**3. 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 (Mateos et al., 2012). 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.

#### **3.1. 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).

#### **3.2. 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 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 MM.

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

#### **3.3. Bortezomib–based regimens**

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

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 (Mateos et al., 2012). 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 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 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‐

when a CR is achieved with a novel agent induction treatment.

144 Multiple Myeloma - A Quick Reflection on the Fast Progress

**3.1. Bendamustine**

**3.2. Thalidomide–based regimens**

**3. Induction therapy for patients ineligible for HDT–ASCT**

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‐


that is seen in thalidomide relapses. The survival data of the VISTA trial was updated at 3 years and 5 years and the survival benefit of VMP protocol remained significant (Mateos et al., 2010a; San Miguel et al., 2011). A part of the VISTA trial investigated the efficacy of VMP protocol in renal impairment excluding patients with Cr >2mg/dl. Response rates with VMP and TTP in both arms did not appear significantly different between patients with GFR ≤ 50 or > 50 mL/min. Moreover, VMP resulted in 44% renal impairment reversal suggesting that this protocol is also an active and well-tolerated treatment option for patients with moderate

**MP**

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

**N=338 <sup>p</sup> References**

0.008 HRa =0.61

<0.001 HRa =0.653

0.0004 HRa

San Miguel 2008

Mateos 2010

=0.695 San Miguel 2011

Induction Therapy in Multiple Myeloma http://dx.doi.org/10.5772/55151 147

renal impairment (Dimopoulos et al., 2009).

OS

mos

OS

mos

OS

mos

Median follow-up 16.3

Median follow-up 36.7

Median follow-up 60

a Hazard Ratio

**VMP N=344**

**3-yr OS** 68.5% 54%

**Table 10.** Results of the VISTA trial and the long-tem follow-up

**ORR (≥PR)** 71% 35% <0.001

**CR** 30% 4% <0.001 **TTP** 24 mos 16.6 mos <0.001

Not reached 43 mos

56.4 mos 43.1 mos

M:Melphalan; P:Prednisone; T:Thalidomide; PD:Progressive disease; PFS:Progression free survival; DFS: Disease free survival; GIMEMA: Italian Myeloma Network IFM: Intergroupe Francophone du Mye´lome; NMSG: Nordic Myeloma Study Group; HOVON: Dutch-Belgium Hemato-Oncology Cooperative Group; TMSG:Turkish Myeloma Study Group

**Table 9.** Phase III Studies comparing MPT versus MP for newly diagnosed MM ineligible for HDT-ASCT

ular PNP as well as discontinuation of the drug was significantly reduced without affecting the efficacy when once weekly bortezomib schedule was used (Mateos et al., 2010a; Brignhen et al., 2010). In the VISTA trial, patients with high risk cytogenetic profile had similar response rate and OS with the patients with standard risk profile suggesting that addition of bortezomib may overcome the poor prognosis confered to high risk cytogenetics. Another important point of this study was that first-line bortezomib use did not induce more resistant relapse unlike that is seen in thalidomide relapses. The survival data of the VISTA trial was updated at 3 years and 5 years and the survival benefit of VMP protocol remained significant (Mateos et al., 2010a; San Miguel et al., 2011). A part of the VISTA trial investigated the efficacy of VMP protocol in renal impairment excluding patients with Cr >2mg/dl. Response rates with VMP and TTP in both arms did not appear significantly different between patients with GFR ≤ 50 or > 50 mL/min. Moreover, VMP resulted in 44% renal impairment reversal suggesting that this protocol is also an active and well-tolerated treatment option for patients with moderate renal impairment (Dimopoulos et al., 2009).


#### **Table 10.** Results of the VISTA trial and the long-tem follow-up

ular PNP as well as discontinuation of the drug was significantly reduced without affecting the efficacy when once weekly bortezomib schedule was used (Mateos et al., 2010a; Brignhen et al., 2010). In the VISTA trial, patients with high risk cytogenetic profile had similar response rate and OS with the patients with standard risk profile suggesting that addition of bortezomib may overcome the poor prognosis confered to high risk cytogenetics. Another important point of this study was that first-line bortezomib use did not induce more resistant relapse unlike

**Table 9.** Phase III Studies comparing MPT versus MP for newly diagnosed MM ineligible for HDT-ASCT

**Regimen N Schedule ORR% CR%**

M: 4mg/m2, d1-7 P: 40mg/m2, d1-7 T: 100mg/d 6 cycles every 4 wks until relapse

M:0.25mg/kg, d1-4 P: 2mg/kg, d1-4 T:100-400mg/d 12 cycles every 6 wks

M:0.20mg/kg, d1-4 P: 2mg/kg, d1-4 T:100mg/d 12 cycles every 6 wks

M:0.25mg/kg, d1-4 P: 100mg/d, d1-4 T:200-400mg/d Until plateau every 6 wks Maintenance T 200mg

M:0.25mg/kg, d1-5 P: 1mg/kg, d1-5 T:200mg/d 8 cycles every 4 wks Maintenance T 50mg

M: 9mg/m2, d1-4 P: 60mg/m2, d1-4 T: 100mg/d 8 cycles every 6 wks 76 48

76 35

62 31

57 40

66 45

58 38

M:Melphalan; P:Prednisone; T:Thalidomide; PD:Progressive disease; PFS:Progression free survival; DFS: Disease free survival; GIMEMA: Italian Myeloma Network IFM: Intergroupe Francophone du Mye´lome; NMSG: Nordic Myeloma Study Group; HOVON: Dutch-Belgium Hemato-Oncology Cooperative Group; TMSG:Turkish Myeloma Study Group

16 2.4

13 2

> 7 1

13 4

27 10 ≥VGPR

> 9 9

MPT+T(until PD)

No maintenance

No maintenance

MPT+T(until PD)

MPT+T(until PD)

No maintenance

129 126

146 Multiple Myeloma - A Quick Reflection on the Fast Progress

125 196

113 116

148 179

165 168

> 62 60

MP

MPT MP

MPT MP

MP

MP

MPT MP

**TTP (months)**

> 22 15 p=0.004

> > 28 18

24 19 P=0.001

> 15 14 ns

13 9 P<0.001 PFS

21 14 P=0.34 DFS

**OS (median)**

> 45 47.6 p=0.79

52 33 P=0.0006

44 29 P=0.028

> 29 32 ns

40 31 P=0.05

26 28 P=0.65 **Reference**

GIMEMA Palumbo 2008

> IFM-I Facon 2007

IFM-II Hulin 2009

NMSG Waage 2010

HOVON Wijermans 2010

> TMSG Beksac 2011

> > 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; Nieviz‐ sky 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 3 years 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 (Palumbo et al., 2010). Due to significantly increased adverse events with 4-drug regimen, VMP or MPT are better alternatives for induction of elderly myeloma patients.

(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

Bortezomib

Thalidomide, bortezomib, bendamustin can be administered at full dose, Lenalidomide requires dose

Induction Therapy in Multiple Myeloma http://dx.doi.org/10.5772/55151 149

reduction according to creatinin clearence

TD or VD can be used instead of MP

Pre-existing neuropathy Lenalidomide (MPR, Rd) or bendamustin (BP)

Frail patients Prednisone is beter tolerated than dexamethasone

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 (Palumbo A et al. 2011). 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.

(10%) and thromboembolism (5%)(Palumbo et al., 2012).

**Various circumstances Suggestions**

History of venous thromboembolism Bortezomib

**Table 12.** Individualized treatment strategies for non-transplant candidate patients

Rapid reversal of spinal cord compression or renal

Contraindications to use of alkyllating agents such as presence myelodysplasia or increased risk of

impairment

In cases with renal failure

myelosuppression


VD:Bortezomib dexamethasone; VTD: Bortezimib, thalidomide, dexamethasone; VMP: Bortezomib, melphalan, prednisone; VT: Bortezomib, thalidomide; mos: months; NA: Not available

**Table 11.** Phase III Studies comparing bortezomib containing regimens

#### **3.4. Lenalidomide–based regimens**

In a randomized controlled trial lenalidomide (25 mg/d on d 1-21) plus high dose dexametha‐ sone (480 mg/28d cycle) (RD) produced higher response rates compared with lenalidomide (25 mg/d on d 1-21) plus low dose dexamethasone (Rd) (160 mg/28d cycle). However, this did not translate into superior PFS (Median 19.1 months vs 25.3 months). 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 (Rajkumar et al.,2010; 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).


**Table 12.** Individualized treatment strategies for non-transplant candidate patients

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; Nieviz‐ sky 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 3 years 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 (Palumbo et al., 2010). Due to significantly increased adverse events with 4-drug regimen, VMP or MPT are better alternatives for induction of elderly myeloma

> **ORR % CR % After induction**

> > 20 28

38 24 P<0.001

> 24 36 31

VD:Bortezomib dexamethasone; VTD: Bortezimib, thalidomide, dexamethasone; VMP: Bortezomib, melphalan,

In a randomized controlled trial lenalidomide (25 mg/d on d 1-21) plus high dose dexametha‐ sone (480 mg/28d cycle) (RD) produced higher response rates compared with lenalidomide (25 mg/d on d 1-21) plus low dose dexamethasone (Rd) (160 mg/28d cycle). However, this did not translate into superior PFS (Median 19.1 months vs 25.3 months). 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 (Rajkumar et al.,2010; 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

37 mos 32 mos

3-year 56% 41% p=0.008

80 81

89 81

73 80 69 **PFS OS Reference**

Mateos 2010

Palumbo 2010

60mos median 5-yr 53%

> 3-year 89% 87% p=0.77

NA NA Nievizsky 2011

patients.

VMP VTP

VD VTD VMP

VMPT + VT

maintenance VP or VT

VMP + no maintenance 254

**3.4. Lenalidomide–based regimens**

**N**

148 Multiple Myeloma - A Quick Reflection on the Fast Progress

130 130

257

168 167 167

prednisone; VT: Bortezomib, thalidomide; mos: months; NA: Not available

**Table 11.** Phase III Studies comparing bortezomib containing regimens

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 (Palumbo A et al. 2011). 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.

#### **3.5. 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 appropri‐ ate dose reductions should be done. Thus, the treatment should be individualized. Melpha‐ lan-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 recommenda‐ tions 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 (Palumbo et al., 2010) suggested some PFS benefit in response to VMPT+VT over VMP regarding the highrisk cytogenetics, other studies did not confirm this.

**Regimen Usual dosing schedule Reference**

Repeated every 35 days

(or 40 mg days 1,8,15,22) Repeated every 4 weeks

Repeated every 4 weeks

(or 40 mg days 1,8,15,22) Repeated every 3 weeks

Thalidomide 50 mg/day

weeks

Cyclophosphamide 500mg/week

every 4 weeks to a maximum 200mg/day

Bortezomib 1.3 mg/m2 iv days 1,4,8,11 Lenalidomide 15 mg oral days 1-14 Dexamethasone 40 mg days 1,8,15 Cyclophosphamide 500mg/ m2 days 1,8

Bortezomib 1.3 mg/m2 iv days 1,8,15,22 Melphalan 9 mg/ m2 oral days 1-4 Prednisone 60 mg/ m2 oral days 1-4

Bortezomib 1.3 mg/m2 iv days 1,8,15,22 Thalidomide 100-200 mg oral days 1-21

Bortezomib 1.3 mg/m2 iv days 1,8,15,22 Dexamethasone 40 mg oral days 1,8,15,22

Bortezomib 1.3 mg/m2 iv days 1,4,8,11

Bortezomib 1.3 mg/m2 iv days 1,8 and 15 Lenalidomide 25 mg oral days 1-14

Dexamethasone 20 mg on day of and day after bortezomib

Cyclophosphamide 300mg/ m2 oral days 1,8,15,22

Cyclophosphamide 900mg/ m2 on day 1 every 3 weeks Dexamethasone 40 mg on day of and day after bortezomib

Dexamethasone 20 mg on day of and day after bortezomib

Melphalan 0.18 mg/kg on days 1-4 every 4 weeks x 9 cycles Prednisone 2mg/kg on days 1-4 every 4 weeks x 9 cycles Lenalidomide 10 mg on days 1-21 then 10mg/d until relapse

Thalidomide 50 mg/day for 4 weeks, 50 mg increments

Dexamethasone 20 mg/day on days 1- 4 and 15-18 every 4

Bortezomib 1.3 mg/m2 iv days 1,8,15,22 every 35 days Melphalan 9 mg/ m2 oral days 1-4 every 35 days Prednisone 60 mg/ m2 oral days 1-4 every 35 days

San Miguel et al., 2008

151

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

> Cavo et al., 2009

Reeder et al., 2009

Einsele et al., 2009

Richardson et al., 2010

Palumbo et al.,

Palumbo et al.,

Morgan et al., 2011

Kumar et al., 2010

2010

2012

Bortezomib-Melphalan-Prednisone

Bortezomib-Thalidomide-Dexamethasone (VTD)

Cyclophosphamide-Bortezomib-Dexamethasone (CyBorD)

Bortezomib-Cyclophosphamide-

Dexamethasone (VCD)

Bortezomib-Lenalidomide-Dexamethasone (VRD)

Thalidomide (VMPT)

(MPR-R)

(CTD a)

(VRDC)

Bortezomib-Melphalan-Prednisone-

Melphalan-Prednisone-Lenalidomide

Cyclophosphamide-Thalidomide-Dexamethasone (atenuated dose)

Bortezomib-Lenalidomide-

Dexamethasone-Cyclophosphamide

**Table 13.** Main treatment protocols in Multiple Myeloma

(VMP)



**Table 13.** Main treatment protocols in Multiple Myeloma

**3.5. Conclusions**

150 Multiple Myeloma - A Quick Reflection on the Fast Progress

Melphalan-Prednisone (MP-7 day Schedule)

Thalidomide-Dexamethasone (Td)

Lenalidomide-Dexamethasone (Rd)

Bortezomib –dexamethasone (Vd)

Melphalan-Prednisone-Thalidomide

risk cytogenetics, other studies did not confirm this.

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 appropri‐ ate dose reductions should be done. Thus, the treatment should be individualized. Melpha‐ lan-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 recommenda‐ tions 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 (Palumbo et al., 2010) suggested some PFS benefit in response to VMPT+VT over VMP regarding the high-

**Regimen Usual dosing schedule Reference**

Melphalan 8-10 mg oral days 1-7 Prednisone 60mg/d oral days 1-7 Repeated every 6 weeks

Thalidomide 200 mg oral days 1-28 Dexamethasone 40 mg oral days 1,8,15,22

Lenalidomide 25 mg oral days 1-21 Dexamethasone 40 mg oral days 1,8,15,22

Bortezomib 1.3 mg/m2 iv days 1,8,15,22

Dexamethasone 20 mg on day of and day after bortezomib

Repeated every 4 weeks

Repeated every 4 weeks

(or 40 mg days 1,8,15,22) Repeated every 4 weeks

(MPT) Different MPT protocols are described in table…

Kyle et al., 2004

Rajkumar et al.,

Rajkumar et al.,

Harousseau et al., 2006

2006

2010

#### **Author details**

Sule Mine Bakanay1 and Meral Beksac2


#### **References**

[1] Anderson, K. C, Jagannath, S, Jakubowiak, A, Lonial, S, Raje, N, Alsina, M, Ghobrial, I, & Knight, R. Esseltine D & Richardson J Clin Oncol, abstr 8536., 2009.

[8] Bringhen, S, Larocca, A, Rossi, D, Cavalli, M, Genuardi, M, Ria, R, Gentili, S, Patriar‐ ca, F, Nozzoli, C, Levi, A, Guglielmelli, T, Benevolo, G, Callea, V, Rizzo, V, Cangialo‐ si, C, Musto, P, De Rosa, L, Liberati, A. M, Grasso, M, Falcone, A. P, Vangelista, A, Cavo, M, & Gaidano, G. Boccadoro M & Palumbo A. ((2010). Efficacy and safety of once-weekly bortezomib in multiple myeloma patients. Blood,, 116(23), 4745-53.

Induction Therapy in Multiple Myeloma http://dx.doi.org/10.5772/55151 153

[9] Cavo, M. Di Raimondo F, Zamagni E, Patriarca F, Tacchetti P, Casulli AF, Volpe S, Perrone G, Ledda A, Ceccolini M, Califano C, Bigazzi C, Offidani M, Stefani P,Baller‐ ini F, Fiacchini M, de Vivo A, Brioli A, Tosi P & Baccarani M. ((2009). Short-term tha‐ lidomide incorporated into double autologous stem-cell transplantation improves outcomes in comparison with double autotransplantation for multiple myeloma. J

[10] Cavo, M, Rajkumar, S. V, Palumbo, A, Moreau, P, Orlowski, R, Bladé, J, Sezer, O, Ludwig, H, Dimopoulos, M. A, Attal, M, Sonneveld, P, Boccadoro, M, Anderson, K. C, Richardson, P. G, Bensinger, W, Johnsen, H. E, Kroeger, N, Gahrton, G, Bergsagel, P. L, Vesole, D. H, Einsele, H, Jagannath, S, Niesvizky, R, & Durie, B. G. San Miguel J & Lonial S; International Myeloma Working Group. ((2011). International Myeloma Working Group consensus approach to the treatment of multiple myeloma patients who are candidates for autologous stem cell transplantation. Blood,, 117(23), 6063-73.

[11] Cavo, M, Tacchetti, P, Patriarca, F, Petrucci, M. T, Pantani, L, & Galli, M. Di Raimon‐ do F,Crippa C, Zamagni E, Palumbo A, Offidani M, Corradini P, Narni F, Spadano A,Pescosta N, Deliliers GL, Ledda A, Cellini C, Caravita T, Tosi P & Baccarani M;GI‐ MEMA Italian Myeloma Network. ((2010). Bortezomib with thalidomide plus dexa‐ methasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after,double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet,,

[12] Cavo, M, Zamagni, E, Tosi, P, Cellini, C, Cangini, D, Tacchetti, P, Testoni, N, Tonelli, M, De Vivo, A, & Palareti, G. Tura S & Baccarani M. ((2004). First-line therapy with thalidomide and dexamethasone in preparation for autologous stem cell transplanta‐

[13] Cavo, M, Zamagni, E, Tosi, P, Tacchetti, P, Cellini, C, Cangini, D, De Vivo, A, Testo‐ ni, N, Nicci, C, Terragna, C, Grafone, T, Perrone, G, & Ceccolini, M. Tura S & Baccar‐ ani M; Bologna 2002 study. ((2005). Superiority of thalidomide and dexamethasone over vincristine-doxorubicindexamethasone (VAD) as primary therapy in prepara‐ tion for autologous transplantation for multiple myeloma. Blood ;, 106(1), 35-9.

[14] Chanan-Khan AA & Giralt S(2010). Importance of achieving a complete response in multiple myeloma, and the impact of novel agents. J Clin Oncol.,, 28(15), 2612-24. [15] Cherry, B. M, Korde, N, & Kwok, M. Roschewski M & Landgren O. ((2012). Evolving therapeutic paradigms for multiple myeloma: back to the future. Leuk Lymphoma.

tion for multiple myeloma. Haematologica, , 89(7), 826-31.

Clin Oncol.,, 27(30), 5001-7.

376(9758), 2075-85.

[Epub ahead of print].


[8] Bringhen, S, Larocca, A, Rossi, D, Cavalli, M, Genuardi, M, Ria, R, Gentili, S, Patriar‐ ca, F, Nozzoli, C, Levi, A, Guglielmelli, T, Benevolo, G, Callea, V, Rizzo, V, Cangialo‐ si, C, Musto, P, De Rosa, L, Liberati, A. M, Grasso, M, Falcone, A. P, Vangelista, A, Cavo, M, & Gaidano, G. Boccadoro M & Palumbo A. ((2010). Efficacy and safety of once-weekly bortezomib in multiple myeloma patients. Blood,, 116(23), 4745-53.

**Author details**

Sule Mine Bakanay1

**References**

91-7.

4630-4.

and Meral Beksac2

2 Ankara University School of Medicine,Department of Hematology, Ankara, Turkey

I, & Knight, R. Esseltine D & Richardson J Clin Oncol, abstr 8536., 2009.

[1] Anderson, K. C, Jagannath, S, Jakubowiak, A, Lonial, S, Raje, N, Alsina, M, Ghobrial,

[2] Attal, M, Harousseau, J. L, Stoppa, A. M, Sotto, J. J, Fuzibet, J. G, Rossi, J. F, Casassus, P, Maisonneuve, H, Facon, T, & Ifrah, N. Payen C & Bataille R. ((1996). A prospec‐ tive, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Français du Myélome. N Engl J Med., 11;, 335(2),

[3] Avet-loiseau, H, Leleu, X, Roussel, M, Moreau, P, Guerin-charbonnel, C, Caillot, D, Marit, G, Benboubker, L, Voillat, L, Mathiot, C, Kolb, B, Macro, M, Campion, L, Wet‐ terwald, M, Stoppa, A. M, Hulin, C, Facon, T, & Attal, M. Minvielle S & Harousseau JL. ((2010). Bortezomib plus dexamethasone induction improves outcome of patients with t(4;14)myeloma but not outcome of patients with del(17p). J Clin Oncol.,, 28(30),

[4] Barlogie, B, Tricot, G, Anaissie, E, Shaughnessy, J, Rasmussen, E, Van Rhee, F, Fassas, A, Zangari, M, Hollmig, K, Pineda-roman, M, Lee, C, Talamo, G, Thertulien, R, Ki‐ wan, E, Krishna, S, Fox, M, & Crowley, J. Thalidomide and hematopoietic-cell trans‐ plantation for multiple myeloma. N Engl J Med. (2006). Mar 9;, 354(10), 1021-30.

[5] Beksac, M. Delforge M & Richardson The evolving treatment paradigm of multiple myeloma: From past to present and future. Turk J Hematol., 25(2): 60-70., 2008.

[6] Beksac, M, Haznedar, R, Firatli-tuglular, T, Ozdogu, H, Aydogdu, I, Konuk, N, Su‐ cak, G, Kaygusuz, I, Karakus, S, Kaya, E, Ali, R, Gulbas, Z, & Ozet, G. Goker H & Undar L. ((2011). Addition of thalidomide to oral melphalan/prednisone in patients with multiple myeloma not eligible for transplantation: results of a randomized trial

[7] Bird, J. M, Owen, R. G, Sa, D, Snowden, S, Pratt, J. A, Ashcroft, G, Yong, J, Cook, K, Feyler, G, Davies, S, Morgan, F, Cavenagh, G, Low, J, Behrens, E, & Haemato-oncolo‐ gy, J. Task Force of British Committee for Standards in Haematology (BCSH) and UK Myeloma Forum. ((2011). Guidelines for the diagnosis and management of multiple

from the Turkish Myeloma Study Group. Eur J Haematol., , 86(1), 16-22.

myeloma 2011. Br J Haematol,, 154(1), 32-75.

1 Ataturk Hospital, Hematology Unit, Ankara, Turkey

152 Multiple Myeloma - A Quick Reflection on the Fast Progress


[16] Child, J. A, Morgan, G. J, Davies, F. E, Owen, R. G, Bell, S. E, Hawkins, K, & Brown, J. Drayson MT & Selby PJ; Medical Research Council Adult Leukaemia Working Party. ((2003). Highdose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. NEngl J Med, 8;, 348(19), 1875-83.

dexamethasone in newly diagnosed multiple myeloma: a comparative analysis of

Induction Therapy in Multiple Myeloma http://dx.doi.org/10.5772/55151 155

[23] Gay, F, Rajkumar, S. V, Coleman, M, Kumar, S, Mark, T, Dispenzieri, A, Pearse, R, Gertz, M. A, Leonard, J, Lacy, M. Q, Chen-kiang, S, Roy, V, Jayabalan, D. S, Lust, J. A, Witzig, T. E, Fonseca, R, Kyle, R. A, & Greipp, P. R. Stewart AK & Niesvizky R. ((2010). Clarithromycin (Biaxin)-lenalidomide-low-dose dexamethasone (BiRd) ver‐ sus lenalidomide-low-dose dexamethasone (Rd) for newly diagnosed myeloma. Am

[24] Harousseau, J. L. Attal M & Avet-Loiseau H. ((2009). The role of complete response

[25] Harousseau, J. L, Attal, M, Avet-loiseau, H, Marit, G, Caillot, D, Mohty, M, Lenain, P, Hulin, C, Facon, T, Casassus, P, Michallet, M, Maisonneuve, H, Benboubker, L, Ma‐ loisel, F, Petillon, M. O, & Webb, I. Mathiot C & Moreau Bortezomib plus dexametha‐ sone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 phase III trial. J Clin Oncol.,28(30):4621-9., 2010.

[26] Harousseau, J. L, Attal, M, Avet-loiseau, H, Marit, G, Caillot, D, Mohty, M, Lenain, P, Hulin, C, Facon, T, Casassus, P, Michallet, M, Maisonneuve, H, Benboubker, L, Ma‐ loisel, F, Petillon, M. O, & Webb, I. Mathiot C & Moreau Bortezomib plus dexametha‐ sone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 phase III trial. J Clin Oncol.,28(30):4621-9., 2010.

[27] Harousseau, J. L, Attal, M, Leleu, X, Troncy, J, Pegourie, B, Stoppa, A. M, Hulin, C, Benboubker, L, Fuzibet, J. G, & Renaud, M. Moreau P & Avet-Loiseau H. ((2006). Bortezomib plus dexamethasone as induction treatment prior to autologous stem cell transplantation in patients with newly diagnosed multiple myeloma: results of an

[28] Haslett, P. A, & Hanekom, W. A. Muller G & Kaplan G. ((2003). Thalidomide and a thalidomide analogue drug costimulate virus-specific CD8+ T cells in vitro. J Infect

[29] Hideshima, T, Chauhan, D, Shima, Y, Raje, N, Davies, F. E, Tai, Y. T, Treon, S. P, Lin, B, Schlossman, R. L, Richardson, P, & Muller, G. Stirling DI & Anderson KC. ((2000). Thalidomide and its analogs overcome drug resistance of human multiple myeloma

[30] Hideshima, T, Chauhan, D, Shima, Y, Raje, N, Davies, F. E, Tai, Y. T, Treon, S. P, Lin, B, Schlossman, R. L, Richardson, P, & Muller, G. Stirling DI & Anderson KC. ((2000). Thalidomide and its analogs overcome drug resistance of human multiple myeloma

[31] Hideshima, T, Richardson, P, Chauhan, D, Palombella, V. J, & Elliott, P. J. Adams J &Anderson KC. ((2001). The proteasome inhibitor PS-341 inhibits growth, induces

411 patients. Blood,, 115(7), 1343-50.

in multiple myeloma. Blood, , 114(15), 3139-46.

IFM phase II study. Haematologica,, 91(11), 1498-505.

cells to conventional therapy. Blood,, 96(9), 2943-50.

cells to conventional therapy. Blood,, 96(9), 2943-50.

J Hematol.,, 85(9), 664-9.

Dis.,, 187(6), 946-55.


dexamethasone in newly diagnosed multiple myeloma: a comparative analysis of 411 patients. Blood,, 115(7), 1343-50.

[16] Child, J. A, Morgan, G. J, Davies, F. E, Owen, R. G, Bell, S. E, Hawkins, K, & Brown, J. Drayson MT & Selby PJ; Medical Research Council Adult Leukaemia Working Party. ((2003). Highdose chemotherapy with hematopoietic stem-cell rescue for multiple

[17] Dimopoulos, M. A, Richardson, P. G, Schlag, R, Khuageva, N. K, Shpilberg, O, Kas‐ tritis, E, Kropff, M, Petrucci, M. T, Delforge, M, Alexeeva, J, Schots, R, Masszi, T, Ma‐ teos, M. V, Deraedt, W, Liu, K, & Cakana, A. van de Velde H & San Miguel JF. ((2009). VMP (Bortezomib, Melphalan, and Prednisone) is active and well tolerated in newly diagnosed patients with multiple myeloma with moderately impaired renal function,and results in reversal of renal impairment: cohort analysis of the phase III

[18] Einsele, H, Liebisch, P, Langer, C, et al. Velcade, intravenous cyclophosphamide and dexamethasone (VCD) induction for previously untreated multiple myeloma (Ger‐

[19] Facon, T, Mary, J. Y, Hulin, C, Benboubker, L, Attal, M, Pegourie, B, Renaud, M, Har‐ ousseau, J. L, Guillerm, G, Chaleteix, C, Dib, M, Voillat, L, Maisonneuve, H, Troncy, J, Dorvaux, V, Monconduit, M, Martin, C, Casassus, P, Jaubert, J, Jardel, H, Doyen, C, Kolb, B, Anglaret, B, Grosbois, B, & Yakoub-agha, I. Mathiot C & Avet-Loiseau H;In‐ tergroupe Francophone du Myélome. ((2007). Melphalan and prednisone plus thali‐ domide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a

[20] Fayers, P. M, Palumbo, A, Hulin, C, Waage, A, Wijermans, P, Beksaç, M, Bringhen, S, Mary, J. Y, Gimsing, P, Termorshuizen, F, Haznedar, R, Caravita, T, Moreau, P, Tur‐ esson, I, Musto, P, Benboubker, L, & Schaafsma, M. Sonneveld P & Facon T; Nordic Myeloma Study Group; Italian Multiple Myeloma Network; Turkish Myeloma Study Group; Hemato-Oncologie voor Volwassenen Nederland; Intergroupe Francophone du Myélome; European Myeloma Network. ((2011). Thalidomide for previously un‐ treated elderly patients with multiple myeloma: meta-analysis of 1685 individual pa‐

[21] Fermand, J. P, Katsahian, S, Divine, M, Leblond, V, Dreyfus, F, Macro, M, Arnulf, B, Royer, B, Mariette, X, Pertuiset, E, Belanger, C, Janvier, M, & Chevret, S. Brouet JC & Ravaud P; Group Myelome-Autogreffe. ((2005). High-dose therapy and autologous blood stemcell transplantation compared with conventional treatment in myeloma patients aged 55 to 65 years: long-term results of a randomized control trial from the

[22] Gay, F, Hayman, S. R, Lacy, M. Q, Buadi, F, Gertz, M. A, Kumar, S, Dispenzieri, A, Mikhael, J. R, Bergsagel, P. L, Dingli, D, Reeder, C. B, Lust, J. A, Russell, S. J, Roy, V, Zeldenrust, S. R, Witzig, T. E, Fonseca, R, Kyle, R. A, & Greipp, P. R. Stewart AK & Rajkumar SV. ((2010). Lenalidomide plus dexamethasone versus thalidomide plus

tient data from 6 randomized clinical trials. Blood, , 118(5), 1239-47.

Group Myelome-Autogreffe. J Clin Oncol, 20;, 23(36), 9227-33.

man DSMM XIa Trial). ((2009). ASH Annual Meeting Abstracts. Abstract 131.

myeloma. NEngl J Med, 8;, 348(19), 1875-83.

154 Multiple Myeloma - A Quick Reflection on the Fast Progress

VISTA study. J Clin Oncol.,, 27(36), 6086-93.

randomised trial. Lancet, , 370(9594), 1209-18.


apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res.,, 61(7), 3071-6.

diagnosed multiple myeloma: A systematic review and meta-analysis of randomized

Induction Therapy in Multiple Myeloma http://dx.doi.org/10.5772/55151 157

[40] Kumar, S, Dispenzieri, A, Lacy, M. Q, Hayman, S. R, Buadi, F. K, Gastineau, D. A, Litzow, M. R, Fonseca, R, & Roy, V. Rajkumar SV& Gertz MA. ((2007). Impact of le‐ nalidomide therapy on stem cell mobilization and engraftment post-peripheral blood stem cell transplantation in patients with newly diagnosed myeloma. Leukemia, , 21,

[41] Kumar, S, Flinn, I, Richardson, P. G, Hari, P, Callander, N, Noga, S. J, Stewart, A. K, Turturro, F, Rifkin, R, Wolf, J, Estevam, J, Mulligan, G, & Shi, H. Webb IJ & Rajkumar SV. ((2012). Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib,dexamethasone, cyclophosphamide, and lenalidomide in previously

[42] Kumar, S, Giralt, S, Stadtmauer, E. A, Harousseau, J. L, Palumbo, A, Bensinger, W, Comenzo, R. L, Lentzsch, S, Munshi, N, & Niesvizky, R. San Miguel J, Ludwig H, Bergsagel L, Blade J,Lonial S, Anderson KC, Tosi P, Sonneveld P, Sezer O, Vesole D, Cavo M, Einsele H,Richardson PG, Durie BG & Rajkumar SV; International Myeloma Working Group. ((2009). Mobilization in myeloma revisited: IMWG consensus per‐ spectives on stem cell collection following initial therapy with thalidomide-, lenalido‐

[43] Kumar, S. K, Rajkumar, S. V, Dispenzieri, A, Lacy, M. Q, Hayman, S. R, Buadi, F. K, Zeldenrust, S. R, Dingli, D, Russell, S. J, Lust, J. A, & Greipp, P. R. Kyle RA & Gertz MA. ((2008). Improved survival in multiple myeloma and the impact of novel thera‐

[44] Kyle RA & Rajkumar SV(2004). Multiple myeloma. N Engl J Med.,, 351(18), 1860-73.

[45] Lokhorst, H. M, Schmidt-wolf, I, Sonneveld, P, Van Der Holt, B, Martin, H, Barge, R, Bertsch, U, Schlenzka, J, Bos, G. M, Croockewit, S, Zweegman, S, Breitkreutz, I, Joos‐ ten, P, Scheid, C, Van Marwijk-kooy, M, Salwender, H. J, Van Oers, M. H, Schaafsma, R, Naumann, R, Sinnige, H, Blau, I, Delforge, M, De Weerdt, O, Wijermans, P, Witte‐ bol, S, & Duersen, U. Vellenga E & Goldschmidt H; Dutch-Belgian HOVON; German GMMG. ((2008). Thalidomide in induction treatment increases the very good partial response rate before and after high-dose therapy in previously untreated multiple

[46] Lokhorst, H. M, Van Der Holt, B, Zweegman, S, Vellenga, E, Croockewit, S, & Van Oers, M. H. von dem Borne P, Wijermans P, Schaafsma R, de Weerdt O, Wittebol S, Delforge M, Berenschot H, Bos GM, Jie KS, Sinnige H, van Marwijk-Kooy M, Joosten P, Minnema MC, van Ammerlaan R & Sonneveld P; Dutch-Belgian Hemato-Oncolo‐ gy Group (HOVON). ((2010). A randomized phase 3 study on the effect of thalido‐ mide combined with adriamycin,dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma. Blood, ,

mide-, or bortezomib-containing regimens. Blood, 27;, 114(9), 1729-35.

controlled trials. Biol Blood Marrow Transplant, , 13(2), 183-96.

untreated multiple myeloma. Blood,, 119(19), 4375-82.

pies. Blood,, 111(5), 2516-20.

myeloma. Haematologica,, 93(1), 124-7.

115(6), 1113-20.

2035-42.


diagnosed multiple myeloma: A systematic review and meta-analysis of randomized controlled trials. Biol Blood Marrow Transplant, , 13(2), 183-96.

apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer

[32] Hulin, C, Facon, T, Rodon, P, Pegourie, B, Benboubker, L, Doyen, C, Dib, M, Guil‐ lerm, G, Salles, B, Eschard, J. P, Lenain, P, Casassus, P, Azaïs, I, Decaux, O, Garderet, L, Mathiot, C, Fontan, J, & Lafon, I. Virion JM & Moreau Efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed

[33] Jagannath, S, Barlogie, B, Berenson, J, Siegel, D, Irwin, D, Richardson, P. G, Niesviz‐ ky, R, Alexanian, R, Limentani, S. A, Alsina, M, Adams, J, Kauffman, M, & Esseltine, D. L. Schenkein DP & Anderson KC. ((2004). A phase 2 study of two doses of borte‐

[34] Jagannath, S, Durie, B. G, Wolf, J, Camacho, E, Irwin, D, Lutzky, J, Mckinley, M, Ga‐ bayan, E, & Mazumder, A. Schenkein D&Crowley J. ((2005). Bortezomib therapy alone and in combination with dexamethasone for previously untreated symptomat‐

[35] Jagannath, S, Richardson, P. G, Sonneveld, P, Schuster, M. W, Irwin, D, Stadtmauer, E. A, Facon, T, & Harousseau, J. L. Cowan JM & Anderson KC. ((2007). Bortezomib appears to overcome the poor prognosis conferred by chromosome 13 deletion in

[36] Jakubowiak, A. J, Griffith, K. A, Reece, D. E, Hofmeister, C. C, Lonial, S, Zimmerman, T. M, Campagnaro, E. L, Schlossman, R. L, Laubach, J. P, Raje, N. S, Anderson, T, Mietzel, M. A, Harvey, C. K, Wear, S. M, Barrickman, J. C, Tendler, C. L, Esseltine, D. L, Kelley, S. L, & Kaminski, M. S. Anderson KC & Richardson PG. ((2011). Lenalido‐ mide, bortezomib, pegylated liposomal doxorubicin, and dexamethasone in newly diagnosed multiple myeloma: a phase 1/2 Multiple Myeloma Research Consortium

[37] Jakubowiak, A. J, Kendall, T, Al-zoubi, A, Khaled, Y, Mineishi, S, Ahmed, A, Cam‐ pagnaro, E, Brozo, C, & Braun, T. Talpaz M & Kaminski MS. ((2009). Phase II trial of combination therapy with bortezomib, pegylated liposomal doxorubicin, and dexa‐ methasone in patients with newly diagnosed myeloma. J Clin Oncol,, 27(30), 5015-22.

[38] Kastritis, E, Zervas, K, Symeonidis, A, Terpos, E, Delimbassi, S, Anagnostopoulos, N, Michali, E, Zomas, A, Katodritou, E, Gika, D, Pouli, A, Christoulas, D, Roussou, M, & Kartasis, Z. Economopoulos T & Dimopoulos MA. ((2009). Improved survival of pa‐ tients with multiple myeloma after the introduction of novel agents and the applica‐ bility of the International Staging System (ISS): an analysis of the Greek Myeloma

[39] Koreth, J, Cutler, C. S, Djulbegovic, B, Behl, R, Schlossman, R. L, Munshi, N. C, Ri‐ chardson, P. G, & Anderson, K. C. Soiffer RJ & Alyea EP 3rd. ((2007). High-dose ther‐ apy with single autologous transplantation versus chemotherapy for newly

multiple myeloma: IFM 01/01 trial. J Clin Oncol., 27(22):3664-70., 2009.

zomib in relapsed or refractory myeloma. Br J Haematol.,, 127(2), 165-72.

ic multiple myeloma. Br J Haematol.,, 129(6), 776-83.

phase 2 and 3 trials. Leukemia,, 21(1), 151-7.

Study Group (GMSG). Leukemia, , 23(6), 1152-7.

trial. Blood,, 118(3), 535-43.

Res.,, 61(7), 3071-6.

156 Multiple Myeloma - A Quick Reflection on the Fast Progress


[47] Ludwig, H, Beksac, M, Bladé, J, Cavenagh, J, Cavo, M, Delforge, M, Dimopoulos, M, Drach, J, Einsele, H, Facon, T, Goldschmidt, H, Harousseau, J. L, Hess, U, & Kropff, M. Leal da Costa F, Louw V, Magen-Nativ H, Mendeleeva L, Nahi H, Plesner T, San-Miguel J,Sonneveld P, Udvardy M, Sondergeld P & Palumbo A. ((2011). Multiple myeloma treatment strategies with novel agents in 2011: a European perspective. On‐ cologist,, 16(4), 388-403.

[53] Mazumder, A, Kaufman, J, Niesvizky, R, & Lonial, S. Vesole D & Jagannath S. ((2008). Effect of lenalidomide therapy on mobilization of peripheral blood stem cells

Induction Therapy in Multiple Myeloma http://dx.doi.org/10.5772/55151 159

[54] Mitsiades, N, Mitsiades, C. S, Poulaki, V, Chauhan, D, Richardson, P. G, Hideshima, T, & Munshi, N. C. Treon SP & Anderson KC. ((2002). Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: ther‐

[55] Moreau, P, Avet-loiseau, H, Facon, T, Attal, M, Tiab, M, Hulin, C, Doyen, C, Garder‐ et, L, Randriamalala, E, Araujo, C, Lepeu, G, Marit, G, Caillot, D, Escoffre, M, Lioure, B, Benboubker, L, Pégourié, B, Kolb, B, Stoppa, A. M, Fuzibet, J. G, Decaux, O, Dib, M, Berthou, C, Chaleteix, C, Sebban, C, Traullé, C, Fontan, J, Wetterwald, M, & Le‐ nain, P. Mathiot C & Harousseau JL. ((2011). Bortezomib plus dexamethasone versus reduced-dose bortezomib, thalidomide plus dexamethasone as induction treatment before autologous stem cell transplantation in newly diagnosed multiple myeloma.

[56] Moreau, P, Hulin, C, Marit, G, Caillot, D, Facon, T, Lenain, P, Berthou, C, Pégourié, B, Stoppa, A. M, Casassus, P, Michallet, M, Benboubker, L, Maisonneuve, H, Doyen, C, Leyvraz, S, Mathiot, C, & Avet-loiseau, H. Attal M & Harousseau JL; IFM group. ((2010). Stem cell collection in patients with de novo multiple myeloma treated with thecombination of bortezomib and dexamethasone before autologous stem cell trans‐

[57] Morgan, G. J, Davies, F. E, Gregory, W. M, Bell, S. E, & Szubert, A. J. Navarro Coy N, Cook G, Feyler S, Johnson PR, Rudin C, Drayson MT, Owen RG, Ross FM, Russell NH, Jackson GH & Child JA; National Cancer Research Institute Haematological On‐ cology Clinical Studies Group. ((2012). Cyclophosphamide, thalidomide, and dexa‐ methasone as induction therapy for newly diagnosed multiple myeloma patients destined for autologous stem-cell transplantation: MRC Myeloma IX randomized tri‐

[58] Morgan, G. J, Davies, F. E, Gregory, W. M, Russell, N. H, Bell, S. E, & Szubert, A. J. Navarro Coy N, Cook G, Feyler S, Byrne JL, Roddie H, Rudin C, Drayson MT, Owen RG, Ross FM, Jackson GH & Child JA; NCRI Haematological Oncology Study Group. Cyclophosphamide, thalidomide, and dexamethasone (CTD) as initial therapy for patients with multiple myeloma unsuitable for autologous transplantation. Blood, ,

[59] Niesvizky, R, Flinn, I. W, Rifkin, R. M, Gabrail, N. Y, Charu, V, Clowney, B, Essell, J, Gaffar, Y. A, Warr, T. A, & Neuwirth, R. Corzo D & Reeves JA. ((2010). Phase 3b UP‐ FRONT Study: Safety and Efficacy of Weekly Bortezomib Maintenance Therapy Af‐ ter Bortezomib-Based Induction Regimens In Elderly, Newly Diagnosed Multiple

Myeloma Patients. Blood (ASH Annual Meeting Abstracts) 116: Abstract 619.

plantation according to IFM 2005-01 trial. Leukemia,, 24(6), 1233-5.

in previously untreated multiple myeloma patients. Leukemia, , 22(6), 1280-1.

apeutic implications. Blood,, 99(12), 4525-30.

al results. Haematologica,, 97(3), 442-50.

118(5), 1231-8.

Blood,, 118(22), 5752-8.


[53] Mazumder, A, Kaufman, J, Niesvizky, R, & Lonial, S. Vesole D & Jagannath S. ((2008). Effect of lenalidomide therapy on mobilization of peripheral blood stem cells in previously untreated multiple myeloma patients. Leukemia, , 22(6), 1280-1.

[47] Ludwig, H, Beksac, M, Bladé, J, Cavenagh, J, Cavo, M, Delforge, M, Dimopoulos, M, Drach, J, Einsele, H, Facon, T, Goldschmidt, H, Harousseau, J. L, Hess, U, & Kropff, M. Leal da Costa F, Louw V, Magen-Nativ H, Mendeleeva L, Nahi H, Plesner T, San-Miguel J,Sonneveld P, Udvardy M, Sondergeld P & Palumbo A. ((2011). Multiple myeloma treatment strategies with novel agents in 2011: a European perspective. On‐

[48] Ludwig, H, Hajek, R, Tóthová, E, Drach, J, Adam, Z, Labar, B, Egyed, M, Spicka, I, Gisslinger, H, Greil, R, & Kuhn, I. Zojer N & Hinke A. ((2009). Thalidomide-dexame‐ thasone compared with melphalan-prednisolone in elderly patients with multiple

[49] Mateos MV & San Miguel JFOld and new treatments in non-transplant candidate newly diagnosed MM patients. Hematology education programme fort he annual congress of the European Hematology Association. ((2012). Haematologica,, 6(1),

[50] Mateos, M. V, Oriol, A, Martínez-lópez, J, Gutiérrez, N, Teruel, A. I, De Paz, R, Gar‐ cía-laraña, J, Bengoechea, E, Martín, A, Mediavilla, J. D, Palomera, L, De Arriba, F, González, Y, Hernández, J. M, Sureda, A, Bello, J. L, Bargay, J, Peñalver, F. J, Ribera, J. M, Martín-mateos, M. L, García-sanz, R, Cibeira, M. T, Ramos, M. L, Vidriales, M. B, Paiva, B, Montalbán, M. A, & Lahuerta, J. J. Bladé J & Miguel JF.Bortezomib, mel‐ phalan, and prednisone versus bortezomib, thalidomide, and prednisone as induc‐ tion therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple mye‐

[51] Mateos, M. V, Oriol, A, Martínez-lópez, J, Gutiérrez, N, Teruel, A. I, De Paz, R, Gar‐ cía-laraña, J, Bengoechea, E, Martín, A, Mediavilla, J. D, Palomera, L, De Arriba, F, González, Y, Hernández, J. M, Sureda, A, Bello, J. L, Bargay, J, Peñalver, F. J, Ribera, J. M, Martín-mateos, M. L, García-sanz, R, Cibeira, M. T, Ramos, M. L, Vidriales, M. B, Paiva, B, Montalbán, M. A, & Lahuerta, J. J. Bladé J & Miguel JF. ((2010). Bortezo‐ mib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalido‐ mide versus bortezomib and prednisone in elderly patients with untreated multiple

[52] Mateos, M. V, Richardson, P. G, Schlag, R, Khuageva, N. K, Dimopoulos, M. A, Shpilberg, O, Kropff, M, Spicka, I, Petrucci, M. T, Palumbo, A, Samoilova, O. S, Dmoszynska, A, Abdulkadyrov, K. M, Schots, R, Jiang, B, Esseltine, D. L, Liu, K, & Cakana, A. van de Velde H & San Miguel JF. ((2010). Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated mul‐ tiple myeloma: updated follow-up and impact of subsequent therapy in the phase III

loma: a randomised trial. Lancet Oncol.,, 11(10), 934-41.

myeloma: a randomised trial. Lancet Oncol.,, 11(10), 934-41.

VISTA trial. J Clin Oncol.,, 28(13), 2259-66.

cologist,, 16(4), 388-403.

158 Multiple Myeloma - A Quick Reflection on the Fast Progress

221-227.

myeloma. Blood, , 113(15), 3435-42.


[60] Palumbo A & Anderson K(2011). Multiple myeloma. N Engl J Med.,, 364(11), 1046-60.

[68] Pönisch, W, Andrea, M, Wagner, I, Hammerschmidt, D, Kreibich, U, Schwarzer, A, Zehrfeld, T, Schwarz, M, Winkelmann, C, Petros, S, & Bachmann, A. Lindner T & Niederwieser D. ((2012). Successful treatment of patients with newly diagnosed/ untreated multiple myeloma and advanced renal failure using bortezomib in combi‐ nation with bendamustine and prednisone. J Cancer Res Clin Oncol.,, 138(8), 1405-12.

Induction Therapy in Multiple Myeloma http://dx.doi.org/10.5772/55151 161

[69] Pönisch, W, Mitrou, P. S, Merkle, K, Herold, M, Assmann, M, Wilhelm, G, Dachselt, K, Richter, P, Schirmer, V, Schulze, A, Subert, R, Harksel, B, Grobe, N, Stelzer, E, Schulze, M, Bittrich, A, Freund, M, Pasold, R, & Friedrich, T. Helbig W & Nieder‐ wieser D; East German Study Group of Hematology and Oncology (OSHO). ((2006). Treatment of bendamustine and prednisone in patients with newly diagnosed multi‐ ple myeloma results in superior complete response rate, prolonged time totreatment failure and improved quality of life compared to treatment with melphalan and pre‐ dnisone--a randomized phase III study of the East German Study Group of Hematol‐

[70] Popat, R, Oakervee, H. E, Hallam, S, Curry, N, Odeh, L, Foot, N, Esseltine, D. L, & Drake, M. Morris C & Cavenagh JD. ((2008). Bortezomib, doxorubicin and dexame‐ thasone (PAD) front-line treatment of multiple myeloma: updated results after long-

[71] Popat, U, Saliba, R, Thandi, R, Hosing, C, Qazilbash, M, Anderlini, P, Shpall, E, Mcmannis, J, Körbling, M, Alousi, A, Andersson, B, Nieto, Y, Kebriaei, P, Khouri, I, De Lima, M, Weber, D, Thomas, S, Wang, M, & Jones, R. Champlin R & Giralt S. ((2009). Impairment of filgrastim-induced stem cell mobilization after prior lenalido‐ mide in patients with multiple myeloma. Biol Blood Marrow Transplant, , 15, 718-23.

[72] Rajkumar, S. V, Blood, E, & Vesole, D. Fonseca R & Greipp PR; Eastern Cooperative Oncology Group. ((2006). Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clini‐ cal trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol.,,

[73] Rajkumar, S. V, Hayman, S, Gertz, M. A, Dispenzieri, A, Lacy, M. Q, Greipp, P. R, Geyer, S, Iturria, N, Fonseca, R, & Lust, J. A. Kyle RA & Witzig TE. ((2002). Combina‐ tion therapy with thalidomide plus dexamethasone for newly diagnosed myeloma. J

[74] Rajkumar, S. V, Hayman, S. R, Lacy, M. Q, Dispenzieri, A, Geyer, S. M, Kabat, B, Zel‐ denrust, S. R, Kumar, S, Greipp, P. R, Fonseca, R, Lust, J. A, Russell, S. J, & Kyle, R. A. Witzig TE & Gertz MA. ((2005). Combination therapy with lenalidomide plus dexa‐

methasone (Rev/Dex) for newly diagnosed myeloma. Blood,, 106(13), 4050-3.

[75] Rajkumar, S. V, Jacobus, S, Callander, N. S, Fonseca, R, Vesole, D. H, Williams, M. E, Abonour, R, & Siegel, D. S. Katz M & Greipp PR; Eastern Cooperative Oncology Group. ((2010). Lenalidomide plus high-dose dexamethasone versus lenalidomide

ogy and Oncology (OSHO). J Cancer Res Clin Oncol.,, 132(4), 205-12.

term follow-up. Br J Haematol,, 141(4), 512-6.

24(3), 431-6.

Clin Oncol.,, 20(21), 4319-23.


[68] Pönisch, W, Andrea, M, Wagner, I, Hammerschmidt, D, Kreibich, U, Schwarzer, A, Zehrfeld, T, Schwarz, M, Winkelmann, C, Petros, S, & Bachmann, A. Lindner T & Niederwieser D. ((2012). Successful treatment of patients with newly diagnosed/ untreated multiple myeloma and advanced renal failure using bortezomib in combi‐ nation with bendamustine and prednisone. J Cancer Res Clin Oncol.,, 138(8), 1405-12.

[60] Palumbo A & Anderson K(2011). Multiple myeloma. N Engl J Med.,, 364(11),

[61] Palumbo, A, Bringhen, S, Caravita, T, Merla, E, Capparella, V, Callea, V, Cangialosi, C, Grasso, M, Rossini, F, Galli, M, Catalano, L, Zamagni, E, Petrucci, M. T, De Stefa‐ no, V, Ceccarelli, M, Ambrosini, M. T, Avonto, I, Falco, P, Ciccone, G, & Liberati, A. M. Musto P & Boccadoro M; Italian Multiple Myeloma Network, GIMEMA. ((2006). Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: rando‐

[62] Palumbo, A, Bringhen, S, Liberati, A. M, Caravita, T, Falcone, A, Callea, V, Monta‐ naro, M, Ria, R, Capaldi, A, Zambello, R, Benevolo, G, Derudas, D, Dore, F, Cavallo, F, Gay, F, Falco, P, Ciccone, G, & Musto, P. Cavo M & Boccadoro M. ((2008). Oral melphalan, prednisone, and thalidomide in elderly patients with multiple myeloma:

[63] Palumbo, A, Bringhen, S, Ludwig, H, Dimopoulos, M. A, Bladé, J, Mateos, M. V, Ros‐ iñol, L, Boccadoro, M, Cavo, M, Lokhorst, H, Zweegman, S, Terpos, E, Davies, F, Driessen, C, Gimsing, P, Gramatzki, M, Hàjek, R, & Johnsen, H. E. Leal Da Costa F, Sezer O, Spencer A,Beksac M, Morgan G, Einsele H, San Miguel JF & Sonneveld Per‐ sonalized therapy in multiple myeloma according to patient age and vulnerability: a report of the European Myeloma Network (EMN). Blood,118(17):4519-29., 2011. [64] Palumbo, A, Bringhen, S, Rossi, D, Cavalli, M, Larocca, A, Ria, R, Offidani, M, Patri‐ arca, F, Nozzoli, C, Guglielmelli, T, Benevolo, G, Callea, V, Baldini, L, Morabito, F, Grasso, M, Leonardi, G, Rizzo, M, Falcone, A. P, Gottardi, D, Montefusco, V, Musto, P, & Petrucci, M. T. Ciccone G & Boccadoro M. ((2010). Bortezomib-melphalan-pre‐ dnisone-thalidomide followed by maintenance with bortezomib-thalidomide com‐ pared with bortezomib-melphalan-prednisone for initial treatment of multiple

updated results of a randomized controlled trial. Blood,, 112(8), 3107-14.

myeloma: a randomized controlled trial. J Clin Oncol.,, 28(34), 5101-9.

myeloma. N Engl J Med., , 366(19), 1759-69.

lidomide in myeloma. Leukemia, , 22(6), 1282-4.

[65] Palumbo, A, Giaccone, L, Bertola, A, Pregno, P, Bringhen, S, Rus, C, Triolo, S, & Gal‐ lo, E. Pileri A & Boccadoro M. ((2001). Low-dose thalidomide plus dexamethasone is an effective salvage therapy for advanced myeloma. Haematologica.,, 86(4), 399-403.

[66] Palumbo, A, Hajek, R, Delforge, M, Kropff, M, Petrucci, M. T, Catalano, J, Gisslinger, H, Wiktor-jedrzejczak, W, Zodelava, M, Weisel, K, Cascavilla, N, Iosava, G, Cavo, M, Kloczko, J, Bladé, J, Beksac, M, Spicka, I, Plesner, T, Radke, J, & Langer, C. Ben Yehu‐ da D, Corso A, Herbein L, Yu Z, Mei J, Jacques C & Dimopoulos MA; MM-015 Inves‐ tigators. ((2012). Continuous lenalidomide treatment for newly diagnosed multiple

[67] Paripati, H, Stewart, A. K, Cabou, S, Dueck, A, Zepeda, V. J, Pirooz, N, Ehlenbeck, C, Reeder, C, Slack, J, Leis, J. F, Boesiger, J, & Torloni, A. S. Fonseca R & Bergsagel PL. ((2008). Compromised stem cell mobilization following induction therapy with lena‐

mised controlled trial. Lancet, , 367(9513), 825-31.

1046-60.

160 Multiple Myeloma - A Quick Reflection on the Fast Progress


plus low-dose dexamethasone as initial therapy for newly diagnosed multiple mye‐ loma: an open-label randomised controlled trial. Lancet Oncol.,, 11(1), 29-37.

multiple myeloma: efficacy,characterization of peripheral neuropathy, and molecular

Induction Therapy in Multiple Myeloma http://dx.doi.org/10.5772/55151 163

[84] Rosiñol, L, Oriol, A, Mateos, M. V, Sureda, A, García-sánchez, P, Gutiérrez, N, Ale‐ gre, A, Lahuerta, J. J, De La Rubia, J, Herrero, C, & Liu, X. Van de Velde H, San Mi‐ guel J & Bladé J. ((2007). Phase II PETHEMA trial of alternating bortezomib and dexamethasone as induction regimen before autologous stem-cell transplantation in younger patients with multiple myeloma: efficacy and clinical implications of tumor

[85] Rosiñol, L, Oriol, A, Teruel, A. I, Hernández, D, López-jiménez, J, De La Rubia, J, Granell, M, Besalduch, J, Palomera, L, González, Y, Etxebeste, M. A, Díaz-mediavilla, J, Hernández, M. T, De Arriba, F, Gutiérrez, N. C, Martín-ramos, M. L, Cibeira, M. T, Mateos, M. V, Martínez, J, Alegre, A, & Lahuerta, J. J. San Miguel J & Bladé J; on be‐ half of the Programa para el Estudio y la Terapéutica de las Hemopatías Malignas/ Grupo Español de Mieloma (PETHEMA/GEM) group. ((2012). Superiority of borte‐ zomib, thalidomide, and dexamethasone (VTD) as induction pretransplantation ther‐ apy in multiple myeloma: a randomized phase 3 PETHEMA/GEM study. Blood,,

[86] San Miguel JFSchlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M,Spicka I, Petrucci MT, Palumbo A, Samoilova OS, Dmoszynska A, Abdulkadyrov KM, Schots R, Jiang B, Mateos MV, Anderson KC, Esseltine DL, Liu K, Cakana A, van de Velde H & Richardson PG; VISTA Trial Investigators. ((2008). Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J

[87] Singhal, S, Mehta, J, Desikan, R, Ayers, D, Roberson, P, Eddlemon, P, Munshi, N, Anaissie, E, Wilson, C, & Dhodapkar, M. Zeddis J& Barlogie B. ((1999). Antitumor ac‐ tivity of thalidomide in refractory multiple myeloma.N Engl J Med., , 341(21),

[88] Sonneveld, P, Schmidt-wolf, I. G, Van Der Holt, B, El Jarari, L, Bertsch, U, Salwender, H, Zweegman, S, Vellenga, E, Broyl, A, Blau, I. W, Weisel, K. C, Wittebol, S, Bos, G. M, Stevens-kroef, M, Scheid, C, Pfreundschuh, M, Hose, D, Jauch, A, Van Der Velde, H, Raymakers, R, Schaafsma, M. R, Kersten, M. J, Van Marwijk-kooy, M, Duehrsen, U, Lindemann, W, & Wijermans, P. W. Lokhorst HM & Goldschmidt HM. ((2012). Bortezomib Induction and Maintenance Treatment in Patients With Newly Diag‐ nosed Multiple Myeloma: Results of the Randomized Phase III HOVON-65/ GMMG-

[89] Sonneveld, P, Schmidt-wolf, I. G, Van Der Holt, B, El Jarari, L, Bertsch, U, Salwender, H, Zweegman, S, Vellenga, E, Broyl, A, Blau, I. W, Weisel, K. C, Wittebol, S, Bos, G. M, Stevens-kroef, M, Scheid, C, Pfreundschuh, M, Hose, D, Jauch, A, Van Der Velde, H, Raymakers, R, Schaafsma, M. R, Kersten, M. J, Van Marwijk-kooy, M, Duehrsen, U, Lindemann, W, & Wijermans, P. W. Lokhorst HM& Goldschmidt HM. ((2012). Bortezomib Induction and Maintenance Treatment in Patients With Newly Diag‐

correlations with response and neuropathy.J Clin Oncol.,, 27(21), 3518-25.

response kinetics. J Clin Oncol.,, 25(28), 4452-8.

120(8), 1589-1596.

Med, , 359(9), 906-17.

HD4 Trial. J Clin Oncol.,, 30(24), 2946-55.

1565-71.


multiple myeloma: efficacy,characterization of peripheral neuropathy, and molecular correlations with response and neuropathy.J Clin Oncol.,, 27(21), 3518-25.

plus low-dose dexamethasone as initial therapy for newly diagnosed multiple mye‐

loma: an open-label randomised controlled trial. Lancet Oncol.,, 11(1), 29-37.

J Clin Oncol.,, 26(13), 2171-7.

162 Multiple Myeloma - A Quick Reflection on the Fast Progress

tion, and management. Am J Hematol., , 87(1), 78-88.

phase II clinical trial. Leukemia,, 23(7), 1337-41.

[76] Rajkumar, S. V, Rosiñol, L, Hussein, M, Catalano, J, Jedrzejczak, W, Lucy, L, Oles‐ nyckyj, M, Yu, Z, & Knight, R. Zeldis JB & Bladé J. ((2008). Multicenter, randomized, double-blind, placebo-controlled study of thalidomide plus dexamethasone com‐ pared with dexamethasone as initial therapy for newly diagnosed multiple myeloma.

[77] Rajkumar, S. V. (2012). Multiple myeloma: 2012 update on diagnosis, risk-stratifica‐

[78] Reeder, C. B, Reece, D. E, Kukreti, V, Chen, C, Trudel, S, Hentz, J, Noble, B, Pirooz, N. A, Spong, J. E, Piza, J. G, Zepeda, V. H, Mikhael, J. R, Leis, J. F, & Bergsagel, P. L. Fonseca R & Stewart AK. ((2009). Cyclophosphamide, bortezomib and dexametha‐ sone induction for newly diagnosed multiple myeloma: high response rates in a

[79] Richardson, P. G, Barlogie, B, Berenson, J, Singhal, S, Jagannath, S, Irwin, D, Rajku‐ mar, S. V, Hideshima, T, Xiao, H, & Esseltine, D. Schenkein D & Anderson KC; SUM‐ MIT Investigators. ((2005). Clinical factors predictive of outcome with bortezomib in

[80] Richardson, P. G, Schlossman, R. L, Weller, E, Hideshima, T, Mitsiades, C, & Davies, F. LeBlanc R, Catley LP, Doss D, Kelly K, McKenney M, Mechlowicz J, Freeman A,Deocampo R, Rich R, Ryoo JJ, Chauhan D, Balinski K, Zeldis J & Anderson KC. ((2002). Immunomodulatory drug CC-5013 overcomes drug resistance and is well

patients with relapsed,refractory multiple myeloma. Blood,, 106(9), 2977-81.

tolerated in patients with relapsed multiple myeloma. Blood,, 100(9), 3063-7.

sone for relapsed multiple myeloma. N Engl J Med.,(2487). , 352(24), 2487-98.

patients with newly diagnosed multiple myeloma. Blood,, 116(5), 679-86.

[82] Richardson, P. G, Weller, E, Lonial, S, Jakubowiak, A. J, Jagannath, S, Raje, N. S, Avi‐ gan, D. E, Xie, W, Ghobrial, I. M, Schlossman, R. L, Mazumder, A, Munshi, N. C, Ve‐ sole, D. H, Joyce, R, Kaufman, J. L, Doss, D, Warren, D. L, Lunde, L. E, Kaster, S, Delaney, C, Hideshima, T, Mitsiades, C. S, & Knight, R. Esseltine DL & Anderson KC. ((2010). Lenalidomide, bortezomib, and dexamethasone combination therapy in

[83] Richardson, P. G, Xie, W, Mitsiades, C, Chanan-khan, A. A, Lonial, S, Hassoun, H, Avigan, D. E, Oaklander, A. L, Kuter, D. J, Wen, P. Y, Kesari, S, Briemberg, H. R, Schlossman, R. L, Munshi, N. C, Heffner, L. T, Doss, D, Esseltine, D. L, & Weller, E. Anderson KC & Amato AA. ((2009). Single-agent bortezomib in previously untreated

[81] Richardson, P. G, Sonneveld, P, Schuster, M. W, Irwin, D, Stadtmauer, E. A, Facon, T, Harousseau, J. L, Ben-yehuda, D, Lonial, S, Goldschmidt, H, Reece, D, San-miguel, J. F, Bladé, J, Boccadoro, M, Cavenagh, J, Dalton, W. S, Boral, A. L, Esseltine, D. L, & Porter, J. B. Schenkein D & Anderson KC; Assessment of Proteasome Inhibition for Extending Remissions (APEX) Investigators. Bortezomib or high-dose dexametha‐


nosed Multiple Myeloma: Results of the Randomized Phase III HOVON-65/ GMMG-HD4 Trial. J Clin Oncol. 2012 Aug 20;, 30(24), 2946-55.

**Chapter 8**

**Allogeneic Hematopoetic Cell Transplantation in**

The improvement in the survival of multiple myeloma patients has been attributed to autol‐ ogous stem cell transplantation (ASCT) after induction with novel agents [1,2]. Nevertheless, ASCT has not been considered to have a curative potential, maintenance treatment seems to be one of the solutions to decrease the high relapse rates after ASCT [3]. Therefore, allogeneic stem cell transplantation (Allo-SCT) is a potentially curative approach; the role of allo-SCT is still an ongoing debate due to high transplant-related mortality and lack of large prospective randomized studies in the newly diagnosed patients. A retrospective case-matched analysis was performed comparing myeloma patients treated with Allo-SCT with an equal number of patients who received ASCT by European Group for Blood and Bone Marrow Transplant (EBMT) [4]. Overall survival (OS) for the whole patient group was significantly better for the ASCT group compared with those for allo-SCT (Median survival: 34 months vs 18 months, p=. 001). Therefore, we should answer the question of which patients with multiple myeloma have

Prognosis of myeloma patients have been found strongly associated with their cytogenetic features and gene expression profiling [5,6]. Increasing data on the poor prognosis of the 'high risk myeloma patients' changed the trends towards to the allo-transplantation in the earlier period. The Société Française de Greffe de Moelle et de Thérapie Cellulaire evaluated the role of allo-SCT for cytogenetically high-risk myeloma patients in a retrospective multicenter analysis [7]. They showed that allo-SCT could potentially be of benefit to the patients carrying cytogenetic abnormalities such as deletion (del) of (13q), t(4;14), t(14;16) and del(17p) compared

and reproduction in any medium, provided the original work is properly cited.

© 2013 Topcuoglu et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

**Multiple Myeloma**

http://dx.doi.org/10.5772/54762

to be directed to allo-SCT modality.

to those without the same abnormalities.

Taner Demirer

**1. Introduction**

Pervin Topcuoglu, Sinem Civriz Bozdag and

Additional information is available at the end of the chapter

