Multiparameter Flow Cytometry Evaluation of Plasma Cell DNA Content and Proliferation in 595 Transplant-Eligible Patients with Myeloma Included in the Spanish GEM2000 and GEM2005<65y Trials

The incorporation of high-dose therapy/autologous stem cell transplantation (HDT/ASCT) and novel agents has significantly improved survival in patients with multiple myeloma (MM), but whether this improvement also benefits patients harboring poor prognostic features, such as nonhyperdiploid MM (NH-MM) and a high proliferation index, remains largely unknown. We analyzed the DNA content and proliferation index of bone marrow plasma cells (PCs) by multiparameter flow cytometry in 595 newly diagnosed transplant-eligible patients with MM included in two consecutive PETHEMA/GEM trials: GEM2000 [VBMCP/VBAD (vincristine, carmustine, melphalan, cyclophosphamide, prednisone/vincristine, bischloroethylnitrosourea, adriamycin, and dexamethasone) followed by HDT/ASCT; n = 319] and GEM2005<65y (randomized induction with VBMCP/VBAD/bortezomib or thalidomide/dexamethasone or bortezomib/thalidomide/dexamethasone followed by HDT/ASCT: n = 276). Of the 595 patients, 295 were classified as NH-MM (49.6%) and 336 (56.5%) as high-proliferative MM (>= 1% PCs in S-phase). Detection of NH-MM DNA content and >= 1% PCs in S-phase were of independent prognostic value for overall survival. Treatment with bortezomib-based regimens abrogated the inferior overall survival of patients with >= 1% PCs in S-phase but not of patients with NH-MM. Finally, a comparative analysis of PC proliferation index at diagnosis versus disease progression showed a two-fold increase at relapse in 44 of 52 patients (85%) analyzed at both time points. NH-MM and a high proliferation index assessed by multiparameter flow cytometry remain as independent prognostic factors in MM, but the latter may be overcome by incorporating novel agents in the HDT/ASCT setting. (Am J Pathol 2012, 181:1870-1878. http://dx.doi.org/S0002-9440(12)00587-1)