**1. Introduction**

[77] Vermorken AJ, Zhu J, Van de Ven WJ. Is curcumin for monoclonal gammopathy of undetermined significance without risk?-letter. Clin Cancer Res. 2010;16(7):2225. [78] Rajkumar SV. Preventive strategies in monoclonal gammopathy of undetermined significance and smoldering multiple myeloma. Am J Hematol. 2012;87(5):453-54.

132 Multiple Myeloma - A Quick Reflection on the Fast Progress

Today, multiple myeloma (MM) can be defined as a heterogenous disease composed of different clinical conditions. The differences are a result of patient related factors (age, sex, comorbidity), disease related complications (renal failure, bone disease, neuropathy, throm‐ bosis) and biological characteristics (cytogenetics, lactate dehydrogenase level, plasma cell labelling index, beta2-microglobulin, gene expression profiles). The widely used international scoring system is a powerful tool for determining survival. However, it cannot be used for treatment planning. The biological determinants of disease determined by flourescein in situ hybridization (FISH) and/or conventional cytogenetics are better tools to stratify myeloma subgroups with different survival profiles. Thus these are better tools for designing therapeutic approaches. A risk stratification of newly diagnosed MM according to FISH/Karyotyping has been recently reviewed by Rajkumar (Rajkumar, 2012).

High dose melphalan supported by autologous stem cell transplantation (ASCT) can increase response rates and prolong progression free and overal survival compared to conventional chemotherapies (Attal et al., 1996; Child et al., 2003; Fermand et al., 2005; Koreth et al., 2007). The initial induction regimen is chosen according to whether the patient is eligible or ineligible for a subsequent HDT-ASCT as well as the risk stratification of the patient. Advanced age or significant comorbidity are important limitations for ASCT. High dose therapy has been generally considered for patients ≤ 65 years. However, in medically fit patients, this can be extended up to age 70-75 years. Achievement of high quality responses (VGPR, CR/nCR) at the time of transplantation has been demostrated to be an early predictor of improved outcomes after ASCT (Harousseau et al., 2009; Chanan-Khan&Giralt, 2010). Elderly patients or patients ineligible for transplantation may also benefit from chemotherapy by achieving high quality responses preferably CR in terms of progression free survival (PFS) and overall survival (OS). As such, the choice of induction therapy is crucial for survival for most patients with MM. The emergence of novel agents (thalidomide, lenalidomide and bortezomib) and

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incorporation of these agents in to the current induction protocols has increased the rate of CR and at least VGPR before ASCT and significantly improved the OS in MM (Kumar et al., 2008; Kastritis et al., 2009). This opened a new area of debate 'upfront' versus 'delayed' transplantation. However, current recommendations from experts is that high dose therapy supported by autologous stem cell transplantation (HDT-ASCT) should be the standard of care for eligible patients (Ludwig et al., 2011).

( ≥PR; 76% vs 52%, respectively, p<0.001) (Cavo et al., 2005). Based on the subsequent phase III studies which confirmed the superior response rates achieved with thalidomide containing regimens compared with the conventional induction therapies, TD regimen received an accelerated approval in patients with newly diagnosed MM (Rajkumar et al.,2006; Rajkumar et al., 2008). The summary of the phase II-III studies involving thalidomide-based induction

Induction Therapy in Multiple Myeloma http://dx.doi.org/10.5772/55151 135

Rajkumar et al. in a randomized double blind placebo-controlled study, provided the first data on significant prolongation of time to progression (TTP) and progression free survival (PFS) with TD compared with dexamethasone alone in patients with newly diagnosed MM ( 14.9 vs. 6.5 months; p<0.001). However, this study was not powered enough to compare the differences in OS (Rajkumar et al., 2008). Barlogie et al. randomized their patients to receive two cycles of high dose melphalan based chemotherapy each supported with ASCT (Total therapy-2) with or without thalidomide added from outset until disease progression and reported that addition of thalidomide improved the rate of CR and EFS but failed to prolong OS (Barlogie et al., 2006). In a retrospective pair-matched analysis, thalidomide incorporated to induction regimen and continued until the second ASCT revealed significantly improved clinical outcomes and a trend towards extended OS at 5 years ( 69% vs. 53%; p=0.07) (Cavo et al., 2009). The HOVON-50 trial incorporated doxorubicin to TD (TAD) and compared this regimen with conventional VAD as frontline therapy showing a better response before and after HDT-ASCT (Lokhorst et al., 2008). After long term follow-up, the TAD arm folowed by thalidomide maintenance after ASCT was able to induce longer event free survival compared to the VAD arm folloowed by interferon ( 34 vs. 22 months; p<0.001) but this did not translate into an improved OS (73 vs. 60 months; p=0.77). Which can be explained by a decreased survival from relapse while on thalidomide maintenance (Lokhorst et al., 2010). A recent MRC Myeloma IX randomized trial compared oral combination therapy CTD (cyclophosphamide, thalidomide, dexamethasone) with oral cyclophosphamide incorporated into conventional VAD (CVAD). Significantly superior response rates were attained with CTD compared with CVAD both after induction and after ASCT. CTD could not significantly prolong PFS or OS but longer followup suggests a trend towards a late OS advantage(Morgan et al., 2012).

Thalidomide does not compromise successful harvest of stem cells. However, it is associated with an increased risk of venous thromboembolism (VTE) and sensory peripheral neuropathy (PNP). Without thromboprophylaxis, the thrombosis risk is 15-17%, which is more frequent during the first 3 months of treatment and warrants prophylactic anticoagulation. Peripheral neuropathy improves within 3-4 months after dose reduction or cessation of the drug in most patients. However, thalidomide induced PNP may be irreversible if appropriate action is not taken when an emerging neuropathy is encountered. Thalidomide at low dose may be effective in the management of patients with renal failure, but close monitorization for complications is required in patients with serious renal and hepatic failure. Major thalidomide toxicities and the summary of the supportive care guidelines regarding the approach to PNP is given in

It is clearly understood that thalidomide-based regimens have produced better post-induction response rates (≥PR; 63-82.5%) and PFS than conventional high dose dexamethasone based

tables 7 and 8, respectively (Beksac et al., 2008, Bird et al., 2011).

regimens is shown in table-1.
