**2. 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 (Cavo et al., 2011; 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.

#### **2.1. 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 (Hideshima et al., 2000).

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.

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

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 (Cavo et al., 2011; Ludwig et al.,

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

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 (Hideshima et al.,

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

care for eligible patients (Ludwig et al., 2011).

134 Multiple Myeloma - A Quick Reflection on the Fast Progress

even 4-drug combinations applied before ASCT.

**2.1. Thalidomide–based regimens**

2011).

2000).

**2. Induction therapy for patients eligible for HDT–ASCT**

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 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 al., 2006; Barlogie et al., 2006;, Cavo et al., 2009; Lokhorst et al., 2010; 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. **2.2. 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

Induction Therapy in Multiple Myeloma http://dx.doi.org/10.5772/55151 137

Bortezomib received FDA approval in 2003 after showing significant activity in relapsedrefractory MM (Jagannath et al., 2004; Richardson et al., 2005). The initial phase II study of single agent bortezomib in previously untreated MM revealed a response rate of 41% (Richardson et al., 2009). Other phase 2 studies incorporating bortezomib ± dexamethasone to induction regimens were consistent with superior responses ranging from 66% to 95% with 6% to 24% CR rates (Jagannath et al., 2005; Harousseau et al., 2006; Rosinol et al., 2007).

The IFM2005-01 Phase III trial compared VD with VAD as induction before ASCT and lenalidomide was given as post-ASCT maintenance in both arms in a randomized fashion. Post-induction at least VGPR (38% vs 15%) and CR/nCR (15% vs 6%) were superior with VD. This response difference was also maintained after ASCT. However, there was only slight improvement in PFS without an OS benefit. Responses with bortezomib were higher regardless

Popat et al. added doxorubicin at escalating doses (0, 4.5 and 9 mg/m2 ) to standard dose bortezomib-dexamethasone (PAD) and demonstrated 95% post-induction response rate with 62% high quality responses (≥ VGPR) (Popat et al., 2008). Addition of pegylated-liposomal doxorubicin to bortezomib-dexamethasone revealed similar responses ( ≥ PR 85% and ≥ VGPR 57.5%) which was further enhanced in patients who underwent ASCT (≥ VGPR 76.6%) (Jakubowiak et al., 2009). A very recent HOVON-65/GMMG-HD4 trial compared pretransplant PAD (Bortezomib, Adriamycin, Dexamethasone) induction and bortezomib maintenance after ASCT with pre-transplant VAD induction and thalidomide maintenance after ASCT and demonstrated that bortezomib during induction and maintenance significantly improved response rates, quality of response. Similar to other bortezomib containing 3-drug combinations, PFS was significantly improved. Additionally, unlike the other studies, OS was also prolonged in this study (61% vs 55%). Subgroup analysis also indicated that superior outcome with bortezomib was predominantly accomplished in high risk patients presenting

Reeder et al. incorporated cyclophosphamide to bortezomib-dexamethasone (CyBorD/VCD) and reported 71% ≥VGPR after 4 cycles and 74% ≥VGPR after ASCT (Reeder et al., 2009). The German Myeloma Study Group reported 84% response rate (≥PR) with 10% CR after 3 cycles of VCD. Over 60% of their patients had high-risk cyctogenetics. The response rate in cytoge‐ netically high-risk patients were 83.7% (del13q) and 90% t(4;14). However, del17p group had

of the disease stage or high-risk cytogenetics (Harousseau et al., 2010).

with renal failure and del17p (≥ VGPR; 72% vs 43%) (Sonneveld et al., 2012).

lower response rate at 69.2% (Einsele et al., 2009).

as alkylating agents and anthracyclines (Hideshima et al., 2001; Cherry et al., 2012).


ASCT: autologous stem cell transplantation ; CTD: cyclophosphamide, thalidomide, dexamethasone; CVAD: cyclophos‐ phamide added to VAD (vincristine, doxorubicin, dexamethasone); nr: not reported; TAD: thalidomide, doxorobicin, dexametahsone; TD: thalidomide, dexamethasone; T: thalidomide; TT2: Total therapy-2. a per-protocol analysis

**Table 1.** Phase II- III studies of thalidomide-based regimens as induction therapy before HDT-ASCT

#### **2.2. Bortezomib–based regimens**

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 al., 2006; Barlogie et al., 2006;, Cavo et al., 2009; Lokhorst et al., 2010; 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.

**After induction After ASCT**

4 0

nr nr

7.7 2.6

> 3 2

13 8

dexametahsone; TD: thalidomide, dexamethasone; T: thalidomide; TT2: Total therapy-2. a

**Table 1.** Phase II- III studies of thalidomide-based regimens as induction therapy before HDT-ASCT

**CR % ≥PR %**

nr nr

nr nr

nr nr

84 76

92 90

ASCT: autologous stem cell transplantation ; CTD: cyclophosphamide, thalidomide, dexamethasone; CVAD: cyclophos‐ phamide added to VAD (vincristine, doxorubicin, dexamethasone); nr: not reported; TAD: thalidomide, doxorobicin,

**≥VGPR %**

> nr nr

> nr nr

> nr nr

68 49

54 44

62a 74a **CR %**

nr nr

62 43

nr nr

14 12

50a 37a nr nr

5-year 56% 44% P=0.01

14.9 mos 6.5 mos P<0.001

4-year 51% 31% P=0.001

Median 34 mos 22 mos P<0.001

Median 27a mos 25a mos P=0.56

**PFS OS Reference**

Rajkumar 2006

Barlogie 2006

Rajkumar 2008

Cavo 2009

Lokhorst 2010

Morgan 2012

nr nr

5-year 65% 65% P=0.90

> nr nr

5-year 69% 53% P=0.07

Median 73 mos 60 mos P=0.77

Median Not reach. 63a mos P=0.29

per-protocol analysis

**Regimen N**

**TD vs. D**

**TD vs. D**

**Double ASCT + T vs. Double ASCT**

**TAD vs. VAD**

**CTD vs.CVAD**

**TT2 with T vs. TT2 without T** **≥PR %**

136 Multiple Myeloma - A Quick Reflection on the Fast Progress

63 41

nr nr

63 46

71 57

82.5 71

103 104

323 345

235 235

135 135

268 268

555 556 **≥VGPR %**

> nr nr

> nr nr

43.8 15.8

> 30 15

> 37 18

43 27.5 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 al., 2001; Cherry et al., 2012).

Bortezomib received FDA approval in 2003 after showing significant activity in relapsedrefractory MM (Jagannath et al., 2004; Richardson et al., 2005). The initial phase II study of single agent bortezomib in previously untreated MM revealed a response rate of 41% (Richardson et al., 2009). Other phase 2 studies incorporating bortezomib ± dexamethasone to induction regimens were consistent with superior responses ranging from 66% to 95% with 6% to 24% CR rates (Jagannath et al., 2005; Harousseau et al., 2006; Rosinol et al., 2007).

The IFM2005-01 Phase III trial compared VD with VAD as induction before ASCT and lenalidomide was given as post-ASCT maintenance in both arms in a randomized fashion. Post-induction at least VGPR (38% vs 15%) and CR/nCR (15% vs 6%) were superior with VD. This response difference was also maintained after ASCT. However, there was only slight improvement in PFS without an OS benefit. Responses with bortezomib were higher regardless of the disease stage or high-risk cytogenetics (Harousseau et al., 2010).

Popat et al. added doxorubicin at escalating doses (0, 4.5 and 9 mg/m2 ) to standard dose bortezomib-dexamethasone (PAD) and demonstrated 95% post-induction response rate with 62% high quality responses (≥ VGPR) (Popat et al., 2008). Addition of pegylated-liposomal doxorubicin to bortezomib-dexamethasone revealed similar responses ( ≥ PR 85% and ≥ VGPR 57.5%) which was further enhanced in patients who underwent ASCT (≥ VGPR 76.6%) (Jakubowiak et al., 2009). A very recent HOVON-65/GMMG-HD4 trial compared pretransplant PAD (Bortezomib, Adriamycin, Dexamethasone) induction and bortezomib maintenance after ASCT with pre-transplant VAD induction and thalidomide maintenance after ASCT and demonstrated that bortezomib during induction and maintenance significantly improved response rates, quality of response. Similar to other bortezomib containing 3-drug combinations, PFS was significantly improved. Additionally, unlike the other studies, OS was also prolonged in this study (61% vs 55%). Subgroup analysis also indicated that superior outcome with bortezomib was predominantly accomplished in high risk patients presenting with renal failure and del17p (≥ VGPR; 72% vs 43%) (Sonneveld et al., 2012).

Reeder et al. incorporated cyclophosphamide to bortezomib-dexamethasone (CyBorD/VCD) and reported 71% ≥VGPR after 4 cycles and 74% ≥VGPR after ASCT (Reeder et al., 2009). The German Myeloma Study Group reported 84% response rate (≥PR) with 10% CR after 3 cycles of VCD. Over 60% of their patients had high-risk cyctogenetics. The response rate in cytoge‐ netically high-risk patients were 83.7% (del13q) and 90% t(4;14). However, del17p group had lower response rate at 69.2% (Einsele et al., 2009).

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 (Harousseau et al., 2010; Cavo et al.,2010; Rosinol et al., 2012; Sonneveld et al.,2012; Moreau et al., 2010). However, neurotoxicity is a major concern especially when bortezomib is combined with thalidomide. Neurotoxicity can be reduced by reducing bortezomib dose once weekly without affecting the efficacy or by using subcutenous bortezomib (Mateos et al., 2010). Moreover, Moreau et al. used reduced doses of bortezomib (1 mg/m2) and thalidomide (100 mg/d) in vtD regimen and found that this regimen provided higher VGPR rates compared with VD and the dose reduction of both drugs could resulted in reduced incidence of poly‐ neuropathy (Moreau et al., 2011). Major bortezomib toxicities and the summary of the supportive care guidelines regarding the approach to emerging PNP is given in tables 7 and 8, respectively (Bird et al.,2011).

Bortezomib has become an important component of therapy for patients with high risk MM associated with del13q and t(4;14) (Richardson et al., 2005; Jagannath et al., 2007). 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).

**Progression free survival Reference Overall del13q t(4;14) del(17p)**

> 28mos (median) 16mos (median)

28% (at 3-yr) 20% (at 3-yr)

69% (at 3-yr) 37% (at 3-yr)

**Table 3.** Impact of bortezomib incorporated into ASCT on PFS according to cytogenetic abnormalities (Cavo 2012)

Lenalidomide is another IMID and has more potent in vitro activity; inhibition of angiogenesis, cytokine modulation and T-cell costimulation than thalidomide (Hideshima et al., 2000 ; 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 (Mitsiades et al., 2002). 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 (Richardson et al., 2002). 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 (Rajkumar et al., 2010). The multicenter, placebo controlled SWOG

14mos (median)

22% (at 3-yr) 16% (at 3-yr)

nr

nr Avet-Loiseau 2010

Induction Therapy in Multiple Myeloma http://dx.doi.org/10.5772/55151 139

nr Cavo 2010

Sonneveld 2010

**Regimen**

**VD + R ± R vs. VAD + R ± R**

**PAD + Bort vs. VAD + T**

**VTD + VTD vs. TD + TD**

36 mos (median) 30 mos (median)

48% (at 3-yr) 40% (at 3-yr)

68% (at 3-yr) 56% (at 3-yr)

**2.3. Lenalidomide–based regimens**

nr nr

40% (at 3-yr) 29% (at 3-yr)

62% (at 3-yr) 46% (at 3-yr)


VD: Bortezomib, dexamethasone; VAD: Vincristine, doxorubicin, dexamethasone; VTD: Bortezomib, thalidomide, dexamethasone; TD: Thalidomide,dexamethasone; VBMCP/VBAD+V: Vincristine, carmustine, melphalan,cyclophospha‐ mide, prednisone/ vincristine, carmustine, doxorubicin, dexamethasone + bortezomib; PAD: Bortezomib, doxorubicin, dexamethasone; vtD: Reduced dose bortezomib, reduced dose thalidomide, dexamethasone; mos: months

**Table 2.** Phase III studies of bortezomib-based regimens in preparation for HDT-ASCT

Bortezomib has become an important component of therapy for patients with high risk MM associated with del13q and t(4;14) (Richardson et al., 2005; Jagannath et al., 2007). 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).


**Table 3.** Impact of bortezomib incorporated into ASCT on PFS according to cytogenetic abnormalities (Cavo 2012)

#### **2.3. Lenalidomide–based regimens**

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 (Harousseau et al., 2010; Cavo et al.,2010; Rosinol et al., 2012; Sonneveld et al.,2012; Moreau et al., 2010). However, neurotoxicity is a major concern especially when bortezomib is combined with thalidomide. Neurotoxicity can be reduced by reducing bortezomib dose once weekly without affecting the efficacy or by using subcutenous bortezomib (Mateos et al., 2010). Moreover, Moreau et al. used reduced doses of bortezomib (1 mg/m2) and thalidomide (100 mg/d) in vtD regimen and found that this regimen provided higher VGPR rates compared with VD and the dose reduction of both drugs could resulted in reduced incidence of poly‐ neuropathy (Moreau et al., 2011). Major bortezomib toxicities and the summary of the supportive care guidelines regarding the approach to emerging PNP is given in tables 7 and

**After induction After ASCT**

15 6

31 11

21 35 14

> 7 2

31 29

**CR % ≥PR %**

80 77

93 84

73 77 58

88 75

86 89

VD: Bortezomib, dexamethasone; VAD: Vincristine, doxorubicin, dexamethasone; VTD: Bortezomib, thalidomide, dexamethasone; TD: Thalidomide,dexamethasone; VBMCP/VBAD+V: Vincristine, carmustine, melphalan,cyclophospha‐ mide, prednisone/ vincristine, carmustine, doxorubicin, dexamethasone + bortezomib; PAD: Bortezomib, doxorubicin,

dexamethasone; vtD: Reduced dose bortezomib, reduced dose thalidomide, dexamethasone; mos: months

**≥VGPR %**

> 54 37

> 82 64

> 51 65 40

> 62 36

> 58 74

**CR %**

35 18

55 41

38 46 24

21 9

22 31 Median 36 mos 30 mos P=0.06

3-year 68% 56% P=0.005

Median 38 mos 27 mos Not reach. P=0.006

> Median 35 mos 28 mos P=0.002

Median 30 mos 26 mos P=0.22

**PFS OS Reference**

Harousseau 2010 IFM 2005-02

Cavo 2010 GIMEMA-MMY 3006

Rosinol 2012 PETHEMA/ GEM

Sonneveld 2012 HOVON65/ GMMG HD4

Moreau 2011 IFM2007-02

3-year 81% 77% P=0.5

3-year 86% 84% P=0.03

> Nr Nr Nr

5-year 61% 55%

> Nr nr

8, respectively (Bird et al.,2011).

138 Multiple Myeloma - A Quick Reflection on the Fast Progress

**≥PR %**

78.5 63

> 93 79

> 75 85 62

> 78 54

> 81 88

223 218

236 238

129 130 127

413 414

99 100 **≥VGPR %**

> 38 15

> 62 28

> 36 60 29

> 42 14

> 36 49

**Table 2.** Phase III studies of bortezomib-based regimens in preparation for HDT-ASCT

**Regimen N**

VD vs. VAD

VTD vs. TD

VTD vs. TD

PAD vs. VAD

VD vs. vtD

VBMCP/VBAD+V vs.

Lenalidomide is another IMID and has more potent in vitro activity; inhibition of angiogenesis, cytokine modulation and T-cell costimulation than thalidomide (Hideshima et al., 2000 ; 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 (Mitsiades et al., 2002). 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 (Richardson et al., 2002). 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 (Rajkumar et al., 2010). 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. The have reported significantly better responses with BiRd and the PFS was significantly longer. However, 3- year OS was not statistically different between the two study arms (Gay et al., 2010).

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 cyclophos‐ phamide with bortezomib and dexamethasone. A phase II study of four-drug combination VDCR, VDR, VDC and VDC-mod (modification of the cyclophosphamide dose ) was per‐ formed 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 (Table-6). After a median 15.5 months followup, PFS and OS were not reached. The estimated 18-month PFS and OS were 80.8% and 98.6%, respectively. Among patients who proceeded to ASCT and were evaluable for posttransplant response, response rate further improved reaching 85% of patients ≥VGPR and 61% of those with CR/n CR at 3 months after ASCT. In patients who continued RVDD beyond 4 cycles, depth of response further improved reaching 65% ≥VGPR and 35% CR/n CR at the completion

**PFS OS Reference**

Induction Therapy in Multiple Myeloma http://dx.doi.org/10.5772/55151 141

2-yr 75% 87%

3-yr 79% 73% P=0.28

Median Notreach 57.2 mos P=0.018

Median 89.7% 73% P=0.170 Rajkumar 2010

Zonder 2010

Gay 2010

Gay 2010

**After induction**

**≥PR % ≥VGPR % CR %**

42 24

37.8 15

73.6 33

**Table 4.** Results of phase II-III Studies of induction with lenalidomide and dexamethasone

**RD** 34 91 38 6 Rajkumar 2005

13.6 3.3

45.8 13.9

Median 19 mos 25 mos P=0.026

> 3-yr 52% 32%

Median 26.7mos 17.1 mos P=0.036

Median 48.3 mos 27.5 mos P=0.044

(Richardson et al., 2010).

of 8 cycles (Jakuboviak et al., 2011).

222

95

183

72

79 68

78 48

80 61

**Regimen N**

**Rd** 223

**D** 97

**TD** 228

**Rd** 72

**RD vs.**

**RD vs.**

**RD vs.**

**BiRd vs.**

Lenalidomide can cause myelosuppression and concerns have been raised that its use may negatively impact the ability to mobilize stem cells in patients who received lenalidomide as part of their induction therapies (Kumar et al., 2007; Mazumder et al., 2008; Paripati et al., 2008; Popat et al., 2009). It is suggested that stem cells should be collected within 6 months of initiation of lenalidomide therapy and the IMWG recommends that patients >65 years or patients who have received ≥ 4 cycles Rd must undergo stem cell mobilization with cyclo‐ phosphamide + G-CSF or G-CSF + plerixafor (Kumar 2007; Kumar 2009). Dose reduction is required in presence of renal impairment. Patients may require thromboprophylaxis due to higher incidence of thromboembolic events. Major lenalidomide toxicities are summarized in table-10 (Bird et al., 2011).

#### **2.4. 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 cytoge‐ netics (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/m2 , dexame‐ thasone 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 (Richardson et al., 2010).

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. The have reported significantly better responses with BiRd and the PFS was significantly longer. However, 3- year OS was not

Lenalidomide can cause myelosuppression and concerns have been raised that its use may negatively impact the ability to mobilize stem cells in patients who received lenalidomide as part of their induction therapies (Kumar et al., 2007; Mazumder et al., 2008; Paripati et al., 2008; Popat et al., 2009). It is suggested that stem cells should be collected within 6 months of initiation of lenalidomide therapy and the IMWG recommends that patients >65 years or patients who have received ≥ 4 cycles Rd must undergo stem cell mobilization with cyclo‐ phosphamide + G-CSF or G-CSF + plerixafor (Kumar 2007; Kumar 2009). Dose reduction is required in presence of renal impairment. Patients may require thromboprophylaxis due to higher incidence of thromboembolic events. Major lenalidomide toxicities are summarized in

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 cytoge‐

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

thasone 20mg/day and in phase II portion of the same study, 100% response rate (≥PR) could

, dexame‐

maximum tolerated dose was set as lenalidomide 25mg/day, bortezomib 1.3mg/m2

statistically different between the two study arms (Gay et al., 2010).

table-10 (Bird et al., 2011).

netics (Rosinol et al., 2012).

**2.4. Novel agent triplet combinations**

140 Multiple Myeloma - A Quick Reflection on the Fast Progress

In phase II trials the most promising combinations were either lenalidomide or cyclophos‐ phamide with bortezomib and dexamethasone. A phase II study of four-drug combination VDCR, VDR, VDC and VDC-mod (modification of the cyclophosphamide dose ) was per‐ formed 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 (Table-6). After a median 15.5 months followup, PFS and OS were not reached. The estimated 18-month PFS and OS were 80.8% and 98.6%, respectively. Among patients who proceeded to ASCT and were evaluable for posttransplant response, response rate further improved reaching 85% of patients ≥VGPR and 61% of those with CR/n CR at 3 months after ASCT. In patients who continued RVDD beyond 4 cycles, depth of response further improved reaching 65% ≥VGPR and 35% CR/n CR at the completion of 8 cycles (Jakuboviak et al., 2011).


**Table 4.** Results of phase II-III Studies of induction with lenalidomide and dexamethasone


**Thalidomide Lenalidomide Bortezomib**

Somnolence Neuropathy Fatigue

Diarrhea

**Grade of neuropathy Bortezomib Thalidomide**

No action No action

Reduce bortezomib dose to 1mg/m2

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 cyclophospha‐ mide(VTD or VCD) appear to be the most active regimens. So, 3-6 cycles of a triplet bortezomib

Suspend bortezomib until disappearence of toxicity then reinitiate at 0.7 mg/m2 and administer

once weekly

Grade 4 Discontinue Discontinue

**Table 8.** Guidelines for the management of bortezomib and thalidomide induced PNP

Rashes Skin rash

Congenital malformations due to

**Table 7.** Major toxicities of novel agents

Paresthesia, weakness and/or loss of reflexes without painor loss of function

Grade 1 with pain or grade 2 interfering with function but not with

Grade 2 with pain or grade 3

**2.5. Conclusions**

fetal exposure

Grade 1

daily activities

Arrhythmias Muscle cramps Thyroid dysfunction Thyroid dysfunction

Hematological toxicity Fatigue Thrombocytopenia

Increased incidence of varicella zoster

Induction Therapy in Multiple Myeloma http://dx.doi.org/10.5772/55151 143

Reduce thalidomide dose to 50% or

suspend thalidomide until disappearence of toxicity, then reinitiate at 50% dose

Suspend thalidomide until disappearence of toxicity, then reinitiate at low dose if PNP grade 1

infections

**Table 5.** Results of EVOLUTION Study comparing bortezomib-based multi-drug combinations


**Table 6.** Phase II Trials of triplet or quadruplet lenalidomide-based induction



#### **Table 7.** Major toxicities of novel agents

**VDCR N=39**

> 5% 33% 80%

> 25% 58% 88%

> 83% 92%

100% 100%

**Table 5.** Results of EVOLUTION Study comparing bortezomib-based multi-drug combinations

> 96 95

Venous thromboembolism Cytopenias Peripheral neuropathy Sensory peripheral neuropathy Venous thromboembolism Gastrointestinal toxicity

Constipation Constipation Postural hypotension and pre-syncope

**Table 6.** Phase II Trials of triplet or quadruplet lenalidomide-based induction

**Thalidomide Lenalidomide Bortezomib**

**1-yr PFS** 86% 83% 93% 100%

After 4 cycles

Best response across all cycles (median=6

142 Multiple Myeloma - A Quick Reflection on the Fast Progress

After censoring patients going to ASCT

**N**

Patients who undergo ASCT

CR ≥VGPR ≥PR

cycles) CR ≥VGPR ≥PR

1-yr PFS 1-yr OS

1-yr PFS 1-yr OS

VDCR vs. VDR vs. VDC vs. VDC-mod

RVDD After 4 cycles

After 8 cycles 74

**VDR N=36**

7% 32% 73%

24% 51% 85%

68% 100%

100% 100%

**Best response after induction (%)**

**≥PR ≥ VGPR CR**

57 65

**RVD** 66 100 67 39 Richardson 2010

**VDC N=31**

3% 13% 63%

22% 41% 75%

97% 100%

88% 100%

29 35

secondary to autonomic neuropathy

**VDC-mod N=16**

> 12% 41% 82%

47% 53% 100%

100% 100%

100% 100%

**Reference**

Kumar 2012

Jakubowiak 2011


**Table 8.** Guidelines for the management of bortezomib and thalidomide induced PNP

#### **2.5. 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 cyclophospha‐ mide(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.

gation in the PFS with MPT was also translated in to OS advantage (Facon et al., 2007; Hulin et al., 2009; Wijermans et al., 2010). Despite in the other three studies the PFS advantage was not translated into OS advantage (Palumbo et al., 2008; Waage et al., 2010; Beksac et al., 2011), a metaanalysis of the pooled data of 1682 patients from these six trials showed that the addition of thalidomide to MP improves OS and PFS in previously untreated elderly patients with multiple myeloma, extending the median survival time by on average 20%. In this metaanal‐ ysis, median PFS was prolonged by 5.4 months (HR 0.67 (0.55-0.80) p<0.0001) and the median OS was prolonged 6.6 months (HR 0.82 (0.66-1.02) p=0.004) (Fayers et al., 2011). This improve‐ ment was less pronounced in patients aged ≥ 75 years and no favorable effect of thalidomide on OS in this population could be demonstrated. The most frequent grade 3-4 adverse events with MPT protocol were polyneuropathy (6-23%) and VTE (3-12%), infections (10-13%), cardiac complications (2-7%), gastrointestinal events (5%). The discontinuation rate ranged 16-45% (Hulin et al., 2009; Wijermans et al., 2010; Fayers et al., 2011). Based on these results, MPT became one of the new standard therapies for elderly patients with newly diagnosed

Induction Therapy in Multiple Myeloma http://dx.doi.org/10.5772/55151 145

Thalidomide-dexamethasone (TD) combination was also compared with MP in 289 elderly patients with MM. Patients achieving stable disease or better were randomly assigned to maintenance therapy with either thalidomide 100 mg daily or interferon alpha-2b. Thalido‐ mide-dexamethasone resulted in a higher proportion of ≥VGPR (26% vs 13%; P=.006) and ORR (68% vs 50%; P=.002) compared with MP. However, PFS was similar (16.7 vs 20.7 months; P=. 1) and OS was significantly shorter in the TD group (41.5 vs 49.4 months; P=.024). Decreased survival was more evident in patients older than 75 years due to increased non-disease related deaths during the first year (Ludwig et al., 2009). Combinations with high dose dexamethasone is not recommended for elderly patients especially those ≥ 75 years due to increased toxicity. 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

After showing significant efficacy in relapsed-refractory myeloma, bortezomib was also incorporated into trials for initial therapy of MM in transplant ineligible patients. The clinical value of adding bortezomib to the standard MP regimen (VMP) was explored in Velcade as Initial Standard Therapy (VISTA) Study (San Miguel et al., 2008). In this phase III study, 682 newly diagnosed myeloma patients were randomly assigned to receive nine 6-week cycles of melphalan (9 mg/m2) and prednisone (60 mg/m2) on days 1 to 4, either alone or with borte‐ zomib (1.3 mg/m2) on days 1, 4, 8, 11, 22, 25, 29 and 32 during cycles 1 to 4 and on days 1, 8, 22, and 29 during cycles 5 to 9. Addition of bortezomib to MP significantly improved all responses, PFS as well as the OS (Table-10). The main adverse events associated with VMP were neutropenia (40%), thrombocytopenia (37%), peripheral neuropathy (14%), infection (10%) and gastrointestinal events (7%). A recent update of the VISTA study and a subsequent study showed that grade 3-4 hematological and non-hematological adverse events in partic‐

higher rates of adverse events compared to MP (Morgan et al., 2011).

**3.3. Bortezomib–based regimens**

MM.
