Pretransplant induction with VTD (Bortezomib/Thalidomide/Dexamethasone) significantly improves PFS: long-term results of the randomized phase 3 PETHEMA/GEM study

Kingdom; Department of Hematopathology, Aalborg University Hospital, Denmark; Clinical Cancer Research Center, Aalborg University Hospital, Denmark and The Department of Clinical Medicine, Aalborg University, Denmark Background: Today’s diagnostic tests for multiple myeloma (MM) reflect the criteria of the updatedWHO classification based on biomarkers and clinicopathologic heterogeneity. To that end, we propose a new biological subtyping of myeloma plasma cells (PC) by B-cell subset associated gene signatures (BAGS), from the normal Bcell hierarchy in the bone marrow (BM). Here we document the prognostic and biological value of subtyping, as shown for DLBCL (JCO 2015 Apr 20;33:1379). Patients and Methods: We combined FACS and GEP to generate BAGS classifiers for the PreB-I, PreB-II, immature, naive, memory (M) and PC subsets in normal BM. Construction was based onmedian-centered probe sets from the BM data using regularized multinomial regression with six discrete outcomes representing BAGS, by a total of 55 genes varying from 1524 per subtype. Each patient underwent BAGS assignment according to the highest predicted probability score above 0.45 or was otherwise unclassified. The impact of BAGS was analyzed using six clinical cohorts, gathered across geographical regions, time eras, and sampling methods. The analysis estimated subtype frequencies and included a prognostic meta-analysis of 926 patients treated with high dose melphalan as first line therapy in 3 prospective trials: UAMS, HOVON65/GMMG-HD4, MRC Myeloma IX data with the Affymetrix U133 plus 2.0 microarray data available from myeloma PC samples. To compensate for cohort-wise technical batch effects, each cohort was median centered and adjusted probe set-wise to have same variance as the BM data. Results: The resultant tumor assignments exhibited similar BAGS subtype frequencies across 1302 individual MM cases with identical frequencies in the six cohorts. The BAGS subtypes were significantly associated with overall and progression free survival (OS, P1⁄41.1e-16 and PFS, P1⁄47.3e-9) in the metaanalysis of 926 pts. The major impact was observed within the PreB-II and M subtypes conferred with significant inferior prognosis compared to the Im, N and PC subtypes as illustrated in Figure 2. Cox proportional hazard meta-analysis showed that the BAGS subtypes added significant and independent prognostic information to the TC classification system and ISS staging. In parallel we found significant correlation between the PreBII subtypes and the proliferation index, risk profiling (P<0.001). Conclusion: We have documented myeloma PC differences with prognostic impact in support of reversible phenotypic plasticity in MM. 2. Multiple Myeloma Therapy in Newly Diagnosed Patients including Transplantation