Background


I.    Clinical consideration of drug resistance


Therapy

Knowledge of the mode of action of current drugs in use in MM is necessary to assess emergence of resistant MMCs in patients. D is cytotoxic to MMCs and blocks the production of inflammatory factors supporting MMC growth. B blocks the degradation of proteins through the proteasome resulting in blockade of cell cycle and apoptosis of MMCs. T and L show pleiotropic mechanisms of action (anti-angiogenesis, T and NK cell stimulation, apoptosis induction and cell cycle arrest (Escoubet-Lozach et al. 2009; Huang et al. 2010; Li et al. 2010b; Verhelle et al. 2007), that are not fully elucidated (Li et al. 2010a). HDM is a DNA intercalating molecule that blocks DNA replication and induces death of replicating MMCs. HDM also destroys the proliferating hematopoietic stem cells that need to be rescued by ASCT. All three “novel agents” (B, T, L) are under investigation as consolidation or maintenance therapy after HDM and ASCT for variable periods of time to control or eliminate remaining MMCs (Palumbo et al. 2010b; Sonneveld et al. 2010). For patients ineligible for intensive treatment, combinations of MP (Melphalan and Prednisone) are used in combination with a novel agent, i.e. T, or B (Facon et al. 2007; San Miguel et al. 2008) and eventually L (Palumbo et al. 2010a). Both groups of patients are treated with bisphosphonates that decrease bone turnover by inducing osteoclast apoptosis (Berenson et al. 2002; Weinstein et al. 2002). Relapse treatment is typically based on the use of combinations of novel agents with D, mainly TD, LD, BD, and eventually HDM and ASCT. BD and LD are used in most patients in first and second relapse (Engelhardt et al. 2010; Raab et al. 2009). Thereafter, therapy becomes more and more heuristic including the use of less effective (e.g. bendamustine) or experimental agents (Michael et al. 2010; Raab et al. 2009). Typically, the time to relapse in responsive patients decreases in each sequential relapse. Ultimately MMCs become refractory to all treatment options, or patients do not tolerate further treatment due to side effects, most often hematological. Systematic studies on the percentage in MM in which a drug is active in relapse if used in induction treatment are lacking.


Conventional and molecular prognostic factors

MMCs harbor a high median number of chromosomal aberrations (Fonseca et al. 2004) and multiple changes in gene expression compared to normal BM plasma cells (Hose et al. 2009a; Hose et al. 2009b; Seckinger et al. 2009; Zhan et al. 2002; Zhan et al. 2006). This molecular heterogeneity is thought to transmit into the very different survival times ranging from a few months to 15 or more years (Barlogie et al. 2006). Relapse appears at any time from early, intermediately to lately. Two main approaches are currently used to predict when relapse appears, that is for risk stratification in myeloma: i) readily obtainable clinical prognostic factors (Greipp et al. 2005) and ii) molecular diagnostics assessing chromosomal aberrations and changes in gene expression.


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