**2. The intensity of conditioning regimen**

The early data on myeloablative conditioning (MAC) regimen can be obtained from the transplant registries [8-12]. Cyclophosphamide (Cy) with total body irradiation (Cy-TBI) and busulfan with Cy were the mostly used conditioning regimens. Transplant-related mortality (TRM) rates ranged from 30% to 50%. Actuarial survival for the EBMT-registered patients was 28% at 7 years [9], 15 % for the Hutchinson Center–registered patients [10]. IBMTR data showed that the probabilities of survival at 4 years was 35% for patients with Karnofsky performance scores higher than 70 at pretransplantation and approximately 15% for patients with scores lower than 70 [11]. Thus, due to the exceedingly high TRM, myeloablative Allo-SCT was largely abandoned worldwide in the 1990s.

The use of reduced intensity conditioning (RIC) regimens in allo-SCT was introduced in an attempt to reduce the regimen-related toxicities while preserving an effect of graft versus tumor effect. First study was performed in a canine model conditioned with low-dose (2 Gy) total body irradiation (TBI) in combination of postgrafting mycofenolatemofetil (MMF) and cyclosporine (CSP). This approach permitted to stable engraftment with minimal toxicity [13, 14]. Seattle group introduced the strategy of autologous SCT followed by a RIC allo-SCT in 2-4 months with low-dose TBI as conditioning regimen [15]. Forty eight percent of 52 multiple myeloma patients had relapsed or refractory disease prior to SCT and the overall response rate was 81 % (51% CR + 29% PR). In this tandem modality, the 100-day TRM after the allo-RIC was 2%, progression free survival (PFS) and overall survival (OS) at 2 years were 48% and 69%, respectively. Preliminary clinical studies [15-25] were also encouraging with low TRM rates (Table1). Kröger, et al performed tandem auto/Allo-RIC in 17 myeloma patients using unrelated or mismatched related donors and fludarabine, melphalan, anti-thymocyte globulin (ATG) as conditioning regimen [16]. Early TRM (day 100) was reported as 11% and estimated 1-year disease free survival (DFS) and OS were 56% and 74%.

One of the largest data related to a RIC-allograft in myeloma was published by the EBMT in which the outcome of 229 patients with MM from 33 centers was reported [18]. One-year TRM was 22%, the 3-year estimated PFS and OS were 41% and 21%, respectively. The adverse outcomes were seen in chemo-resistant disease prior to allo-SCT, transplantation to the pair of male recipient- female donor, no-chronic GvHD and the use of alemtuzumab.

The EBMT has also retrospectively compared 320 patients allografted a RIC regimen with 196 received a MAC regimen in multiple myeloma. They have reported markedly lower non relapse mortality in RIC than MAC setting (24% vs 32%, p<.002) [19]. However PFS and OS were not affected by the intensity of conditioning regimen. This was attributed to higher relapse rates in RIC group than the MAC group. Progressive disease at transplantation was associated with an adverse effect on non-relapse mortality, PFS and OS. T cell depletion with alemtuzumab or other(s) led to high relapse rates as well.

In this chapter, we discussed the role of allo-HCT in MM patients, and also we tried to clarify the issues as the intensity of conditioning regimen, the timing of the transplantation, and post-

The early data on myeloablative conditioning (MAC) regimen can be obtained from the transplant registries [8-12]. Cyclophosphamide (Cy) with total body irradiation (Cy-TBI) and busulfan with Cy were the mostly used conditioning regimens. Transplant-related mortality (TRM) rates ranged from 30% to 50%. Actuarial survival for the EBMT-registered patients was 28% at 7 years [9], 15 % for the Hutchinson Center–registered patients [10]. IBMTR data showed that the probabilities of survival at 4 years was 35% for patients with Karnofsky performance scores higher than 70 at pretransplantation and approximately 15% for patients with scores lower than 70 [11]. Thus, due to the exceedingly high TRM, myeloablative Allo-SCT was largely

The use of reduced intensity conditioning (RIC) regimens in allo-SCT was introduced in an attempt to reduce the regimen-related toxicities while preserving an effect of graft versus tumor effect. First study was performed in a canine model conditioned with low-dose (2 Gy) total body irradiation (TBI) in combination of postgrafting mycofenolatemofetil (MMF) and cyclosporine (CSP). This approach permitted to stable engraftment with minimal toxicity [13, 14]. Seattle group introduced the strategy of autologous SCT followed by a RIC allo-SCT in 2-4 months with low-dose TBI as conditioning regimen [15]. Forty eight percent of 52 multiple myeloma patients had relapsed or refractory disease prior to SCT and the overall response rate was 81 % (51% CR + 29% PR). In this tandem modality, the 100-day TRM after the allo-RIC was 2%, progression free survival (PFS) and overall survival (OS) at 2 years were 48% and 69%, respectively. Preliminary clinical studies [15-25] were also encouraging with low TRM rates (Table1). Kröger, et al performed tandem auto/Allo-RIC in 17 myeloma patients using unrelated or mismatched related donors and fludarabine, melphalan, anti-thymocyte globulin (ATG) as conditioning regimen [16]. Early TRM (day 100) was reported as 11% and estimated

One of the largest data related to a RIC-allograft in myeloma was published by the EBMT in which the outcome of 229 patients with MM from 33 centers was reported [18]. One-year TRM was 22%, the 3-year estimated PFS and OS were 41% and 21%, respectively. The adverse outcomes were seen in chemo-resistant disease prior to allo-SCT, transplantation to the pair

The EBMT has also retrospectively compared 320 patients allografted a RIC regimen with 196 received a MAC regimen in multiple myeloma. They have reported markedly lower non relapse mortality in RIC than MAC setting (24% vs 32%, p<.002) [19]. However PFS and OS were not affected by the intensity of conditioning regimen. This was attributed to higher relapse rates in RIC group than the MAC group. Progressive disease at transplantation was

of male recipient- female donor, no-chronic GvHD and the use of alemtuzumab.

transplantation approaches in relapse or refractory patients.

1-year disease free survival (DFS) and OS were 56% and 74%.

**2. The intensity of conditioning regimen**

166 Multiple Myeloma - A Quick Reflection on the Fast Progress

abandoned worldwide in the 1990s.

Long-term follow-up data was reported in a RIC allo-graft for salvage setting of relapse and/or refractory myeloma patients (Table 1). These data showed that long term remission can be feasible for a subset of myeloma patients with allo-RIC performed in the salvage setting [21]. Seattle group reported the long term comparison data of RIC and MAC regimens [23]. Although the intensity of regimens changed time dependently, RIC regimens resulted in significantly lower overall mortality, improved PFS and much lower TRM.


**Abbreviations:** ASCT: Autologous Stem Cell Transplantation; GvHD: Graft versus Host Disease; TRM: Transplant-Related Mortality; NRM: Non-Relapse Mortality; CR: Complete Remission; PFS. Progression-Free Survival; OS: Overall Survival; TBI: Total Body Irradiation; ATG: Anti-Thymocyte Globulin; CSP: Cyclosporine; MMF: Mycofenolate Mofetif; TAC: Tacrolimus; MTX: Methotrexate; MP: Methyl-Prednisolone; URD: Unrelated Donor; MRD: Matched Related Donor

**Table 1.** Reduced intensity allogeneic transplantation alone or following autogous-SCT

A prospective multicenter study by the Gruppo ItalianoTrapianti di Midollo Osseo (GITMO) enrolled 100 newly diagnosed multiple myeloma patients who were < 65 years of age and who had a sibling donor [24]. Allo-RIC transplantation was performed 2 to 4 months after ASCT in 96 patients. Disease sensitivity at the transplantation was significantly associated with longer OS and event-free survival (EFS). Overall survival were not significantly affected by the presence of del(13q) whereas EFS was better in patients without del(13q). Similarly, the Eastern Cooperative Oncology Group (ECOG) performed a trial of ASCT followed by RIC-allo from matched sibling donor to provide maximal tumor cytoreduction to allow for a subsequent graft versus myeloma (GvM) effect [25]. With a median follow up of 4.6 years from registration, 23 patients who completed both transplantations had a median PFS of 3.6 years and a 2-year survival rate of 78%. Cumulative non-relapse mortality on day 100 was 8.7%. In contrast to Italian study, plateau in PFS or OS was not observed with this treatment approach even in patients achieving CR.

**Auto/auto vs**

**Conditioning for allo- RIC**

busulfan, ATG

80 vs 82 Low-dose TBI 26 vs 55

Melphalan

366 vs156 Low-dose TBI 13 vs 9

46 vs58 Low-dose TBI 26 vs 55

**Table 2.** Double transplantation comparing tandem ASCT with auto/allo RIC

the patients received double ASCT (p=.002).

**CR (%) (auto/auto vs**

p=.004

40 vs 11 p=.001

p=.0004

p=.003

TRM: Transplant-Related Mortalitiy; TBI: Total Body Irradiation; ATG: Anti-Thymocyte Globulin

**auto/allo RIC)**


**PFS/EFS (months) (auto/auto vs**

**OS (months) (auto/auto vs**

Allogeneic Hematopoetic Cell Transplantation in Multiple Myeloma

**auto/allo RIC)**

57 vs 41 p=.08

80 vs 54 p=.01

3 years 80% vs 77% P:0.19

5.3 years vs not reached P=.02

60% vs 61.8% (5y) p=.9

**TRM % P(auto/auto**

**auto/allo RIC)**

169

Not evaluated

46 pts. vs 58pts. P=.09

5 vs 16 p=.09

Not evaluated

16 vs 2

**vs**

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

**auto/allo RIC)**

p=.88

35 vs 29 p=.02

p=.08 26 vs 19.6 p=.4

46% vs 43% (3 y) p=.7

33 vs39 p=0.02

**Abbreviations:** CR: Complete Remission; PFS: Progression-Free Survival; EFS: Event-Free Survival; OS: Overall Survival;

The Italian group enrolled 162 consecutive younger patients ≤ 65 years of age with newly diagnosed myeloma who had at least one sibling [29]. Patients with an HLA-identical sibling donor received NMA TBI (2Gy) and stem cells median 94 days after ASCT (n=58). Patients without an HLA-identical sibling received tandem ASCT with high-dose melphalan (n=46). The rate of complete remission was significantly higher in the auto-allograft group (55% vs 26%, p=.004). Treatment-related mortality was similar (p=.009) but disease-related mortality was significantly higher in the double ASCT group (43% vs 7%, p<.001). There was a trend of higher EFS in auto-allograft arm (p=.07) while survival in the auto-allo setting was superior to

Another prospective study has been performed by the Spanish PETHEMA group [30]. They enrolled 110 patients with newly diagnosed failing to achieve at least near-CR after a 1st ASCT were scheduled to receive either 2nd ASCT (n=85) or allo-RIC (n=25), depending on the

31 vs not reached

**Auto/allo RIC**

166 vs 46 Fludarabine,

85 vs 25 Fludarabine,

**(n)**

Moreau [28]

Bruno [29]

Rosinol [30]

Krishnan [31]

Giaccone [32]

Another prospective study for myeloma as part of first-line therapy, a donor versus no-donor analysis was performed of the patients treated in the HOVON-50 study [26]. This study allowed the patients with an HLA-identical sibling donor to proceed to the HOVON-54 study of allo-RIC between 2 and 6 months after ACST. Their results did not support allo-SCT as a frontline therapy.
