Autograft-Allograft Tandem Improves Multiple Myeloma Survival

TURIN, Italy, March 15 -- For patients with newly diagnosed multiple myeloma, a hematopoietic stem-cell autograft followed by an allograft from an HLA-identical sibling outperformed standard bone-marrow ablation and autografts, found investigators here.

Among 162 patients with multiple myeloma treated with induction chemotherapy and autologous stem-cell rescue, those who went on to have non-myeloablative total body irradiation and stem cell grafts from an HLA-identical sibling had significantly better overall survival and event-free survival.

Their overall survival and event-free survival exceeded that of patients treated with two courses of myeloblative melphalan, each followed by autologous stem cell grafts, reported Benedetto Bruno, M.D., Ph.D., of the University of Turin, and colleagues at the Fred Hutchinson Cancer Research Center in Seattle, in the March 15 issue of the New England Journal of Medicine.

"High-dose melphalan with rescue by autologous stem cells has become the standard treatment for young patients with myeloma," the authors wrote. "However, eradication of all malignant cells by this procedure is problematic. The curative potential of hematopoietic allografts presumably relies on an immune attack of donor cells against myeloma cells."

The investigators conducted a two-arm treatment study in which assignment of therapy was based solely on whether patients had HLA-identical siblings who were able to donate stem cells.

They enrolled 162 consecutive patients with newly diagnosed myeloma into the study. All the patients were 65 or younger, and had at least one living sibling.

All patients were initially treated with the VAD chemotherapy regimen, consisting of vincristine (Oncovin), doxorubicin (Adriamycin), and dexamethasone (Decadron), followed by melphalan (Alkeran) and autologous stem-cell rescue.

Those patients who had an HLA-identical sibling then received a standard hematopoietic stem-cell autograft, followed by a stem-cell allograft from the sibling. The autograft was delivered following a dose of melphalan at 200 mg/m², and the allograft was given after a course of non-myeloablative total body irradiation.

Those patients who had mismatched siblings -- as well as those who did not want the allograft because of the risks, and others whose HLA-matched donors were ineligible or unable to donate -- received two courses consisting of melphalan at 100 to 200 mg/m² followed by autologous stem cell grafts. This group also received 5 ?g of granulocyte-colony stimulating factor per kilogram from day one or three, until neutrophil counts above 1,000 per mm³ were reached.

The primary outcome measures were overall survival and event-free survival.

A total of 58 patients completed the autograft-allograft protocol, and 46 completed the double-autograft protocol.

At a median follow-up of 46 months (range 22 to 88 months), the median overall survival had not been reached in the group that received the allografts, whereas the median overall survival in the autograft-autograft group was 58 months (hazard ratio for autograft-allograft, 0.46, 95% CI, 0.23 to 0.93; P=0.03).

Event-free survival was 10 months longer among patients who received allografts, at 43 versus 33 months (hazard ratio, 0.63; 95% CI, 0.39 to 1.04; P= 0.07).

In a multivariate analysis of all patients who completed a hematopoietic stem-cell graft, the authors found that grafts from an HLA-identical sibling donor were associated with significantly longer overall survival (hazard ratio, 0.33; 95% CI, 0.14 to 0.80; P=0.01) and event-free survival (hazard ratio, 0.47; 95% CI, 0.27 to 0.83; P=0.009) compared with patients who underwent the high-dose-melphalan, double-autograft procedure.

Among the 104 patients who completed their assigned treatment protocols, there were no significant differences in treatment-related mortality, but patients in the double-autograft group were significantly more likely to die from disease than patients in the autograft-allograft group: 43% versus 7%, respectively (P<0.001).

The cumulative incidence rates of grades II, III, and IV graft-versus-host disease (GvHD) combined was 43% in the allograft group, and the incidence rate of grade IV GvHD was 4%.

In all, 21 of 58 patients (36%) in the autograft-allograft group were in complete remission after a median follow-up of 38 months (range 10 to 72 months); four patients in complete remission died of transplant-related causes.

In the double autograft group, at median of 53 months from diagnosis (range 21 to 88 months), and 36 months from the second autograft (range 15 to 69 months), 27 of 46 patients had had a relapse from a previous complete or partial remission, and four were in complete remission. Twenty-five of the 46 patients (54%) died.

The authors speculated that a graft-versus-disease effect may have given some of the patients a survival advantage.

"With a maximal follow-up period of seven years, we have seen only seven relapses among 32 patients in complete remission," they wrote. "There was no correlation between complete remission and the development of chronic GvHD. This phenomenon may be due to the non-myeloablative conditioning, which does not favor GvHD yet allows a graft-versus-myeloma effect."