The role of allogeneic stem cell transplantation in multiple myeloma in the new drug era

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1 DCTH The role of allogeneic stem cell transplantation in multiple myeloma in the new drug era N. Kröger Department for Stem Cell Transplantation, University Hospital Hamburg-Eppendorf, Germany SUMMARY Multiple myeloma is considered to be an incurable disease. Despite the introduction of autologous stem cell transplantation and more recently novel agents, such as lenalidomide and bortezomib, still induces the highest rate of clinical complete and molecular remission and it can induce long-term freedom from disease in about 30-40% of the cases. The major disadvantage is the higher morbidity and mortality of this approach, which are caused by immunological complications after transplantation such as graft-versushost disease and infectious diseases. However, donor derived T-cells and may also NK cells can also induce a graft versus myeloma effect. This graft versus tumor effect seems to be less strong than in other hematological diseases, but donor-lymphocyte infusions given to patients who relapsed after allogeneic stem cell transplantation can induce response rate between 40% and 67%. Allogeneic stem cell therapy studies suggest that achievement of molecular remission after transplantation is associated with long-term freedom from disease. Modern myeloma therapy approaches should lower the therapy related mortality of allogeneic stem cell transplantation and use this immunological platform for immunological-or drug based therapies post transplantation to achieve molecular remission and ultimately cure. Key words: graft-versus-myeloma effect,, multiple myeloma, reduced intensity conditioning, unrelated donor. Correspondence: Nicolaus Kröger Department of Stem Cell Transplantation University Hospital Hamburg-Eppendorf Martinistrasse, Hamburg, Germany nkroeger@uke.uni-hamburg.de INTRODUCTION Compared with other treatment modalities in multiple myeloma, allogeneic stem cell transplantation induces the highest rate of clinical complete and molecular remission (1, 2), and it can induce long-term freedom from disease in about 30-40% of the cases (3-7). Despite the recent improvement in performing allogeneic stem cell procedure (8), it is still the treatment

2 60 N. Kröger modality with the highest treatmentrelated morbidity and mortality. Both morbidity and mortality are related to organ toxicity induced by the conditioning regimen and to immunological complications after transplantation such as graft-versus-host disease and infectious diseases. Evidence of a strong immunologically mediated antimyeloma effect came from donorlymphocyte infusions given to patients who relapsed after allogeneic stem cell transplantation. Response rate (CR/PR) between 40% and 67% can be achieved but only in a minority of patients these remissions are durable (9, 10). INTENSITY OF THE CONDITIONING REGIMEN Since the toxicity of the conditioning regimen prior to allogeneic stem cell transplantation contributes to treatment-related morbidity and mortality, a strategy to reduce treatment-related mortality by reducing the toxicity of the conditioning regimen by either toxicity - or dose - reduced regimens has been investigated. Since low-intensity-conditioning approach, which is mainly focused on immuno-competent donor-t-cells, is not sufficient to control advanced disease in myeloma patients (11) it became clear that further effective cytoreductive treatment might be necessary, especially since it became obvious that there is a positive correlation between higher CR rate as well as higher treatmentrelated mortality and the intensity of the conditioning regimen. This is in accordance with a retrospective comparison from the European Group for Blood and Marrow Transplantation (EBMT) reporting a higher CR-rate for myeloablative conditioning in comparison to reduced intensity conditioning (53% vs 34%, P<0.001) (12). There are also more reports suggesting that standard myeloablative conditioning has improved in time, especially with respect to treatment-related mortality. The Myeloma Subcommittee of EBMT reported a better survival for myeloma patients transplanted after 1994 in comparison to those who received an allograft before 1994 (overall survival at three years: 56% vs 35%) (8). This major improvement is due to a marked reduction in treatment-related mortality (30% vs 46%) probably due to better patient selection and improved supportive care. More recently, smaller phase II studies using myeloablative conditioning reported TRM rates of less than 20% suggesting only marginal difference in TRM between myeloablative and reduced-intensity conditioning (5-7). However, the medium age of the patients treated with standard conditioning were about ten years younger in comparison to those treated with reduced-intensity conditioning. The already above-mentioned study of the Myeloma Subcommittee of the EBMT comparing a reduced-intensity conditioning (n=320) with myeloablative conditioning (n=196) showed a reduced non-relapse mortality for RIC transplantation (24% vs 37%, P=0.002), but a lower progression-free survival (19% vs 35%, P=0.001) and no statistical difference in overall survival (38% vs 51%, n.s.). On multivariate analysis RIC was associated with lower non-relapse mortality (HR: 0.5) but a higher risk of re-

3 The role of in multiple myeloma in the new drug era 61 lapse (HR: 2.0) (12). A more recent performed study using busulfan/cyclophosphamide based toxicity reduced myeloablative conditioning regimen resulted in only 6% non-relapse mortality in advanced myeloma patients who relapsed to an autograft (13). COMBINING AUTOLOGOUS AND ALLOGENEIC STEM CELL TRANSPLANTATION To maintain the efficacy of intensive chemotherapy, the concept of autologous-allogeneic-tandem transplantation was introduced (14). In this treatment concept, high-dose chemotherapy and adoptive immunotherapy by immuno-competent donor-t-cells were splitted within an interval of two to three months in order to lower toxicity and treatment-related mortality but maintain high-dose chemotherapy as well as the immuno-mediated graftversus-myeloma effect (14-17). The randomized IFM99 protocol comparing auto-allo tandem approach with tandem autologous stem cell transplantation in high-risk patients could not show any benefit for the auto-allo approach. This could be due to the very-high-risk group of patients included or, more likely, to the use of high-dose anti-thymocyte-globulin (12.5 mg/kg Thymoglobulin ), which might have offset the graft-versus-myeloma effect by profound T-cell depletion. This randomized study did not show any significant difference in event-free and overall survival between the auto-allo- and the tandem-auto-arm after a median follow-up of 24 months (17). The Italian study group compared 54 patients with multiple myeloma who received autoallo-tandem transplantation from HLAidentical sibling and compared the results with 54 patients who receive tandem-autologous stem cell transplantation within the same time period (15). They reported a higher CR rate (54% vs 26%) and an improved progressionfree (75% vs. 41%, P<0.001) and overall survival (84% vs 62%, P=0.006) for patients who received an allograft. The BMT CTN study reported results after a relative short follow up of 36 months. At this time results were 77% OS and 43% PFS with auto RICallo and 80% OS and 46% PFS with auto/auto in the BMT CTN study. The non-relapsed mortality was 11% with the auto/ricallo procedure and 3% with auto/auto respectively (18). The HOVON study (19) had a somewhat different approach using conditioning with TBI 2Gy without fludarabine and maintenance therapy with thalidomide in some of the auto patients. OS at 6 years was 55% in patients with or without a donor. PFS at 6 years was 28% in patients with a donor, compared to 22% without a donor in the HOVON study. Although not significant in the HOVON study, there was a trend for a lower relapse/ progression rate in the auto/ RICallo arm. It has to be taken into account that the auto patients received maintenance treatment with thalidomide contrary to the allo arm. In the EBMT trial which used also 2 Gy TBI/fludaraine in the allo arm the PFS and OS at 60 months was significantly higher in the auto-allo arm (35% and 65%) in comparison to auto transplantation (18% and 58%). The same was true for the achievement of complete remission (51% vs 41%, P=0.02) (20).

4 62 N. Kröger REDUCING RISK OF RELAPSE Despite the obvious graft versus myeloma effect the risk of relapse is substantial and is the major cause of treatment failure after allogeneic stem cell transplantation in myeloma patients. Several investigators have showed the importance of achieving complete remission on duration of event-free survival after autologous stem cell transplantation (21). Complete remission in patients with multiple myeloma is defined by negative immunofixation. However, the sensitivity of immunofixation to detect residual disease is low. Since residual disease is associated with relapse risk, more sensitive methods to detect residual disease in myeloma patients have been investigated. The most sensitive method is based on clonal markers derived from the re-arrangement of immu noglobulin heavy-chain genes, which have to be generated from each patient at diagnosis. Using these patient-specific primers, residual myeloma cells can be detected by polymerase-chain reaction (PCR) with a sensitivity of 10 4 to 10 6 (1, 2). Molecular remissions are seen more often after allogeneic than after autologous stem cell trans plantation. In patients who achieved clinical complete remission, nine out of 14 allograft-patients, but only two out of 15 autograftpatients entered molecular remission. It is of interest that molecular remission after allografting occurred in some patients more than three years after transplantation (1). The importance of achieving molecular remission for long-term disease freedom has been shown for myeloablative in a retrospective EBMT-study (22). In this study using high sensitive patientspecific primers to monitor residual disease with PCR-technique, it could be shown that durable PCR-negativity after allografting had a cumulative risk of relapse at five years of 0%, in comparison to 33% for PCR-mixed patients and 100% for patients who never achieved PCR-negativity. More recently using auto-allo tandem approach molecular remission could be achieved in 41% of the patients and was sustained in 21% of the patients. The progression-free and overall survival correlated well with the depth of remission and for those with sustained molecular remission the 5 year PFS was 85%, which included also high risk patients defined by del17q or t(4;14) (23). POST-TRANSPLANT STRATEGIES The importance of molecular remission on long-term freedom of disease has been mentioned above. Therefore, post-transplant strategies either as maintenance therapy or better to improve remission status are of clinical importance. After autologous stem cell transplantation, therapy with thalidomide given as maintenance therapy resulted in an improved event-free and overall survival (24). Despite the high risk of relapse after allografting, there are only few reports about posttransplant strategies after allogeneic stem cell transplantation in multiple myeloma in the literature. The commonly used adoptive immunotherapy after is donor-lymphocyte infusion (DLI) (25). In multiple myeloma in most reports DLI was given for relapse (9, 10,

5 The role of in multiple myeloma in the new drug era ), and only few reported about prophylactic DLI (30-32). Response rates be tween 40% and 67% were reported but in some studies additional chemotherapy or interferon-a were given (9, 10). Nearly 30% of the patients achieved complete remission, and response to DLI was correlated for occurrence and severity of acute graft-versus-host disease (GvHD). The inci dence of acute GvHD ranges between 52% and 56% and of chronic GvHD between 26% and 44% (9, 10). DLI given after reduced intensity conditioning in a dose escalating way resulted in less acute and chronic GvHD (29, 31). In a European survey, the effect of DLI after reduced-intensity conditioning was investigated in patients with relapse (n=48) or persistent disease (n=15) after allograft. Nineteen percent of the patients achieved partial remission, and 19% complete remission (33). The median time to progres sion was seven months for patients with partial remission, and 28 months for patients who achieved complete remission. To enhance the anti-myeloma effect of DLI after allografting, low-dose thalidomide (100 mg) in combination with DLI was investigated. The overall response rate was 67% with 22% complete remission. Interestingly, no grade II-IV acute GvHD was seen, and only a small minority developed limited chronic GvHD (34). Other new drugs such as the proteasome-inhibitor bortezomib might have a major role after since it could be shown in preclinical mice models that proteasome-inhibition inhibits T-cell proliferation and acute GvHD with retaining the graftversus-tumor effect (35). In a clinical study investigating bortezomib as post-transplant treatment to enhance remission status, a complete or partial remission could be induced in 30% and 50%, respectively (36). Even in patients refractory to DLI, salvage treatment with thalidomide or bortezomib can induce complete or partial remission in 83% of the cases (37). Another aim to improve the results in allografting of myeloma patients is the introduction of lenalidomide post transplant. Lenalidomide maintenance therapy which started at a median of 168 days after transplantation induces some toxicity which was mainly GvHD-related. 28% of the patients experienced grade II-III acute GvHD after lenalidomide, and a previous dose-finding study has shown an increase of NK cytotoxicity but also an early increase of interferon gamma secreting T-cells (38). In a similar study by the HOVON group investigating 10 mg lenalidomide after for myeloma patients, 37% developed acute GvHD (39). Other toxicities were myelosuppression and fatigue and according to the recently published dose-finding study the starting dose should not exceed 5 mg. Nevertheless due to the described toxicity, about 50% of the patients had to discontinue the lenalidomide treatment periodically or permanently. Even if the true value of lenalidomide post allograft cannot be determined from the design of the current study the relative long progression-free survival of 52% at 3 years is higher than the reported 3 year PFS in similar allogeneic studies without lenalidomide. Further improvement of immunologically based strategies post-allo-trans-

6 64 N. Kröger plant lies in the separation of the graftversus-myeloma effect from the graftversus-host reaction, which would allow a more specific tumor-targeting without or lesser risk of GvHD. Potential candidates for a more specific T-cell response are minor histocompatibility antigens such as HA-1. HA-1 specific T- cells could be generated and induced complete remission in a patient with relapsed multiple myeloma after allogeneic stem cell transplantation (40). Another potential target is cancertestis-antigens, especially MAGEC2 or MAGEA3 which are expressed in more than 50% of myeloma cells (41). More recently activated donor KIR genes may be protective against relapse, suggesting a potential role of alloreactive NK-cells after allografting to enhance remission status and prevent relapse (42). Overall post-transplant immunotherapy with DLI and novel agents can upgrade remission into molecular remission (43). Acknowledgements: we thank the staff of the BMT unit for providing excellent care of our patients and the medical technicians for their excellent work in the BMT laboratory. This work was supported by a grant from the Deutsche Krebsgesellschaft e.v., the Deutsche José Carreras Leukämie-Stiftung e.v., and the Wilhelm Sander-Stiftung. REFERENCES 1. Corradini P, Voena C, Tarella C, et al. Molecular and clinical remissions in multiple myeloma: role of autologous and allogeneic transplantation of hematopoietic cells. J Clin Oncol 1999; 17: Martinelli G, Terragna C, Zamagni E, et al. Molecular remission after allogeneic or autologous transplantation of hematopoietic stem cells for multiple myeloma. J Clin Oncol 2000; 18: Bensinger WI, Buckner CD, Anasetti C, et al. Allogeneic marrow transplantation for multiple myeloma: an analysis of risk factors on outcome. Blood 1996; 88: Hunter HM, Peggs K, Powles R, et al. Clinical Trials Committee of the British Society of Blood and Marrow Transplantation (BSBMT). Analysis of outcome following allogeneic haemopoietic stem cell transplantation for myeloma using myeloablative conditioning - evidence for a superior outcome using melphalan combined with total body irradiation. Br J Haematol 2005; 128: Kröger N, Einsele H, Wolff D, et al. German Study-group Multiple Myeloma (DSMM). Myeloablative intensified conditioning regimen with in vivo T-cell depletion (ATG) followed by allografting in patients with advanced multiple myeloma. A phase I/II study of the German Study-group Multiple Myeloma (DSMM). Bone Marrow Transplant 2003; 31: Rabitsch W, Prinz E, Ackermann J, et al. Long-term follow up of patients with multiple myeloma after high-dose chemotherapy and allogeneic stem cell transplantation. Eur J Haematol 2004; 72: Majolino I, Corradini P, Scime R, et al. Allogeneic transplantation of unmanipulated peripheral blood stem cells in patients with multiple myeloma. Bone Marrow Transplant 1998; 22: Gahrton G, Svensson H, Cavo M, et al. European Group for Blood and Marrow Transplantation. Progress in allogenic 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 centres. Br J Haematol 2001; 113:

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