This symposium covered three major topics: the comparison between single and double transplants, evaluation of residual disease, and allogeneic transplantation including analysis of the role of donor-lymphocyte infusions (DLI) and nonmyeloablative (mini-allogeneic) transplants.
Dr. Harousseau discussed best-option conditioning regimen. Based on his data, high-dose melphalan alone is superior to the combination of melphalan and total body irradiation (TBI) in terms of reduction in days of neutropenia and thrombocytopenia, transfusion, and days of hospitalization. There is also a trend favoring melphalan alone in response rate and survival. At present, the French group is exploring new conditioning regimens with higher doses of melphalan or a combination with anti-interleukin-6.
The comparison of one versus two autologous transplants was addressed in three presentations from French, Italian and Dutch groups. Dr. M. Attal analyzed the results of the Inter Groupe Francais du Myéloma, which included 400 patients less than 60 years of age with double randomization. The first randomization compared one transplant conditioned with melphalan (140 mg/m2) plus TBI (8 Gy) with two transplants, one conditioned with melphalan only (140 mg/m2) and the other identical to the first group. The second randomization compared the use of bone marrow versus peripheral blood (PB) stem cells. The results showed that double transplant supported with PB stem cells improves response rate, event-free survival (EFS), and overall survival (OS). The achievement of complete response (CR) or very good partial response was the most important prognostic factor. Regarding the current strategies of the French group, they have decided to stratify patients at diagnosis based on the level of B2-microglobulin and cytogenetics (deletion of chromosome 13). For low-risk patients, they will use a double transplant and then randomly compare thalidomide and pamidronate as maintenance therapy. For high-risk patients, they will intensify the dose of melphalan (220 mg/m2), or, if a sibling donor is available, the second transplant will be allogeneic.
A total of 320 patients were enrolled in the Italian study ("Bologna 96"). The randomization was one transplant with melphalan (200 mg/m2) versus two transplants (the first with the same regimen and the second with melphalan 120 mg/m2 plus Busulfan 12 mg/kg). The results failed to show significant differences in CR and OS rates. In contrast, patients receiving two transplants enjoyed longer EFS.
The Dutch-Belgian (HOVON) study is slightly different, since in one arm they use intermediate but nonmyeloablative doses of melphalan (two pulses of 70 mg/m2) without stem cell support, and in the other arm they use the same regimen followed by myeloablative treatment with cyclophosphamide (12 mg/kg) and TBI. Although 453 patients have been enrolled into the study, only 255 have so far been randomized after the initial four courses of VAD. The preliminary results show that there were no significant differences between the two arms for response rate, OS, or EFS.
It could be concluded that, although so far the benefit of double transplant is not clear and some of the studies presented require longer follow-up, at least two of the three studies demonstrated a prolongation of disease control (EFS). In addition, it should be mentioned that transplant-related mortality (TRM) was very low (<5%) in all three studies.
The second topic was the evaluation of residual disease. Dr. Robert Vescio, of Cedars-Sinai Comprehensive Cancer Center discussed why we need more sensitive techniques for following tumor burden. He concentrated on the value of molecular measurements of residual disease, using the pattern of immunoglobulin gene rearrangement as the patient-specific tumor marker and a highly sensitive polymerase chain reaction technique. He has observed that tumor burden rarely fell more than 2 logs after transplantation and that in most patients' residual disease persists at the molecular level. Dr. Vescio reported that changes from baseline (pretransplant) in circulating tumor burden correlated with disease relapse; he concluded that molecular monitoring may help evaluate maintenance therapy programs, which will be needed to further improve treatment outcome in multiple myeloma (MM).
Dr. Jesus San Miguel discussed the role of multiparametric flow cytometry immunophenotyping for evaluation of changes in plasma cell (PC) compartments following treatment. This technique allows discrimination between normal and malignant PCs. Compared with chemotherapy, autologous transplantation produced a significantly higher reduction in the number of myelomatous PCs together with a higher recovery of normal PCs. Moreover, while in MM patients at diagnosis normal PCs are almost absent (<5%), after treatment some patients showed more than 30% of total PCs phenotypically normal and had longer progression-free survival. Accordingly, it can be concluded that this new method allows a sensitive evaluation of the PC compartment and that, in MM patients, the recovery of high percentages of normal PCs (a pattern similar to that observed in patients with monoclonal gammopathy of undetermined significance) is associated with a favorable outcome.
Three other presentations discussed the role of allogeneic transplantation. First, Dr. Gösta Gahrton analysed experience reported by the European Bone Marrow Transplant Group. The data indicate a marked improvement over the years both in the reduction of TRM (from 46% to 30%) and in OS (from 32% to 50% at 4 years). Another relevant change was the shift from bone marrow to PB stem cells. Although the latter has a clear benefit in terms of more rapid engraftment, it is not so clear whether the survival benefit is any better when PB is used. Dr. Gahrton discussed 54 patients transplanted with non-myeloablative regimens. Although follow-up is too short, the potential efficacy of this strategy, which is associated with reduced toxicity and TRM, is evident. Recently, a Phase II/III study including autologous transplantation followed by mini-allogeneic transplantation has begun.
Dr. Lokhorst from Utrecht University addressed the graft-versus-myeloma (GVM) effect induced by DLI in 39 MM patients relapsing after allogeneic transplantation. The overall response rate was 52%, including 22% CR. Based on these data, he concluded that the GVM effect has curative potential. In the new HOVON trial, patients who undergo allogeneic stem cell transplantation are randomized between pre-emptive DLI 6 months after transplant and DLI administered in the event of relapse.
Finally, Dr. William Bensinger of the Fred Hutchinson Cancer Center reported on the Seattle experience with non-ablative allogeneic transplants. The conditioning regimen is based on their canine model and uses a very low dose of TBI (200c Gy) together with fludarabine. This drug was introduced because they observed a high rejection rate in patients conditioned with TBI alone. At present they are using a "tandem" transplant approach in which patients initially undergo autologous transplant (to provide cytoreduction with low morbidity) and then receive a mini-allogeneic transplant, 2 to 4 months after the autotologous transplant, to exploit the GVM effect. So far, 32 patients have received transplants: 53% achieved CR and 81% are alive, with TRM of only 19%. Although the results seem encouraging, the incidence of chronic graft-versus-host disease is of concern, and longer follow-up is needed to define the long-term outcome for patients receiving non-myeloablative allogeneic transplants.