Gene expression profiles of multiple myeloma plasma cell fractions from bone marrow I

Todays diagnostic tests for multiple myeloma (MM) reflect the criteria of the updated WHO classification based on biomarkers and clinicopathologic heterogeneity. To that end, we propose a new subtyping of myeloma plasma cells (PC) by B-cell subset associated gene signatures (BAGS), from the normal B-cell hierarchy in the bone marrow (BM). To do this, we combined FACS and GEP data from normal BM samples to generate classifiers by BAGS for the PreBI, PreBII, immature (Im), nave (N), memory (M) and PC subsets. The resultant tumor assignments in available clinical datasets exhibited similar BAGS subtype frequencies in four cohorts across 1302 individual cases. The prognostic impact of BAGS was analyzed in patients treated with high dose melphalan as first line therapy in three prospective trials: UAMS, HOVON65/GMMG-HD4 and MRC Myeloma IX with Affymetrix U133 plus 2.0 microarray data available from diagnostic myeloma PC samples. The BAGS subtypes were significantly associated with progression free (PFS) and overall survival (OS) (PFS, P=3.05e06 and OS, P=1.06e11) in a meta-analysis of 926 pts. The major impact was observed within the PreBII and M subtypes conferred with significant inferior prognosis compared to the Im, N and PC subtypes. Cox proportional hazard meta-analysis documented that the BAGS subtypes added significant and independent prognostic information to the TC classification system and ISS staging. BAGS subtype analysis identified transcriptome differences and a number of novel differentially spliced genes. We have identified hierarchal subtype differences in the myeloma plasma cells, with prognostic impact. This observation support an acquired reversible B-cell trait and phenotypic plasticity as a hallmark, also in MM.

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Bødker JS, Brøndum RF, Schmitz A, Schönherz AA, Jespersen DS, Sønderkær M, Vesteghem C, Due H, Nørgaard CH, Perez-Andres M, Samur MK, Davies F, Walker B, Pawlyn C, Kaiser M, Johnson D, Bertsch U, Broyl A, van Duin M, Shah R, Johansen P, Nørgaard MA, Samworth RJ, Sonneveld P, Goldschmidt H, Morgan GJ, Orfao A, Munshi N, Johnson HE, El-Galaly T, Dybkær K, Bøgsted M