Induction Therapy in Multiple Myeloma

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).


Introduction
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, thrombosis) 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 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 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 ).

Induction therapy for patients eligible for HDT-ASCT
In patients for whom HDT-ASCT is planned, the goal of induction treatment before HDT-ASCT should be to achieve the deepest response preferably up to the level of ≥ VGPR as quickly as possible, to reverse disease related complications and ameliorate patient's symptoms. The protocol should not induce stem cell toxicity and impair stem cell collection. Hence, it is important to avoid melphalan prior to stem cell collection Ludwig et al., 2011).
Prior to novel agents, the standard of care for patients eligible for ASCT was based on high dose dexamethasone alone or VAD (Vincristine, adriamycin, high dose dexamethasone). Over the last few years, the emergence of novel agents (thalidomide, bortezomib and lenalidomide) has shifted the choice of induction regimen from conventional VAD or VAD-like regimens to novel-agent containing protocols. In the earlier studies, the combinations of novel agents with high dose dexamethasone were shown to be superior to VAD regimen before ASCT. The more recent trials have concentrated on upfront use of initially 2-drug and more recently 3-drug or even 4-drug combinations applied before ASCT.

Thalidomide-based regimens
Thalidomide is the first immunomodulatory drug used in the treatment of MM. Apart from the anti-angiogenic activity, this group of drugs also induce apoptosis in myeloma cells. Thalidomide induces responses in MM patients refractory to conventional and even high dose therapy suggesting that it can overcome drug resistance. It may alter the secretion and bioactivity of cytokines (e.g. TNF-α) secreted into bone marrow microenvironment by myeloma and bone marrow stromal cells that induce myeloma cell growth and survival. Thalidomide mediates its immunomodulatory action by induction of Th-1 T cell response with secretion of IFN-Y and IL-2 and regulation of adhesion molecule expression .
After the initial studies showing that single agent thalidomide could produce significant reponses and that combination of thalidomide with dexamethasone (TD) results in synergism in refractory/relapsed MM, thalidomide was introduced to the induction therapy for newly diagnosed MM (Singhal et al., 1999;Palumbo et al., 2001). The phase II studies demonstrated the efficacy of TD as front line therapy with 64%-66% response rates (Rajkumar et al., 2002;Cavo et al., 2004). In 2005, a retrospective matched case-control analysis provided the first demonstration of superior rate and depth of response by TD compared with VAD as induction ( ≥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 regimens is shown in table-1.
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 . 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 . 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 tables 7 and 8, respectively (Beksac et al., 2008, Bird et al., 2011. 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 regimens. However, OS was not prolonged. Poorer response to salvage therapy and decreased survival have been observed in patients who relapsed while on thalidomide. This may be the result of emergence of resistant clones after thalidomide (Rajkumar et Morgan et al., 2012). Thalidomide-dexamethasone is less active and more toxic than lenalidomide-based regimens and not recommended as first line therapy anymore. However, in countries where lenalidomide is not available as initial first line therapy and in patients with renal failure, thalidomide combinations may be preferred. On the other hand, thalidomide is still being investigated in combination with other drugs as induction and maintenance regimens for both transplant eligible and ineligible MM patients.

Bortezomib-based regimens
Bortezomib is an effective inhibitor of proteosome. The ubiquinitin-proteosome pathway plays an important role in intracellular protein homeostasis by regulating degradation of proteins, including mediators of cell cycle progression and apoptosis. Bortezomib also blocks TNF-α mediated upregulation of NF-KB resulting in decreased binding of myeloma cells to bone marrow stromal cells and results in myeloma cell apoptosis. This activity is observed even in cell lines resistant to conventional anti-myeloma therapies. Bortezomib also cleaves DNA repair enzymes increasing the susceptibility of myeloma cells to DNA damaging agents such as alkylating agents and anthracyclines (Hideshima et  These studies demonstrate that bortezomib-based induction studies produce high response rates (≥ PR; 78%-93% and CR 7%-35%) without any adverse effect on stem cell mobilization (  . Bortezomib has also proven effective in management of MM patients with renal dysfunction. It has been suggested that in patients with acute renal failure secondary to light chain cast nephropathy VTD can be first choice due to lack of nephrotoxicity. The Mayo Clinic recommends plasma exchange until serum free light chain (FLC)<50 mg/dl and repeated as needed until VTD is fully effective (Rajkumar et al., 2011). Bortezomib is also beneficial for individuals with significant disease related bone-disease due to its inhibitory effect on osteoclastogenesis and stimulatory effect on osteoblast differentiation and proliferation (Zavrski et al., 2005).

Lenalidomide-based regimens
Lenalidomide is another IMID and has more potent in vitro activity; inhibition of angiogenesis, cytokine modulation and T-cell costimulation than thalidomide Haslett et al., 2003). Lenalidomide primarily triggers the caspase-8 mediated apoptotic pathway and also down-regulates NF-KB activity via a mechanism distinct from bortezomib . Lenalidomide alone (R) or with dexamethasone (RD) has shown significant activity in relapsed/refractory MM. Responses were observed even in patients in whom thalidomide therapy has previously failed . Several phase II studies of lenalidomide and dexamethasone +/-chemotherapy have demonstrated response rates ranging 76-91% (Table-4). In a randomized controlled trial lenalidomide plus high dose dexamethasone (RD) (480 mg/28d cycle) was compared with lenalidomide plus low dose dexamethasone (Rd) (160 mg/28d cycle). Patient enrollment to study was not restricted with age or eligibility for ASCT. In each group lenalidomide was administered as 25 mg/d on 1-21 days. In accordance with others, this study demonstrated that lenalidomide in combination with dexamethasone is an efficient initial therapy for MM. Although RD produced higher response rates, this did not result in superior TTP, PFS or OS compared with Rd. The cause of inferior OS with high dose dexamethasone seems to be related to increased deaths due to toxicity, particularly in first 4 months and in eldely patients. The major grade 3 or higher toxicities including thromboembolic events and infections were significantly higher in the high dose dexamethasone group . The multicenter, placebo controlled SWOG trial has confirmed the superiority of lenalidomide in combination with dexamethasone over dexamethasone alone as initial therapy of MM in terms of response rate and PFS but not in OS. This study received early closure and open-label lenalidomide and dexamethasone was made available to all patients (Zonder et al., 2010). In a retrospective case-control study, RD produced better responses than TD including superior PFS and OS. However, this study was not a randomized trial and the choice of post-induction therapy was not standardized (Gay et al., 2010a). Claritromycin is an antibiotic that has shown efficacy in association with steroids and both thalidomide and lenalidomide. The same investigators added clarithromycin (Bioxin) to Rd(BiRd) and compared with Rd in a case-match study.

Novel agent triplet combinations
To enhance response rates and prolong PFS combination of Bortezomib with an IMID has been attempted. Bortezomib-thalidomide-dexamethasone (VTD) resulted better response rates and PFS compared to TD or VD in initial randomized trials (Wang et al., 2005; Cavo et al., 2009). In a Phase III study of VTD compared with TD as induction before and consolidation after double ASCT, VTD was superior to TD in all response categories (CR/n CR; 31% vs 11% ; ≥VGPR; 62% vs 28%) as well as the 3 year estimated PFS (68% vs 56%). Progression free survival was also superior with VTD compared to TD in poor prognostic groups including del13q, increased LDH, age>60 years, t(4;14) ± del17p, increased bone marrow plasma cell ratio and ISS-II and III (Cavo et al., 2010). The results of the PETHEMA/GEM study also provided a strong support to VTD as a highly effective induction regimen compared with a combination chemotherapy containing bortezomib and with TD. Additionally, VTD resulted in a higher post-transplantation CR rate and a significantly longer PFS. However, this did not result in a significant prolongation of OS and could not overcome poor prognosis of high-risk cytogenetics (Rosinol et al., 2012).
Synergy has been demonstrated between bortezomib and lenalidomide. Moreover, both bortezomib and immunomodulatory drugs enhance the activity of dexamethasone. In a phase I study combining these three agents (RVD) in patients with newly diagnosed MM, the maximum tolerated dose was set as lenalidomide 25mg/day, bortezomib 1.3mg/m 2 , dexamethasone 20mg/day and in phase II portion of the same study, 100% response rate (≥PR) could be obtained with ≥VGPR and CR rates 74% and 37%, respectively. This was the first study to result in 100% response rate. The 18-month PFS and OS were 75% and 97%, respectively .
In phase II trials the most promising combinations were either lenalidomide or cyclophosphamide with bortezomib and dexamethasone. A phase II study of four-drug combination VDCR, VDR, VDC and VDC-mod (modification of the cyclophosphamide dose ) was performed to evaluate the feasibility and activity of these combinations. The response seen with VDCR appear to be similar to those seen with VDR or VDC-mod arms (Table-5). However, the toxicities with VDCR appear to be more than the other arms, especially hematological toxicity. This study does not support an advantage of four drug combination (Kumar et al.,2012).
In another phase I/II study RVD was combined with pegylated-doxorubicin (RVDD) and this regimen was highly active and well-tolerated with response rates ≥PR 96% and 95%, ≥VGPR 57% and 65% after 4 and 8 cycles, respectively (

Conclusions
High dose melphalan supported by autologous stem cell transplantation after novel agentbased induction regimen is the standard of care for patients younger than 65. The quality of response achieved with induction regimens before ASCT affect PFS and potentially the OS. In this regard, the availability of novel anti-myeloma drugs, thalidomide, bortezomib and lenalidomide has improved the pre-transplantation responses. Recent data suggest that 3-drug induction regimens, containing at least one novel agent result in better responses than 2-drug combinations. The results of studies with combinations of VD with either doxorubicin (PAD), cyclophosphamide (CyBorRd), thalidomide (VTD) or lenalidomide (VRD) have demonstrated that the responses can be further enhanced and PFS ± OS can be improved. Within the 3-drug combinations, bortezomib-dexamethasone combined with thalidomide or cyclophosphamide(VTD or VCD) appear to be the most active regimens. So, 3-6 cycles of a triplet bortezomib based regimen should be considered the standard induction for patients eligible for ASCT. The objective of treatment should be the achievement of a sustained CR with a good quality of life. Current studies concentrate on best approach to combine available drugs to affect long-term disease control as well as consolidation and maintenance after ASCT and minimize the longterm toxicities, especially neurotoxicity. Bortezomib is effective not only in patients with standard risk disease but also in the presence of high risk cytogenetic abnormalities especially in presence of t(4;14). Current question under evaluation is whether to apply or delay ASCT when a CR is achieved with a novel agent induction treatment.

Induction therapy for patients ineligible for HDT-ASCT
Melphalan was the first alkylating agent used for treatment of MM and melphalan -prednisone (MP) has been the standard therapy for over 30 years although it yielded only PR in 40-60% of patients with CR <5% and PFS about 18 months and OS 2-3 years. Trials comparing MP with high dose dexamethasone-based combinations revealed no survival advantage . During the last decade, with the emergence of novel agents and the studies revealing the importance of achieving VGPR/CR on survival of myeloma patients, the historical goals of induction have changed to achieving a high quality response in elderly patients as well.

Bendamustine
Bendamustine is a novel bifunctional drug which has similarities to both alkylating agents and purine analogs. It has promising activity in low grade lymphoid malignancies. The East German Study Group conducted a phase III trial comparing bendamustine and prednisone (BP) with standard MP in previously untreated patients with MM who are ineligible for transplantation. Bendamustine -prednisone was superior to MP with respect to CR rate (32% vs 13%, p=0.007) and TTF (14 mos vs 10 mos, p=0.02). There was no significant difference with regard to OS between the two treatment groups and the toxicity profile was comparable (Pönisch et al., 2006). Mainly based on the results of this study, bendamustine is currently approved for treatment of newly diagnosed MM patients who are not candidates for HDT-ASCT and who can not receive thalidomide or bortezomib due to peripheral neuropathy. The same investigators in a recent study demonstrated that bendamustine in combination with bortezomib and prednisone (BPV) is also effective in patients with newly diagnosed MM and renal failure. Eighty-three percent of the patients treated with this protocol responded to therapy and 72% had their renal function improved after treatment (Pönisch et al., 2012).

Thalidomide-based regimens
Thalidomide incorporated in to the MP regimen (MPT) has been compared with the standard MP regimen in six randomized phase III studies. Each protocol had some minor differences in their schedules which is shown in table-9. The overall response rate (57%-76%) with MPT was significantly higher than MP (31%-48%).The CR rates with MPT ranged between 7%-13%, one study reported ≥ VGPR rate as 27%. In the IFM-I/II studies and in HOVON study, the prolon-gation in the PFS with MPT was also translated in to OS advantage (Facon et  In a randomized MRC Myeloma IX trial, cyclophosphamide, thalidomide and dexamethasone (CTDa) in which dexamethasone dose was reduced, produced higher response rates than MP but was not associated with improved PFS and OS. Additionally, CTDa was associated with higher rates of adverse events compared to MP (Morgan et al., 2011).

Bortezomib-based regimens
After showing significant efficacy in relapsed-refractory myeloma, bortezomib was also incorporated into trials for initial therapy of MM in transplant ineligible patients.   In the PETHEMA trial Mateos et al. have demonstrated that reduced intensity induction with a bortezomib based regimen followed by maintenance is a safe and effective treatment. The investigators compared VMP with VTP (bortezomib, thalidomide, prednisone) as initial therapy in newly diagnosed patients with MM ineligible for transplantation. In both protocols, a reduced intensity bortezomib schedule consisting of one cycle of bortezomib twice per week for 6 weeks followed by five cycles of bortezomib once per week for 5 weeks was used. Patients who completed the six induction cycles were randomly assigned to maintenance therapy with bortezomib plus prednisone (VP) or bortezomib plus thalidomide (VT). The response rates were higher with VTP compared to VMP (CR 28% vs 20% ; ORR 81% vs 80%). Maintenance with VT significantly improved time to progression compared with that for patients who received VP. The support to better response rates with VTP also came from the initial results of UPFRONT study which compared VD, VTD and VMP and revealed better response rates with VTD (Table-11). On the other hand, in both studies patients treated with VTP had more frequent serious adverse events especially PNP and thrombosis (Mateos et al., 2010b;Nievizsky et al., 2011). Combining four drugs (bortezomib, melphalan, prednisone, thalidomide) followed by maintenance with bortezomib-thalidomide (VMPT-VT) was superior to VMP alone in patients with MM who are ineligible for autologous stem-cell transplantation. The 3years PFS was also improved with VMPT-VT. However, no significant difference in 3-year OS was observed. Additionally, grade 3 to 4 neutropenia, cardiologic events and thromboembolic events were more frequent among patients assigned to the VMPT-VT group than among those assigned to the VMP group . Due to significantly increased adverse events with 4-drug regimen, VMP or MPT are better alternatives for induction of elderly myeloma patients.  ). Moreover, Rd was associated with significantly improved 1-year OS than with RD (96% vs 87%, p=0.0002) and treatment related toxicity was significantly reduced. The cause of inferior OS with high dose dexamethasone seems to be related to increased deaths due to toxicity particularly in first 4 months and in elderly patients. Hence, the advantages of Rd over RD were more pronounced in patients aged > 70 years Zonder et al., 2010). A recent double-blind, multicenter, randomized study compared melphalan-prednisone-lenalidomide induction followed by lenalidomide maintenance (MPR-R) with melphalan-prednisone-lenalidomide (MPR) or melphalan-prednisone (MP) followed by placebo. Response rates were superior with MPR-R compared with MPR or MP (ORR, 77% vs 68% vs 50%; CR, 18% vs 13% vs 5%; respectively). MPR-R significantly prolonged PFS in patients with newly diagnosed multiple myeloma who were ineligible for transplantation, with the greatest benefit observed in patients 65 to 75 years of age. This study also underlines the importance of lenalidomide maintenance after MPR induction as another treatment option for elderly myeloma patients The toxicity profile was excessive for frail patients, which negatively affected the efficacy. Main grade 3-4 adverse events of MPR were neutropenia (52-71%), thrombocytopenia (23-38%), infections (10%) and thromboembolism (5%) (Palumbo et al., 2012). It is clear that the novel agents have prolonged the survival of patients with MM. However, this benefit is more pronounced in younger patients. Age has been reported to be a negative prognostic factor. It is not because the elderly patients have biologically different disease but because they can not tolerate high intensity therapy protocols, have lower bone marrow reserves, increased tendency for infections and also difficulty in recovering from infections and have more frequent drug toxicities. A patient's overall physical condition, fraility, comorbidity and disability should be asessed before starting therapy in order to choose the appropriate treatment protocol and dosing. These terms are fully explained in a review by Palumbo et al ). Although the novel agents offer important survival for patients with MM, the incidence of grade 3-4 adverse events and drug discontinuations are significantly higher with combination regimens that are based on novel agents than with traditional chemotherapy regimens. It has been suggested that modifying drug doses at the start of therapy and management of adverse events during the therapy improves tolerability so that the patients can receive the drugs for a longer time to get survival benefit. Secondly, the tolerability of treatment can be further improved with full supportive therapy with bisphosphanates, antivirals, anticoagulants, growth factors and appropriate pain control.

Conclusions
At present, the induction regimen for patients ineligible for HDT/ASCT is either MP or high/ lower dose of Dexamethasone combined with one of the three novel agents (thalidomide or bortezomib or lenalidomide). Selection between these combinations depends on the patients' presenting symptoms such as presence of neuropathy, renal impairment or the rapidity required to reverse the symptoms. In countries where lenalidomide is not yet allowed as first line therapy, induction can be started with thalidomide or bortezomib containing triple regimens and in case of unresponsiveness or intolerability, lenalidomide can be used as second line therapy. Fraility, comorbidity and disability of the elderly patients should be taken into account before choosing the induction protocol and appropriate dose reductions should be done. Thus, the treatment should be individualized. Melphalan-based regimens are used for a fixed duration (9-18 months) and then observed. However, the duration of treatment with revlimid (Rd) is unclear either continue until relapse or a fixed duration of 18 months has been tested in ongoing phase III trials. Evidence is now emerging that maintenance or continuous therapy with novel agents is improving PFS with a potential to improve OS. However, in elderly patients, it is particularly important to start treatment at a dose that can be tolerated over the long term. Specific recommendations yet can not be made regarding the impact of novel treatment regimens on prognosis of elderly patients with high-risk cytogenetics. Although the Italian study  suggested some PFS benefit in response to VMPT+VT over VMP regarding the highrisk cytogenetics, other studies did not confirm this.