**3. Tandem autologous vs Allo-RIC transplantation**

Recent trials have compared tandem auto-allo HSCT with a tandem autologous modality (Table 2). The IFM initiated two trials in high-risk (β-2 microglobulin level greater than 3 mg/ L and chromosome 13 deletion at diagnosis) de novo multiple myeloma [27]. Patients with an HLA-identical sibling donor were randomized with allo-RIC arm following 1st ASCT (IFM99-03) (n=65), and patients without an HLA identical sibling donor were randomly assigned to undergo 2nd ASCT with or without anti-IL-6 monoclonal antibody (IFM99-04) (n=219). In IFM99-03 trial, 46 patients completed the entire program. When compared the OS and EFS between two trials, IFM99-03 and 04 did not significantly differ (OS: 35 months versus 41 months, p=.27; 25 months vs 30 months, p=.56). IFM group submitted the updated results in 2008 [28]. When the results of patients in IFM99-04 were compared with those of the 46 patients completed the tandem ASCT/Allo-RIC program, there was a trend of better OS for ASCT followed by allo-RIC transplantation (47.2 months vs 35 months, p=.07). As they compared of the results of the 166 patients out of 219 who completed the whole tandem ASCT protocol with those of the 46 patients out of 65 who underwent the entire auto/allo-RIC program, no difference was observed regarding EFS (median 25 vs 21 months, p=.88), but there was a trend for a superior OS in favor of double ASCT (57 vs 41 months, P =.08), due to a longer survival after relapse in the tandem ASCT arm.

These findings suggest that patients with high-risk myeloma did not benefit from a mini-allo transplantation following ASCT in comparison of tandem ASCT.


**Abbreviations:** CR: Complete Remission; PFS: Progression-Free Survival; EFS: Event-Free Survival; OS: Overall Survival; TRM: Transplant-Related Mortalitiy; TBI: Total Body Irradiation; ATG: Anti-Thymocyte Globulin

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

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

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

Recent trials have compared tandem auto-allo HSCT with a tandem autologous modality (Table 2). The IFM initiated two trials in high-risk (β-2 microglobulin level greater than 3 mg/ L and chromosome 13 deletion at diagnosis) de novo multiple myeloma [27]. Patients with an HLA-identical sibling donor were randomized with allo-RIC arm following 1st ASCT (IFM99-03) (n=65), and patients without an HLA identical sibling donor were randomly assigned to undergo 2nd ASCT with or without anti-IL-6 monoclonal antibody (IFM99-04) (n=219). In IFM99-03 trial, 46 patients completed the entire program. When compared the OS and EFS between two trials, IFM99-03 and 04 did not significantly differ (OS: 35 months versus 41 months, p=.27; 25 months vs 30 months, p=.56). IFM group submitted the updated results in 2008 [28]. When the results of patients in IFM99-04 were compared with those of the 46 patients completed the tandem ASCT/Allo-RIC program, there was a trend of better OS for ASCT followed by allo-RIC transplantation (47.2 months vs 35 months, p=.07). As they compared of the results of the 166 patients out of 219 who completed the whole tandem ASCT protocol with those of the 46 patients out of 65 who underwent the entire auto/allo-RIC program, no difference was observed regarding EFS (median 25 vs 21 months, p=.88), but there was a trend for a superior OS in favor of double ASCT (57 vs 41 months, P =.08), due to a longer

These findings suggest that patients with high-risk myeloma did not benefit from a mini-allo

**3. Tandem autologous vs Allo-RIC transplantation**

survival after relapse in the tandem ASCT arm.

transplantation following ASCT in comparison of tandem ASCT.

patients achieving CR.

168 Multiple Myeloma - A Quick Reflection on the Fast Progress

frontline therapy.

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

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 availability of HLA-identical donor. There was a higher increase in CR rate (40% vs 11%, p=. 001) and a trend toward a longer PFS (p=.08) in favor of tandem auto-allo transplantation. In contrast, TRM was higher in the tandem auto-allo transplantation (16% vs 5%, p=.07), EFS and OS was not significantly different between 2nd ASCT and allo-RIC.

Immunomodulatory agents, thalidomide or lenalidomide have both have T cell and NK cell activity [39]. Effect of low dose thalidomide after allo-SCT was evaluated in the French study and found that 13 of 31 patients responded [40]. Nineteen percent of patients stopped treatment due to toxicity. Although thalidomide is used for treatment of GvHD, authors observed GvHD in the follow up of 5 patients. Kröger et al, showed improved responses with low dose thalidomide followed by DLI in patients who were refractory to sole DLI [41]. Lenalidomide increased the frequency of human leukocyte antigen-DR (+) T cells and regulatory T cells. Improved response rates were reported with lenalidomide with / without dexamethasone for relapsed/refractory patients [42,43]. Recently, HOVON group investigated maintenance of lenalidomide after allo-SCT; it is not found a feasible treat‐

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

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The use of proteasome inhibitor, bortezomib for in vitro depletion of alloreactive T cells after allo-SCT can control GvHD [45]. In retrospective analyses bortezomib administration in relapse or progression of MM after allo-HSCT was shown to be effective treatment without

The role and timing of allo SCT still cannot be defined clearly. Due to high TRM rates, myeloablative conditioning in allo-SCT has shifted to reduced intensity conditioning. The studies can be summarized as: (1) -early-day 100 TRM as low as 0 -20%, (2) Acute grade II-IV GvHD and chronic GvHD rates as 30 to 70%, (3) chemosensitivity prior to the transplantation as main factors of survival after transplantation (4) negative PFS effects of in vitro T cell

Most of the studies were performed in the relapsed/refractory setting and currently there is no strong data to support allo-RIC as part of a frontline therapy. Reduction of tumor burden by high dose therapy with autologous stem cell rescue has found to have impacts on the transplant outcome and these results brought the comparative studies of auto/auto vs auto/ allo transplantation. There are contradictory results in this era and lack of strong evidence to

Relapse after allo RIC transplantation is still a remaining problem to be solved. Introduction of novel agents such as bortezomib, thalidomide, and lenalidomide with/without DLI(s) can

In conclusion, allo-SCT has been recognized as a potential therapeutic modality in MM, especially since the introduction of RIC regimens and the use of a tandem auto-allo transplants has shown promise by reducing the TRM and inducing high CR rates. Nevertheless, long-term control of the disease remains a key issue, even in patients treated first by RIC allo-SCT. The role of allo-SCT should be re-evaluated when taking into consideration of promising effects of

novel agents in myeloma treatment in randomized clinical trials.

ment due to induction of GvHD [44].

worsening of GVHD symptoms (46).

depletion with Alemtuzumab or other(s).

support one to the other procedure.

provide solutions to this problem.

**5. Conclusion**

The Blood and Marrow Transplant Clinical Trials Network reported a multicenter phase III trial (BMT CTN 0102) in which patients were biologically assigned based on the availability of a matched related donor to either tandem ASCT using melphalan 200sqm or tandem autoalloHCT using melphalan 200 sqm followed by alloHCT with 2 Gy TBI [31]. Among the 710 patients enrolled between 2003 and 2007 from 37 US centers, 625 patients had standard risk. Patients assigned to receive an ASCT followed by an allo-SCT or tandem ASCT on the basis of the availability of an HLA-matched sibling donor. The study showed no difference of median estimated PFS and OS in comparison of double auto with tandem auto-allo.

Recently, the long-term results of a trial in which treatment of newly diagnosed myeloma patients (n=245) was based on the presence or absence of HLA-identical donor was reported from Italy [32]. Patients with HLA-identical siblings were offered by a standard autograft with high-dose melphalan (200sqm) followed by an allograft with NMA TBI (2 Gy) (n=82), while patients without HLA-identical siblings were assigned to double ASCT after intermediatedose (100 sqm) or high-dose (140-200 sqm) melphalan (n=80). At a median follow-up of 7.1 year, both OS and EFS were significantly longer in patients with HLA-identical siblings than those without, and median OS and EFS remained significantly longer in the patients trans‐ planted with tandem auto-allo than those patients treated double ASCT. This comparative study showed that allograft conferred a long-term survival and disease-free survival advant‐ age over standard autografting.

## **4. Post-transplant approaches**

High rate of CR after allo-SCT was reported in above studies. But relapse still seems to be a remaining problem. The importance of molecular remission on long-term disease control has been mentioned in the studies of allogeneic transplantation with MAC or RIC regimes. Therefore, post-transplant strategies for preventing and treatment of relapse/refractory disease are of clinical importance. The role of adaptive immunotherapy, donor lymphocyte infusion (DLI), and novel agents has been assessed in several studies.

Donor lymphocyte infusion can enhance GvM and also induce graft versus host disease (GvHD) rates [33,34] Van de Donk, et al evaluated DLIs given in eight European transplan‐ tation centers for relapsed (n=48) or persistent (n=15) myeloma following NMA allo-SCT [35]. Overall response was 38%, acute GvHD was 38% and chronic GvHD was 42%. The development of GvHD and response to DLI seems to be associated with GvM effect, and durable remissions are restricted to a minority of patients who achieve CR in this retrospec‐ tive evaluation. Escalating doses of DLI were found to have lower GvHD risk and better survival rates [36-38].

Immunomodulatory agents, thalidomide or lenalidomide have both have T cell and NK cell activity [39]. Effect of low dose thalidomide after allo-SCT was evaluated in the French study and found that 13 of 31 patients responded [40]. Nineteen percent of patients stopped treatment due to toxicity. Although thalidomide is used for treatment of GvHD, authors observed GvHD in the follow up of 5 patients. Kröger et al, showed improved responses with low dose thalidomide followed by DLI in patients who were refractory to sole DLI [41]. Lenalidomide increased the frequency of human leukocyte antigen-DR (+) T cells and regulatory T cells. Improved response rates were reported with lenalidomide with / without dexamethasone for relapsed/refractory patients [42,43]. Recently, HOVON group investigated maintenance of lenalidomide after allo-SCT; it is not found a feasible treat‐ ment due to induction of GvHD [44].

The use of proteasome inhibitor, bortezomib for in vitro depletion of alloreactive T cells after allo-SCT can control GvHD [45]. In retrospective analyses bortezomib administration in relapse or progression of MM after allo-HSCT was shown to be effective treatment without worsening of GVHD symptoms (46).
