Bruno B, Rotta M, Patriarca F, Mordini N, Allione B, Carnevale-Schianca F, Giaccone L, Sorasio R, Omedè P, Baldi I, Bringhen S, Massaia M, Aglietta M, Levis A, Gallamini A, Fanin R, Palumbo A, Storb R, Ciccone G, Boccadoro M. (San Giovanni Battista Hospital, University of Turin, Turin; University of Udine, Udine; Santa Croce e Carle Hospital, Cuneo; Santi Antonio e Biagio Hospital, Alessandria; Institute for Cancer Research and Treatment, Candiolo; Centro Prevenzione Oncologica Regione Piemonte, Turin, Italy; Fred Hutchinson Cancer Research Center, University of Washinton, Seattle, USA.) A comparison of allo-grafting with autografting for newly diagnosed myeloma.

N Engl J Med 2007;356:1110–20.

SUMMARY
This study compared autologous peripheral blood stem cell transplantation (ASCT, autograft) followed by reduced intensity allogeneic stem cell transplantation (allograft) from an HLA-identical sibling to the tandem ASCT (double autograft) in newly diagnosed patients of multiple myeloma. Two hundred and forty-five newly diagnosed, consecutive patients (age <65 years) were enrolled into this 5-centre study in Italy. The presence of an HLA-identical sibling was the only criterion for randomization. Among 245 patients, 199 had siblings; and 162 of these 199 underwent HLA typing to determine if they had potential HLA-identical donors. Eighty of 162 patients who had an HLA-identical sibling were assigned to ASCT followed by reduced intensity allogeneic stem cell transplantation (autograft–allograft group). The remaining 82 patients were assigned to double or tandem ASCT (autograft group). All patients initially received induction chemotherapy (vincristine, adriamycin and dexamethasone) and, following recovery from chemotherapy all patients underwent the first ASCT. Following ASCT, patients with an HLA-identical sibling donor (n=80) were advised reduced intensity allogeneic SCT within 1–3 months. Patients with no HLA-identical sibling (n=82) were advised a second ASCT. The overall and event-free survival were primary endpoints and an intention-to-treat analysis was done. Complete (CR) and partial response (PR), and relapse were defined as per standard criteria.
   Among 80 patients with an HLA-identical sibling, 15 refused allografting as first-line treatment and 5 did not have an eligible donor. Thus, 60 were assigned for the autograft–allograft treatment but only 58 completed treatment. Following recovery from ASCT, patients underwent allografting at a median of 94 days. Post-allograft, 32 (55%) achieved CR and 18 (31%) had PR. Overall, 21 of 58 patients (36%) were in CR after a median follow up of 38 months (range: 10–72 months). The cumulative incidence rates of grades II–III and IV acute graft-versus-host disease (GVHD) were 43% and 4%, respectively. Thirty-seven patients had evidence of chronic GVHD. The cumulative incidence of treatment-related mortality at 2 years was 10%.
   Of the 82 patients who did not have an HLA-identical sibling, 59 patients were assigned to receive a double autologus transplant. Of these, only 46 patients received a second autotransplant at a median interval of 123 days after the first transplant. Following the second transplant, 12 patients (26%) achieved CR and 29 (63%) had PR. After a median follow up of 36 months from the second transplant, 27 patients had relapsed and only 4 were in CR. The cumulative incidence of transplant-related mortality at 2 years was 2%.
   The overall response rates after induction chemotherapy and first autograft did not differ significantly between the 2 groups (p=0.74 and p=0.83, respectively). However, CR was significantly higher in the autograft–allograft group than in the double autotransplant group (55% v. 26%, p=0.004). The 2 groups did not differ significantly with respect to treatment-related mortality after a median follow up of 45 months (p=0.09) but disease-related mortality was significantly higher in the double autologous transplant group than in the autograft–allograft group (43% v. 7%, p<0.001). At a median follow up of 46 months (range: 22–88 months) the median overall survival was not reached in the autograft–allograft group and was 58 months in 46 patients who had completed double autografts (hazard ratio 0.46; 95% CI: 0.23–0.93; p=0.03). Multivariate analysis of all 104 patients who completed the assigned treatment revealed that patients in the autograft–allograft group had a significantly longer overall (p<0.01) and event-free survival (p<0.009) compared with those who received a double autograft.

COMMENT
High dose chemotherapy followed by ASCT is currently the standard treatment approach for newly diagnosed patients of multiple myeloma who are <65 years of age. A number of randomized studies have confirmed that this approach is associated with a higher complete remission (CR) rate, and improved event-free and overall survival compared with conventional chemo-therapy.1 Relapse (due to persistent disease or re-infusion of malignant plasma cells in the stem cell graft) is the main cause of failure following ASCT. The absence of a plateau in the survival curve following single ASCT has led investigators to explore ways of prolonging the duration of remission achieved with ASCT. These strategies include the use of maintenance therapy with interferon-a, low dose thalidomide post-ASCT, a second or double (tandem) ASCT, or mini- or reduced intensity allogeneic transplant.
   The prognosis of patients with multiple myeloma has improved during the past decade as a result of improved supportive care, newer drugs and the use of high dose chemotherapy followed by ASCT.1,2 Second or tandem autologous transplant within 1–6 months of recovery from first ASCT has been attempted to improve the CR rates and survival. Barlogie et al. were first to develop this concept of a second transplant.2 The results of 5 randomized trials3–7 have been reported recently.
   The CR rate was significantly superior in one study (p<0.002)7 and event-free survival was prolonged with double transplant compared with single transplant in 4 of 5 trials. However, overall survival was superior only in one study by the French group.3 Even in this study, divergence of the survival curve was seen at 4 years of follow up. On subgroup analysis, the benefit of a second transplant was more in patients with less than very good PR (<90% response).3 The overall survival at 7 years was 11% in the group receiving single against 43% in the group receiving double transplant (p<0.001). Results from these studies suggest that a second or double ASCT may be a reasonable option for younger patients with multiple myeloma who achieve less than very good PR with the first transplant or have high risk factors such as high b2 microglobulin and low serum albumin (<3.5g/dl), and chromosome 13 abnormalities.
   Allogeneic bone marrow transplantation (BMT) has the potential to eradicate the myeloma clone due to a graft-versus-myeloma effect by immunocompetent donor lymphocytes, resulting in a higher rate of molecular remission.8 However, the role of conventional or myeloablative allogeneic BMT in myeloma is limited due to (i) high transplant-related mortality (20%–40%) due to severe GVHD, (ii) availability of HLA-identical sibling donor for one-third of patients, and (iii) age (median age at diagnosis is 55–58 years, about 5%–10% of patients are young).
   This study compared double ASCT with initial ASCT followed by reduced intensity allogeneic stem cell transplant from an HLA-identical sibling donor. A reduced intensity allogeneic stem cell transplant is associated with a lower degree of myelosuppression, higher degree of immunosuppression, and lower frequency and severity of GVHD. It also allows a graft-versus-myeloma effect to occur while avoiding transplant-related mortality. Therefore, this approach has allowed such transplants to be done even in patients up to 65 years of age.9 The results of recent trials that include 320 patients show a median CR of 48.5% (range 10%–73%) with a median treatment-related mortality of 22% (range 0%–41%) and a median overall survival of 58% at 2–4 years follow up from the time of transplant.10–20 CR and survival rates are better when a planned, tandem, reduced intensity allogeneic transplantation is done.10,11,15 Crawley et al. for the European Group for Blood and Marrow Transplant (EBMT) registry have reported the results of 229 patients who underwent reduced intensity allogeneic stem cell transplants in 33 centres.21 The regimens varied widely but almost all utilized fludarabine with a large majority receiving low-dose total body irradiation, melphalan or cyclophosphamide. The transplant-related mortality at 1 year was 22%. The 3-year overall and progression-free survival was 41% and 21%, respectively, and 31% of patients had grade II–IV acute GVHD.
   Thus, reduced intensity allogeneic SCT seems to be an appropriate option for young patients with myeloma and high risk features. From the available literature and the results of this study it appears that the results are better if the transplant is done electively as a tandem–ASCT followed by allogeneic SCT from an HLA-identical sibling. The data on use of unrelated donors is too small to derive any definitive conclusion. A reduction in morbidity and mortality due to acute GVHD and judicious use of donor lymphocyte infusion to increase the graft-versus-myeloma effect (to reduce the risk of relapse) would be possible areas of future research.