ Ž ƒ ƒžƒ ƒ ƒž ˆ Ž Ž Ž ƒ ˆ ŽŽ ˆ ƒ ƒ Š ƒ ƒ Žƒ ƒ ƒž ƒ œ ƒž ± œ ƒž ƒžš ˆ Ž Ž ƒƒ ƒžž Ž Ž Ž ƒ Ž ƒ Ž ƒž š ƒ ˆ ƒžž ƒ ƒž Žƒ ƒ ŽŽ Ž ƒ ƒ Ž Ž Šƒ ƒžž ƒžƒ Ž ƒžˆ ƒ ˆ Ž Ž Ž ƒƒ Š ƒ ƒ ƒƒš ŽŽ ƒž Ž Ž Ž ƒ ƒ ƒ ˆƒ ˆ š Ž Š ƒ ƒž Š ƒ Ž ƒ Ž ƒ Žƒ Š ƒ ƒ Ž Ž Š ƒ Ž ƒ ƒ Š ƒƒ Š ƒžš ƒš Š Ž ƒ ˆ ƒ Š Šƒ ƒ ˆ ƒ ƒ ƒž Ž Š Š ƒžž Š Žƒ ˆŠ ƒ Ž ƒ Ž ŽŽ Šƒ ƒž Žƒ Š Š Žƒ ƒ ƒ Žƒ ƒ ƒƒ ƒ ƒ ƒš ŽŽ ƒ Ž ƒž š ˆ ƒ ƒ ˆ Š Ž Šƒ ƒ œ ƒžž Ž Ž Ž ƒ ƒ Ž Ž ƒœ ƒ ƒ ˆ ƒ ƒ ƒ ˆ ƒ ƒ ƒ ˆ Ž Ž Ž ƒ ƒ Šƒ Ž ƒ ƒ ƒž ƒ ˆ ŽŽ ˆˆ Žƒ Š ˆƒ š ƒ ƒ Žƒ Žƒ ƒ ŽŽ ˆŽ ƒ Š Ž Ž Ž ƒ ƒ ƒ Ž ƒˆˆ ƒ Šƒ ƒž Ž ƒž Š ƒ ˆ Ž ƒž ƒ ƒ ƒ Ž Š Žƒ Ž ƒ ƒ ƒ Š ƒž ƒ Šƒ Š Ž ƒˆ ƒ ƒ ƒ Ž ƒ ƒž Ž ƒž Š ƒ Š Žƒ Ž Š ƒž ƒ ƒ

10 ƒ Ž ƒ Ž Šƒ ƒ ˆ ƒ ƒ ƒ Š ƒ ƒ Š ƒ Breakpoint MB4-1 MB4-2 MB4-3 MGUS/Stage I MM n=38 (%) 28 (74) 2 (5) 8 (21) Symptomatic MM n=256 (%) 159(62) 53 (21) 44 (17) Median age (years) 58 (36-91) 56 (33-76) 59 (46-74) IgA isotype n=101/235 (%) 57 (38) 25 (53) 19 (47) Median % of bone marrow plasma cells (range) 22 (1-90) 29 (0-81) 36 (1-94) Calcemia >2.7mmol/l n=30/137 (%) 19 (22) 7 (27) 4 (17) Creatinine>170µmol/l n=27/138 (%) 14 (16) 5 (19) 8 (35) Elevated LDH n=29/102 (%) 16 (25) 4 (21) 3 (21) Anemia (Hg<10g/dl) n=74/137 (%) 46 (52) 13 (52) 15 (65) International Staging System n=134 (%) ISS 1 20 (30) 6 (33) 4 (20) ISS 2 27 (41) 4 (22) 8 (40) ISS 3 19 (29) 8 (44) 8 (40) FGFR3 expression n=256 (%) Yes 129 (81) 43 (81) 36 (82) No 30 (19) 10 (19) 8 (18) Treatment n=256 (%) Bortezomib based regimen 109 (69) 41 (77) 31 (70) Bortezomib+Imid combo regimen 28 (18) 17 (32*) 4 (10) High dose therapy + ASCT 113 (71) 40 (75) 34 (77) Response n=142 (%) Overall response 68 (78) 24 (89) 20 (76) >very good partial response 44 (49) 19 (70*) 12 (44) Partial response 24 (29) 5 (19) 8 (32) Stable disease 8 (10) 0 (0) 2 (8) Progressive disease 8 (10) 3 (11) 3 (12) *Signifiicant differences between the three groups: percentage of response superior to very good partial response (p=0.049) and percentage of Imid based regimen (p=0.0228)

11 Ž ˆ ƒž ƒžž ƒžƒ ƒžƒˆ Š ˆ Žƒ ˆ Š ƒ Š ƒ ƒ Š ƒ Ž ƒ ƒ ƒ ƒž ˆ ƒ ƒ Š Š ƒ Ž ƒ Žƒ ƒƒž ƒžž ƒž ˆ Š ƒ Š ƒƒž ƒ ƒ ƒ Žƒ Ž ƒ Š ƒ ƒ Ž ƒ ƒž ˆ ƒ Ž ƒ Š Š ƒ ƒ Žƒ ƒƒž Ž Ž Ž Ž Ž Ž

Association of Acute Myeloid Leukemia s Most Immature Phenotype with Risk Groups and Outcomes

Published Ahead of Print on January 27, 2016, as doi:10.3324/haematol.2015.135194. Copyright 2016 Ferrata Storti Foundation. Association of Acute Myeloid Leukemia s Most Immature Phenotype with Risk Groups