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Background In this trial of the treatment of newly diagnosed multiple myeloma, we compared a protocol that entailed a hematopoietic stem-cell autograft followed by an allograft from an HLA-identical sibling with a protocol of tandem autografts.
Methods We enrolled 162 consecutive patients with newly diagnosed myeloma who were 65 years of age or younger and who had at least one sibling. All patients were initially treated with vincristine, doxorubicin, and dexamethasone, followed by melphalan and autologous stem-cell rescue. Patients with an HLA-identical sibling then received nonmyeloablative total-body irradiation and stem cells from the sibling. Patients without an HLA-identical sibling received two consecutive myeloablative doses of melphalan, each of which was followed by autologous stem-cell rescue. The primary end points were overall survival and event-free survival.
Results After a median follow-up of 45 months (range, 21 to 90), the median overall survival and event-free survival were longer in the 80 patients with HLA-identical siblings than in the 82 patients without HLA-identical siblings (80 months vs. 54 months, P=0.01; and 35 months vs. 29 months, P=0.02, respectively). Among patients who completed their assigned treatment protocols, treatment-related mortality did not differ significantly between the double-autologous-transplant group (46 patients) and the autograft–allograft group (58 patients, P=0.09), but disease-related mortality was significantly higher in the double-autologous-transplant group (43% vs. 7%, P<0.001). The cumulative incidence rates of grades II, III, and IV graft-versus-host disease (GVHD) combined and of grade IV GVHD in the autograft–allograft group were 43% and 4%, respectively. Overall, 21 of 58 patients (36%) were in complete remission after a median follow-up of 38 months (range, 10 to 72) after allografting. Of the 46 patients who received two autografts, 25 (54%) died.
Conclusions Among patients with newly diagnosed myeloma, survival in recipients of a hematopoietic stem-cell autograft followed by a stem-cell allograft from an HLA-identical sibling is superior to that in recipients of tandem stem-cell autografts. (ClinicalTrials.gov number, NCT00415987
[ClinicalTrials.gov]
.)
Methods
Patients
From September 1998 through July 2004, we enrolled 245 consecutive patients 65 years of age or younger with stage II or III myeloma at five Italian centers. Of these 245 patients, 199 had siblings, and 162 of the patients who had siblings underwent HLA typing to determine whether they had potential HLA-identical donors (Figure 1). Written informed consent was obtained on enrollment, and the study was approved by the institutional review boards of the five centers and conducted according to the procedures of the Declaration of Helsinki.
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All eligible patients received induction chemotherapy consisting of two or three courses of vincristine, Adriamycin (doxorubicin), and dexamethasone (VAD). Peripheral-blood stem cells mobilized by granulocyte colony-stimulating factor (G-CSF) were collected after the patient had recovered from VAD treatment and had received 3 to 4 g of cyclophosphamide per square meter of body-surface area, with or without 250 mg of paclitaxel per square meter. These cells constituted the autografts that were used in subsequent treatment. The eligibility criteria for the induction phase of VAD chemotherapy were a serum bilirubin level no higher than twice normal, serum alanine aminotransferase and aspartate aminotransferase levels no higher than four times normal, a left ventricular ejection fraction of at least 40%, a creatinine clearance of at least 40 ml per minute, and a Karnofsky performance score of at least 60%.
Patients with an HLA-identical sibling (mean age of the siblings, 54 years; range, 35 to 69) were offered the induction protocol described above followed by a standard hematopoietic stem-cell autograft, which was to be followed by a stem-cell allograft from the sibling. The autograft was to be administered after a dose of 200 mg of melphalan per square meter; the allograft was to be administered after preparation with nonmyeloablative total-body irradiation.11 This group will be referred to as the autograft–allograft group.
Recovery from the initial autografting, which usually occurred 2 to 4 months after the procedure, was defined by resolution of mucositis, the absence of detectable cytomegalovirus antigen in the blood, and the absence of a need for intravenous medications. Recovered patients were prepared for allografting with a nonmyeloablative dose of 200 cGy of total-body irradiation on day 0. Hematopoietic stem cells were mobilized from the sibling's blood by administering G-CSF at a dose of 16 µg per kilogram of body weight from day –4 to day 0, with apheresis on days –1 and 0. Both collections of nucleated cells were infused immediately after the radiotherapy (day 0). After infusion of the allogeneic cells, mycophenolate mofetil and cyclosporine were administered.11 Analysis of hematopoietic chimerism was performed as previously described.11 Patients who did not have graft-versus-host disease (GVHD) but who had a relapse or progression of disease after receiving the allograft were allowed to receive infusions of lymphocytes from the donor. Standard criteria were used for the diagnosis and clinical grading of acute and chronic GVHD.13,14
Patients without an HLA-identical sibling and those who refused allografting or whose donor was ineligible were assigned to double autologous transplantation after receiving intermediate doses (100 mg per square meter) or high doses (140 to 200 mg per square meter) of melphalan. They received 5 µg of G-CSF per kilogram from day 1 or 3 until neutrophil counts above 1000 per cubic millimeter were achieved. This group will be referred to as the double-autologous-transplant group.
Criteria for Response
The criteria for complete remission were the absence of detectable monoclonal immunoglobulin in serum and of discernible light chains in urine by standard electrophoresis, the absence of visible monoclonal bands on immunofixation, less than 1% plasma cells in marrow aspirates, the absence of evidence of clonal disease according to flow cytometry of marrow cells, and the absence of an increase in the size or number of osteolytic lesions. Partial remission was defined as a reduction of at least 75% in monoclonal immunoglobulin in serum, a reduction of at least 90% in 24-hour urinary light-chain excretion, no increase in the size or number of osteolytic lesions, and no increase in infiltration of the bone marrow by plasma cells.
The disease was considered refractory in patients with less than a partial remission after induction chemotherapy or autografting; the disease was considered stable if neither complete nor partial remission was observed after allografting. The response criteria had to be met on two occasions at least 6 weeks apart. Progressive disease was defined as an increase of at least 25% in serum monoclonal immunoglobulin or urinary light chains in patients with refractory or stable disease.
For patients in complete remission, relapse was defined as the reappearance of plasma cells in the marrow, the reappearance of monoclonal immunoglobulin in the serum or light chains in the urine, or the appearance of new bone lesions; for patients in partial remission, relapse was defined as a 25% increase in any disease marker. The patients were assessed for response before each treatment, monthly for the first 6 months after transplantation, and at least every 3 months thereafter, or as clinically indicated.
Statistical Analysis
The primary end points were overall survival and event-free survival from the time of diagnosis. The analyses were performed according to the intention-to-treat principle. The secondary end points included overall survival and event-free survival, disease response, and transplant-related death in patients in whom the procedure was completed. Overall survival from the date of diagnosis until the date of death from any cause was estimated according to the Kaplan–Meier method; event-free survival was estimated from the date of diagnosis until the date of disease progression, relapse, or death from any cause.15 Estimates of the incidence rates of acute and chronic GVHD and of treatment-related mortality were made according to the cumulative incidence method of Gooley et al.16 The significance of differences between curves of treatment-related mortality was assessed with Gray's test.17 Deaths not related to relapse of myeloma or to nonhematologic cancers were classified as transplant-related deaths.
Proportions were compared between groups with the use of Fisher's exact test. To assess differences in overall survival and event-free survival, hazard ratios and corresponding 95% confidence intervals (CIs) were estimated with the use of the Cox proportional-hazards method.18 All P values in regression models were determined with the use of the Wald test. To check the assumptions of the proportional-hazards model, an interaction term between the group variable and a log function of time was included in both the overall survival and the event-free survival models; the assumptions were always satisfied. In addition to the presence or absence of an HLA-identical sibling, all multivariate models included age; sex; disease stage; serum level of β2-microglobulin, albumin, lactate dehydrogenase, and creatinine; platelet count at diagnosis; and the isotype of the myeloma protein. Standard prognostic factors were dichotomized in accordance with the International Staging System for multiple myeloma.19 Follow-up ended on June 1, 2006. SAS software, version 8.2, and R 2.1.0 software, package cmprsk, were used.
Results
Patients and Treatment Assignments
Figure 1 shows the design of the trial. Table 1 shows the characteristics of the patients; 162 of 199 patients and their siblings underwent HLA typing (Figure 1), and 80 of the 162 patients had an HLA-identical sibling. Of these 80 patients, 15 refused allografting and 5 had ineligible sibling donors; the remaining 60 were assigned to the autograft–allograft group, and 58 of them completed the protocol (Figure 1).
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Responses and Transplant-Related Mortality
Autograft–Allograft Protocol
After receiving total-body irradiation (200 cGy), 58 of the 60 patients who were assigned to the autograft–allograft group received an infusion of allogeneic stem cells at a median of 94 days after receiving 200 mg of melphalan per square meter and an autologous hematopoietic cell transplant. Two patients in this group became ineligible after assignment because of disease-related renal failure requiring dialysis before autografting. In all 58 patients who received an allograft, complete donor hematopoietic chimerism was found by day 84.
Of the 58 patients who completed the autograft–allograft protocol, 3 were in complete remission and 29 were in partial remission at the time of allografting, whereas 8 were in complete remission and 36 were in partial remission at the time of allografting. Of these 58 patients, 32 (55%) had a complete remission and 18 (31%) had a partial remission after allografting. At a median follow-up time of 46 months from diagnosis (range, 23 to 85) and 37 months from receipt of the allograft (range, 10 to 72), 7 of the 32 patients with a complete remission and 6 of the 18 with a partial remission had had a relapse. Overall, 11 of 58 patients (19%) received postgrafting donor lymphocyte infusions at a starting dose of 1x106 T cells per kilogram of body weight for relapse or progressive disease, but only 4 had a transient partial remission. Overall, 21 of 58 patients (36%) were in complete remission after a median follow-up of 38 months (range, 10 to 72) from allografting. Four patients in complete remission died of transplant-related causes.
Acute grade II, III, or IV GVHD developed in 25 of the 58 patients at a median of 40 days (range, 22 to 115) after allografting. Two of these patients had grade IV disease. The cumulative incidence rates for grade II, III, and IV GVHD and for grade IV GVHD were 43% and 4%, respectively (Figure 2A). Extensive chronic GVHD developed in 21 patients, with a cumulative incidence of 32% at 2 years (Figure 2B). Chronic GVHD developed in 22 of 32 patients in complete remission and in 15 of 26 patients who were not in complete remission. There was no association between the clinical response to therapy and either acute GVHD (P=0.72) or chronic GVHD (P=0.44). Thirty-six of 50 patients were receiving immunosuppressive therapy at 1 year after allografting, 19 of 36 at 2 years, and 5 of 10 at 4 years. Most of these patients had a Karnofsky performance score of 90 to 100.
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Double-Autologous-Transplant Protocol
All 59 patients in the group assigned to receive a high dose of melphalan and a double autologous transplant received the first autologous transplant, but only 46 received the second (at a median of 123 days after the first transplant). Of the 13 patients who received only the first transplant, 4 had disease progression, 3 had disease-related renal failure, 1 had transplant-related adverse effects, 3 withdrew consent, and 2 had poor mobilization of peripheral-blood stem cells.
Of the 46 patients who received two autografts, 1 had entered a complete remission and 22 had entered a partial remission after the induction chemotherapy that was given before the first autograft. Before receiving the second autograft, 4 patients were in complete remission and 31 were in partial remission. Eleven patients had refractory disease. After the second transplant, 12 patients (26%) had a complete remission and 29 (63%) had a partial remission. At a median follow-up time of 53 months from diagnosis (range, 21 to 88) and 36 months from the second transplant (range, 15 to 69), 27 patients had had a relapse from a previous complete or partial remission, and only 4 were in complete remission.
Twenty-five of the 46 patients died: 21 from disease progression, 1 from transplant-related invasive aspergillosis, 1 from gallbladder cancer, and 2 from complications during salvage treatments. The cumulative incidence of treatment-related mortality at 2 years was 2% (Figure 2C).
The overall response rates (complete remission plus partial remission) after induction chemotherapy and after the first autograft did not differ significantly between the two groups (P=0.74 and P=0.83, respectively). However, the rate of complete remission was significantly higher in the autograft–allograft group than in the double-autologous-transplant group (55% vs. 26%, P=0.004). The two 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% vs. 7%, P<0.001) (Figure 2D).
Survival
On June 1, 2006, at a median follow-up period of 45 months (range, 21 to 90), the median overall survival for all 245 patients was 63 months, and there were no significant differences in overall survival between the 162 HLA-typed patients, the 37 non–HLA-typed patients, and the 46 patients without siblings (P=0.98) (Figure 3A and 3B). Prognostic factors were evenly distributed in all groups (Table 1).
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Table 2 and Figure 3C and 3D show that, according to intention-to-treat analyses, median overall survival and event-free survival were significantly longer in patients with an HLA-identical sibling, regardless of the treatment received, than in patients without such a sibling: 80 versus 54 months (hazard ratio, 0.51; 95% CI, 0.30 to 0.86; P=0.01) and 35 versus 29 months (hazard ratio, 0.63; 95% CI, 0.43 to 0.92; P=0.02), respectively. Univariate and multivariate analyses of overall and event-free survival in all 162 patients with a sibling and the 104 patients who completed their assigned protocols included as variables age; sex; serum levels of β2-microglobulin, albumin, lactate dehydrogenase, and creatinine; platelet count; and the isotype of the myeloma protein (Table 2). The availability of an HLA-identical sibling and, therefore, the possibility of receiving an allograft were significantly associated with longer overall survival (hazard ratio, 0.35; 95% CI, 0.19 to 0.64; P=0.001) and event-free survival (hazard ratio, 0.54; 95% CI, 0.35 to 0.81; P=0.003) (Table 2). In a stratified analysis that classified patients with high β2-microglobulin levels or with chromosome 13 abnormalities as being at high risk, the adjusted hazard ratios were 0.34 (95% CI, 0.10 to 1.18) for overall survival and 0.52 (95% CI, 0.22 to 1.21) for event-free survival; these ratios were similar to those for all 162 patients combined.
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At a median follow-up of 46 months (range, 22 to 88), the median overall survival had not been reached in the group of 58 patients who had completed the autograft–allograft protocol and was 58 months in the 46 who had completed the double-autologous-transplant protocol (hazard ratio, 0.46; 95% CI, 0.23 to 0.93; P=0.03) (Figure 3E). Event-free survival was 43 and 33 months, respectively, in the two groups (hazard ratio, 0.63; 95% CI, 0.39 to 1.04; P=0.07) (Figure 3F). Multivariate analysis of all 104 patients who completed a hematopoietic stem-cell grafting procedure showed that patients who received a hematopoietic stem-cell graft from an HLA-identical sibling donor had 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) than patients who underwent the high-dose-melphalan, double-autologous-transplant procedure (Table 2).
Discussion
We investigated a protocol for the treatment of multiple myeloma that began with VAD chemotherapy followed by melphalan, with rescue of the hematopoietic system by an autologous stem-cell transplant. After recovering from the autologous stem-cell transplantation, patients with an HLA-identical sibling received total-body irradiation with rescue of the marrow by allogeneic hematopoietic stem cells from the sibling. The outcome of this three-part procedure was compared with that of a protocol in patients who lacked an HLA-identical sibling, in which the patient first received the same VAD chemotherapy and underwent the same first autologous-transplant procedure but then received a high dose of melphalan and a second autologous transplant. Overall survival and event-free survival were significantly longer in the first group than in the second group (P=0.001 and P=0.003, respectively). The novel feature of this study is the assignment of treatment according to a single criterion: the presence or absence of an HLA-identical sibling donor. This type of genetic randomization has been applied to the assessment of outcomes in patients with hematologic disorders who were treated with allografting or other therapies.21,22,23,24 A comparison by the intention-to-treat principle of outcomes in consecutive patients who were enrolled in the study on the sole criterion of having a sibling, either HLA-identical or not, is a surrogate for an unbiased randomization.
The median overall survival of all 245 patients who were enrolled in this study was more than 5 years. Overall survival and event-free survival were significantly longer (P=0.01 and P=0.009, respectively) in patients who completed the autograft–allograft protocol than in patients who completed the high-dose, double-autograft protocol. Nineteen percent of the eligible patients refused the autograft–allograft protocol, mostly because of concerns about the high transplant-related mortality previously reported for myeloablative conditioning.6,7,8,9
High-dose melphalan with rescue by autologous stem cells has become the standard treatment for young patients with myeloma.1,2,3,4 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.25,26,27 In the Intergroup Trial S9321,28 the study design included myeloablative allografting for patients 55 years of age or younger with a suitable sibling donor. The treatment option was discontinued early in this group of patients because of a transplant-related mortality rate of 53%. However, 22% of the patients in this group were alive and free of disease progression 7 years after allografting.
In our study, the frequency of deaths that were unrelated to relapse was low in both groups; GVHD and its complications accounted for most treatment-related mortality in the autograft–allograft group. A regimen of total lymphoid irradiation (800 cGy total) plus antithymocyte globulin can decrease the incidence of GVHD after allogeneic stem-cell transplantation to 3% without impairing graft-versus-tumor activity.29 This immunosuppressive protocol may cause a greater reduction in the alloreactivity of donor CD4+ T cells than would a single dose of total-body irradiation (200 cGy).
With a maximal follow-up period of 7 years, we have seen only seven relapses among 32 patients in complete remission. There was no correlation between complete remission and the development of chronic GVHD. This phenomenon may be due to the nonmyeloablative conditioning, which does not favor GVHD yet allows a graft-versus-myeloma effect.
Comparison of our results with the outcomes of other reduced-intensity conditioning protocols is difficult, since the preparative regimen and the intensity of immune suppression after allografting are pivotal in treating myeloma. Garban et al. did not find an advantage of allografting over melphalan-based autografting in patients with high-risk myeloma (i.e., those with an elevated β2-microglobulin level plus chromosome 13 abnormalities).30 This study, unlike ours, did not enroll patients who were at intermediate or good risk, nor were additional prognostic factors evaluated by intention-to-treat analysis. Furthermore, the potent pretransplantation immune suppression with antithymocyte globulin used in the study of Garban et al. may have prevented graft-versus-myeloma effects. In our study, neither chromosome 13 abnormalities nor β2-microglobulin levels appeared to affect the outcome after allografting.
Supported in part by Progetti di Ricerca ex-60% (Ministero dell'Università e della Ricerca Scientifica); Regione Piemonte Ricerca Finalizzata 2005 (Progetto Clinico-scientifico e di Coordinamento Regionale); Compagnia di San Paolo; Fondazione Cassa di Risparmio di Torino and Comitato Regionale Piemontese Gigi Ghirotti (Progetto Vita Vitae); Fondazione Neoplasie Sangue Onlus; and a grant (CA78902) from the National Cancer Institute.
No potential conflict of interest relevant to this article was reported.
We thank the nurses and medical staff for caring for the patients, the data coordinators for collecting the study and follow-up information, and Dr. John Iliffe for his critical reading of the manuscript and thoughtful suggestions.
Source Information
From San Giovanni Battista Hospital, University of Turin, Turin (B.B., M.R., L.G., R. Sorasio, P.O., S.B., M.M., A.P., M.B.); the University of Udine, Udine (F.P., R.F.); Santa Croce e Carle Hospital, Cuneo (N.M., A.G.); Santi Antonio e Biagio Hospital, Alessandria (B.A., A.L.); the Institute for Cancer Research and Treatment, Candiolo (F.C.-S., M.A.); and San Giovanni Battista Hospital and Centro Prevenzione Oncologica Regione Piemonte, Turin (I.B., G.C.) — all in Italy; and the Fred Hutchinson Cancer Research Center, University of Washington, Seattle (R. Storb).
Address reprint requests to Dr. Bruno at the Divisione Universitaria di Ematologia, Azienda Ospedaliera San Giovanni Battista, Via Genova 3, Turin 10126, Italy, or at benedetto.bruno{at}unito.it.
References
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Related Letters:
Allografting or Autografting for Myeloma
van Rhee F., Crowley J., Barlogie B., Rajkumar S. V., Kyle R. A., Moreau P., Harousseau J.-L., Attal M., Bruno B., Ciccone G., Boccadoro M.
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N Engl J Med 2007;
356:2646-2648, Jun 21, 2007.
Correspondence
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