Multiple Myeloma (MM) is an incurable malignant plasma cell disease with an incidence of 5 per 100,000 inhabitants, affecting approximately 25,000 new patients per year in the EU, with a debilitating impact on personal lives and health management. MM locates primarily to the bone marrow (BM) - in multiple “niches” that provide a microenvironment which promotes tumor survival. In turn, multiple myeloma cells (MMCs) profoundly alter the BM, resulting in osteolytic lesions, anemia, and immunosuppression. On a molecular level, MM is characterized by a marked disease heterogeneity as defined by chromosomal aberrations and gene expression profiles, with at least 7 groups definable at presentation (Zhan et al. 2006). Concordantly, intraclonal variation between tumor cells in a given patient, as defined for example by interphase fluorescence in situ hybridization (iFISH) (Hose et al. 2009b), are indicative of on-going disease evolution.

The current treatment paradigm differentiates between symptomatic patients (Durie et al. 2006) eligible for intensive treatment, and those not, which include elderly patients above the age of about 65-70 years. Intensive treatment typically comprises an induction regimen to decrease tumor mass and improve patient’s status including high dose corticosteroids (dexamethasone, D), and at least one so-called “novel agent”. The latter comprise the proteasome inhibitor (bortezomib, B, Velcade) and the immunomudulatory drugs thalidomide (T) or lenalidomide (L, also termed Revlimid) (Cavo et al. 2010; Goldschmidt et al. 2003; Harousseau et al. 2010). These compounds are likely to be the mainstay of treatment in MM for the foreseeable future. They act on MMCs, “niche cells”, and their interaction (Davies et al. 2001; Gorgun et al. 2010; Perez et al. 2010). After induction treatment, MMCs are further eliminated with high dose of an alkylating agent (high dose melphalan, HDM) with hematopoietic stem cells rescue by autologous stem cell transplantation (ASCT). The overall survival (OS) of intensively treated patients below 65-70 is 8-9 years and the event free survival (EFS) is 3-4 years (Barlogie et al. 2010; Harousseau and Moreau 2009).

Patients invariably relapse after each subsequent treatment regimen, become resistant to treatment, and succumb to their disease.

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