We evaluated the effect of acute and chronic GVHD on relapse and survival after allogeneic hematopoietic SCT (HSCT) for multiple myeloma using non-myeloablative conditioning (NMA) and reduced-intensity conditioning (RIC). The outcomes of 177 HLA-identical sibling HSCT recipients between 1997 and 2005, following NMA (n=98) or RIC (n=79) were analyzed. In 105 patients, autografting was followed by planned NMA/RIC allogeneic transplantation. The impact of GVHD was assessed as a time-dependent covariate using Cox models. The incidence of acute GVHD (aGVHD; grades I–IV) was 42% (95% confidence interval (CI), 35–49%) and of chronic GVHD (cGVHD) at 5 years was 59% (95% CI, 49–69%), with 70% developing extensive cGVHD. In multivariate analysis, aGVHD (⩾grade I) was associated with an increased risk of TRM (relative risk (RR)=2.42, P=0.016), whereas limited cGVHD significantly decreased the risk of myeloma relapse (RR=0.35, P=0.035) and was associated with superior EFS (RR=0.40, P=0.027). aGVHD had a detrimental effect on survival, especially in those receiving autologous followed by allogeneic HSCT (RR=3.52, P=0.001). The reduction in relapse risk associated with cGVHD is consistent with a beneficial graft-vs-myeloma effect, but this did not translate into a survival advantage.
Some studies suggest a graft-vs-myeloma effect after allogeneic hematopoietic SCT (HSCT) for multiple myeloma (MM).1, 2, 3, 4 For example, donor lymphocyte infusions have induced remission in patients with recurrent MM after HSCT. In recipients of allogeneic HSCT after traditional myeloablative conditioning, the graft-vs-myeloma effect is suggested by the fact that chronic GVHD (cGVHD) correlates with CR.5 However, other studies report no correlation.6 Despite the beneficial graft-vs-myeloma effect, the high treatment-related mortality, mainly related to GVHD, has made myeloablative HSCT unattractive compared with autologous transplants or new drugs.7, 8, 9
Recently, allogeneic transplantations have been used earlier in the course of MM and with reduced conditioning intensity, in an attempt to reduce TRM after HSCT.10 A promising approach is the combination of high-dose chemotherapy and autologous transplant, followed by reduced-intensity HSCT.11 This approach relies on a maximal disease control strategy with autologous transplantation, followed by lower-intensity conditioning allogeneic HSCT to achieve an immune-mediated graft-vs-myeloma effect.6, 11, 12, 13, 14 Two randomized studies in high-risk MM patients indicated that autologous followed by allogeneic HSCT had similar outcomes compared with tandem autologous transplantation.13, 14 Studies not limited to high-risk MM patients with autologous followed by allogeneic approach, compared with tandem autologous transplantation, have shown discordant results with an earlier Italian study showing a survival advantage, whereas the recently reported Bone Marrow Transplant Clinical Trials Network 0102 Study showed no benefit to allogeneic transplantation.12, 15
With reduction in conditioning intensity, any beneficial effect of allogeneic HSCT is likely to be derived from an immune-mediated graft-vs-MM effect, but the relative impact of this effect has been difficult to characterize. A retrospective study by Crawley et al.16 showed that cGVHD was associated with superior survival in patients treated with reduced-intensity allogeneic transplantation. Another prospective study suggested no correlation between cGVHD and response in patients undergoing autologous followed by allogeneic HSCT for MM.6 Interestingly, the study by Crawley et al.16 did not specifically address the upfront planned autologous followed by allogeneic HSCT approach.
We analyzed the impact of acute and chronic GVHD on outcomes in myeloma patients undergoing allogeneic HSCT, following reduced-intensity conditioning (RIC), both in the planned autologous followed by allogeneic (auto-allo) and the single upfront allogeneic HSCT (not preceded by autotransplant) settings.
Patients and methods
Recipients of HLA-identical sibling BM and/or PBSC allogeneic transplants for MM within 18 months of diagnosis, between 1997 and 2005, reported to the CIBMTR(Center for International Blood and Marrow Transplant Research) were identified. Reduced-intensity regimens were defined and classified as non-myeloablative conditioning (NMA) or RIC based on the standard definitions.17 The patients were grouped into those receiving a single allogeneic HSCT (allo-only) and those receiving a planned autologous followed by allogeneic HSCT (auto-allo). Patients who received an autologous HSCT followed by an unplanned allogeneic HSCT at progression (n=16) were excluded from the study.
The CIBMTR is a research organization with more than 450 transplant centers worldwide, which contribute detailed data on consecutive transplants. Patients are followed longitudinally, with yearly follow-up. Computerized checks for errors, physician reviews of submitted data and on-site audits of participating centers ensure data quality.
OS was defined as the time from date of transplant to date of death, with survivors censored at the time of last contact. TRM was defined as death occurring in the absence of relapse/progressive disease, and summarized by the cumulative incidence estimate with relapse as the competing risk. Relapse/progression was defined as the time to first evidence of laboratory recurrence or progression of myeloma according to the standard EBMT/IBMTR criteria18 and summarized by the cumulative incidence estimate with TRM as the competing risk. EFS was defined as survival without progressive disease or relapse from CR. Progressive disease, relapse from CR and death in remission were the considered events. Probabilities of survival and EFS were calculated using the Kaplan–Meier estimator and compared using the Log-rank test. The incidence and stage of acute GVHD (aGVHD) were measured by the standard criteria.19 The incidence of chronic GVHD (cGVHD) was measured according to the standard criteria.20
Multivariate analyses were performed using Cox proportional hazards models. A stepwise model-building approach was used to identify the significant risk factors associated with outcomes of TRM, relapse, EFS and OS. The variables considered in the model-building procedures were as follows: age at transplant (<50 years vs ⩾50 years), gender (male vs female), Karnofsky performance score (<90 vs ⩾90 vs unknown), Durie–Salmon stage at diagnosis (I/II vs III), disease status and sensitivity of MM to chemotherapy before transplant (sensitive vs not sensitive vs others), prior lines of chemotherapy (⩽1 line vs 2 lines vs >2 lines), type of transplant (allo-only vs auto-allo), donor–recipient sex match (male-to-male vs male-to-female vs female-to-male vs female-to-female), conditioning (NMA vs RIC), year of transplant (⩽2001 vs >2001) and acute and chronic GVHD. At the time of transplantation, it is unknown who will and who will not develop GVHD. Therefore, GVHD was treated as a time-dependent covariate. Because acute and chronic GVHD effects are the main interests of this study, they were included in each step of model building. Factors that were significant at a 5% level were kept in the final model. The potential interactions between main effects and all significant risk factors were tested. The relative risks of significant covariates based on final models were reported. In addition to considering GVHD as a time-dependent covariate, we used a landmark analysis method to compute outcomes stratified by patients who developed aGVHD within 100 days. Patients surviving more than 100 days were included in aGVHD landmark analysis. A similar landmark study for those who developed cGVHD within 1 year of transplant was also performed. Landmark analysis results are presented in figures.
Table 1 summarizes patient, disease and transplant-related variables of interest. In all, 55% of the patients had IgG MM and 63% had Salmon–Durie stage III. About 72% of the patients were in complete or PR at the time of transplantation and 56% received NMA regimens. The most common immunosuppressive protocols were CY combined with mycophenolate mofetil, or CY combined with MTX.
The cumulative incidence of aGVHD grades I–IV at 100 days was 42% (95% confidence interval (CI), 35–49%). Overall aGVHD grades II–IV was observed in 53 patients (30%; Table 2).
cGVHD at 1 year was 45% (95% CI, 37–52%). At 5 years, it was 59% (95% CI, 49–69%) with 70% of extensive cGVHD.
At 1 year, TRM was 15% (95% CI, 10–20%), and at 5 years it was 25% (95% CI, 17–34%). In multivariate analysis, aGVHD was associated with an increased risk of TRM (Table 3, relative risk (RR)=2.42, P=0.016). cGVHD, whether limited or extensive, had no significant impact on TRM. Figures 1a and b represent the landmark analyses for TRM in those developing aGVHD within 100 days vs those who did not, and those developing cGVHD within 1 year vs those who did not.
Cumulative incidence of relapse at 1 year was 22% (95% CI, 16–28%). At 5 years, the incidence of relapse was 52% (95% CI, 41–63%). aGVHD had no statistically significant effect on the risk of relapse. cGVHD overall was associated with a reduced risk of relapse in the multivariate analysis, but the beneficial effect was confined to those with limited cGVHD (RR=0.35, P=0.035) and was not statistically significant in those with extensive cGVHD (RR=0.58, P=0.14; Table 3). Figure 2 represents the additional landmark analysis for relapse in those who developed any cGVHD within 1 year of HSCT vs those who did not.
The cumulative incidence of relapse at 1 year was 32% (95% CI, 21–43%) in the allo-only group vs 15% (95% CI, 8–22%) in the auto-allo group. The auto-allo group had a significantly lower risk of relapse in multivariate analysis compared with the allo-only group (Table 3, RR=0.59, P=0.043).
At 1 year, EFS was 64% (95% CI, 57–71%), and at 5 years it was 22% (95% CI, 13–34%). In the multivariate analysis, aGVHD and cGVHD overall had no impact on EFS (Table 3). However, limited cGVHD was associated with superior EFS (RR for relapse/death=0.40, P=0.027), whereas extensive cGVHD had no statistically significant impact on EFS. Figure 3 depicts a landmark analysis of EFS in those developing any cGVHD within 1 year of HSCT vs those who did not. At 1 year, EFS was 48% (95% CI, 36–60%) in the allo-only group, compared with 74% (95% CI, 66–83%) in the auto-allo group. At 5 years, EFS was 17% (95% CI, 7–29%) and 24% (95% CI, 7–48%) in the two groups, respectively. In the multivariate analysis, the auto-allo group had superior EFS (Table 3, RR=0.57, P=0.008).
At 1 year, survival was 75% (95% CI, 69–82%) and at 5 years it was 38% (95% CI, 26–50%). aGVHD was not associated with survival in the allo-only cohort (Table 3, RR of death=0.90, P=0.75). In the auto-allo cohort, aGVHD was associated with a higher risk of death (RR=3.52, P=0.001). cGVHD on the other hand, had no significant impact on survival.
Causes of death
The most common cause of death was relapsed or progressive MM in 33% patients, followed by infections and organ failure.
The aim of this analysis was to define the impact of GVHD on outcomes after allogeneic HSCT for MM. aGVHD is the major underlying cause of morbidity and TRM, following allogeneic HSCT in patients with MM.6 High TRM, mainly related to GVHD, made myeloablative HSCT unacceptable for most patients with MM.8, 21 In addition, only a limited number of myeloma patients are candidates for myeloablative allogeneic HSCT, because of age, non-availability of HLA-matched donors and pre-transplant comorbidities. The advent of RIC has led to an increased number of patients becoming eligible for HSCT as well as hope of reduced risk of TRM. However, the success of this modality is dependent on immune-mediated graft-vs-myeloma effect, because anti-neoplastic effect derived from the conditioning regimen is modest. We attempted to evaluate the relative impact of aGVHD and cGVHD on TRM, relapse and survival endpoints.
In the present study, patients receiving allogeneic HSCT for MM had a significant late risk of relapse (52% at 5 years). A striking finding is the high number of late relapses, especially among the patients who did not develop cGVHD (Figure 2). This is especially striking when we do a landmark analysis, because relapses occurring during the first year are not included in the figure. The continuous increase in relapses is not specific for this study, but is often seen in patients undergoing HSCT for myeloma.6, 8, 10, 22
There were significant risks of acute and chronic GVHD consistent with previous observations.22 The probability of grade III–IV aGVHD after RIC/NMA was 15%. In this group, mortality from GVHD is typically high.23 Similar to previous studies in leukemia patients, aGVHD was associated with a significant increase in the risk of TRM (Table 3), whereas cGVHD overall was not associated with increased TRM (Table 3, Figure 1b). The negative impact of aGVHD on survival was marked in the planned auto-allo cohort.
Several small studies have suggested a graft-vs-MM effect in patients receiving allogeneic HSCT after myeloablative conditioning.1, 2, 3, 4, 5, 16 Our study demonstrates that in the setting of RIC or NMA, cGVHD, especially limited cGVHD, is associated with beneficial impact with a decreased risk of myeloma relapse and superior EFS (Table 3). aGVHD on the other hand had no impact on relapse. This is in keeping with most studies of the GVL effect, showing that cGVHD has the strongest association with decreased relapse, whereas the effect of aGVHD on relapse was manifested in some, but not in all studies.24, 25, 26, 27
A reduced relapse risk was significantly associated with limited, but not extensive cGVHD. This is in contrast to a study of patients with acute leukemia, showing that there was no difference in relapse in patients with limited or extensive cGVHD.25 There may be several reasons why we did not find a reduced relapse risk in patients with extensive cGVHD. First, this is a multicenter study and there may be difficulties associated with the distinction between limited and extensive disease. Furthermore, there are a limited number of patients included and there may not have been sufficient number of patients to find a significant effect in patients with extensive cGVHD. We may also speculate that patients with extensive cGVHD are treated with more heavy immunosuppressive therapy that may abrogate the graft-vs-myeloma effect to a larger extent than the milder immunosuppression used in patients with limited disease.
In the comparison between allo-only and auto-allo cohorts, there were significantly lower early relapses and superior EFS in the auto-allo group, compared with the allo-only group (Table 3). The reason for the reduction in early relapse and improved EFS in the auto-allo group may be because of a selection bias favoring more high-risk patients, proceeding to an initial allogeneic transplant without a preceding autograft (supplementary data not shown). The allo-only group had markers of worse prognosis at baseline, including a higher proportion of patients with light chain and non-secretory disease (P<0.001), those with three or more lines of pre-transplant chemotherapy (P=0.01), and fewer patients with chemotherapy sensitive disease compared with the auto-allo group. The allo-only group also received RIC including melphalan (P<0.001)-based conditioning more often, suggesting a higher intensity of conditioning within the reduced-intensity category. This is also consistent with the notion that some of these patients were selected because they had more advanced disease and were considered for more ‘intensive conditioning’ within the RIC spectrum.
There was no increase in TRM associated with cGVHD (Table 3). This suggests that any graft-vs-MM effect induced by cGVHD not only decreased the probability of relapse, but also had no adverse effect on survival. A study by Crawley et al.16 showed that cGVHD was associated with improved EFS. No significant impact on EFS by aGVHD was observed despite of its association with higher risk of TRM. The reason for this mitigating effect may be an association between aGVHD and cGVHD (P=0.03). The increased mortality risk associated with aGVHD was statistically significant in the auto-allo group, but not in the allo-only group. The reason for this may also be because of the selection of higher-risk patients in the allo-only group.
cGVHD had no impact on OS despite lower relapse and unchanged TRM. Also the impact of cGVHD on quality of life and comorbidities cannot be measured in this analysis. This also suggests that currently the role of allotransplantation in MM remains limited by lack of adequate long-term disease control, a persistent risk of relapse and death from recurrent myeloma. These findings are consistent with emerging data from randomized studies such as the BMTCTN 0102 study.15
In conclusion, our analysis demonstrates a beneficial effect on relapse risk reduction associated with limited cGVHD without an increased risk of TRM. These findings have implications for clinical practice and future trials in allogeneic HSCT for MM. In this study, 59% of the patients with aGVHD developed cGVHD and 30% of them had limited cGVHD. In clinical practice, this figure may be increased by an early discontinuation of immunosuppression in the absence of GVHD.28 However, early immunosuppression should be best available to prevent aGVHD, because it was associated with an increased risk of TRM and decreased survival. These findings could also prompt wider use of donor lymphocyte infusions to induce graft-vs-myeloma effect in selected settings. Despite the promise of a graft-vs-myeloma effect, the major current shortcoming of allogeneic transplantation in MM is the ongoing risk of relapse. These are best addressed in prospective trials incorporating more novel conditioning and maintenance strategies.
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The CIBMTR is supported by Public Health Service Grant/Cooperative Agreement U24-CA76518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases; a Grant/Cooperative Agreement 5U01HL069294 from NHLBI and NCI; a contract HHSH234200637015C with Health Resources and Services Administration (HRSA/DHHS); two Grants N00014-06-1-0704 and N00014-08-1-0058 from the Office of Naval Research; and grants from AABB; Aetna; American Society for Blood and Marrow Transplantation, Amgen, Inc.; Anonymous donation to the Medical College of Wisconsin; Astellas Pharma US, Inc.; Baxter International, Inc.; Bayer HealthCare Pharmaceuticals; Be the Match Foundation; Biogen IDEC; BioMarin Pharmaceutical, Inc.; Biovitrum AB; BloodCenter of Wisconsin; Blue Cross and Blue Shield Association; Bone Marrow Foundation; Buchanan Family Foundation; Canadian Blood and Marrow Transplant Group; CaridianBCT; Celgene Corporation; CellGenix, GmbH; Centers for Disease Control and Prevention; Children's Leukemia Research Association; ClinImmune Labs; CTI Clinical Trial and Consulting Services; Cubist Pharmaceuticals; Cylex, Inc.; CytoTherm; DOR BioPharma, Inc.; Dynal Biotech (an Invitrogen Company); Eisai, Inc.; Enzon Pharmaceuticals, Inc.; European Group for Blood and Marrow Transplantation; Gamida Cell, Ltd.; GE Healthcare; Genentech, Inc.; Genzyme Corporation; Histogenetics, Inc.; HKS Medical Information Systems; Hospira, Inc.; Infectious Diseases Society of America; Kiadis Pharma; Kirin Brewery Co., Ltd.; The Leukemia and Lymphoma Society; Merck and Company; The Medical College of Wisconsin; MGI Pharma, Inc.; Michigan Community Blood Centers; Millennium Pharmaceuticals, Inc.; Miller Pharmacal Group; Milliman USA, Inc.; Miltenyi Biotec, Inc.; National Marrow Donor Program; Nature Publishing Group; New York Blood Center; Novartis Oncology; Oncology Nursing Society; Osiris Therapeutics, Inc.; Otsuka America Pharmaceutical, Inc.; Pall Life Sciences; Pfizer, Inc.; Saladax Biomedical, Inc.; Schering Corporation; Society for Healthcare Epidemiology of America; Soligenix, Inc.; StemCyte, Inc.; StemSoft Software, Inc.; Sysmex America, Inc.; THERAKOS, Inc.; Thermogenesis Corporation; Vidacare Corporation; Vion Pharmaceuticals, Inc.; ViraCor Laboratories; ViroPharma, Inc.; and Wellpoint, Inc. The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense or any other agency of the US Government. Olle Ringdén is supported by grants from the Swedish Cancer Society, the Children's Cancer Foundation, the Swedish Research Council, the Cancer Society in Stockholm, and Karolinska Institutet.
The authors declare no conflict of interest.
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