The aim of this retrospective analysis was to assess the benefit of reduced-intensity conditioning allo SCT (RIC allo-SCT) in a cohort of 32 relapsed multiple myeloma (MM) patients. A total of 19 patients had an HLA-identical sibling donor (‘donor’ group), while 13 patients had no donor (‘no-donor’ group). There were no significant differences between these two groups as for prognosis risk factors. Eighteen patients from the ‘donor’ group could actually proceed to RIC allo-SCT. With a median follow-up of 36 (range, 21–60) months, six patients died from transplant-related toxicity (cumulative incidence, 33% (95% CI, 11–55%)). Only 4 patients from the 18 transplanted patients (22%; 95% CI, 7–48%) progressed after RIC allo-SCT, as compared to 12 (86%; 95% CI, 56–98%; P=0.0003) among the nontransplanted patients. In an ‘intention-to-treat’ analysis, the Kaplan–Meier estimate of PFS was significantly higher in the ‘donor’ group as compared to the ‘no-donor’ group (P=0.01; 46 versus 8% at 3 years). There was no difference in terms of overall survival. However, in multivariate analysis, actual performance of RIC allo-SCT was associated with better PFS (relative risk, 0.35; 95% CI, 0.15–0.82; P=0.01). These data suggest a potential benefit for RIC allo-SCT in the management of relapsed MM warranting further prospective investigations.
Multiple myeloma (MM) is a lymphoid malignancy with a median survival of 3 years.1 High-dose chemotherapy with auto-SCT can result in prolonged response duration and survival.2, 3, 4 Unfortunately, few if any, patients with MM who receive high-dose therapy are cured. On the other hand, it has been shown that an allogeneic graft-versus-myeloma (GVM) effect can be induced even in patients who have been heavily pretreated or relapsed after high-dose therapy.5, 6, 7, 8 The advent of reduced-intensity conditioning (RIC) regimens has resulted in renewed interest in allo-SCT as a treatment modality for MM,9, 10, 11, 12 since it may temper the frequency of transplant-related toxicities.13, 14, 15 However, the potential benefit of RIC allo-SCT as a front-line treatment in patients with high-risk de novo MM has been challenged in different studies.16, 17, 18 Similarly, only sparse data of allo-SCT versus other therapies are available in patients who have been heavily pretreated, or who have relapsed after auto-SCT.15 Using a genetic allocation through a ‘donor’ versus ‘no-donor’ comparison, this single center study aimed to evaluate the role of RIC allo-SCT for relapsed MM and its impact on clinical outcome.
Patients and methods
This was a single center retrospective analysis. Between January 2002 and December 2004, 32 consecutive patients with relapsed or refractory MM were referred to the allogeneic transplantation unit of the Institut Paoli-Calmettes (IPC, Marseille, France) for HLA typing, because they were considered as potential candidates for salvage RIC allo-SCT. Only patients with a family sibling were referred and none of them had already an identified donor. HLA typing was determined serologically for the A and B loci and molecularly for the DR locus. During the study period, RIC allo-SCT using a matched unrelated donor was not offered as per institutional policy. Written informed consent was obtained from each patient and donor, and the study was approved by the IPC institutional review board. HLA typing was performed at time of relapse, and no patient progressing soon after HLA typing was excluded from this analysis.
Before diagnosis of relapse, patients included in this analysis received first-line induction chemotherapy according to institutional protocols or the Intergroupe Francophone du Myélome (IFM) guidelines (mainly VAD chemotherapy), followed by at least one course of high-dose chemotherapy (melphalan 200 mg/m2) with auto-SCT. After relapse, and prior to RIC allo-SCT, patients were treated according to institutional guidelines and received salvage therapy with dexamethasone, thalidomide, bortezomib, additional high-dose melphalan with auto-SCT, as single-agent therapy or in association (full details provided in Table 1). None of the patients included in this study was initially treated according to a tandem auto–allo-SCT approach.11
Conditioning regimen and GVHD prophylaxis
During the study period, two different RIC preparative regimens prior to allo-SCT were actually used. The first RIC protocol (FBA) included fludarabine (Fludara; Schering AG, Lys-Lez-Lannoy, France) 30 mg/m2 for 5 consecutive days, oral BU 4 mg/kg per day for 2 consecutive days and antithymocyte globulins (Thymoglobulin; Genzyme, Lyon, France) 2.5 mg/kg per day for 1 day. The second RIC protocol (FT) included fludarabine 30 mg/m2 for 3 days in combination with low-dose TBI (2 Gy). All transplanted patients received G-CSF-mobilized allogeneic PBSC. None of the patients received allo-SCT from a matched unrelated-donor. For GVHD prophylaxis, patients received CsA (FBA regimen) alone or in association with mycophenolate mofetil (MMF; FT regimen). The CsA doses were adjusted to achieve blood levels between 150 and 250 ng/ml and to prevent renal dysfunction. CsA was tapered starting on day 90 if no GVHD appeared. Supportive care was performed as previously described.19
Clinical outcomes and GVHD assessment
Clinical outcomes after allo-SCT that were recorded included time to neutrophil and platelet engraftment, time to start and severity of acute GVHD (aGVHD), chronic GVHD (cGVHD), disease relapse or progression, PFS, overall survival (OS) and TRM. Time to neutrophil engraftment was defined as the first of 3 consecutive days in which the ANC exceeded 500 per μl. Time to platelet engraftment was defined as the first of 3 days a platelet count of 20 000 per μl without a need for platelet transfusions during a 5-day period. Acute and cGVHD were graded according to standard criteria. Chronic GVHD was defined as any GVHD developing after day 100 including the progressive form if it followed a direct extension of aGVHD.
Donor leukocyte infusions
Patients who relapsed after allo-SCT or who showed evidence of disease progression or had persistent disease without any sign of GVHD after immunosuppressive therapy withdrawal were candidates for donor leukocyte infusions (DLIs) ranging between 1 × 105 and 1 × 107 CD3+ T cells per kg. Donors underwent a leukapheresis without cytokine mobilization for donor lymphocyte procurement.
Assessment of response
Disease progression was defined as re-emergence of MM (if a CR had been reached), or implied at least a 25% increase in M-protein from a prior stable condition, or development of new extramedullary disease. TRM was defined as death without evidence of disease progression. The response to treatment was defined according to the European Group for Blood and Marrow Transplantation (EBMT) criteria.20
All data were computed using SPSS for Windows (SPSS Inc., Chicago, IL, USA) and SEM software (SILEX, Mirefleurs, France). The Mann–Whitney test was used for comparison of continuous variables. Categorical variables were compared using the χ2-square test. The probability of developing aGVHD or cGVHD was depicted by calculating the cumulative incidence method as previously described.21 Cumulative incidence estimates were also used to measure the probability of relapse or progression. PFS and OS were estimated from the time of relapse using the Kaplan–Meier product-limit estimates. Differences between groups were tested using the log-rank test.22
Study population characteristics are summarized in Table 2. In all, 19 patients (59%, ‘donor’ group) had an HLA-identical sibling donor, while the remaining 13 patients (41%, ‘no-donor’ group) had no HLA-identical sibling donor. Median time between diagnosis and HLA typing was 38 months and between relapse and HLA typing was 62 days. There were no significant differences between these two groups that were statistically comparable as for demographic features (though there were more males in the ‘donor’ group), disease characteristics and prognosis risk factors (Table 2). Median age was 54 (range, 37–65), and all patients had previously failed at least one auto-SCT. Of note, 56% of them had chemoresistant disease after salvage treatment (stable disease and progressive disease). Patients from the ‘no-donor’ group continued to receive salvage therapy including thalidomide, bortezomib and/or additional high-dose chemotherapy. Among the 19 patients from the ‘donor’ group, 18 (95%) could actually proceed to the RIC allo-SCT, whereas 1 patient refused allo-SCT.
Engraftment, GVHD and donor leukocyte infusions
Table 3 describes allo-SCT patients' characteristics (‘transplant’ group) and transplant-related events. Median time between HLA typing and allo-SCT was 144 days. Hematopoietic recovery (ANC>500 per μl and platelets>20 000 per μl) was achieved in all patients from the RIC allo-SCT group, at a median of 16 (range, 0–28) and 5 (range, 0–30) days, respectively. None of the transplanted patients experienced secondary graft failure. The cumulative incidence of grades II–IV and grades III–IV aGVHD was 56% (95% CI, 33–79%) and 33% (95% CI, 11–55%), respectively. Among the 14 patients assessable for cGVHD, the cumulative incidence of extensive cGVHD was 57% (95% CI, 31–83%). At time of last follow-up, eight patients (44%) were off immunosuppressive therapy, and the median time for immunosuppressive therapy discontinuation was 128 days post-allo-SCT (range, 90–240). Overall, four nonresponding patients (22%) (patients nos. 1, 6, 7, 9) in this series received up to four escalating doses of DLI, starting at a median time of 270 (range, 167–395) days post-allo-SCT. Interestingly, two patients (patients nos. 6 and 7) showed objective disease response after DLI, concomitantly to limited DLI-induced GVHD.
Disease response and survival
With a median follow-up of 36 (range, 21–60) months, 11 patients (85%, 95% CI, 54–98%) from the ‘no-donor’ group continued to experience disease progression despite salvage therapy, and only 6 (46%) of them are still alive, of whom 5 (80%) are in progressive disease at last follow-up. In this ‘no-donor’ group, of 13 patients, only 2 had a sustained response to salvage therapy, but 1 died from infection 20 months after salvage therapy, and the other is still under thalidomide treatment (disease status of this patient at last follow-up: PR). In the ‘donor’ group, median time between disease diagnosis and allo-SCT was 53 (range, 15–160) months. In all, six patients died from transplant-related toxicity at a median of 83 (range, 65–464) days after allo-SCT for an overall incidence of TRM of 33% (95% CI, 11–55%) in this population of heavily pretreated and relapsed or refractory patients. Three patients died from aGVHD, one from cGVHD, one from infection and one from pulmonary embolism. When looking at disease progression after RIC allo-SCT, only four patients from the group of 18 transplanted patients (22%; 95% CI, 7–48%), progressed at a median of 215 (range, 90–1044) days after RIC allo-SCT as compared to 12 progressions (86%; 95% CI, 56–98%; P=0.0003) among the 14 nontransplanted patients. At last follow-up, among the 18 patients who received an allo-SCT, 10 (56%, 95% CI, 33–79%) are still alive with four patients being in CR, and five in PR or very good PR. Only one patient (patient no. 7) is currently experiencing disease progression and receiving additional salvage therapy. In all, 11 patients (61%, 95% CI, 39–83%) from the RIC allo-SCT group showed objective disease response, usually concurrent to cGVHD (patients nos. 2, 4, 5, 6, 7, 11, 12, 14, 15, 16, 18; Table 3). In an ‘intention-to-treat’ analysis comparing the 19 patients from the ‘donor’ group and the 13 patients from the ‘no-donor’ group, the Kaplan–Meier estimate of PFS was significantly higher in the ‘donor’ group as compared to the ‘no-donor’ group (P=0.01; 46 versus 8% at 3 years). (Figure 1). However, the latter did not translate into a statistically significant difference in terms of OS (95% for the donor group versus 92% for the ‘no-donor’ group at 6 months; and 50 versus 49% at 3 years; P=NS). However, in multivariate analysis for PFS (including relevant demographic and prognostic factors, namely presence or absence of a donor, actual performance of allo-SCT, gender, recipient age, disease status, disease stage, ISS and β-2-microglobulin) performed in the whole study population of 32 patients (and despite the relatively limited size of the cohort), actual performance of RIC allo-SCT was the strongest factor significantly associated with better PFS (relative risk, 0.35; 95% CI, 0.15–0.82; P=0.01), suggesting a potential benefit for RIC allo-SCT in the management of relapsed MM patients.
Myeloma patients who relapse after high-dose chemotherapy have few therapeutic options. Novel antimyeloma agents such as thalidomide, lenalidomide or bortezomib can induce marked responses in relapsed MM patients.25, 26, 27 However, despite these advances, progression-free intervals after salvage treatment using these new drugs are often short, and virtually all patients will continue to experience disease progression. Among treatment modalities employed to control MM, allo-SCT is potentially curative, in large part due to the immune GVM effect.5, 12, 15, 28, 29, 30 However, although treatment with high-dose chemoradiotherapy followed by allo-SCT is capable of producing remissions and long-term survival, the high rate of TRM limits the application of this approach.15, 31, 32 Furthermore, the majority of patients who develop MM are older than 55 years, and less than 10% would be therefore eligible for standard myeloablative allo-SCT, while RIC allo-SCT can be considered for a larger number of patients. However, despite initial enthusiasm, the role of RIC allo-SCT in the myeloma therapeutic armatarium is still to be determined. At our institution, it is the treatment policy to offer RIC allo-SCT to all relapsed MM patients aged less than 65 years, if a sibling-related donor is available. The main objective of the current analysis was to evaluate the outcome of such patients based on this treatment strategy, and to determine whether all such patients should receive a RIC allo-SCT. We found that PFS was significantly higher in the ‘donor’ group as compared to the ‘no-donor’ group. Moreover, the immune GVM effect induced after RIC allo-SCT is likely capable to overcome disease resistance, since objective disease responses were observed whereas more than 50% of the patients were in stable or progressive disease prior to transplantation. Such relatively high rate of objective responses was seen in the ‘transplant’ group, usually concurrent to cGVHD, further supporting the hypothesis of an immunological GVM effect.
Results from our study suggesting a beneficial GVM effect after RIC allo-SCT in relapsed MM (no significant difference was found between patients transplanted in PR versus others) may be considered somewhat at odds with another study from the EBMT registry, which concluded that heavily pretreated patients and/or patients with progressive disease do not benefit from RIC allo-SCT.13 In our study, the comparator arm was not defined therapeutically, and therefore one may question whether our data can rigorously assess the relative value of RIC allo-SCT. However, and to our knowledge, there have been no randomized trials in which relapsed MM patients with a matched sibling donor have been randomized between RIC allo-SCT versus conventional salvage therapy, making it difficult thus far, to draw firm conclusions. In this context, in comparison to a retrospective multicenter study,13 a single center ‘genetic’ allocation as used in our analysis, and despite a smaller number of patients (but with a minimum follow-up of 21 months), can be a suitable way of comparing RIC allo-SCT with other salvage treatment modalities.33
In this study, we found a relatively high frequency of HLA-identical sibling donor (59%; 95% CI, 42–76%). Although rather high, this figure is in accordance with our population in the south of France (high rate of siblings within the age category of this study). We could not also assess the impact of dose intensity on patients’ outcome. Indeed, it has been shown recently that the potential benefit of RIC allo-SCT in MM in terms of TRM is offset by an increased incidence of relapse as compared to standard myeloablative allo-SCT.14 However, given the age, clinical status, and associated-comorbid conditions24 of relapsed MM patients, the controversy over the putative benefit of a standard myeloablative allo-SCT in such patients is rather theoretical, since standard allo-SCT approaches are not likely to be proposed to such patients.
In all, results from this study suggest that RIC allo-SCT using an HLA-identical sibling is a feasible and potential therapy that can be proposed for relapsed MM patients, since a GVM effect can be induced despite heavy pretreatments. Moreover, these results are expected to be further improved with the advent of new post-RIC allo-SCT strategies aiming to redirect the donor T cells toward the residual myeloma cells without enhancing GVHD as it was suggested with novel antimyeloma agents such as bortezomib, thalidomide and revlimid that may preferentially stimulate the GVM effect with little or no GVHD.34, 35, 36, 37
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We thank the nursing staff for providing excellent care for our patients, and the physicians of the Hematology Department at the Institut Paoli-Calmettes for their important study contributions and dedicated patient care. We also thank the ‘Association pour la Recherche sur le Cancer (ARC)’ (Pole ARECA; ITAC protocols), the ‘Ligue Nationale contre le Cancer’, the ‘Fondation de France’, the ‘Fondation contre la Leucémie’, the ‘Agence de Biomédecine’, the ‘Association Cent pour Sang la Vie’ and the ‘Association Laurette Fuguain’, for their generous and continuous support for our clinical and basic research work. Our group is supported by several grants from the French ministry of health as part of the ‘Programme Hospitalier de Recherche Clinique (PHRC)’. HDL was supported by a grant from the ‘Fondation de France’ (Paris, France).
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de Lavallade, H., El-Cheikh, J., Faucher, C. et al. Reduced-intensity conditioning allogeneic SCT as salvage treatment for relapsed multiple myeloma. Bone Marrow Transplant 41, 953–960 (2008). https://doi.org/10.1038/bmt.2008.22
- allogeneic transplantation
- reduced-intensity conditioning
- genetic randomization
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