**Proteasome Inhibition and Hematopoietic Stem Cell Transplantation in Multiple Myeloma**

Helgi van de Velde and Andrew Cakana

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/54117

## **1. Introduction**

type and Lack Suppressive Function. ASH Annual Meeting Abstracts. 2006 Novem‐

[115] Lonial S, Vij R, Harousseau JL, Facon T, Moreau P, Mazumder A, et al. Elotuzumab in combination with lenalidomide and low-dose dexamethasone in relapsed or re‐ fractory multiple myeloma. Journal of clinical oncology : official journal of the Amer‐

[116] Chow AW, Lee CH, Hiwase DK, To LB, Horvath N. Relapsed Multiple Myeloma: Who Benefits from Salvage Autografts? Internal Medicine Journal. 2012.

[117] Jimenez-Zepeda VH, Mikhael J, Winter A, Franke N, Masih-Khan E, Trudel S, et al. Second autologous stem cell transplantation as salvage therapy for multiple myelo‐ ma: impact on progression-free and overall survival. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplanta‐

[118] Olin RL, Vogl DT, Porter DL, Luger SM, Schuster SJ, Tsai DE, et al. Second auto-SCT is safe and effective salvage therapy for relapsed multiple myeloma. Bone marrow

[119] Qazilbash MH, Saliba R, De Lima M, Hosing C, Couriel D, Aleman A, et al. Second autologous or allogeneic transplantation after the failure of first autograft in patients

[120] Shah N, Ahmed F, Bashir Q, Qureshi S, Dinh Y, Rondon G, et al. Durable remission with salvage second autotransplants in patients with multiple myeloma. Cancer.

[121] Gonsalves WI, Gertz MA, Lacy MQ, Dispenzieri A, Hayman SR, Buadi FK, et al. Sec‐ ond auto-SCT for treatment of relapsed multiple myeloma. Bone marrow transplan‐

[122] Fenk R, Liese V, Neubauer F, Bruns I, Kondakci M, Balleisen S, et al. Predictive fac‐ tors for successful salvage high-dose therapy in patients with multiple myeloma re‐ lapsing after autologous blood stem cell transplantation. Leuk Lymphoma. 2011

[123] Mehta J, Tricot G, Jagannath S, Ayers D, Singhal S, Siegel D, et al. Salvage autologous or allogeneic transplantation for multiple myeloma refractory to or relapsing after a

first-line autograft? Bone marrow transplantation. 1998;21[9]:887-92.

ican Society of Clinical Oncology. 2012;30[16]:1953-9.

with multiple myeloma. Cancer. 2006;106[5]:1084-9.

Aug;52[8]:1455-62. PubMed PMID: 21657961.

ber 16, 2006;108[11]:1741-.

220 Innovations in Stem Cell Transplantation

tion. 2012;18[5]:773-9.

2012;118[14]:3549-55.

tation. 2012.

transplantation. 2009;43[5]:417-22.

Multiple myeloma is a malignant plasma cell disorder in which the proliferation of the ma‐ lignant plasma cells leads to anemia, infections, bone fractures, hypercalcemia and renal dysfunction [1]. Affecting approximately 32,000 people each year worldwide, with a median age of onset of approximately 68 years, it is the second most common hematological malig‐ nancy after non-Hodgkin's lymphoma (NHL). Two major advances have occurred in the treatment of multiple myeloma in the last two decades: the introduction of high-dose che‐ motherapy with autologous stem cell transplantation (ASCT), and the development of active drugs with a novel mechanism of action (proteasome inhibition and immunomodulation). Both advances have led to significant improvements in overall survival in this disease.

The superiority of ASCT over conventional chemotherapy treatment in younger subjects with newly diagnosed multiple myeloma was first established in a French IFM Phase 3 study in the 1990s [2]. The ASCT approach led to higher tumor response rates, better eventfree survival (EFS) and overall survival (OS). This superiority of ASCT over conventional treatment was later confirmed in a British phase 3 study [3]. Both EFS and OS appear direct‐ ly related to the depth of the tumor response to treatment [4]. Due to this correlation achiev‐ ing complete response (CR) or at least very good partial response (VGPR) has become an important goal of the ASCT approach. ASCT can be complicated by severe myelosuppres‐ sion and infections and has therefore been reserved for patients who are <65-70 years old without significant comorbidities [5].

ASCT is preceded by an *induction regimen* the primary objective of which is to debulk the tumor without causing damage to the hematopoietic progenitor cells. Until recently, the standard induction regimens in myeloma were vincristine, doxorubicin and dexame‐ thasone (VAD), which has 5-7% CR rate post induction [6], or Thalidomide-Dexametha‐

sone (Thal-Dex), which has a 4% CR rate post induction [7]. After induction therapy autologous CD34+ hematopoietic stem cells are harvested from peripheral blood, and less often collected as part of bone marrow cells, and reinfused after conditioning with high-dose chemotherapy regimen with high-dose melphalan (*conditioning regimen*). The conditioning and reinfusion of CD34+ stem cells can be done once or twice (single or double ASCT). The addition of a limited number of cycles of standard dose chemothera‐ py (*consolidation treatment*) or of a prolonged exposure to low dose therapy (*maintenance treatment*) after the ASCT is increasingly being used to further improve EFS and OS, al‐ though their value has not been fully established [5]

standard chemotherapy with melphalan-prednisone also resulted in improvement in time to progression, response rate and complete rate, and overall survival. Complete response rate of patients treated with the bortezomib-melphalan-prednisone combination was 30% as compared to 4% in the melphalan-prednisone control group (p<0.001) [18]. Median survival of patients treated with the bortezomib-melphalan-prednisone combination was 56.4 months as compared to 43.1 months in the melphalan-prednisone control group (p=0.0004) [19]. Based on these significant improvements in outcomes in other settings in multiple mye‐ loma, the introduction of bortezomib in autologous stem cell transplant approaches in mye‐

Proteasome Inhibition and Hematopoietic Stem Cell Transplantation in Multiple Myeloma

http://dx.doi.org/10.5772/54117

223

The approved single agent bortezomib dose and schedule in multiple myeloma is 1.3

We followed published guidelines for medical literature reviews [22,23,24]. The medical lit‐ erature was searched in the OVID database (Medline; Derwent Drug File; Your journals @ Ovid; Biosis Previews; and Embase). The search was limited to the English language and ar‐ ticles published without a data range limit to August 1, 2012. The following search strategy was used with the following words being entered in the basic search section of OVID:

**1.** randomized AND phase AND 3 AND bortezomib OR velcade AND stem AND cell

**2.** the second phase of searching showed the addition of 'myeloma AND proteosome in‐

**3.** the third phase of searching substituted 'bone AND marrow' for the words 'stem

Further selection of the identified studies included in this review was based on following criteria: (1) prospective study design; (2) publication in peer-reviewed journals; (3) random‐ ized phase 3 or phase 2 design, or single arm phase 2 design with sample size >25 patients. These criteria were chosen to increase likelihood of scientific quality and interpretability of the selected studies. Twenty-nine studies were initially retained in the search and 16 studies

, on days 1, 4, 8, and 11, followed by a 10-day rest period (21 day cycle). The most clinically significant side-effect is a cumulative dose-related peripheral neuropathy which is managed by treatment interruptions and dose modifications [20]. Other common adverse events include lower grade gastro-intestinal adverse events and thrombocytopenia [16]. In most clinical studies, including those reviewed in this chapter, bortezomib has been given intravenously. Recent data in relapsed multiple myeloma have indicated that the subcutane‐ ous administration of bortezomib is as efficacious and results in less neurotoxicity [21]. However, data on subcutaneous administration of bortezomib as part of transplant regi‐

loma has been an area of intense clinical study activity.

mens in myeloma are currently still lacking.

mg/m2

**2. Methodology**

AND cell

AND transplantation.

hibitor' with 'autologous'

were subsequently selected based on these criteria.

If the ASCT approach is not used in the treatment of a newly diagnosed patient with multi‐ ple myeloma, it can still be applied upon relapse. A randomized study by the French GMA group indicated that a second-line rescue with high dose therapy and ASCT resulted in sim‐ ilar overall survival as compared to initial treatment with this approach [8].

The value of allogeneic bone marrow transplantation (Allo-SCT) in multiple myeloma is controversial [9]. The high treatment related mortality associated with myeloablative condi‐ tioning in allo-SCT has led to the development of reduced-intensity conditioning (Allo-RIC). Convincing evidence is sofar lacking that Allo-RIC can improve the survival compared with autologous stem-cell transplantation. For this reason, allo-RIC in myeloma is currently only recommended in the context of clinical trials.

It is still unclear whether any of these treatment approaches can be curative, even in a subset of patients, although they have extended the median overall survival of patients with newly diagnosed multiple myeloma beyond 5-6 years [10]. Improvement of out‐ comes by incorporation of the proteasome inhibitor bortezomib into autologous stem cell transplantation approaches has been an area of intense clinical research over the last dec‐ ade and is the topic of this review.

Bortezomib is a first-in-class proteasome inhibitor which was originally approved for the treatment of relapsed or refractory multiple myeloma by the US Food and Drug Administra‐ tion (FDA) in 2003 and by the European Agency for the Evaluation of Medicinal Products (EMEA) in 2004 [11,12]. Bortezomib is a reversible inhibitor of the 26S proteasome which is a large protein complex that degrades ubiquitinated proteins. Regulatory proteins relevant to the initiation and progression of cancers including multiple myeloma are known to be de‐ graded during the cell cycle by the ubiquitin-proteasome pathway [13]. Binding of bortezo‐ mib to the 20S β5 subunit of the proteasome results in a reversible inhibition of the chymotrypsin-like protease in the proteasome. In multiple myeloma cells, this results in in‐ hibition of NF-kB activation, in attenuation of interleukin-6-mediated cell growth, and direct apoptotic and anti-angiogenic effects [14,15].

In relapsed multiple myeloma, single agent bortezomib was shown to improve time to pro‐ gression, response rate and overall survival as compared to high-dose dexamethasone [16]. Median survival of patients treated with bortezomib was 29.9 months as compared to 23.7 months in the dexamethasone control group (p=0.027) [17]. In patients with newly diag‐ nosed multiple myeloma who were not candidate for ASCT, the addition of bortezomib to standard chemotherapy with melphalan-prednisone also resulted in improvement in time to progression, response rate and complete rate, and overall survival. Complete response rate of patients treated with the bortezomib-melphalan-prednisone combination was 30% as compared to 4% in the melphalan-prednisone control group (p<0.001) [18]. Median survival of patients treated with the bortezomib-melphalan-prednisone combination was 56.4 months as compared to 43.1 months in the melphalan-prednisone control group (p=0.0004) [19]. Based on these significant improvements in outcomes in other settings in multiple mye‐ loma, the introduction of bortezomib in autologous stem cell transplant approaches in mye‐ loma has been an area of intense clinical study activity.

The approved single agent bortezomib dose and schedule in multiple myeloma is 1.3 mg/m2 , on days 1, 4, 8, and 11, followed by a 10-day rest period (21 day cycle). The most clinically significant side-effect is a cumulative dose-related peripheral neuropathy which is managed by treatment interruptions and dose modifications [20]. Other common adverse events include lower grade gastro-intestinal adverse events and thrombocytopenia [16]. In most clinical studies, including those reviewed in this chapter, bortezomib has been given intravenously. Recent data in relapsed multiple myeloma have indicated that the subcutane‐ ous administration of bortezomib is as efficacious and results in less neurotoxicity [21]. However, data on subcutaneous administration of bortezomib as part of transplant regi‐ mens in myeloma are currently still lacking.

## **2. Methodology**

sone (Thal-Dex), which has a 4% CR rate post induction [7]. After induction therapy autologous CD34+ hematopoietic stem cells are harvested from peripheral blood, and less often collected as part of bone marrow cells, and reinfused after conditioning with high-dose chemotherapy regimen with high-dose melphalan (*conditioning regimen*). The conditioning and reinfusion of CD34+ stem cells can be done once or twice (single or double ASCT). The addition of a limited number of cycles of standard dose chemothera‐ py (*consolidation treatment*) or of a prolonged exposure to low dose therapy (*maintenance treatment*) after the ASCT is increasingly being used to further improve EFS and OS, al‐

If the ASCT approach is not used in the treatment of a newly diagnosed patient with multi‐ ple myeloma, it can still be applied upon relapse. A randomized study by the French GMA group indicated that a second-line rescue with high dose therapy and ASCT resulted in sim‐

The value of allogeneic bone marrow transplantation (Allo-SCT) in multiple myeloma is controversial [9]. The high treatment related mortality associated with myeloablative condi‐ tioning in allo-SCT has led to the development of reduced-intensity conditioning (Allo-RIC). Convincing evidence is sofar lacking that Allo-RIC can improve the survival compared with autologous stem-cell transplantation. For this reason, allo-RIC in myeloma is currently only

It is still unclear whether any of these treatment approaches can be curative, even in a subset of patients, although they have extended the median overall survival of patients with newly diagnosed multiple myeloma beyond 5-6 years [10]. Improvement of out‐ comes by incorporation of the proteasome inhibitor bortezomib into autologous stem cell transplantation approaches has been an area of intense clinical research over the last dec‐

Bortezomib is a first-in-class proteasome inhibitor which was originally approved for the treatment of relapsed or refractory multiple myeloma by the US Food and Drug Administra‐ tion (FDA) in 2003 and by the European Agency for the Evaluation of Medicinal Products (EMEA) in 2004 [11,12]. Bortezomib is a reversible inhibitor of the 26S proteasome which is a large protein complex that degrades ubiquitinated proteins. Regulatory proteins relevant to the initiation and progression of cancers including multiple myeloma are known to be de‐ graded during the cell cycle by the ubiquitin-proteasome pathway [13]. Binding of bortezo‐ mib to the 20S β5 subunit of the proteasome results in a reversible inhibition of the chymotrypsin-like protease in the proteasome. In multiple myeloma cells, this results in in‐ hibition of NF-kB activation, in attenuation of interleukin-6-mediated cell growth, and direct

In relapsed multiple myeloma, single agent bortezomib was shown to improve time to pro‐ gression, response rate and overall survival as compared to high-dose dexamethasone [16]. Median survival of patients treated with bortezomib was 29.9 months as compared to 23.7 months in the dexamethasone control group (p=0.027) [17]. In patients with newly diag‐ nosed multiple myeloma who were not candidate for ASCT, the addition of bortezomib to

ilar overall survival as compared to initial treatment with this approach [8].

though their value has not been fully established [5]

222 Innovations in Stem Cell Transplantation

recommended in the context of clinical trials.

ade and is the topic of this review.

apoptotic and anti-angiogenic effects [14,15].

We followed published guidelines for medical literature reviews [22,23,24]. The medical lit‐ erature was searched in the OVID database (Medline; Derwent Drug File; Your journals @ Ovid; Biosis Previews; and Embase). The search was limited to the English language and ar‐ ticles published without a data range limit to August 1, 2012. The following search strategy was used with the following words being entered in the basic search section of OVID:


Further selection of the identified studies included in this review was based on following criteria: (1) prospective study design; (2) publication in peer-reviewed journals; (3) random‐ ized phase 3 or phase 2 design, or single arm phase 2 design with sample size >25 patients. These criteria were chosen to increase likelihood of scientific quality and interpretability of the selected studies. Twenty-nine studies were initially retained in the search and 16 studies were subsequently selected based on these criteria.

VELCADE (Bortezomib for Injection) is a small molecule proteasome inhibitor being code‐ veloped by Millennium Pharmaceuticals, Inc. (Millennium) and Janssen Research & Devel‐ opment. The selection of the identified was solely based on the criteria indicated above and no studies were de-selected due a conflict-of-interest.

4, and dexamethasone 40 mg daily po on days 1 to 4 (all cycles) and days 9 to 12 and days 17 to 20 (cycles 1 and 2 only). Bortezomib plus dexamethasone comprised four 3 week cycles of

(all cycles) and days 9 to 12 (cycles 1 and 2 only). DCEP comprised two 4-week cycles of

after priming with granulocyte stimulating factor alone or cyclophosphamide for those who mobilize poorly. The CR/nCR rate was significantly higher (14.8%) for patients receiving bortezomib plus dexamethasone compared to patients receiving VAD (6.4%, p-value=0.004). ORR was 78.5% vs 62.8% (p=<0.001). Patients with del13, a negative prognostic cytogenetic abnormality in multiple myeloma, also reported higher response rates in the bortezomib containing arm : ORR was 78.2% vs 65.1% (p=0.037); and CR/nCR was 20.8% compared to 5.8%( p=0.002). The study showed that the addition of DCEP did not further improve the outcomes wither either regimen. The PFS for the bortezomib group was 36 months vs 29.7 months in the VAD arm after 32.2 months follow-up (p=0.064 unadjusted). Median OS was not yet reached but the 3 year OS rate was 81.4% compared to 77.4% in favor of the bortezo‐ mib-dexamethasone combination. Stem cell collection was adequate in both arms. The safety profile was similar between the groups for most adverse events except for all grade periph‐ eral neuropathy (45.6% for bortezomib and dexamethasone and 28% for VAD) and grade 3/4

A second phase 3 study by the Dutch-German HOVON-GMMG groups randomized 827 pa‐ tients to receive 3 cycles of either bortezomib combined with adriamycin and dexametha‐ sone (PAD) or VAD during induction given every 28 days [26,26,27]. This HOVON-65/ GMMG-HD4 study had a maintenance part post ASCT in which patients on VAD further received thalidomide 50 mg po daily for a further 2 years while those on PAD received bor‐ tezomib 1.3 mg/m2 iv every two weeks for 2 years. The primary objective of the study was to compare PFS of the two arms. Response rates post induction were analyzed as secondary objectives. The CR/nCR rate post induction was 5% in patients who were randomized to VAD and 11% in patients who received PAD (*P* <.001). The post transplant response rate for nCR/CR was 15% (VAD) versus 31% (PAD), (*P* <.001). Overall nCR/CR rates were 34% ver‐ sus 49%, (*P* <.001) for patients on VAD and PAD respectively. The median PFS was 28 months for the VAD arm and 35 months for the PAD arm (p=0.002). Median OS was not reached after 66 months of follow-up, with 5-year OS of 55% (VAD) versus 61% (PAD). In patients with del17p, the worst prognostic cytogenetic abnormality in multiple myeloma, both PFS (median PFS, 12 vs 22 months, p=0.01) and OS (median OS, 24 vs > 54 months, p=0.003) were significantly better in the PAD arm. In patients with del13, a negative impact on PFS was observed in both treatment arms. OS in patients with this deletion was similar to the OS in patients with no del13 in the PAD arm and significantly better than OS in the VAD arm (median OS for VAD 49 vs 59 months for the PAD arm, p=0.007). Stem cell collection was adequate in both treatment arms. In patients presenting with a baseline serum creati‐ nine of more than 2 mg/dL, bortezomib significantly improved CR/nCR rates which were 27% (VAD) compared to 53% (PAD) (p=0.02). The PFS in the same population improved from a median of 13 months to 30 months (p= 0.004) and OS from a median of 21 months to

dexamethasone 40 mg/daily on days 1 to 4; plus cyclophosphamide 400 mg/m2

iv days 1, 4, 8 and 11 plus dexamethasone po 40 mg/d on days 1 to 4

Proteasome Inhibition and Hematopoietic Stem Cell Transplantation in Multiple Myeloma

by continuous iv infusion day 1 to 4. Stem cells were collected

, etoposide 40

225

http://dx.doi.org/10.5772/54117

bortezomib 1.3 mg/m2

and cisplatin 15 mg/m2

neuropathy (7.1% and 2.1%, respectively).

mg/m2

## **3. Results**

#### **3.1. Bortezomib in induction therapy**

The search of an optimal induction regimen prior to high-dose therapy and ASCT in multi‐ ple myeloma is still ongoing. An ideal induction regimen should, among others, have the following characteristics:


All randomized studies published in peer reviewed journals and investigating the role of bortezomib in induction therapy have been analyzed in this section. Some of the random‐ ized phase 2 and 3 studies compare a bortezomib containing regimen with a non-bortezo‐ mib containing regimen, while other studies investigate various combinations and doses with all treatment groups containing bortezomib. Further, all single arm phase 2 studies with more than 25 patients are also included in this review.

Early studies started soon after the introduction of bortezomib into the treatment of relapsed myeloma compared the role of a bortezomib-containing induction regimen against VAD, the standard regimen at that time.

A first phase 3 study by the French IFM group provided evidence that the combination of bortezomib plus dexamethasone was superior to VAD as induction regimen [25]. In this IFM2005-01 study 481 patients who were eligible for autologous stem cell transplantation (≤65 years) were randomized to receive VAD (n = 121); VAD plus DCEP (n=121); bortezomib plus dexamethasone (n = 121) or bortezomib plus dexamethasone plus DCEP (n = 119). DCEP (dexamethasone, cyclophosphamide, etoposide and cisplatin) were given as a consoli‐ dation course, soon after 4 induction cycles and before the high dose melphalan for condi‐ tioning. The study allowed a second high-dose therapy and stem cell transplant procedure for patients failing to attain at least a VGPR after first transplant. The primary endpoint was post induction CR/nCR rate. Patients in the VAD group were treated with four 4-week cy‐ cles of vincristine 0.4 mg/d and doxorubicin 9 mg/m2 /d by continuous infusion on days 1 to 4, and dexamethasone 40 mg daily po on days 1 to 4 (all cycles) and days 9 to 12 and days 17 to 20 (cycles 1 and 2 only). Bortezomib plus dexamethasone comprised four 3 week cycles of bortezomib 1.3 mg/m2 iv days 1, 4, 8 and 11 plus dexamethasone po 40 mg/d on days 1 to 4 (all cycles) and days 9 to 12 (cycles 1 and 2 only). DCEP comprised two 4-week cycles of dexamethasone 40 mg/daily on days 1 to 4; plus cyclophosphamide 400 mg/m2 , etoposide 40 mg/m2 and cisplatin 15 mg/m2 by continuous iv infusion day 1 to 4. Stem cells were collected after priming with granulocyte stimulating factor alone or cyclophosphamide for those who mobilize poorly. The CR/nCR rate was significantly higher (14.8%) for patients receiving bortezomib plus dexamethasone compared to patients receiving VAD (6.4%, p-value=0.004). ORR was 78.5% vs 62.8% (p=<0.001). Patients with del13, a negative prognostic cytogenetic abnormality in multiple myeloma, also reported higher response rates in the bortezomib containing arm : ORR was 78.2% vs 65.1% (p=0.037); and CR/nCR was 20.8% compared to 5.8%( p=0.002). The study showed that the addition of DCEP did not further improve the outcomes wither either regimen. The PFS for the bortezomib group was 36 months vs 29.7 months in the VAD arm after 32.2 months follow-up (p=0.064 unadjusted). Median OS was not yet reached but the 3 year OS rate was 81.4% compared to 77.4% in favor of the bortezo‐ mib-dexamethasone combination. Stem cell collection was adequate in both arms. The safety profile was similar between the groups for most adverse events except for all grade periph‐ eral neuropathy (45.6% for bortezomib and dexamethasone and 28% for VAD) and grade 3/4 neuropathy (7.1% and 2.1%, respectively).

VELCADE (Bortezomib for Injection) is a small molecule proteasome inhibitor being code‐ veloped by Millennium Pharmaceuticals, Inc. (Millennium) and Janssen Research & Devel‐ opment. The selection of the identified was solely based on the criteria indicated above and

The search of an optimal induction regimen prior to high-dose therapy and ASCT in multi‐ ple myeloma is still ongoing. An ideal induction regimen should, among others, have the

**1.** Able to give the optimum post induction tumor response, since better response is asso‐

**2.** Able to act quickly to debulk the tumor, as often the patients present with advanced

**3.** Able to work even in renal failure, since this is a common feature of multiple myeloma;

**4.** Allowing collection of an adequate of viable hematopoietic stem cells necessary for suc‐

All randomized studies published in peer reviewed journals and investigating the role of bortezomib in induction therapy have been analyzed in this section. Some of the random‐ ized phase 2 and 3 studies compare a bortezomib containing regimen with a non-bortezo‐ mib containing regimen, while other studies investigate various combinations and doses with all treatment groups containing bortezomib. Further, all single arm phase 2 studies

Early studies started soon after the introduction of bortezomib into the treatment of relapsed myeloma compared the role of a bortezomib-containing induction regimen against VAD,

A first phase 3 study by the French IFM group provided evidence that the combination of bortezomib plus dexamethasone was superior to VAD as induction regimen [25]. In this IFM2005-01 study 481 patients who were eligible for autologous stem cell transplantation (≤65 years) were randomized to receive VAD (n = 121); VAD plus DCEP (n=121); bortezomib plus dexamethasone (n = 121) or bortezomib plus dexamethasone plus DCEP (n = 119). DCEP (dexamethasone, cyclophosphamide, etoposide and cisplatin) were given as a consoli‐ dation course, soon after 4 induction cycles and before the high dose melphalan for condi‐ tioning. The study allowed a second high-dose therapy and stem cell transplant procedure for patients failing to attain at least a VGPR after first transplant. The primary endpoint was post induction CR/nCR rate. Patients in the VAD group were treated with four 4-week cy‐

/d by continuous infusion on days 1 to

no studies were de-selected due a conflict-of-interest.

**3.1. Bortezomib in induction therapy**

ciated with better long-term outcomes;

disease and complicated presentations;

cessful bone marrow rescue and engraftment.

with more than 25 patients are also included in this review.

cles of vincristine 0.4 mg/d and doxorubicin 9 mg/m2

the standard regimen at that time.

following characteristics:

224 Innovations in Stem Cell Transplantation

**3. Results**

A second phase 3 study by the Dutch-German HOVON-GMMG groups randomized 827 pa‐ tients to receive 3 cycles of either bortezomib combined with adriamycin and dexametha‐ sone (PAD) or VAD during induction given every 28 days [26,26,27]. This HOVON-65/ GMMG-HD4 study had a maintenance part post ASCT in which patients on VAD further received thalidomide 50 mg po daily for a further 2 years while those on PAD received bor‐ tezomib 1.3 mg/m2 iv every two weeks for 2 years. The primary objective of the study was to compare PFS of the two arms. Response rates post induction were analyzed as secondary objectives. The CR/nCR rate post induction was 5% in patients who were randomized to VAD and 11% in patients who received PAD (*P* <.001). The post transplant response rate for nCR/CR was 15% (VAD) versus 31% (PAD), (*P* <.001). Overall nCR/CR rates were 34% ver‐ sus 49%, (*P* <.001) for patients on VAD and PAD respectively. The median PFS was 28 months for the VAD arm and 35 months for the PAD arm (p=0.002). Median OS was not reached after 66 months of follow-up, with 5-year OS of 55% (VAD) versus 61% (PAD). In patients with del17p, the worst prognostic cytogenetic abnormality in multiple myeloma, both PFS (median PFS, 12 vs 22 months, p=0.01) and OS (median OS, 24 vs > 54 months, p=0.003) were significantly better in the PAD arm. In patients with del13, a negative impact on PFS was observed in both treatment arms. OS in patients with this deletion was similar to the OS in patients with no del13 in the PAD arm and significantly better than OS in the VAD arm (median OS for VAD 49 vs 59 months for the PAD arm, p=0.007). Stem cell collection was adequate in both treatment arms. In patients presenting with a baseline serum creati‐ nine of more than 2 mg/dL, bortezomib significantly improved CR/nCR rates which were 27% (VAD) compared to 53% (PAD) (p=0.02). The PFS in the same population improved from a median of 13 months to 30 months (p= 0.004) and OS from a median of 21 months to 54 months (HR, 0.33; p < 0.001) respectively. There was more neuropathy in the PAD arm (40% grades 2 to 4) compared to the VAD arm (18%, p<0.001). The contribution of the main‐ tenance regimens in this study is discussed later in this chapter.

to TD plus bortezomib 1.3 mg/m2 iv on days 1, 4, 8 and 11 of each cycle. The duration of the induction therapy was 24 weeks in all arms. Three months after ASCT patients were randomized to receive maintenance therapy with interferon alfa-2b subcutaneously versus thalidomide 100 mg po daily versus thalidomide 100 mg/day po daily plus one cycle of bor‐ tezomib iv on days 1, 4, 8 and 11 every three months (see below). The CR rate after induc‐ tion was significantly higher with VTD (35%) compared to TD (14%) and VBMCP/VBAD/B (21%) (p=0.0001 and p=0.01, respectively). Of significance in the VBMCP/VBAD/Bortezomib arm, the CR rate increased from 8% after the 4 cycles of VBMCP/VBAD to 21% after the completion of the 2 bortezomib courses. The progressive disease (PD) rate during induction was significantly lower with VTD than with TD (7% vs. 23%, p= 0.0004). In patients with ex‐ tramedullary soft-tissue plasmacytomas the CR rate after induction was significantly higher with VTD as compared with TD (42% vs. 14%, p=0.02). In all the above analysis the VBMCP/ VBAD/Bortezomib arm showed an intermediate efficacy between VTD and TD. In this study VTD also had superior CR rates in the subgroup of patients with high-risk cytogenetic ab‐ normalities as compared to the two other regimens. After a median duration of follow-up of 35.2 months, the median PFS was significantly higher for VTD (56.2m) than with VBMCP/ VBAD/Bortezomib (35.3m) or with TD (28.2 m, p=0.01). The difference in the four-year sur‐ vival rates between VTD (74%), VPMCP/VVBAD/bortezomib (70%) and TD (65%) is not statistically significant at this point. There were two stem cell mobilization failures in the VBMCP/VBAD/Bortezomib group. Peripheral neuropathy grade ≥ 3 with VTD (14%) was significantly higher than with TD (5%) (p=0.01) but not significantly different from VBMCP/ VBAD/B (9%). An additional 46% of patients in the VTD arm developed grade 2 peripheral neuropathy compared with 8% and 15% in the TD and VBMCP/VBAD/B arms, respectively (p<0.001). Grade 3 and 4 neutropenia was significantly higher with VBMCP/VBAD/B (22%) than with remaining two arms TD (14%) and VTD (10%). There were no significant differ‐

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ence in incidence of all grade ≥ 3 adverse events between the three treatment groups.

corporated bortezomib in the induction regimens.

bortezomib at 1 mg/m2

In conclusion, all currently published phase 3 studies indicate that induction regimens con‐ taining bortezomib lead to improvements in CR/nCR rates after induction which are main‐ tained after ASCT, and also lead to improved PFS as compared to standard regimens. Where reported, the time to response appear shorter, and the regimens have important activity in poor prognosis situations such as high-risk cytogenetic disease and renal insufficiency. After a relatively short duration of follow-up, a trend towards improved overall survival with the bortezomib regimens has been noted in several studies. All phase 3 studies also provide evi‐ dence of good hematopoietic stem cell collection but indicate a higher incidence of neuropa‐ thy in patients treated with a bortezomib combination. This phase 3 evidence is further supported by a plethora of randomized and non-randomized phase 2 studies which have in‐

In a randomized phase 2 study by the French IFM (IFM2007-02) a lower dose of bortezomib was investigated in combination with thalidomide and dexamethasone in order to reduce the peripheral neuropathy risk. One hundred ninety-nine patients were randomized to re‐ ceive VD or vTD over four 3 week cycles prior to ASCT [31]. vtD was composed of reduced

iv on days 1, 4, 8, and 11, thalidomide 100 mg/day po, and dexame‐

The above two large studies showed significant improvement of bortezomib-containing reg‐ imens as compared to VAD in terms of post-induction response and PFS, with a positive trend on overall survival. Later studies focused on comparing bortezomib-containing regi‐ mens against non-bortezomib containing regimens other than VAD.

The bortezomib-thalidomide-dexamethasone (VTD) regimen was compared to the thalido‐ mide-dexamethasone (TD) regimen in a Phase 3 study randomizing 480 patients over four 21-day cycles [28,29]. The patients received thalidomide 100 mg po daily for the first 14 days and 200 mg daily thereafter, plus dexamethasone (40 mg po daily on 8 of the first 12 days, but not consecutively; total of 320 mg per cycle), either alone or with bortezomib (1 3 mg/m2 iv on days 1, 4, 8, and 11). Post double ASCT the patients received two 35-day cycles of their assigned drug regimen, VTD or TD, as consolidation therapy (see below). The primary end‐ point was the CR/nCR rate to induction therapy. After induction therapy, complete or near complete response was achieved in 31% patients receiving VTD compared to 11% for those on TD (p<0 0001). Rates of complete or near complete response continued to be significantly higher in the VTD group than in the TD group after the first and second autologous stemcell transplantations (55% vs 41%, p=0.0024). Median time to best complete or near complete response was significantly shorter for patients receiving VTD (9 months) than in those on TD (14 months). The contribution of the consolidation therapy is discussed below. The esti‐ mated 3-year PFS was 60% in the VTD arm compared to 48% in the TD arm. Overall, PFS was significantly longer with VTD compared to TD (median not reached vs 32 months, p=0.0061). The estimated 3-year probability of progression or relapse was 29% in the VTD group versus 39% in the TD group (p=0 0061 by Kaplan-Meier analysis with an HR of 0 61. In the VTD group, the PFS of subjects with or without high-risk cytogenetic abnormalities [del13q, or del17p or t(4;14)] were similar (59% with abnormalities and 60% without). This contrasted with the TD group in which a much lower PFS of 19% for patients with high-risk cytogenetics was observed as compared to the 48% attained by patients without high-risk cytogenetics in the same TD group. Stem cell collection was adequate in both arms. Grade 3 or 4 adverse events were more frequent on VTD (56%) than on TD (33%), with a higher oc‐ currence of grade 3 or higher peripheral neuropathy in patients on VTD (10%) than on TD (2%).

A further phase 3 study (GEM05-MENOS65) performed by the Spanish GIMEMA group randomized 390 patients in a three arm study to receive VTD versus TD versus a regimen called VBMCP/VBAD with bortezomib [30]. Combination chemotherapy with VBMCP/ VBAD and bortezomib consisted of a total of 4 cycles of alternating VBMCP (vincristine, BCNU, melphalan, cyclophosphamide, prednisone) and VBAD (vincristine, BCNU, doxor‐ rubicine, dexamethasone ) followed by 2 cycles of bortezomib (1.3 mg/m2 iv on days 1, 4, 8 and 11 at 3 weeks intervals), TD consisted of thalidomide 200 mg po daily (escalating doses in the first cycle: 50 mg on days 1 to 14 and 100 mg on days 15 to 28) and dexamethasone 40 mg po on days 1-4 and 9-12 at 4-week intervals for 6 cycles and the VTD arm was identical to TD plus bortezomib 1.3 mg/m2 iv on days 1, 4, 8 and 11 of each cycle. The duration of the induction therapy was 24 weeks in all arms. Three months after ASCT patients were randomized to receive maintenance therapy with interferon alfa-2b subcutaneously versus thalidomide 100 mg po daily versus thalidomide 100 mg/day po daily plus one cycle of bor‐ tezomib iv on days 1, 4, 8 and 11 every three months (see below). The CR rate after induc‐ tion was significantly higher with VTD (35%) compared to TD (14%) and VBMCP/VBAD/B (21%) (p=0.0001 and p=0.01, respectively). Of significance in the VBMCP/VBAD/Bortezomib arm, the CR rate increased from 8% after the 4 cycles of VBMCP/VBAD to 21% after the completion of the 2 bortezomib courses. The progressive disease (PD) rate during induction was significantly lower with VTD than with TD (7% vs. 23%, p= 0.0004). In patients with ex‐ tramedullary soft-tissue plasmacytomas the CR rate after induction was significantly higher with VTD as compared with TD (42% vs. 14%, p=0.02). In all the above analysis the VBMCP/ VBAD/Bortezomib arm showed an intermediate efficacy between VTD and TD. In this study VTD also had superior CR rates in the subgroup of patients with high-risk cytogenetic ab‐ normalities as compared to the two other regimens. After a median duration of follow-up of 35.2 months, the median PFS was significantly higher for VTD (56.2m) than with VBMCP/ VBAD/Bortezomib (35.3m) or with TD (28.2 m, p=0.01). The difference in the four-year sur‐ vival rates between VTD (74%), VPMCP/VVBAD/bortezomib (70%) and TD (65%) is not statistically significant at this point. There were two stem cell mobilization failures in the VBMCP/VBAD/Bortezomib group. Peripheral neuropathy grade ≥ 3 with VTD (14%) was significantly higher than with TD (5%) (p=0.01) but not significantly different from VBMCP/ VBAD/B (9%). An additional 46% of patients in the VTD arm developed grade 2 peripheral neuropathy compared with 8% and 15% in the TD and VBMCP/VBAD/B arms, respectively (p<0.001). Grade 3 and 4 neutropenia was significantly higher with VBMCP/VBAD/B (22%) than with remaining two arms TD (14%) and VTD (10%). There were no significant differ‐ ence in incidence of all grade ≥ 3 adverse events between the three treatment groups.

54 months (HR, 0.33; p < 0.001) respectively. There was more neuropathy in the PAD arm (40% grades 2 to 4) compared to the VAD arm (18%, p<0.001). The contribution of the main‐

The above two large studies showed significant improvement of bortezomib-containing reg‐ imens as compared to VAD in terms of post-induction response and PFS, with a positive trend on overall survival. Later studies focused on comparing bortezomib-containing regi‐

The bortezomib-thalidomide-dexamethasone (VTD) regimen was compared to the thalido‐ mide-dexamethasone (TD) regimen in a Phase 3 study randomizing 480 patients over four 21-day cycles [28,29]. The patients received thalidomide 100 mg po daily for the first 14 days and 200 mg daily thereafter, plus dexamethasone (40 mg po daily on 8 of the first 12 days, but not consecutively; total of 320 mg per cycle), either alone or with bortezomib (1 3 mg/m2 iv on days 1, 4, 8, and 11). Post double ASCT the patients received two 35-day cycles of their assigned drug regimen, VTD or TD, as consolidation therapy (see below). The primary end‐ point was the CR/nCR rate to induction therapy. After induction therapy, complete or near complete response was achieved in 31% patients receiving VTD compared to 11% for those on TD (p<0 0001). Rates of complete or near complete response continued to be significantly higher in the VTD group than in the TD group after the first and second autologous stemcell transplantations (55% vs 41%, p=0.0024). Median time to best complete or near complete response was significantly shorter for patients receiving VTD (9 months) than in those on TD (14 months). The contribution of the consolidation therapy is discussed below. The esti‐ mated 3-year PFS was 60% in the VTD arm compared to 48% in the TD arm. Overall, PFS was significantly longer with VTD compared to TD (median not reached vs 32 months, p=0.0061). The estimated 3-year probability of progression or relapse was 29% in the VTD group versus 39% in the TD group (p=0 0061 by Kaplan-Meier analysis with an HR of 0 61. In the VTD group, the PFS of subjects with or without high-risk cytogenetic abnormalities [del13q, or del17p or t(4;14)] were similar (59% with abnormalities and 60% without). This contrasted with the TD group in which a much lower PFS of 19% for patients with high-risk cytogenetics was observed as compared to the 48% attained by patients without high-risk cytogenetics in the same TD group. Stem cell collection was adequate in both arms. Grade 3 or 4 adverse events were more frequent on VTD (56%) than on TD (33%), with a higher oc‐ currence of grade 3 or higher peripheral neuropathy in patients on VTD (10%) than on TD

A further phase 3 study (GEM05-MENOS65) performed by the Spanish GIMEMA group randomized 390 patients in a three arm study to receive VTD versus TD versus a regimen called VBMCP/VBAD with bortezomib [30]. Combination chemotherapy with VBMCP/ VBAD and bortezomib consisted of a total of 4 cycles of alternating VBMCP (vincristine, BCNU, melphalan, cyclophosphamide, prednisone) and VBAD (vincristine, BCNU, doxor‐ rubicine, dexamethasone ) followed by 2 cycles of bortezomib (1.3 mg/m2 iv on days 1, 4, 8 and 11 at 3 weeks intervals), TD consisted of thalidomide 200 mg po daily (escalating doses in the first cycle: 50 mg on days 1 to 14 and 100 mg on days 15 to 28) and dexamethasone 40 mg po on days 1-4 and 9-12 at 4-week intervals for 6 cycles and the VTD arm was identical

tenance regimens in this study is discussed later in this chapter.

226 Innovations in Stem Cell Transplantation

mens against non-bortezomib containing regimens other than VAD.

(2%).

In conclusion, all currently published phase 3 studies indicate that induction regimens con‐ taining bortezomib lead to improvements in CR/nCR rates after induction which are main‐ tained after ASCT, and also lead to improved PFS as compared to standard regimens. Where reported, the time to response appear shorter, and the regimens have important activity in poor prognosis situations such as high-risk cytogenetic disease and renal insufficiency. After a relatively short duration of follow-up, a trend towards improved overall survival with the bortezomib regimens has been noted in several studies. All phase 3 studies also provide evi‐ dence of good hematopoietic stem cell collection but indicate a higher incidence of neuropa‐ thy in patients treated with a bortezomib combination. This phase 3 evidence is further supported by a plethora of randomized and non-randomized phase 2 studies which have in‐ corporated bortezomib in the induction regimens.

In a randomized phase 2 study by the French IFM (IFM2007-02) a lower dose of bortezomib was investigated in combination with thalidomide and dexamethasone in order to reduce the peripheral neuropathy risk. One hundred ninety-nine patients were randomized to re‐ ceive VD or vTD over four 3 week cycles prior to ASCT [31]. vtD was composed of reduced bortezomib at 1 mg/m2 iv on days 1, 4, 8, and 11, thalidomide 100 mg/day po, and dexame‐ thasone while VD consisted of bortezomib 1.3 mg/m2 iv on days 1, 4, 8, and 11 plus the same dexamethasone regimen. In case of less than partial response (PR) after cycle 2, the dose of bortezomib was increased to 1.3 mg/m2 and the dose of thalidomide to 200 mg/day in the vTD arm. The primary endpoint of this study was post induction CR rate. The CR rate be‐ tween the groups was the same after 4 cycles, 13% in the vTD arm and 12% in the VD arm. However, both the bortezomib and thalidomide dose had to be increased in 7 patients in the vTD arm. The ORR was 88% in the vTD arm versus 81% in the VD arm, the difference not reaching statistical significance. Further, there was no difference in CR rate post transplant (29% in vTD arm and 31% in VD arm). The target stem cell collection yield of 2 × 106 CD34+ cells/kg was achieved in 93% and 80% of VD and vTD patients, respectively (*P* =.01). While the overall safety profile was similar between the two arms, there was less peripheral neuro‐ pathy in the vTD arm (53% all grade vs 70% on VD, 11% grade 3 or higher vs 11% on VD). Results of the VD control group were consistent with prior observations from the IFM group on this VD induction regimen, both in a single arm phase 2 study [32] and in the random‐ ized phase 3 study (see above).

VDC-mod arms, respectively. The 1-year OS estimate was 100% for all 4 arms. In addition the 1-year PFS for the high-risk patients (n = 24) was 100% and 85% for the standard-risk patients, and was similar across the study arms. The median CD34+ cell yield was 6.8 x

Proteasome Inhibition and Hematopoietic Stem Cell Transplantation in Multiple Myeloma

/kg (VDCR); 7.8 (VDR); 7.95 (VDC) and 7.75 (VDC modified). At least one grade ≥ 3 AE was seen in ~ 80% of patients in each arm. AEs leading to discontinuation were seen in 21%, 19%, 12%, and 6% in the VDCR, VDR, VDC, and VDC-mod arms, respectively. The most common adverse event of grade 3 or higher was neutropenia occurring in 44% (VDCR), 10% (VDR), 30% (VDC) and 24% (VDC modified). Neuropathy grade 3 or higher

**•** In two single arm phase 2 studies, bortezomib was combined with cyclophosphamide and dexamethasone (CyBorD) [36,37]. In one study, 33 patients were treated with four 3

bortezomib and dexamethasone were given in standard doses. ORR was 88%, and 39% were CR/nCR. Responses were rapid with a mean 80% decline in the monoclonal protein at the end of two cycles. All patients undergoing stem cell harvest had a successful collec‐ tion. The most common grade 3-4 adverse events were hematological (anemia in 12%, neutropenia in 13%, thrombocytopenia in 25%) and hyperglycemia (13%). All grade pe‐ ripheral neuropathy adverse events occurred in 66% of the patients while grade 3 occur‐ red in 7%. In the second study, 30 patients were treated with different IV cyclophosphamide dose levels in combination with bortezomib and dexamethasone for 3

The CR rate after induction therapy was 10% and the overall response rate was 90% at the end of the induction therapy. Most frequent adverse events were again hematologic and

**•** The most intense bortezomib-containing induction regimen of VTD-PACE is included in a high-dose therapy approach called Total Therapy 3 and has been investigated in a large cohort of 303 patients [38]. The regimen consists of two cycles of VTD-PACE (bortezomib, thalidomide, dexamethasone and 4-d continuous infusions of cis-platin, doxorubicin, cyclophosphamide, etoposide) during induction and then another two cy‐ cles during consolidation after the ASCT. The patients are then maintained for 3 years on monthly cycles of VTD in the first and TD in the remaining years. The response rates of this Total Therapy 3 approach are among the highest reported in multiple myeloma. The 2 year CR rate was 56% whilst the nCR rate was as high as 83%. Two year OS estimates were also high at 82.9% and EFS of 79.9%. Although no random‐ ized comparison was performed, the investigators consider those results better than a similar approach (Total therapy 2) which did not include bortezomib. Stem cell collec‐ tion was successful. Adverse events grade 3 or higher included thrombo-embolic

In conclusion, these studies have provided evidence of the important role of bortezomib in induction therapy pre-ASCT. Randomized phase 3 studies indicate that induction regimens containing bortezomib lead to improvements in CR/nCR rates after induction which are maintained after ASCT, and also lead to improved PFS as compared to standard non-borte‐

cycles [37]. The recommended dose of IV cyclophosphamide was 900 mg/m2

events in 27% and peripheral neuropathy in 12% of the patients.

given orally and once weekly, while

http://dx.doi.org/10.5772/54117

229

on day 1.

106

occurred in 13%, 17%, 9% and 18% respectively.

weekly cycles with cyclophosphamide 300 mg/m2

neuropathy as well as gastro-intestinal.

Efficacy of VD in induction was also assessed in another phase 2 study with 57 patients, giv‐ en over 4 cycles followed by 2 cycles of DCEP consolidation [33]. The median CR34+ cells collected were 7.5 x 106 /kg and in 86% of these patients the amount was more than twice the minimum required for transplantation. The ORR was 87% and CR 30%. Univariate analysis found no difference between response and cytogenetic abnormalities.

Efficacy of VTD was further confirmed in a single arm phase 2 study of 44 patients treated with bortezomib combined with thalidomide and dexamethasone, administered over eight 3-week cycles [34]. The patient enrolment included both frontline and recurrent disease as long as the patients were eligible for ASCT. Thirty four patients were frontline, 8 with recur‐ rent disease in second line and a further 2 had a third line recurrence. The ORR was 91% with CR/sCR rate of 20%. Post transplant these response rates increased to ORR of 100% and CR/sCR rate of 53%. All 44 patients had successful stem cell collection. Fifty-five percent of the subjects developed neuropathy of all grades, though grade 3 neuropathy was reported in 9%. DVT occurred in 5% of the patients.

Other multidrug combination induction regimens including bortezomib were also investi‐ gated in phase 2:

**•** In a randomized phase 2 study, 140 patients were initially randomized to VDCR, VDR, or VDC to receive eight 3-week cycles of induction therapy followed by four 6-week cycles of bortezomib maintenance therapy [35]. The VDC arm was modified after an interim analysis to add a third dose of cyclophosphamide at 500 mg/m2 on day 15 (VDC-mod). Bortezomib was given in standard doses. Patients could undergo stem cell mobilization any time after 2 cycles and undergo ASCT any time after 4 cycles. After 4 cycles of induc‐ tion therapy, the confirmed ORR was 80%, 73%, 63%, and 82% of patients in the VDCR, VDR, VDC, and VDC-mod arms including VGPR or better in 33%, 32%, 13%, and 41%, respectively. After ASCT, the ORR was 88%, 85%, 75%, and 100% for the VDCR, VDR, VDC, and VDC-mod arms including VGPR or better in 58%, 51%, 41%, and 53%, respec‐ tively. The 1-year PFS was 100%, 100%, 88%, and 100% for the VDCR, VDR, VDC, and VDC-mod arms, respectively. The 1-year OS estimate was 100% for all 4 arms. In addition the 1-year PFS for the high-risk patients (n = 24) was 100% and 85% for the standard-risk patients, and was similar across the study arms. The median CD34+ cell yield was 6.8 x 106 /kg (VDCR); 7.8 (VDR); 7.95 (VDC) and 7.75 (VDC modified). At least one grade ≥ 3 AE was seen in ~ 80% of patients in each arm. AEs leading to discontinuation were seen in 21%, 19%, 12%, and 6% in the VDCR, VDR, VDC, and VDC-mod arms, respectively. The most common adverse event of grade 3 or higher was neutropenia occurring in 44% (VDCR), 10% (VDR), 30% (VDC) and 24% (VDC modified). Neuropathy grade 3 or higher occurred in 13%, 17%, 9% and 18% respectively.

thasone while VD consisted of bortezomib 1.3 mg/m2 iv on days 1, 4, 8, and 11 plus the same dexamethasone regimen. In case of less than partial response (PR) after cycle 2, the dose of

vTD arm. The primary endpoint of this study was post induction CR rate. The CR rate be‐ tween the groups was the same after 4 cycles, 13% in the vTD arm and 12% in the VD arm. However, both the bortezomib and thalidomide dose had to be increased in 7 patients in the vTD arm. The ORR was 88% in the vTD arm versus 81% in the VD arm, the difference not reaching statistical significance. Further, there was no difference in CR rate post transplant (29% in vTD arm and 31% in VD arm). The target stem cell collection yield of 2 × 106 CD34+ cells/kg was achieved in 93% and 80% of VD and vTD patients, respectively (*P* =.01). While the overall safety profile was similar between the two arms, there was less peripheral neuro‐ pathy in the vTD arm (53% all grade vs 70% on VD, 11% grade 3 or higher vs 11% on VD). Results of the VD control group were consistent with prior observations from the IFM group on this VD induction regimen, both in a single arm phase 2 study [32] and in the random‐

Efficacy of VD in induction was also assessed in another phase 2 study with 57 patients, giv‐ en over 4 cycles followed by 2 cycles of DCEP consolidation [33]. The median CR34+ cells

minimum required for transplantation. The ORR was 87% and CR 30%. Univariate analysis

Efficacy of VTD was further confirmed in a single arm phase 2 study of 44 patients treated with bortezomib combined with thalidomide and dexamethasone, administered over eight 3-week cycles [34]. The patient enrolment included both frontline and recurrent disease as long as the patients were eligible for ASCT. Thirty four patients were frontline, 8 with recur‐ rent disease in second line and a further 2 had a third line recurrence. The ORR was 91% with CR/sCR rate of 20%. Post transplant these response rates increased to ORR of 100% and CR/sCR rate of 53%. All 44 patients had successful stem cell collection. Fifty-five percent of the subjects developed neuropathy of all grades, though grade 3 neuropathy was reported

Other multidrug combination induction regimens including bortezomib were also investi‐

**•** In a randomized phase 2 study, 140 patients were initially randomized to VDCR, VDR, or VDC to receive eight 3-week cycles of induction therapy followed by four 6-week cycles of bortezomib maintenance therapy [35]. The VDC arm was modified after an interim analysis to add a third dose of cyclophosphamide at 500 mg/m2 on day 15 (VDC-mod). Bortezomib was given in standard doses. Patients could undergo stem cell mobilization any time after 2 cycles and undergo ASCT any time after 4 cycles. After 4 cycles of induc‐ tion therapy, the confirmed ORR was 80%, 73%, 63%, and 82% of patients in the VDCR, VDR, VDC, and VDC-mod arms including VGPR or better in 33%, 32%, 13%, and 41%, respectively. After ASCT, the ORR was 88%, 85%, 75%, and 100% for the VDCR, VDR, VDC, and VDC-mod arms including VGPR or better in 58%, 51%, 41%, and 53%, respec‐ tively. The 1-year PFS was 100%, 100%, 88%, and 100% for the VDCR, VDR, VDC, and

found no difference between response and cytogenetic abnormalities.

/kg and in 86% of these patients the amount was more than twice the

and the dose of thalidomide to 200 mg/day in the

bortezomib was increased to 1.3 mg/m2

228 Innovations in Stem Cell Transplantation

ized phase 3 study (see above).

in 9%. DVT occurred in 5% of the patients.

collected were 7.5 x 106

gated in phase 2:


In conclusion, these studies have provided evidence of the important role of bortezomib in induction therapy pre-ASCT. Randomized phase 3 studies indicate that induction regimens containing bortezomib lead to improvements in CR/nCR rates after induction which are maintained after ASCT, and also lead to improved PFS as compared to standard non-borte‐ zomib containing regimens. After a relatively short duration of follow-up, a trend towards improved overall survival with the bortezomib regimens has been noted. Particularly in pa‐ tients with high-risk cytogenetic abnormalities, such as del17p and del13, the addition of bortezomib to induction therapy has improved outcomes. All phase 3 studies also provide evidence of good hematopoietic stem cell collection. While bortezomib can safely be com‐ bined with several induction regimens, a higher incidence of neuropathy in patients treated with a bortezomib combination is generally noted. Other toxicities of the induction regimens appear related to the combination partner (such as neutropenia for cyclophosphamide, thrombo-embolic events for thalidomide, hyperglycemia for high-dose dexamethasone) and the optimal combination regimen, as well as the optimal number of induction cycles has not been identified yet. One phase 2 study provided evidence of a lower incidence of neuropa‐ thy with a lower dose of bortezomib.

months after this conditioning regimen. The median time to neutrophil and platelet re‐ covery was 7 days and 3 days after stem cell reinfusion respectively. No engraftment failure or treatment-related death was reported. Three patients developed de novo neuro‐ pathy, while the severity of pre-existing neuropathy was not affected. In a matched con‐

Proteasome Inhibition and Hematopoietic Stem Cell Transplantation in Multiple Myeloma

http://dx.doi.org/10.5772/54117

231

In a randomized phase 2 study, 60 patients not in CR after induction therapy were randomized to receive an unconventional conditioning regimen with melphalan 200 mg/m2 in combination with arsenic trioxide and ascorbic acid either without (group 1) or with bortezomib at either 1mg/m2 (group 2) or 1.3 mg/m2 for 3 doses (group 3). Fiftyeight patients were randomized between the 3 treatment groups. Addition of bortezomib to this regimen was found safe with no apparent increase in time to neutrophil or plate‐ let engraftment, in grade ¾ non-hematologic toxicity or in treatment-related mortality. However, there was no significant improvement in the CR rate, PFS and OS rates in the bortezomib groups. The reason for this lack of improvement was interpreted by the au‐ thors as related to the high proportion of patients with relapsed disease (25%) and by

In conclusion, these studies have provided evidence that the addition of bortezomib to the conditioning regimen is feasible with no negative impact on hematopoietic recovery or treat‐ ment-related mortality after ASCT. From the two phase 2 studies adding bortezomib to high-dose melphalan, high CR rates post-ASCT were noted which appeared superior to his‐ toric data. A small randomized phase 2 study was not able to confirm improved efficacy

At the moment of our search, the results of only one randomized study incorporating borte‐

In the GIMEMA phase 3 study investigating bortezomib-thalidomide-dexamethasone (VTD) vs thalidomide-dexamethasone (TD), the combination regimens were given both in induc‐ tion therapy pre-ASCT and in consolidation therapy post-ASCT[29]. Patients initially randomized to VTD received 2 post-ASCT consolidation cycles of bortezomib 1.3 mg/m2 iv on d1,8,15,22 every 5 weeks in combination with thalidomide 100 mg/d po and dexametha‐ sone, patients initially randomized to TD received 2 post-ASCT consolidation cycles without bortezomib. Of the 236 patients initially randomized to VTD induction, 160 patients (68%) continued with VTD consolidation, while of the 238 patients initially randomized to TD in‐ duction, 161 patients (68%) continued with TD consolidation. VTD consolidation significant‐ ly improved the CR and CR/nCR rates post-ASCT, while the TD consolidation did not. After a median follow-up of 30.4 months from start of consolidation, 3-year PFS was significantly longer for the VTD group (60% vs 48%, p=0.042) but sofar no difference in overall survival from this landmark has been seen (3-year survival rates 90% for VTD and 88% for TD). Grade 2 or 3 peripheral neuropathy (8.1% vs 2.4%) was more frequent with VTD versus TD consolidation. The authors conclude that VTD consolidation therapy significantly contribut‐

outcomes when bortezomib was added to a multi-drug conditioning evidence.

zomib in consolidation therapy has been published in a peer-reviewed paper.

trol analysis, only 11% of CR post-conditioning were reported.

the concomitant administration of ascorbic acid [43].

**3.3. Bortezomib in consolidation treatment**

#### **3.2. Bortezomib during conditioning**

The high-dose chemotherapy regimen which immediately precedes the autologous stem cell transplantation is referred to as the 'conditioning regimen'. Melphalan is the most frequent‐ ly used conditioning agent in multiple myeloma and is given at the high-dose of 200 mg/m2 or at a reduced dose in case of renal function impairment [39].

Two single arm studies have investigated the addition of bortezomib to the high-dose mel‐ phalan conditioning regimen. The rationale to combine the two agents in this setting was based on (1) the synergy between bortezomib and melphalan reported both in vitro and in vivo [14,40], as well as on (2) the lack of overlapping toxicities between the two agents (mainly neurologic for bortezomib and hematologic for melphalan).

In a dose and schedule-finding phase ½ study, 39 patients with newly diagnosed multi‐ ple myeloma who achieved less than VGPR following induction therapy were random‐ ized to receive a single escalating dose of bortezomib (1 mg, 1.3 mg or 1.6 mg/m2 ) either 24 hours before or 24 hours after melphalan (given 100 mg/m2 /d for 2 days) [41]. Stem cells were reinfused 2 days after the last melphalan dose. Median time to neutrophil re‐ covery and platelet recovery was 12 days and 16 days, respectively, for both schedules. Transplant-related toxicities (gastro-intestinal and mucositis) were also similar for the two schedules. No peripheral neuropathy was reported. In the treatment group receiving bortezomib prior to melphalan (n=19) 47% had at least VGPR and 11% had CR posttransplant, while in the treatment group receiving bortezomib after melphalan (n=20) 55% had at least VGPR and 30% had CR. The investigators that the combination was safe with data suggesting improved efficacy and recommend the administration of borte‐ zomib after high-dose melphalan as the preferred schedule.

In a phase 2 study conducted by the French IFM group, 54 patients with newly diag‐ nosed multiple myeloma received melphalan 200 mg/m2 in combination with four ad‐ ministrations of bortezomib at a dose 1 mg/m2 (1 and 4 days prior to melphalan, and 3 and 6 days after melphalan) [42]. The autologous peripheral blood stem cells were rein‐ fused 2 days after melphalan administration. While 4% of patients had CR and 28% had PR at the end of the induction therapy, 32% had CR and 68% had at least VGPR 3 months after this conditioning regimen. The median time to neutrophil and platelet re‐ covery was 7 days and 3 days after stem cell reinfusion respectively. No engraftment failure or treatment-related death was reported. Three patients developed de novo neuro‐ pathy, while the severity of pre-existing neuropathy was not affected. In a matched con‐ trol analysis, only 11% of CR post-conditioning were reported.

In a randomized phase 2 study, 60 patients not in CR after induction therapy were randomized to receive an unconventional conditioning regimen with melphalan 200 mg/m2 in combination with arsenic trioxide and ascorbic acid either without (group 1) or with bortezomib at either 1mg/m2 (group 2) or 1.3 mg/m2 for 3 doses (group 3). Fiftyeight patients were randomized between the 3 treatment groups. Addition of bortezomib to this regimen was found safe with no apparent increase in time to neutrophil or plate‐ let engraftment, in grade ¾ non-hematologic toxicity or in treatment-related mortality. However, there was no significant improvement in the CR rate, PFS and OS rates in the bortezomib groups. The reason for this lack of improvement was interpreted by the au‐ thors as related to the high proportion of patients with relapsed disease (25%) and by the concomitant administration of ascorbic acid [43].

In conclusion, these studies have provided evidence that the addition of bortezomib to the conditioning regimen is feasible with no negative impact on hematopoietic recovery or treat‐ ment-related mortality after ASCT. From the two phase 2 studies adding bortezomib to high-dose melphalan, high CR rates post-ASCT were noted which appeared superior to his‐ toric data. A small randomized phase 2 study was not able to confirm improved efficacy outcomes when bortezomib was added to a multi-drug conditioning evidence.

#### **3.3. Bortezomib in consolidation treatment**

zomib containing regimens. After a relatively short duration of follow-up, a trend towards improved overall survival with the bortezomib regimens has been noted. Particularly in pa‐ tients with high-risk cytogenetic abnormalities, such as del17p and del13, the addition of bortezomib to induction therapy has improved outcomes. All phase 3 studies also provide evidence of good hematopoietic stem cell collection. While bortezomib can safely be com‐ bined with several induction regimens, a higher incidence of neuropathy in patients treated with a bortezomib combination is generally noted. Other toxicities of the induction regimens appear related to the combination partner (such as neutropenia for cyclophosphamide, thrombo-embolic events for thalidomide, hyperglycemia for high-dose dexamethasone) and the optimal combination regimen, as well as the optimal number of induction cycles has not been identified yet. One phase 2 study provided evidence of a lower incidence of neuropa‐

The high-dose chemotherapy regimen which immediately precedes the autologous stem cell transplantation is referred to as the 'conditioning regimen'. Melphalan is the most frequent‐ ly used conditioning agent in multiple myeloma and is given at the high-dose of 200 mg/m2

Two single arm studies have investigated the addition of bortezomib to the high-dose mel‐ phalan conditioning regimen. The rationale to combine the two agents in this setting was based on (1) the synergy between bortezomib and melphalan reported both in vitro and in vivo [14,40], as well as on (2) the lack of overlapping toxicities between the two agents

In a dose and schedule-finding phase ½ study, 39 patients with newly diagnosed multi‐ ple myeloma who achieved less than VGPR following induction therapy were random‐

cells were reinfused 2 days after the last melphalan dose. Median time to neutrophil re‐ covery and platelet recovery was 12 days and 16 days, respectively, for both schedules. Transplant-related toxicities (gastro-intestinal and mucositis) were also similar for the two schedules. No peripheral neuropathy was reported. In the treatment group receiving bortezomib prior to melphalan (n=19) 47% had at least VGPR and 11% had CR posttransplant, while in the treatment group receiving bortezomib after melphalan (n=20) 55% had at least VGPR and 30% had CR. The investigators that the combination was safe with data suggesting improved efficacy and recommend the administration of borte‐

In a phase 2 study conducted by the French IFM group, 54 patients with newly diag‐ nosed multiple myeloma received melphalan 200 mg/m2 in combination with four ad‐ ministrations of bortezomib at a dose 1 mg/m2 (1 and 4 days prior to melphalan, and 3 and 6 days after melphalan) [42]. The autologous peripheral blood stem cells were rein‐ fused 2 days after melphalan administration. While 4% of patients had CR and 28% had PR at the end of the induction therapy, 32% had CR and 68% had at least VGPR 3

) either

/d for 2 days) [41]. Stem

ized to receive a single escalating dose of bortezomib (1 mg, 1.3 mg or 1.6 mg/m2

thy with a lower dose of bortezomib.

230 Innovations in Stem Cell Transplantation

**3.2. Bortezomib during conditioning**

or at a reduced dose in case of renal function impairment [39].

(mainly neurologic for bortezomib and hematologic for melphalan).

24 hours before or 24 hours after melphalan (given 100 mg/m2

zomib after high-dose melphalan as the preferred schedule.

At the moment of our search, the results of only one randomized study incorporating borte‐ zomib in consolidation therapy has been published in a peer-reviewed paper.

In the GIMEMA phase 3 study investigating bortezomib-thalidomide-dexamethasone (VTD) vs thalidomide-dexamethasone (TD), the combination regimens were given both in induc‐ tion therapy pre-ASCT and in consolidation therapy post-ASCT[29]. Patients initially randomized to VTD received 2 post-ASCT consolidation cycles of bortezomib 1.3 mg/m2 iv on d1,8,15,22 every 5 weeks in combination with thalidomide 100 mg/d po and dexametha‐ sone, patients initially randomized to TD received 2 post-ASCT consolidation cycles without bortezomib. Of the 236 patients initially randomized to VTD induction, 160 patients (68%) continued with VTD consolidation, while of the 238 patients initially randomized to TD in‐ duction, 161 patients (68%) continued with TD consolidation. VTD consolidation significant‐ ly improved the CR and CR/nCR rates post-ASCT, while the TD consolidation did not. After a median follow-up of 30.4 months from start of consolidation, 3-year PFS was significantly longer for the VTD group (60% vs 48%, p=0.042) but sofar no difference in overall survival from this landmark has been seen (3-year survival rates 90% for VTD and 88% for TD). Grade 2 or 3 peripheral neuropathy (8.1% vs 2.4%) was more frequent with VTD versus TD consolidation. The authors conclude that VTD consolidation therapy significantly contribut‐ ed to the improved clinical outcomes observed for patients randomly assigned to the VTD arm of the study.

between different maintenance regimens: interferon alfa-2b versus thalidomide 100 mg/d vs

and for a maximum of 3 years [30]. Three-hundred ninety patients were initially random‐ ized between the three induction arms; the initial study publication does not report how many patients were rerandomized between the 3 maintenance arms nor does it address the toxicities observed. However, the publication states that after a median follow-up of 24 months from initiation of maintenance, the PFS is significantly longer with thalidomide/ bortezomib compared with thalidomide alone and with alfa2-interferon (78% vs 63% vs 49% at 2 years, p=0.01). However, at this early analysis, the overall survival is not significantly

In a small phase 2 study of 40 patients post-ASCT, a sequential maintenance therapy includ‐ ing bortezomib was investigated [44]. In this study, 6 4-week cycles of weekly bortezomib at

thalidomide and dexamethasone and then followed by thalidomide single agent until pro‐ gression. Of the 40 patients, 32 (80%) completed the bortezomib therapy and in 9 patients the bortezomib-dexamethasone combination upgraded the response from less than CR to CR. The combination regimen was feasible, with peripheral neuropathy grade 1-2 being re‐ ported in 27 patients. The authors concluded that this bortezomib maintenance regimen was able to upgrade post-ASCT CR responses with no severe grade ¾ peripheral neuropathy. In conclusion, currently available data suggest that maintenance therapy with bortezo‐ mib, either as single agent or in combination with thalidomide, improves the PFS over thalidomide alone. Prolonged maintenance therapy with bortezomib at lower dose inten‐ sity than in the induction setting (either one dose weekly or every 2 weeks, or four doses every 3 months) appears feasible and is able to further improve the CR rate post-ASCT. More follow-up is needed on the impact of these bortezomib maintenance regi‐

There were no studies identified which specifically looked into the use of bortezomib as part

However, one large randomized phase 3 study by the EBMT group (European Group for Blood and Marrow Transplantation) investigated the use of a bortezomib containing regi‐ men to rescue patients with multiple myeloma progressing or relapsing after ASCT [45]. In this study, 269 patients were randomly assigned to receive bortezomib or no bortezomib for one year, in combination with thalidomide (200mg/d) and dexamethasone. Almost half of the patients (47%) had two prior ASCTs. The triplet combination of VTD resulted in a signif‐ icantly longer time to progression (19.5 m vs 13.8 m, p=0.001) and a significantly better CR/nCR rate (45% vs 25%, p=0.001) with a trend towards improved overall survival (71% vs 65% 24-month survival rate, p=0.093) as compared to the TD control group. On the other hand, the triplet combination had a higher incidence of grade 3 peripheral sensory neuropa‐ thy (29% vs 12%, p=0.001) and a higher incidence of grade >=3 thrombocytopenia (17% vs 7%, p=0.016) not associated with serious bleeding complications. The neurotoxicity was at‐

**3.5. Bortezomib during or after ASCT procedure for relapsed myeloma**

of an ASCT procedure for relapsed multiple myeloma.

was given in combination with dexamethasone, followed by 6 cycles of

Proteasome Inhibition and Hematopoietic Stem Cell Transplantation in Multiple Myeloma

d1,4,8,11 q3 month) until progression

http://dx.doi.org/10.5772/54117

233

thalidomide 100 mg/d plus bortezomib (1.3 mg/m2

different between the 3 maintenance groups.

a dose of 1.3 mg/m2

mens on overall survival.

#### **3.4. Bortezomib in maintenance treatment**

There were no studies identified which in a randomized fashion have investigated the role of single agent bortezomib as prolonged maintenance therapy post-ASCT. However, a lot of information on single agent bortezomib maintenance therapy can be derived from the HOV‐ ON-65/GMMG-HD4 study, the largest phase 3 study ever conducted in ASCT in newly di‐ agnosed multiple myeloma. In addition, preliminary data are available from a randomized phase 3 study investigating the bortezomib-thalidomide combination in maintenance thera‐ py (GEM05-MENOS65) and from a phase 2 study investigating a bortezomib-thalidomidedexamethasone combination in maintenance therapy post-ASCT [44].

In the HOVON-65/GMMG-HD4 study, as discussed above, patients randomized to the bor‐ tezomib-doxorubicin-dexamethasone (PAD) induction treatment group continued bortezo‐ mib maintenance 1.3 mg/m2 iv every 2 weeks for 2 years post-ASCT, whereas the control treatment group of vincristine-doxorubicin-dexamethasone (VAD) induction continued to be treated with thalidomide 50 mg/d po for the same treatment duration [26]. In this study, 833 patients were randomized between the PAD and the VAD induction regimens. After ASCT, 229 patients from the PAD treatment group (55%) continued with bortezomib main‐ tenance, while in the VAD treatment group 270 patients (65%) continued with thalidomide maintenance. Of the 229 patients starting bortezomib maintenance, 109 (48%) completed the 2-year maintenance, while 26 (11%) discontinued because of toxicity and 74 (32%) discontin‐ ued earlier because of progression. Of the 270 patients starting thalidomide maintenance, only 73 (27%) completed the 2-year maintenance, while more patients (82 or 30%) discontin‐ ued because of toxicity and a similar percentage (86 or 32%) discontinued because of pro‐ gression. Because of the sequential study design a direct comparison between the two maintenance regimens should be interpreted with caution. However, the main study publi‐ cation indicates a statistically significantly higher incidence of serious adverse events (34% vs 23%, p<0.01) during bortezomib maintenance, mainly related to infection, while on the other hand more peripheral neuropathy was reported during thalidomide maintenance (5% vs 8%, p<0.001). The sequential design also limits the interpretation of the efficacy data of the maintenance regimens. Although in the bortezomib maintenance all patients had al‐ ready been exposed to bortezomib during induction therapy, a similar percentage of pa‐ tients (23%) had an upgrade of their tumor response post-ASCT as compared to the thalidomide maintenance which introduced a new agent (24%). An analysis of progressionfree survival calculated from the last ASCT indicates that bortezomib contributed more to improvement of progression-free survival than thalidomide (31 months vs 26 months). Also, a landmark analysis starting at month 12 shows an improvement in progression-free surviv‐ al (p=0.04) and overall survival (p=0.05) in the bortezomib-containing arm.

In phase 3 study GEM05-MENOS65 performed by the Spanish PETHEMA/GEM group, pa‐ tients initially randomized to answer the induction regimen question of bortezomib-thal-dex vs thal-dex vs VBMCP/VBAD/bortezomib (discussed above) were rerandomized after ASCT between different maintenance regimens: interferon alfa-2b versus thalidomide 100 mg/d vs thalidomide 100 mg/d plus bortezomib (1.3 mg/m2 d1,4,8,11 q3 month) until progression and for a maximum of 3 years [30]. Three-hundred ninety patients were initially random‐ ized between the three induction arms; the initial study publication does not report how many patients were rerandomized between the 3 maintenance arms nor does it address the toxicities observed. However, the publication states that after a median follow-up of 24 months from initiation of maintenance, the PFS is significantly longer with thalidomide/ bortezomib compared with thalidomide alone and with alfa2-interferon (78% vs 63% vs 49% at 2 years, p=0.01). However, at this early analysis, the overall survival is not significantly different between the 3 maintenance groups.

ed to the improved clinical outcomes observed for patients randomly assigned to the VTD

There were no studies identified which in a randomized fashion have investigated the role of single agent bortezomib as prolonged maintenance therapy post-ASCT. However, a lot of information on single agent bortezomib maintenance therapy can be derived from the HOV‐ ON-65/GMMG-HD4 study, the largest phase 3 study ever conducted in ASCT in newly di‐ agnosed multiple myeloma. In addition, preliminary data are available from a randomized phase 3 study investigating the bortezomib-thalidomide combination in maintenance thera‐ py (GEM05-MENOS65) and from a phase 2 study investigating a bortezomib-thalidomide-

In the HOVON-65/GMMG-HD4 study, as discussed above, patients randomized to the bor‐ tezomib-doxorubicin-dexamethasone (PAD) induction treatment group continued bortezo‐

treatment group of vincristine-doxorubicin-dexamethasone (VAD) induction continued to be treated with thalidomide 50 mg/d po for the same treatment duration [26]. In this study, 833 patients were randomized between the PAD and the VAD induction regimens. After ASCT, 229 patients from the PAD treatment group (55%) continued with bortezomib main‐ tenance, while in the VAD treatment group 270 patients (65%) continued with thalidomide maintenance. Of the 229 patients starting bortezomib maintenance, 109 (48%) completed the 2-year maintenance, while 26 (11%) discontinued because of toxicity and 74 (32%) discontin‐ ued earlier because of progression. Of the 270 patients starting thalidomide maintenance, only 73 (27%) completed the 2-year maintenance, while more patients (82 or 30%) discontin‐ ued because of toxicity and a similar percentage (86 or 32%) discontinued because of pro‐ gression. Because of the sequential study design a direct comparison between the two maintenance regimens should be interpreted with caution. However, the main study publi‐ cation indicates a statistically significantly higher incidence of serious adverse events (34% vs 23%, p<0.01) during bortezomib maintenance, mainly related to infection, while on the other hand more peripheral neuropathy was reported during thalidomide maintenance (5% vs 8%, p<0.001). The sequential design also limits the interpretation of the efficacy data of the maintenance regimens. Although in the bortezomib maintenance all patients had al‐ ready been exposed to bortezomib during induction therapy, a similar percentage of pa‐ tients (23%) had an upgrade of their tumor response post-ASCT as compared to the thalidomide maintenance which introduced a new agent (24%). An analysis of progressionfree survival calculated from the last ASCT indicates that bortezomib contributed more to improvement of progression-free survival than thalidomide (31 months vs 26 months). Also, a landmark analysis starting at month 12 shows an improvement in progression-free surviv‐

iv every 2 weeks for 2 years post-ASCT, whereas the control

dexamethasone combination in maintenance therapy post-ASCT [44].

al (p=0.04) and overall survival (p=0.05) in the bortezomib-containing arm.

In phase 3 study GEM05-MENOS65 performed by the Spanish PETHEMA/GEM group, pa‐ tients initially randomized to answer the induction regimen question of bortezomib-thal-dex vs thal-dex vs VBMCP/VBAD/bortezomib (discussed above) were rerandomized after ASCT

arm of the study.

232 Innovations in Stem Cell Transplantation

mib maintenance 1.3 mg/m2

**3.4. Bortezomib in maintenance treatment**

In a small phase 2 study of 40 patients post-ASCT, a sequential maintenance therapy includ‐ ing bortezomib was investigated [44]. In this study, 6 4-week cycles of weekly bortezomib at a dose of 1.3 mg/m2 was given in combination with dexamethasone, followed by 6 cycles of thalidomide and dexamethasone and then followed by thalidomide single agent until pro‐ gression. Of the 40 patients, 32 (80%) completed the bortezomib therapy and in 9 patients the bortezomib-dexamethasone combination upgraded the response from less than CR to CR. The combination regimen was feasible, with peripheral neuropathy grade 1-2 being re‐ ported in 27 patients. The authors concluded that this bortezomib maintenance regimen was able to upgrade post-ASCT CR responses with no severe grade ¾ peripheral neuropathy.

In conclusion, currently available data suggest that maintenance therapy with bortezo‐ mib, either as single agent or in combination with thalidomide, improves the PFS over thalidomide alone. Prolonged maintenance therapy with bortezomib at lower dose inten‐ sity than in the induction setting (either one dose weekly or every 2 weeks, or four doses every 3 months) appears feasible and is able to further improve the CR rate post-ASCT. More follow-up is needed on the impact of these bortezomib maintenance regi‐ mens on overall survival.

#### **3.5. Bortezomib during or after ASCT procedure for relapsed myeloma**

There were no studies identified which specifically looked into the use of bortezomib as part of an ASCT procedure for relapsed multiple myeloma.

However, one large randomized phase 3 study by the EBMT group (European Group for Blood and Marrow Transplantation) investigated the use of a bortezomib containing regi‐ men to rescue patients with multiple myeloma progressing or relapsing after ASCT [45]. In this study, 269 patients were randomly assigned to receive bortezomib or no bortezomib for one year, in combination with thalidomide (200mg/d) and dexamethasone. Almost half of the patients (47%) had two prior ASCTs. The triplet combination of VTD resulted in a signif‐ icantly longer time to progression (19.5 m vs 13.8 m, p=0.001) and a significantly better CR/nCR rate (45% vs 25%, p=0.001) with a trend towards improved overall survival (71% vs 65% 24-month survival rate, p=0.093) as compared to the TD control group. On the other hand, the triplet combination had a higher incidence of grade 3 peripheral sensory neuropa‐ thy (29% vs 12%, p=0.001) and a higher incidence of grade >=3 thrombocytopenia (17% vs 7%, p=0.016) not associated with serious bleeding complications. The neurotoxicity was at‐ tributed by the investigators as due to the combination of the two neurotoxic agents bortezo‐ mib and thalidomide given for a prolonged period of time (1 year) and at higher dose levels (200 mg/d thalidomide). The investigators concluded that the VTD combination may be con‐ sidered as a standard of care for patients relapsing after ASCT, but that the risk for neuro‐ toxicity should be decreased by using lower doses of thalidomide and appropriate dose reductions of bortezomib.

Which future research directions can be expected on this topic in the next decade?

before incorporation in routine ASCT procedures. [51,52].

way to test this hypothesis.

fore definitely be expected.

**Acknowledgements**

First, given the high response rates and complete response rates observed with bortezomib containing regimens, the question will be asked whether in this younger population with newly diagnosed multiple myeloma a non-transplant approach incorporating bortezomib and immunomodulatory agents can delay or prevent the need for a high-dose therapy and autologous transplant approach. Several randomized phase 3 studies are currently under‐

Proteasome Inhibition and Hematopoietic Stem Cell Transplantation in Multiple Myeloma

http://dx.doi.org/10.5772/54117

235

Second, if the ultimate goal of the autologous transplant approach is disease eradication and cure, more rigorous definitions of complete response and more sensitive diagnostic techniques will be required to optimize individual therapy decisions. A stringent CR (sCR) category has already been defined by the IMWG criteria [48]. This stringent CR (sCR) category requires a normalization of the free κ/λ ratio in serum and an immuno‐ phenotypic normalization of the κ/λ ratio in the bone marrow, but sofar has not been routinely reported in high-dose therapy studies. By the most recent criteria, also an im‐ munophenotypic CR category has been defined to exclude minimal residual disease based on a more extensive immunophenotypic analysis of the bone marrow [49]. Charac‐ terization of minimal residual disease by immunophenotyping has only been reported in selected studies [50]. Alternative techniques such as magnetic resonance imaging or posi‐ tron emission tomography have also been reported but require further characterization

Third, second-generation proteasome inhibitors, such as carfilzomib, marizomib and MLN-9708, are currently in development in multiple myeloma [53]. These agents are also potent inhibitors of proteasome activity in vitro but show differences in enzyme binding ki‐ netics which might affect their pharmacology and result in different efficacy and safety pro‐ files [54]. Most data with the second generation proteasome inhibitors have been generated in the relapsed or refractory myeloma setting. As there are no full publications in peer-re‐ viewed journals available addressing the incorporation of such agents in autologous stem cell transplant approaches, these agents were not included in this review. However, data of early studies combining carfilzomib with either thalidomide-dexamethasone or lenalido‐ mide-dexamethasone as induction treatment prior to ASCT have already been reported at international conferences [55,56]. Further research on the incorporation of second-generation proteasome inhibitors in autologous stem cell transplant approaches in myeloma can there‐

The authors would like to thank Margaret Roll (librarian, Janssen Research & Development, High Wycombe, UK) for her help in performing an extensive literature search and An Van Eyken (Janssen Research & Development, Beerse, Belgium) for excellent editorial assistance.

## **4. Conclusions and future directions**

There is an increasing body of literature on the incorporation of bortezomib in the different treatment phases of the autologous stem cell transplantation approach in multiple myeloma. The highest level of evidence on the benefit of bortezomib-containing regimens is available from multiple phase 3 studies in the induction treatment phase. In other treatment phases, the current experimental clinical evidence is more limited. In the conditioning phase, only phase 2 data are available on the addition of bortezomib and comparisons with historic data should be made with caution. In consolidation, only limited phase 3 information is currently available but phase 3 studies comparing bortezomib consolidation versus no consolidation are ongoing or awaiting final publication [46]. In the maintenance phase, randomized phase 3 studies have been published but did not directly test the value of bortezomib maintenance over no maintenance. Despite these limitations some common themes on the incorporation of bortezomib can be observed across the different treatment phases:


The effect of the addition of bortezomib on the overall survival post-ASCT were variable across studies. While several studies appear to report a favorable survival trend, only in the largest phase 3 study (HOVON-65/GMMG-HD4) the survival improvement reached statisti‐ cal significance. Potentially contributing to this could be the short duration of follow-up in the initial study publications, the effect of subsequent therapy (and in particular of crossover use of bortezomib in subsequent therapy lines) and the sample size limitation of the individual studies. An argument for the latter could be found in a recent meta-analysis indi‐ cating a survival benefit of bortezomib-containing induction therapy if the different phase 3 study results are combined [47].

Which future research directions can be expected on this topic in the next decade?

First, given the high response rates and complete response rates observed with bortezomib containing regimens, the question will be asked whether in this younger population with newly diagnosed multiple myeloma a non-transplant approach incorporating bortezomib and immunomodulatory agents can delay or prevent the need for a high-dose therapy and autologous transplant approach. Several randomized phase 3 studies are currently under‐ way to test this hypothesis.

Second, if the ultimate goal of the autologous transplant approach is disease eradication and cure, more rigorous definitions of complete response and more sensitive diagnostic techniques will be required to optimize individual therapy decisions. A stringent CR (sCR) category has already been defined by the IMWG criteria [48]. This stringent CR (sCR) category requires a normalization of the free κ/λ ratio in serum and an immuno‐ phenotypic normalization of the κ/λ ratio in the bone marrow, but sofar has not been routinely reported in high-dose therapy studies. By the most recent criteria, also an im‐ munophenotypic CR category has been defined to exclude minimal residual disease based on a more extensive immunophenotypic analysis of the bone marrow [49]. Charac‐ terization of minimal residual disease by immunophenotyping has only been reported in selected studies [50]. Alternative techniques such as magnetic resonance imaging or posi‐ tron emission tomography have also been reported but require further characterization before incorporation in routine ASCT procedures. [51,52].

Third, second-generation proteasome inhibitors, such as carfilzomib, marizomib and MLN-9708, are currently in development in multiple myeloma [53]. These agents are also potent inhibitors of proteasome activity in vitro but show differences in enzyme binding ki‐ netics which might affect their pharmacology and result in different efficacy and safety pro‐ files [54]. Most data with the second generation proteasome inhibitors have been generated in the relapsed or refractory myeloma setting. As there are no full publications in peer-re‐ viewed journals available addressing the incorporation of such agents in autologous stem cell transplant approaches, these agents were not included in this review. However, data of early studies combining carfilzomib with either thalidomide-dexamethasone or lenalido‐ mide-dexamethasone as induction treatment prior to ASCT have already been reported at international conferences [55,56]. Further research on the incorporation of second-generation proteasome inhibitors in autologous stem cell transplant approaches in myeloma can there‐ fore definitely be expected.

## **Acknowledgements**

tributed by the investigators as due to the combination of the two neurotoxic agents bortezo‐ mib and thalidomide given for a prolonged period of time (1 year) and at higher dose levels (200 mg/d thalidomide). The investigators concluded that the VTD combination may be con‐ sidered as a standard of care for patients relapsing after ASCT, but that the risk for neuro‐ toxicity should be decreased by using lower doses of thalidomide and appropriate dose

There is an increasing body of literature on the incorporation of bortezomib in the different treatment phases of the autologous stem cell transplantation approach in multiple myeloma. The highest level of evidence on the benefit of bortezomib-containing regimens is available from multiple phase 3 studies in the induction treatment phase. In other treatment phases, the current experimental clinical evidence is more limited. In the conditioning phase, only phase 2 data are available on the addition of bortezomib and comparisons with historic data should be made with caution. In consolidation, only limited phase 3 information is currently available but phase 3 studies comparing bortezomib consolidation versus no consolidation are ongoing or awaiting final publication [46]. In the maintenance phase, randomized phase 3 studies have been published but did not directly test the value of bortezomib maintenance over no maintenance. Despite these limitations some common themes on the incorporation

**•** The addition of bortezomib increased the quality of the response (higher complete and

**•** The addition of bortezomb improved the progression-free survival post-ASCT as com‐

**•** Where analyzed, the addition of bortezomib improved the outcomes of patients with poor prognostic features, such as high-risk cytogenetics and renal function impairment

**•** The addition of bortezomib had no negative impact on hematopoietic stem cell collection

The effect of the addition of bortezomib on the overall survival post-ASCT were variable across studies. While several studies appear to report a favorable survival trend, only in the largest phase 3 study (HOVON-65/GMMG-HD4) the survival improvement reached statisti‐ cal significance. Potentially contributing to this could be the short duration of follow-up in the initial study publications, the effect of subsequent therapy (and in particular of crossover use of bortezomib in subsequent therapy lines) and the sample size limitation of the individual studies. An argument for the latter could be found in a recent meta-analysis indi‐ cating a survival benefit of bortezomib-containing induction therapy if the different phase 3

**•** The addition of bortezomib resulted in a higher incidence of peripheral neuropathy

near-complete response rates) as compared to control groups or to historic data

of bortezomib can be observed across the different treatment phases:

reductions of bortezomib.

234 Innovations in Stem Cell Transplantation

**4. Conclusions and future directions**

pared to control groups or to historic data

or engraftment

study results are combined [47].

The authors would like to thank Margaret Roll (librarian, Janssen Research & Development, High Wycombe, UK) for her help in performing an extensive literature search and An Van Eyken (Janssen Research & Development, Beerse, Belgium) for excellent editorial assistance.

## **Author details**

Helgi van de Velde1\* and Andrew Cakana2


2 Oncology R&D, Janssen Research & Development, High Wycombe, UK

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2 Oncology R&D, Janssen Research & Development, High Wycombe, UK

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**Chapter 10**

**Autologous Stem Cell Transplantation for Acute**

In the majority of patients, the therapy of acute myeloid leukemia (AML) has a curative in‐ tent and includes two phases, i.e. induction and consolidation. The former aims at complete remission (CR) achievement, the latter at the eradication of residual leukemic cells, which are undetectable at morphologic examination of bone marrow after induction therapy in pa‐ tients in CR. Current induction regimens, conventionally based on the combination of dau‐ norubicin and cytarabine result in CR rates of 60 – 70% of AML patients younger than 65 years; in order to improve both CR rate and quality, different studies tested alternative an‐ thracyclines [1]-[5], higher schedules of Ara-C[6]-[10], the addition of a third cytotoxic drug [11]-[16] and, more recently, the combination with new agents. Overall, results have been disappointing even though the addition of gemtuzumab ozogamycin (GO), an antiCD33 monoclonal antibody conjugated with the cytotoxic agents chalicheamycin, has been report‐ ed to confer a significant advantage in selected patients with AML [17]-[21]. Notwithstand‐ ing, in absence of intensive post-induction therapy virtually all patients will ultimately relapse, therefore consolidation therapy is strictly needed. At present, after CR achievement all patients receive a consolidation chemotherapy based on intermediate or high dose ARA-C and then in young adult patients three options can be considered, i.e. allogeneic stem cell transplantation (allo-SCT), autologous SCT (ASCT) or repetitive intensive consolidation che‐ motherapy cycles (ICC) with high or intermediate dose ARA-C [22]-[37], depending on age, disease risk and donor availability. In particular, it is widely accepted that ICC and ASCT would be limited to patients with favorable risk, such as AML with t(8;21), AML with inv(16) or t(16;16) and AML with normal karyotype with NPM1 mutation in absence of mu‐

> © 2013 Piccaluga 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.

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,

**Myeloid Leukemia**

http://dx.doi.org/10.5772/54280

Felicetto Ferrara

**1. Introduction**

Pier Paolo Piccaluga, Stefania Paolini, Giovanna Meloni, Giuseppe Visani and

Additional information is available at the end of the chapter

