AUTHORS: A. Broyl1, D. Hose3, Y. de Knegt1, H. Lokhorst2, H. Goldschmidt3, P. Sonneveld1
From the Department of Hematology 1Erasmus Medical Center, Rotterdam (EMCR), Department of Hematology; 2Utrecht University Medical Center Utrecht, Utrecht (UMCU), Department of Internal
Background: The standard treatment of newly diagnosed multiple myeloma (MM) is based on induction treatment followed by high-dose melphalan. CR/nCR percentages range from 20-50% with event free survival (EFS) ranging from 18 months to 28 months. The 5-year survival rates are 25% to 50%, however all patients eventually relapse and succumb to the disease. Classical unfavourable prognostic factors include high serum β2-microglobulin and chromosome aberrations such as-13/13q-, t(4;14) and t(14;16). Bortezomib, a proteasome inhibitor, and Thalidomide, an anti-angiogenic and immunomodulatory drug, have recently shown a remarkable effect in patients with relapsed or refractory MM with 30-40% response rates. In combination with Dexamethasone and/ or other conventional agents overall response rates of 50-70% can be achieved. In newly diagnosed patients the response rates vary from 70 - 85 %. Moreover, Bortezomib was found to overcome poor prognostic factors like a high beta2-microglobulin and/ or deletion of chromosome 13. However, 15-30 % of newly diagnosed patients do not respond to Bortezomib or Thalidomide. Secondly, 30% of the patients treated with these novel agents have to stop prematurely because of intolerable side effects, such as polyneuropathy, thrombocytopenia, thrombosis and gastro-intestinal symptoms. Aims:In order to develop new, genetic prognostic factors for clinical response and toxicity associated with Bortezomib and Thalidomide, we have started to analyze gene expression profiles of myeloma specific genes in plasma cells purified from bone marrow from myeloma patients at diagnosis who have been treated in a prospective randomized trial, HOVON 65. This large multicenter, prospective, randomized phase III trial compares Bortezomib in combination with Adriamycin, Dexamethasone (PAD, arm A) followed by HDM followed by maintenance with Bortezomib vs. VAD (arm B) followed by HDM and maintenance with Thalidomide (HOVON65/GMMG-HD4). This cooperative trial in the Netherlands, Belgium and Germany has recruited over 400 patients since April 2005 and will include 800 patients. Methods: Gene expression profiling of CD138 magnetic cell selected (MACS) myeloma plasma cells were performed using Affymetrix GeneChip Human Genome U133 plus 2.0 arrays. Data obtained from micro-array studies were submitted to Cox regression analysis and multifactorial analysis with the clinical data set from these patients. Results: We will present an unsupervised cluster (SAM) analysis based on the array results from the first cohort of 130 patients. The analysis shows that the majority of cases can be identified according to the TC classification. The initial results of clinical outcome of these cases will be presented.