Medical Transplantation - The Best Place to Be Diagnosed With Kidney Cancer

Transcription

1 DOI: /annonc/mdf638 High-dose therapy in multiple myeloma J.-L. Harousseau Centre Hospitalier Universitaire, Service d Hématologie, Nantes, France Autologous stem cell transplantation The role of autologous stem cell transplantation in multiple myeloma In the absence of significant improvement of conventional chemotherapy (CC), high-dose therapy (HDT) with autologous stem cell transplantation (ASCT) has been increasingly used in the past 15 years in multiple myeloma (MM) [1]. Uncontrolled studies have shown that, for patients responding to initial induction chemotherapy, ASCT is a safe (<5% toxic deaths) and effective consolidation therapy [2]. Most importantly, some of these studies have suggested that levels of 30 50% complete remission (CR) could be achieved with this approach in newly diagnosed MM and that this more important tumor burden reduction could be converted into a prolongation of remission and of survival [2]. However, these pilot studies are difficult to analyze because the recruitment of patients was subject to selection bias regarding age, performance status, renal function and response to initial chemotherapy. One retrospective analysis has suggested that survival of patients <65 years of age responding to initial chemotherapy and receiving only CC was similar to that reported in selected series of patients given early HDT [3]. However, in three historical comparisons, HDT appeared superior to CC (Table 1) [4 6]. The Intergroupe Français du Myelome (IFM) was the first group to conduct a randomized trial showing the superiority of HDT with autologous bone marrow transplantation (ABMT) as compared with CC [7]. In this IFM 90 trial, HDT significantly improved the response rate since 38% of patients enrolled in the HDT arm achieved a CR or a very good partial remission (VGPR) versus 14% of patients enrolled in the CC arm (P <0.001). An updated analysis of this study confirms that, with a median follow-up of 7 years, HDT significantly improves event-free survival (EFS) (median 28 months versus 18 months; 7-year EFS 16% versus 8%, P = 0.01) and overall survival (OS) (median 57 months versus 44 months; 7-year OS 43% versus 25%, P = 0.03). Other randomized studies have compared CC and HDT with autologous transplantation (Table 2). In the trial performed by the French Myelome Auto Grafte (MAG) group, 190 patients aged from 55 to 65 years were randomized to receive CC or HDT [8]. Although the results of HDT appeared Table 1. Conventional chemotherapy versus high-dose therapy: historical comparisons No. of patients Age (years) Median survival (months) P value CC HDT Barlogie et al. [4] 246 < Lenhoff et al. [5] 548 <60 44 NR Palumbo et al. [6] 144 > <0.01 CC, conventional chemotherapy; HDT, high-dose chemotherapy; NR, not reached. Table 2. Conventional chemotherapy versus high-dose therapy: results of randomized studies No. of Age (years) Median follow-up CR rate (%) Median EFS (months) Median OS (months) patients CC HDT CC HDT CC HDT IFM 90 [7] 200 <65 7 years MAG 91 [8] months NE NE PETHEMA [9] 164 Median months Italian MMSG [10] 195 <70 2 years NR NR IFM, Intergroupe Français du Myelome; MAG, Myelome Auto Grafte; MMSG, Multiple Myeloma Study Group; NE, not evaluated; NR, not reached European Society for Medical Oncology

2 50 comparable with those achieved in the IFM 90 trial, there was no significant difference in OS between the two arms, due to an unexpected survival in the CC arm (median 55 months with HDT versus 50 months with CC). It should be noted that in the CC arm, 17 patients received ASCT at the time of relapse. The design of the Spanish trial was different since only patients responding to initial CC were randomized [9]. In this trial, the CR rate was significantly higher in the HDT arm. Although the median EFS and OS were longer in the HDT arm (42 months versus 33 months, 72 months versus 64 months) the differences were not significant. Finally, the Italian study compared the classical combination melphalan/prednisone and two courses of intermediate dose melphalan (100 mg/m 2 ) followed by ASCT in patients up to the age of 70 years [10]. The CR rate and median EFS were significantly better with HDT. However, currently OS is not different between the two arms but more patients received ASCT as salvage therapy in the CC arm. Therefore, HDT improves the CR rate and the median EFS. The fact that OS is not always significantly increased could be explained by the results of another randomized trial conducted by the French MAG group comparing early and late autologous transplantation [11]. In this trial, although early transplantation significantly improved progression-free survival (PFS), OS was not significantly different. These results confirm that ASCT is an effective salvage therapy when CC fails. In randomized trials conducted recently, HDT has been proposed to a significant number of patients relapsing after initial CC. How to improve the results of ASCT? In the IFM 90 trial, the 7-year EFS was only 16% for patients enrolled in the HDT arm and there was no plateau in the survival curves. Therefore strategies to improve these results were clearly warranted. Since in this trial achievement of CR or VGPR was significantly associated with a prolongation of survival, the aim of subsequent studies was to increase the CR rate. Conditioning regimen Improving the conditioning regimen may be one way of attaining this objective. The optimal conditioning regimen for ASCT in MM has not yet been determined. Since its introduction in 1987 [12], total body irradiation (TBI) has been used in multiple uncontrolled studies. The combination of TBI plus high-dose melphalan (HDM) 140 mg/m 2 yields CR rates ranging from 20% to 50% according to disease status at transplantation and to criteria used to define CR. This conditioning regimen was used in the IFM 90 trial and could therefore be considered as the standard one. However, in newly diagnosed patients, the Royal Marsden Group has reported an impressive 70% CR rate with HDM 200 mg/m 2, with a low extramedullary toxicity [13]. In 1995 the IFM initiated a randomized study comparing HDM 200 mg/m 2 and HDM 140 mg/m 2 plus TBI in 282 patients with newly diagnosed MM [14]. In this study, HDM 200 mg/m 2 was significantly less toxic (shorter duration of neutropenia and thrombocytopenia, lower incidence of grade 3 mucositis, no toxic death versus five in the TBI group). Although the response rate and the EFS were identical, OS was superior in the HDM 200 mg/m 2 arm, apparently because of better salvage after relapse. Two other non-randomized trials failed to show a survival benefit for TBI-containing regimens [15, 16]. Therefore, HDM 200 mg/m 2 should be preferred to HDM 140 mg/m 2 plus TBI as the conditioning regimen for ASCT in MM. Knowing the good tolerance of HDM 200 mg/ m 2, higher doses of melphalan alone or in combination with an anti-il6 antibody have been explored with encouraging results [17, 18]. In order to further improve the efficacy of conditioning regimens, studies are ongoing with agents that localize preferentially in the bone and that are coupled with radioelements (Holmium, Samarium). Impact of tandem transplants Another way to increase the CR rate may be to repeat intensive treatments. We were the first group to explore this strategy but the hematopoietic toxicity of the first course of HDT was severe in the absence of any hematopoietic support [19]. Thanks to autologous transplantation of peripheral blood progenitor cells (PBPC) and to hematopoietic growth factors, the sequential use of two courses of HDT appears to be well tolerated, to increase the CR rate [20, 21] and even to induce molecular remission [22]. The largest experience in this setting comes from the Little Rock Group [23]. Out of 495 patients enrolled to undergo two transplants, including 315 pretreated patients, 95% completed the first course of HDM 200 mg/m 2 with PBPC transplantation and 73% went on to have a second PBPC transplantation. The CR rate increased from 24% after the first transplant to 43% after two transplants. This experience has now been extended to >1000 patients [24]. However, the actual impact of such an aggressive strategy on EFS and OS needed further evaluation. In 1994, the IFM initiated a randomized trial (IFM 94) comparing one versus two transplants [25]. From October 1994 to March 1997, 403 untreated patients under the age of 60 years were enrolled by 45 centers. At diagnosis they were randomized to receive either a single ASCT prepared with melphalan (140 mg/m 2 ) and TBI (8 Gy) or a double ASCT: the first one prepared with melphalan (140 mg/m 2 ) and the second one prepared with melphalan (140 mg/m 2 ) and TBI (8 Gy). After initial cytoreduction with VAD (vincristine, doxorubicin, dexamethasone), 343 patients eligible for transplantation underwent a second randomization (PBPC versus bone marrow) to support HDM 140 mg/m 2 plus TBI. Overall 399 patients were evaluable. Out of 199 patients assigned to the single ASCT arm, 177 (85%) actually received the planned transplant and there were three toxic deaths. Out of 200 patients randomized in the double transplant arm, 156 (78%) actually received two transplants and there were five

3 51 Table 3. Single versus double autologous stem cell transplantation (ASCT): results of the IFM 94 trial a Log-rank test. CR, complete remission; EFS, event-free survival; IFM, Intergroupe Français du Myelome; OS, overall survival; VGPR, very good partial remission. toxic deaths. The results are shown in Table 3. There is no significant difference in the CR rate between single and double transplantation. However, with a median follow-up of 5 years the median EFS and OS are superior in the double ASCT arm. Three other studies have also addressed the issue of further intensification (Table 4). Currently none of these studies show a significant survival advantage for the more intensive treatment arm [26 28]. However, it should be noted that in the IFM 94 trial, the EFS and OS curves separate only after 3 years. Therefore, as the median follow-up time of these three studies is still short, a longer observation period is needed before any definite conclusions can be drawn. Source of stem cells Single ASCT (n = 199) P value CR rate (%) CR + VGPR rate (%) Median EFS (months) a 37 6 year EFS (%) Median OS (months) a 58 6 years OS (%) Double ASCT (n = 200) Table 4. Single versus double autologous stem cell transplantation (ASCT): results of multicenter randomized studies No. of patients Median follow-up (months) Results IFM 94 [25] Better EFS and OS a Hovon [26] b Higher CR rate a Bologna [27] c No difference MAG 95 [28] d No difference a In favor of the more intensive treatment arm. b 2 melphalan 70 mg/m 2 plus or minus CTX-TBI/PBPCT. c Melphalan (200 mg/m 2 )/PBPCT plus or minus Bu-Mel/PBPCT. d VAD plus HD chemo plus TBI/PBPCT versus melphalan (140 mg/m 2 )/ PBPCT plus HD chemo plus TBI/PBPCT. CR, complete remission; CTX-TBI, cyclophosphamide-total body irradiation; Bu-Mel, busulfan-melphalan; EFS, event-free survival; HD chemo, high-dose chemotherapy; IFM, Intergroupe Français du Myelome; OS, overall survival; PBPCT, peripheral blood progenitor cell transplantation; TBI, total body irradiation; VAD, vincristine, doxorubicin and dexamethasone. As in other malignancies, PBPC have almost completely replaced bone marrow as the source of stem cells in ASCT for MM. The main reasons for this choice are easier accessibility and availability, faster hematopoietic recovery and possibly lower tumor contamination. However, several issues remain regarding the use of PBPC. Although tumor cell contamination is lower in PBPC harvests than in bone marrow, the superiority of PBPC autologous transplantation as regards the clinical outcome has not yet been demonstrated. Sensitive immunofluorescence studies or PCR-based techniques have demonstrated that virtually all PBPC harvests are contaminated with malignant cells. Although the prognostic significance of detecting malignant cells with such sensitive methods is still unknown, attempts to reduce tumor cell contamination of the grafts appeared logical. Purging marrow with cyclophosphamide derivatives or with monoclonal antibodies has proven feasible, although inducing prolonged myelosuppression. Selection of CD34 + progenitors appears to be a promising alternative with a 2.5 to 4.5 log-depletion of plasma-cells [29, 30]. Several pilot studies have confirmed the feasibility of autologous transplants with CD34 + -selected PBPC in MM. In a multicenter randomized phase III trial comparing selected and unselected PBPC in 131 myeloma patients, successful neutrophil engraftment was achieved in all patients by day 15 and there was no significant difference between the two groups as regards platelet engraftment [31]. However, a recent analysis of this trial failed to show EFS or OS prolongation with CD34 + cell selection [32]. Other randomized studies have not yet been published but preliminary results do not show any benefit of CD34 + -selected PBPC. Moreover, in both studies the incidence of opportunistic infections appears superior in the CD34 + -selected PBPC arm [28, 33]. Sensitive PCR techniques using patient-specific oligonucleotide primers show the persistence of myeloma cells in the CD34 + cell fractions while highly purified CD34 + lin-thy 1 + stem cells do not apparently contain clonal myeloma cells [34]. Thus, an additional purging step might be necessary to obtain tumor-free grafts. The clinical impact of these cumbersome and expensive procedures is unknown. In a pilot study on 10 patients, neutrophil and platelet engraftment was substantially delayed as compared with unmanipulated PBPC grafts [35]. Currently unselected PBPC appear to be the best source of stem cells for ASCT in MM. Maintenance therapy As there is no plateau of the survival curves in published series with adequate follow-up, some form of maintenance therapy appears necessary. Several randomized studies have shown that, in patients responding to CC, α-interferon maintenance prolongs remission duration by 5 12 months as compared with observation. α-interferon has also been used after HDT with the hypothesis that it could be more effective in patients with minimal residual disease. In a retrospective analysis of the European Blood and Marrow Transplantation (EBMT) registry, α-interferon maintenance was associated with improved PFS and OS in patients responding to HDT [36].

4 52 Only one randomized study has been completed to date [37]. This trial compared α-interferon ( UI/kg, 3 times weekly) following recovery from HDT and no further therapy. With a median follow-up of 77 months, the median PFS was significantly longer (42 months versus 27 months for the control arm), but the PFS and OS curves were not significantly different. This means that, although α-interferon delays relapse, most if not all patients ultimately relapse. However, since this study involved only 85 patients, these results should be interpreted with caution. Further studies are needed and a large randomized trial is ongoing in the USA. It should be noted that in the IFM 90 trial, although α-interferon was to be administered to all patients after HDT, there was no plateau in the EFS curve [7]. Therefore, the cure of patients with MM with a single course of HDT followed by α-interferon is unlikely. New strategies to control minimal residual disease after ASCT are necessary. They include the use of maintenance chemotherapy, thalidomide, diphosphonates and immune therapy (idiotypic or DNA vaccination, vaccination with idiotype pulsed dendritic cells). These strategies are currently being evaluated. Prognostic factors Barlogie et al. [38] recently published the results of total therapy with tandem transplants in 231 patients with newly diagnosed MM. In multivariate analysis, superior EFS and OS rates were observed in the absence of unfavorable karyotypes (11q breakpoints and/or partial or complete deletion of chromosome 13) and with low β2 microglobulin levels at diagnosis ( 4 mg/l). When combining these factors, a subgroup of patients with very poor prognosis was identified: patients with unfavorable cytogenetics and β2 microglobulin levels >4 mg/l had a median survival of only 2.1 years, compared with 7 years for the remaining patients. New therapeutics are clearly needed for these patients. Using a larger cohort of 1000 consecutive patients, including previously treated patients, the same authors confirmed that independent favorable features were mainly absence of chromosome 13 deletion, low β2 microglobulin level, plus low C-reactive protein levels and <12 months of prior CC [24]. Plateaus of the EFS and OS curves were noted in 45% and 60% of patients with all these favorable characteristics. Thus, durable remissions and possibly cures can be achieved in a high proportion of good risk patients with an intensive strategy including tandem ASCT. In a recent retrospective analysis of 110 patients treated with HDT, the IFM showed that the detection of chromosome 13 abnormalities (-13, 13 q-) by fluorescence in situ hybridization (FISH) was the most powerful adverse prognostic factor [39]. The combination of FISH analysis, β2 microglobulin and IgA isotype produced a very powerful staging system in the context of HDT. Again, patients with high β2 microglobulin levels and chromosome 13 abnormalities had a very poor prognosis. In addition to pre-hdt features, achievement of CR defined by immunofixation [24, 40, 41] and timely administration [24] of the second ASCT are associated with better outcome. Allogeneic bone marrow transplantation (BMT) Allogeneic BMT is usually performed only in patients <50 years of age and who have an HLA identical sibling. Considering the median age of patients with MM, this strategy can be offered only to a small proportion of patients. The procedure-related death rate remains very high, mainly as a consequence of infections and graft-versus-host disease [42, 43]. A comparison of data compiled by the EBMT group has shown no advantage of allogeneic BMT compared with ASCT [44]. However, if given early in the course of the disease, allogeneic BMT has shown encouraging results: about one third of patients who have a CR after transplantation remain free of disease 6 years later [42]. As a result of the antitumor effect of the graft, allogeneic BMT is possibly the only genuinely curative therapy in MM. Recent reports of CR achieved after the infusion of donor mononuclear cells in patients relapsing after allogeneic BMT are further evidence of the so-called graft-versus-myeloma effect [45, 46]. Two recent series confirm that donor lymphocyte infusions alone or following reinduction chemotherapy may induce 30 50% of remissions including CR. Some of these remissions may last >1 year. However, this obvious anti-myeloma activity is hampered by a high incidence of graft-versus-host disease and by the risk of severe aplasia [47, 48]. A recent survey of the EBMT registry shows a significant improvement in survival for patients with transplants performed between 1994 and 1998, compared with previous experience [49]. This is the result of a significant reduction in transplant-related mortality, mostly a reduction in deaths due to bacterial and fungal infections. This encouraging result corresponds with a better selection of patients with earlier transplantation in patients less heavily pretreated. In this study, the use of PBPC instead of bone marrow was associated with earlier engraftment but yielded no significant survival benefit. Another way of improving results could be the use of attenuated dose conditioning regimens (so-called miniallotransplants) which are currently being evaluated in MM, as well as in other hematopoietic malignancies. The objectives of this strategy are to ensure engraftment and reduce transplantrelated mortality with non-myeloablative immunosuppressive conditioning regimens while harnessing the graft-versusmyeloma effect. Published studies [50, 51] show that DFS and OS are related to disease status at transplantation and a high relapse rate is observed in patients with advanced disease. Therefore the combination of HDT with ASCT to reduce tumor burden and non-myeloablative treatment with allogeneic BMT to produce a graft-versus-myeloma effect is attractive. At the American Society of Hematology (ASH) 2001 meeting, Maloney et al.

5 53 [52] presented encouraging preliminary results with this approach which is currently being tested in the IFM 99 trial. References 1. Bataille R, Harousseau JL. Multiple myeloma (review article). N Engl J Med 1997; 36: Harousseau JL, Attal M. The role of autologous hematopoietic stem cell transplantation in multiple myeloma. Semin Hematol 1997; 34 (Suppl 1): Blade J, San Miguel JF, Montserrat F et al. Survival of multiple myeloma patients who are potential candidates for early high-dose therapy intensification/autotransplantation and who were conventionally treated. J Clin Oncol 1996; 14: Barlogie B, Jagannath S, Vesole D et al. Superiority of tandem autologous transplantation over standard therapy for previously untreated multiple myeloma. Blood 1997; 89: Lenhoff S, Hjorth M, Holmberg E et al. Impact of survival of highdose therapy with autologous stem cell support in patients younger than 60 years with newly diagnosed multiple myeloma. Blood 2000; 95: Palumbo A, Triolo S, Argentin C. Dose intensive melphalan with stem-cell support is superior to standard treatment in elderly myeloma patients. Blood 1999; 94: Attal M, Harousseau JL, Stoppa AM et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med 1996; 335: Fermand JP, Ravaud P, Katsahian S et al. High dose therapy and autologous blood stem cell transplantation versus conventional treatment in multiple myeloma: results of a randomized trial in 190 patients 55 to 65 years of age. Blood 1999; 94 (Suppl 1): 396a (Abstr). 9. Blade J, Sureda A, Ribera JM et al. High-dose therapy autotransplantation/intensification versus continued conventional chemotherapy in multiple myeloma in patients responding to initial treatment chemotherapy. Results of a prospective randomized trial from the Spanish Cooperative Group PETHEMA. Blood 2001; 98: 815a (Abstr). 10. Palumbo A, Bringhen S, Rus C et al. A prospective randomized trial of intermediate dose melphalan (100 mg/m 2 ) versus oral melphalan/ prednisone: an interim analysis. Blood 2001; 98: 849a (Abstr). 11. Fermand JP, Ravaud P, Chevret S et al. High-dose therapy and autologous peripheral blood stem cell transplantation in multiple myeloma: up-front or resume treatment? Results of a multicenter sequential randomized clinical trial. Blood 1998; 92: Barlogie B, Alexanian R, Dicke K et al. High dose chemoradiotherapy and autologous bone marrow transplantation for resistant multiple myeloma. Blood 1987; 70: Cunningham D, Paz-Ares L, Milan S et al. High dose melphalan and autologous bone marrow transplantation as consolidation in previously untreated myeloma. J Clin Oncol 1994; 12: Moreau P, Facon T, Attal M et al. Comparison of 200 mg/m 2 melphalan and 8 Gy total body irradiation plus 140 mg/m 2 as conditioning regimens for peripheral blood stem cell transplantation in patients with newly diagnosed multiple myeloma. Final analysis of the IFM randomized trial. Blood 2002; 99: Goldschmidt H, Hegenbart U, Wallmeier M et al. High-dose therapy with peripheral blood progenitor cell transplantation in multiple myeloma. Ann Oncol 1997; 8: Bjorkstrand B, Svensson H, Goldschmidt H et al autotransplants in multiple myeloma: A registry from the EBMT. Blood 1999; 94 (Suppl 1), 714 a (Abstr). 17. Moreau P, Milpied N, Mahé B. Melphalan 220 mg/m 2 followed by peripheral blood stem cell transplantation in 27 patients with advanced multiple myeloma. Bone Marrow Transplant 1999; 23: Moreau P, Harousseau JL, Wijdenes J et al. A combination of antiinterleukin 6 murine monoclonal antibody with dexamethasone and high-dose melphalan induces high complete response rate in advanced multiple myeloma. Br J Haematol 2000; 109: Harousseau JL, Milpied N, Laporte JP et al. Double intensive therapy in high-risk multiple myeloma. Blood 1992; 79: Vesole D, Barlogie B, Jagannath S et al. High-dose therapy for refractory multiple myeloma: improved prognosis with better supportive care and double transplants. Blood 1994; 84: Weaver CH, Zhen B, Schwartzberg LS et al. Phase I II evaluation of rapid sequence tandem high-dose melphalan with peripheral blood stem cell support in patients with multiple myeloma. Bone Marrow Transplant 1998; 22: Bjorkstrand B, Ljungman P, Bird JM et al. Double high-dose chemoradiotherapy with autologous stem cell transplantation can induce molecular remission in multiple myeloma. Bone Marrow Transplant 1995; 15: Vesole D, Tricot G, Jagannath S et al. Autotransplant in multiple myeloma: what have we learned? Blood 1996; 88: Desikan R, Barlogie B, Sawyer J et al. Results of high dose therapy for 1000 patients with multiple myeloma: durable complete remission and superior survival in the absence of chromosome 13 abnormalities. Blood 2000; 95: Attal M, Harousseau JL, Facon T et al. Single versus double transplant in myeloma: a randomized trial of the IFM. Proc VIIIth Int Myeloma Workshop 2001: S15; 28 (Abstr). 26. Segeren CM, Sonneveld P, Van Der Holt P et al. Myeloablative treatment in following intensified chemotherapy untreated multiple myeloma: a prospective randomized phase III study. Blood 2001; 98: 815a. 27. Cavo M, Tosi P, Zamagni E et al. The Bologna 96 clinical trial of single versus double PBSC transplantation for previously untreated MM: results of an interim analysis. Proc VIIIth Int Myeloma Workshop 2001; S16: Fermand JP, Marolleau JP, Alberti C et al. Single versus tandem high dose therapy supported with autologous stem cell transplantation using unselected or CD 34 enriched ABSC: preliminary results of a two by two designed randomized trial in 23 young patients with multiple myeloma. Blood 2001; 98: 815a (Abstr). 29. Schiller G, Vescio R, Freytes C et al. Transplantation of CD 34 + peripheral blood progenitor cell after high-dose chemotherapy for patients with advanced multiple myeloma. Blood 1995; 86: Lemoli RM, Fortuna A, Motta MR et al. Concomitant mobilization of plasma cells and hematopoietic progenitors into peripheral blood of multiple myeloma patients: positive selection and transplantation of enriched CD 34 + cells to remove circulating tumor cells. Blood 1996; 87: Vescio RA, Schiller G, Stewart K et al. Multicenter phase III trial to evaluate CD 34 + selected versus unselected autologous peripheral blood progenitor cell transplantation in multiple myeloma. Blood 1999; 93: Stewart AK, Vescio K, Schiller G et al. Purging of autologous peripheral blood stem cells using CD34 selection does not improve

6 54 overall or progression free survival after high-dose therapy for multiple myeloma: results of a multicenter randomized controlled trial. J Clin Oncol 2001; 198: Goldschmidt H, Bouko Y, Bourhis JH et al. CD 34 + selected PBPCT results in an increased infective risk without prolongation of event free survival in newly diagnosed myeloma: a randomised study from the EBMT. Blood 2000; 96: 558a (Abstr). 34. Gazitt Y, Reading CC, Hoffman R et al. Purified CD 34 + Lin-thy + stem cells do not contain clonal myeloma cells. Blood 1995; 86: Tricot G, Gazitt Y, Leemhuis S et al. Collection, tumor contamination and engraftment kinetics of highly purified hematopoietic progenitor cells to support high dose therapy in multiple myeloma. Blood 1998; 91: Bjorkstrand B, Svensson H, Goldschmidt H et al. α-interferon maintenance treatment is associated with improved survival after high-dose treatment and autologous stem cell transplantation in patients with multiple myeloma: a retrospective registry study from the EBMT. Bone Marrow Transplant 2001; 27: Cunningham D, Powles R, Malpas J et al. A randomized trial of maintenance interferon following high-dose chemotherapy in multiple myeloma: long term follow-up results. Br J Haematol 1998; 102: Barlogie B, Jagannath S, Desikan KR et al. Total therapy with tandem transplants for newly diagnosed multiple myeloma. Blood 1999; 93: Facon T, Avet-Loiseau H, Guillerm G et al. Chromosome 13 abnormalities identified by FISH analysis and serum β2 microglobulin produce powerful myeloma staging system for patients receiving high-dose therapy. Blood 2001; 97: Lahuerta JJ, Martinez-Lopez J, de la Serna J et al. Remission status defined by immunofixation versus electrophoresis after autologous transplantation has a major impact on the outcome of multiple myeloma patients. Br J Haematol 2000; 109: Davies FE, Forsyth PD, Rawstron AC et al. The impact of attaining a minimal disease state after high-dose melphalan and autologous transplantation for multiple myeloma. Br J Haematol 2001; 112: Gahrton G, Tura S, Ljungman P et al. Prognostic factors in allogeneic bone marrow transplantation for multiple myeloma. J Clin Oncol 1995; 13: Bensinger WI, Buckner D, Anasetti C et al. Allogeneic bone marrow transplantation for multiple myeloma: an analysis of risk factors on outcome. Blood 1998; 88: Björkstrand B, Ljungman P, Svensson H et al. Allogeneic bone marrow transplantation versus autologous stem cell transplantation in multiple myeloma: a retrospective case-matched study from the European Group for Blood and Marrow Transplantation. Blood 1996; 88: Tricot G, Vesole DH, Jagannath S et al. Graft-versus-myeloma effect: proof of principle. Blood 1996; 87: Verdonck L, Lokhorst H, Dekker A et al. Graft versus myeloma effect in two cases. Lancet 1996; 347: Lokhorst HM, Schattenberg A, Cornelissen JJ et al. Donor lymphocyte infusions for relapsed multiple myeloma after allogeneic stem-cell transplantation: predictive factors for response and longterm outcome. J Clin Oncol 2000; 18: Salama M, Vevil T, Marcellus O et al. Donor leucocyte infusions for multiple myeloma. Bone Marrow Transplant 2000; 26: Gahrton G, Svensson H, Cavo M et al. Progress in allogeneic bone marrow and peripheral blood stem cell transplantation for multiple myeloma: a comparison between transplants performed and at European Group for Blood and Marrow Transplantation centers. Br J Haematol 2001; 113: Champlin R, Khouri I, Kornblau S et al. Non-myeloablative preparative regimens and induction of graft versus malignancy effect. Oncology 1999; 13: Sandmaier BM, McSweeney P, Yu C et al. Non-myeloablative transplants: preclinical and clinical results. Semin Oncol 2000; 27: Maloney DG, Sahebi F, Stockerl-Goldstein KE et al. Combining an allogeneic graft versus myeloma effect with high dose autologous stem cell rescue in the treatment of multiple myeloma. Blood 2001; 11: 434a 435a (Abstr 1822).