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Allogeneic Hematopoietic Cell Transplantation in Multiple Myeloma: Impact of Disease Risk and Post Allograft Minimal Residual Disease on Survival
Accepted Manuscript Allogeneic hematopoietic cell transplantation in multiple myeloma: impact of disease risk and post allograft minimal residual disease on survival Binod Dhakal, Anita D’Souza, Michael Martens, Jonathan Kapke, Alexandra Harrington, Marcelo Pasquini, Wael Saber, William R. Drobyski, Mei Jie Zhang, Mehdi Hamadani, Parameswaran N. Hari PII:
S2152-2650(16)30013-1
DOI:
10.1016/j.clml.2016.03.001
Reference:
CLML 768
To appear in:
Clinical Lymphoma, Myeloma and Leukemia
Received Date: 8 January 2016 Revised Date:
26 February 2016
Accepted Date: 21 March 2016
Please cite this article as: Dhakal B, D’Souza A, Martens M, Kapke J, Harrington A, Pasquini M, Saber W, Drobyski WR, Zhang MJ, Hamadani M, Hari PN, Allogeneic hematopoietic cell transplantation in multiple myeloma: impact of disease risk and post allograft minimal residual disease on survival, Clinical Lymphoma, Myeloma and Leukemia (2016), doi: 10.1016/j.clml.2016.03.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Allogeneic hematopoietic cell transplantation in multiple myeloma: impact of disease risk and post allograft minimal residual disease on survival Binod Dhakal, Anita D’Souza, Michael Martens, Jonathan Kapke, Alexandra Harrington,
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Marcelo Pasquini, Wael Saber, William R. Drobyski, Mei Jie Zhang, Mehdi Hamadani,
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Parameswaran N Hari
1. Division of Hematology/Oncology; Medical College of Wisconsin
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2. Division of Biostatistics; Medical College of Wisconsin
3. Department of Medicine; Medical College of Wisconsin
4. Department of Pathology; Medical College of Wisconsin
Corresponding author:
Professor of Medicine
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Parameswaran N Hari, M.D
Medical College of Wisconsin
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Milwaukee, WI 53226 Phone: (414) 805-4600
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Fax: (414)-805-6815
Email: [email protected]
Financial Disclosure and Propriety Statement: Nothing to disclose Running title: Allogeneic transplantation in multiple myeloma Key Words: Allogeneic stem cell transplantation, Multiple myeloma, Risk status and minimal residual disease
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Abstract: Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative
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option for multiple myeloma (MM). We analyzed our experience of allo-HCT in MM and examined outcomes in 77 consecutive MM patients receiving allo-HCT from matched
sibling (n=69) or unrelated donors (n=8). The primary objectives were to assess overall
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survival (OS), progression free survival, (PFS), and non-relapse mortality (NRM) in these patients. Sixty-six patients received non-myeloablative/reduced intensity conditioning
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regimens while 11 received myeloablative regimens. Median follow up of survivors was 50 months (range 2.3-129.3). Twenty-seven (35.1%) had high-risk cytogenetics at diagnosis (t (4:14), 17p deletion, chromosome 1 abnormality, or t (14:16)). All of patients except one had prior auto transplant. On multivariate analysis, older age (HR 1.055, 95% CI 1.001, 1.11; p=0.04) less than complete remission (CR) at allo-HCT (HR 4.3,
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95% CI 1.3, 14.1; p=0.006), and CMV reactivation (HR 3.2, 95% CI 1.38, 7.6, p=0.002) were associated with higher mortality risk. Less than complete remission (CR) at alloHCT was also associated with higher risk for NRM (HR 5.8, 95% CI 1.3, 26.3, p=0.02).
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There was no difference in OS or PFS between high risk and standard risk cytogenetics. No difference in OS and PFS was seen in those who had morphological complete
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response regardless of the minimal residual disease (MRD) status. Allotransplant benefited younger patients and those in CR at the time of transplant. The adverse effect of high-risk cytogenetics may be overcome by the allo-HCT. Micro abstract:
Allogeneic hematopoietic cell transplantation(allo-HCT) is a potentially curative for multiple myeloma. The results from randomized controlled trials, however, have shown conflicting outcomes. We retrospectively analyzed all multiple myeloma patients who underwent allo-HCT at our institution from 2002-2013. Our data suggests that allo-HCT
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can provide long term disease control in young patients and those with high-risk cytogenetics.
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Introduction: Outcomes for patients with multiple myeloma (MM) have improved in the past
decade with the incorporation of novel agents in therapeutic armamentarium, adoption of post autologous hematopoietic cell transplantation (auto-HCT)
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maintenance/consolidation strategies and with general advances in supportive care 1. Despite these advances, nearly all MM patients relapse and eventually develop
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refractory disease. The available options for relapsed patients include bortezomib, lenalidomide retreatment and newer drugs that include carfilzomib, pomalidomide, panabinostat and monoclonal antibodies 2,3. Allogeneic hematopoietic cell transplantation (allo-HCT); a potentially curative option in MM, has several advantages including a tumor-free graft, and the potential graft-versus-myeloma effect mediated by
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the alloreactive donor immune cells 4,5. However, owing to a high non-relapse mortality (NRM) associated with allo-HCT, a clear survival benefit with this modality compared to non-allo HCT approaches remains to be proven 6-8. Development of newer preparative
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regimens as well as improvements in supportive care has led to a decline in NRM from historical rates of 40-50% to 10-15% in recent years 9,10. The role of allo-HCT in the era
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of novel agents is not clearly defined however the approaches are not mutually exclusive 11-14
. Patients with high risk MM by cytogenetic criteria tend to run an aggressive course
despite novel agents15. Whether allo-HCT can improve prognosis of high risk MM is not clear 1. In addition while achieving a minimal residual disease (MRD) negative state in MM has been shown to be a strong favorable prognostic factor 16,for the outcomes of patients achieving a MRD negative remission after allo-HCT is also not known.
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We report here the utility of allo-HCT in a cohort of MM patients and evaluate the impact of allo-HCT on high-risk cytogenetics status. We also evaluate the impact of
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depth for HCT remission and MRD state post allo-HCT on the outcomes.
Materials and Methods: Patient population:
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All adult myeloma patients undergoing allo-HCT for MM from either a matched
sibling donor (MRD) or an unrelated donor (MUD) between 2002-2013 were included in
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the study. The Institutional Review Board at the Medical College of Wisconsin approved this study.
Preparative regimens and GVHD prophylaxis:
Patients received either a myeloablative or a non-myeloablative /reduced intensity conditioning regimens as defined previously 17. Regimen selection was based
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on the physician preference and available clinical trials. All patients received methotrexate and tacrolimus-based acute GVHD prophylaxis after 8/2004 and cyclosporine based prophylaxis before that. Patients received standard anti-microbial
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jiroveci.
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prophylaxis with ciprofloxacin, acyclovir, azoles and prophylaxis for Pneumocystis
Definitions of outcomes: Response, disease progression and relapse were defined according to the
International Myeloma Working Group uniform response criteria 18. For progression-free survival (PFS), a patient was considered a treatment failure at the time of progression/relapse or death from any cause. Death from any cause other than relapse was defined as NRM. Patients alive without evidence of disease relapse or progression were censored at last follow up. Overall survival (OS) was defined as the interval from
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the date of transplantation to the date of death. Surviving patients were censored at last follow up. Acute graft-versus-host disease (aGVHD) 19 and chronic graft-versus-host disease (cGVHD) 20 diagnosis and staging were based as described previously.
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Neutrophil engraftment was defined as first of 3 successive days with absolute neutrophil count >0.5 x 109/L after post-transplantation nadir. Platelet engraftment was
considered to have occurred in the first of three consecutive days with platelet count 20
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x 109/L or higher, in the absence of platelet transfusion for 7 consecutive days. High-risk MM was defined as having high risk chromosomal abnormalities: del 13 or hypodiploidy on conventional cytogenetics, chromosome 1 q abnormality (4:14), t(14:16) or del 17p
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on fluorescence in situ hybridization (FISH) or conventional cytogenetics 18,21. CMV reactivation was defined as more than 1000 copies/ml of CMV DNA by quantitative polymerase chain reaction (qPCR) assay. MRD monitoring by flow cytometry:
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Four or 8-color flow cytometry was perfomed on a FACSCalibur or FACSCanto II (March 2009-2013) using the following antibodies attached to fluorochromes: CD10, CD19, CD20, CD38, CD45, CD56, kappa and lambda. Anti-CD 117 and CD200
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antibodies were analyzed in some cases. Plasma cells were identified by cluster analysis as CD38 bright (+) events. Antigen expression was compared to an isotype
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control containing an anti-CD38 antibody. MRD analysis was performed by analyzing 200,000 events with Paint-a-Gate software (Becton Dickinson) and was defined as at last 0.01% plasma cells with either immunophenotypic aberrance or clonal light chain expression. Aberrancy was defined as lack of CD19 or expression of CD20, CD56, CD117 and/or CD200 in plasma cells; clonality was defined as 0.5 ≤ kappa/lamda ≥4.
Statistical Methods:
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The outcomes of interest included NRM, PFS and OS. Univariate analysis of these outcomes consisted of constructing Kaplan Meier curves of OS and PFS and cumulative incidence estimates of NRM. Cox proportional hazards regression was used
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to assess what factor impact these outcomes and the strength of the effects. For multivariate analysis, a Cox regression model of each outcome was
constructed using stepwise selection of potential risk factors including age, sex,
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International Staging System (ISS), response status at the time of allo-HCT, time from
auto-HCT to allo-HCT, CMV re-activation and aGVHD and cGVHD status. A significance
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level of 0.05 was used as the criterion for inclusion in the final model. Due to sample size limitations, interactions between predictors in the final models were not tested. All analysis was performed in SAS 9.4(SAS institute, Cary, NC). Results: Baseline characteristics
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Seventy-seven patients underwent allo-HCT for MM at our institution between 2002-2013. All except one patient had prior auto-HCT. Twenty-six patients received planned tandem allo-HCT after an auto-HCT. Out of 26 patients undergoing a planned
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tandem auto-allo HCT, 10 patients received planned auto-allo off trial due to high-risk cytogenetics and the remaining were part of BMT CTN 0102. The remaining patients
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received allo-HCT as salvage after auto-HCT relapse. Patient, disease and transplant characteristics are in Table 1. The median age of at transplant was 53 years (range 2369). At the time of allo-HCT, 30% (n= 23) of the patients were in complete remission and majority 62% (n=47) had at least a partial response. Majority had matched sibling donors (90%, n=69). The majority received non-myeloablative/reduced intensity conditioning regimens (86%, n=67). The median follow up of survivors was 50 months (range, 2.3129.3). Twenty-two patients received lenalidomide and three patients received bortezomib as maintenance therapy post allo-HCT.
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Engraftment: The median time to neutrophil engraftment was 13 days (range, 5-13) and 11
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days (range, 6-11) for myeloablative and reduced intensity conditioning regimens respectively. The median time to platelet engraftment was 17 days (range, 5-27) and 13 days (range, 9-15) for myeloablative and reduced intensity conditioning regimens. At day
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CI 91.5-100) of the patients engrafted their platelets.
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100, 97.3% (95% CI 93.7-100) of the patients engrafted their platelets and 95.9% (95%
GVHD:
Grade 2 aGVHD was seen in 14(18%), while grade 3 and grade 4 aGVHD was seen in 5(6.5%) and 3(4%) respectively. Chronic GVHD was seen in 29(37%) of the patients. The cumulative incidence of aGVHD was 23.1% (95% CI 15.4-34.7) at day 100
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and 28.3% (95% CI 19.9-40.4) at 1 year. The cumulative incidence of cGVHD was 28.8 % (95% CI 20.2-41) at 1 year and 33.4% (24.2-46.1) at 3 years.
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Non-relapse mortality:
There were 18 deaths (23.4%) from non-relapse causes overall and these
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etiologies included GVHD (n=5), infections (n=6), cardio or pulmonary failure (n=4) and other causes (n=3). Cumulative incidence of NRM at 1 year was 13% (95% CI 7.3-23.2). On multivariate analysis, lack of CR status at allo-HCT (HR, 5.8 95% CI 1.3-26.2, P=0.021) was associated with higher risk of NRM.
Response/Progression: At day +100 post-transplant evaluation, 14 achieved stringent complete response (sCR), 39 patients were in CR, 5 patients had very good partial response (VGPR), 15
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patients had partial response (PR) and 4 had relapse/progression of the disease. At a median follow up of 50 months, 27(35.1%) had disease progression. The cumulative incidence of disease relapse at day 100 was 2.6% (95% CI, 0.6-10.2) and at 1 year was
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14.4 % (95% CI 8.3-24.9). Progression-free survival:
The PFS at 1 year 72.6% (95% CI, 61.1-81.2) and at 3 year was 47% (95% CI
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34.5-58.2) (Fig 1a). There was no difference in the PFS in patients who had planned tandem allo-HCT vs. those who had salvage allo-HCT (Fig 1b). There was trend for
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improved PFS in patients who had allo-HCT after 2008; however did not reach statistical significance (Fig1c). Number of lines of prior therapies (≤2 prior therapies vs. >2 prior therapies) in patients undergoing salvage allo-HCT did not affect the PFS (Fig 1d). On multivariate analysis, age, stage of disease, time from auto-HCT to allo-HCT and development of GVHD did not have any significant effect on PFS. In our study 8 patients
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received donor lymphocyte infusion (DLI) for progression/relapse, out of which 5 responded i.e. a response rate of 62.5%. The median duration of response to DLI was 8
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months (range, 1-36).
Overall survival:
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The OS at 1 year was 83% (95% CI 72.5-89.8) and at 3 years was 63.8% (95% CI 51-74.2) (Fig 2a). Patients who had planned tandem allo-HCT and those who had salvage allo-HCT had similar OS in our study (Fig 2b). There was no difference in OS in patients who had allo-HCT after 2008(Fig 2c). No difference was seen in OS of patients undergoing salvage allo-HCT when stratified on number of lines of prior therapies (≤2 prior therapies vs. >2 prior therapies) (Fig2d). On multivariate analysis, age (HR 1.05,95% CI 1.001-1.13,p=0.04), lack of CR status at allo-HCT (HR 4.3, 95% CI 1.3-
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7.6,p=0.006) and CMV reactivation (HR 3.2, 95% CI 1.3-7.6,p=0.002) were significantly associated with worse OS (Table 3).
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Risk status: Twenty-seven patients had high-risk disease by FISH or cytogenetics. Fig 3a and 3b shows both the PFS and OS by risk status in these patients. There was no difference
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in high-risk vs. standard risk patients in either PFS (3 year 39% vs. 55%, p= 0.62) or OS (3 year 50% vs. 67%, p=010) respectively. Among the high-risk patients, 5 patients
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(6.4%) were dual-refractory (i.e. refractory to lenalidomide and bortezomib) and 2 patients were refractory to bortezomib only. Of those 5 patients, 3 achieved MRD negative state at day 100 and morphologic CR. These patients were still alive at the time of follow up. The remaining 2 patients had positive MRD at day 100 and died due to nonrelapse causes.
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Minimal residual disease status
Minimal residual disease status at day 100 was available in 46 patients. Of those 46 patients, 32 patients were MRD negative at day 100. Of these, 20 were in CR and 12
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were in sCR. Fourteen patients were MRD positive; 12 were in CR and 2 in sCR at day +100. There was no difference in both OS and PFS by MRD status in those with
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morphological CR/sCR at day 100(Fig4a and 4b). The 3 year PFS and OS for MRD negative vs. positive patients were 63.2% vs. 38.4%(p=0.45) and 78.7% vs. 59.6% (p=0.35)respectively.
Discussion: Our data suggest that allo-HCT in MM can provide sustained long term remissions in patients with high-risk disease or those who have relapsed after auto-HCT. Importantly, there was no difference in the survival between high-risk and standard risk
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cytogenetic risk groups suggesting that this modality may overcome the status conferred by high-risk FISH abnormalities. CMV reactivation was associated with worse overall survival.
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Allogeneic hematopoietic stem cell transplant preceded by classic myeloablative conditioning therapy was explored for MM in the late 1980s through the mid-1990s22-24. A most consistent finding with the use of myeloablative conditioning was high NRM of 40-
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60% leading to alternative approach of non-myeloablative/reduced intensity conditioning (NST/RIC) regimens. Randomized trials have attempted to evaluate tandem AutoHCTalloHCT approach vs. tandem auto-HCT in the upfront transplant setting using non25,26
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myeloablative preparative regimens
. The results of the study showed lower NRM
(10-15%) than the myeloablative conditioning, however survival results were discordant. The BMTCTN 0102, one of the largest myeloma transplant trials conducted in the US showed no difference in the primary end point of 3-year PFS (46% in the tandem auto27
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HCT group vs. 43% in the auto-alloHCT)
. In contrast, the study from the European
Blood and Marrow Transplant network showed that with a median follow up of 8 years, the PFS and OS for the tandem auto-alloHCT was superior to the tandem auto-HCT 28,29
.The difference in outcomes in these
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group with NRM of 13% in the allo-HCT arm
studies could partly be explained by the variability in conditioning regimens used, patient
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selection, MM risk profile etc. In our study, the cumulative incidence of NRM was 13% at 1 year; the 5-year PFS and OS was 38% and 58.6% respectively. These outcomes are similar to and even superior to some other published single institution studies30-32. Given the lack of consistent survival benefit, in both newly diagnosed and relapsed MM, use of allo-HCT in MM should ideally be restricted to well-designed clinical trials. However, in patients with high-risk MM by cytogenetic criteria, long-term prognosis is poor and role of early allo-HCT as part of their initial therapy program or in first chemotherapy-sensitive relapse warrants prospective investigation. The recently launched BMT CTN trial 1302 is
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evaluating the role of early allo-HCT in high risk MM patients followed by maintenance with MLN9708. High-risk cytogenetics are associated with worse outcomes after auto-HCT. The
previously published study
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impact of high- risk cytogenetics on the outcomes disappeared after allo-HCT in 30
. Our study also supports these findings, as both the OS
and PFS in the high-risk groups were similar as the standard risk groups. These findings
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add to the literature that the negative clinical and molecular prognostic factors may be overcome by allo-HCT in MM. The ongoing BMT CTN 1302 assessing the role of allo-
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HCT in high risk MM followed by maintenance with new proteasome inhibitor (ixazomib) may shed more light in this area in the prospective setting.
The role of MRD negativity in multiple myeloma is currently under investigation 33
. Some reports suggest that MRD negativity may translate to improved PFS and OS
34,35
. MRD has also been investigated as a tool to predict relapse free survival after
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alloHCT36. Galimberti et al reported that for patients post alloHCT, persistent PCR (polymerase chain reaction) negativity was associated with a cumulative risk of relapse at five years of 0%, while those with mixed Allele-specific oligonucleotide Polymerase
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chain reaction (ASO-PCR) results had a relapse rate of 33% and those who never achieved ASO-PCR negativity relapsed at a rate of 100%37. Our study did not show any
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survival difference in CR/sCR patients who achieved negative MRD by flow cytomtery at day 100 versus those who were MRD positive; however this could be due to the small sample size of patients with MRD testing in CR/sCR after allo-HCT in our study. Donor lymphocyte infusions are able to induce a clinically meaningful GVM effect
in some patients relapsing after allo-HCT in MM
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. In a series of 54 patients with MM,
DLI yielded overall and complete response rates of 52 and 17 percent, and acute and chronic GVHD in 57 and 47 percent, respectively
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.The response to DLI was 62.5% in
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our series. Allogeneic hematopoeitic stem cell transplant thus remains a platform for additional immune based strategies at relapse or to preempt relapse. The Italian Bone Marrow registry data of 196 patients with MM receiving an
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unrelated donor transplant showed a significant improvement in OS for patients with chronic graft versus host disease (cGVHD)(HR,.55)40 suggesting the graft vs MM effect(GVM). In another single institution study, development of cGVHD was associated 30
.
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with favorable overall and progression free survival further elucidating the GVM effect
However, our study did not show any significant effect of cGVHD on survival presumably
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because of low cGVHD rates. Development of acute GVHD in our study was associated with worse survival in univariate analysis but had no significance in multivariate analysis. Donor and recipient CMV seronegative status has been suggested as a predictor of better OS, PFS and NRM41. Other studies have reported higher rates of CMV reactivation but no effect on the post transplantation outcomes
42
. In our study, CMV
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reactivation was consistently associated with worse overall survival underscoring the need for close monitoring and aggressive preemptive treatment. The strength of the study is the relatively large sample of allo-HCT in the era of
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novel therapeutics. Our study also has its limitations owing to its retrospective nature. There is significant heterogeneity in the study groups (planned tandem vs. salvage
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group), the various induction regimens used over the course of years and also the variability in the conditioning regimens. In conclusion, our study demonstrates that young MM patients with high risk
disease may benefit from allo-HCT. Consideration should be given early in the disease course. Close monitoring of CMV and aggressive pre-emptive treatments should be adopted given the worse outcomes with CMV reactivation. Donor lymphocyte infusion can be a salvage option in these patients relapsing after allo-HCT. While our study
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suggests allo-HCT can mitigate high risk MM, ultimately larger prospective studies are still needed to establish the role of allo-HCT particularly in this setting. Clinical practice points:
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1. Multiple myeloma remains an incurable disease despite the development of novel agents, maintenance/consolidation after autologous stem cell transplant and overall improvement in supportive care.
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2.The outcome of patients with high-risk cytogenetics is even dismal with median overall survival of 10-12 months with therapy.
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3. Allogeneic stem cell transplantation is a potentially curative option for this disease. 4. There was no difference in high-risk vs. standard risk patients in either PFS (3 year 39% vs. 55%, p= 0.62) or OS (3 year 50% vs. 67%, p=010) respectively. 5. On multivariate analysis, age (HR 1.05,95% CI 1.001-1.13,p=0.04), lack of CR status at allo-HCT (HR 4.3, 95% CI 1.3-7.6,p=0.006) and CMV reactivation (HR 3.2, 95% CI
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1.3-7.6,p=0.002) were significantly associated with worse OS.
6. Young MM patients with high risk disease may benefit from allo-HCT.
References:
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Tricot G, Attal M, Merlini G, Powles R, Richardson P, Shimizu K, Tosi P, Morgan G, Rajkumar SV, International Myeloma Working Group. International uniform response criteria for multiple myeloma. Leukemia. 2006;20:1467-73. 19. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, Thomas ED. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995;15:825-8. 20. Shulman HM, Sullivan KM, Weiden PL, McDonald GB, Striker GE, Sale GE, Hackman R, Tsoi MS, Storb R, Thomas ED. Chronic graft-versus-host syndrome in man. A long-term clinicopathologic study of 20 Seattle patients. Am J Med. 1980;69:204-17. 21. Mikhael JR, Dingli D, Roy V, Reeder CB, Buadi FK, Hayman SR, Dispenzieri A, Fonseca R, Sher T, Kyle RA, Lin Y, Russell SJ, Kumar S, Bergsagel PL, Zeldenrust SR, Leung N, Drake MT, Kapoor P, Ansell SM, Witzig TE, Lust JA, Dalton RJ, Gertz MA, Stewart AK, Rajkumar SV, Chanan-Khan A, Lacy MQ, Mayo Clinic. Management of newly diagnosed symptomatic multiple myeloma: updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines 2013. Mayo Clin Proc. 2013;88:360-76. 22. Bensinger WI, Buckner CD, Anasetti C, Clift R, Storb R, Barnett T, Chauncey T, Shulman H, Appelbaum FR. Allogeneic marrow transplantation for multiple myeloma: an analysis of risk factors on outcome. Blood. 1996;88:2787-93. 23. Gahrton G, Tura S, Ljungman P, Belanger C, Brandt L, Cavo M, Facon T, Granena A, Gore M, Gratwohl A. Allogeneic bone marrow transplantation in multiple myeloma. European Group for Bone Marrow Transplantation. N Engl J Med. 1991;325:1267-73. 24. Gahrton G, Tura S, Ljungman P, Blade J, Brandt L, Cavo M, Facon T, Gratwohl A, Hagenbeek A, Jacobs P. Prognostic factors in allogeneic bone marrow transplantation for multiple myeloma. J Clin Oncol. 1995;13:1312-22. 25. Lokhorst HM, van der Holt B, Cornelissen JJ, Kersten MJ, van Oers M, Raymakers R, Minnema MC, Zweegman S, Janssen JJ, Zijlmans M, Bos G, Schaap N, Wittebol S, de Weerdt O, Ammerlaan R, Sonneveld P. Donor versus no-donor comparison of newly diagnosed myeloma patients included in the HOVON-50 multiple myeloma study. Blood. 2012;119:6219,25; quiz 6399. 26. Rosinol L, Perez-Simon JA, Sureda A, de la Rubia J, de Arriba F, Lahuerta JJ, Gonzalez JD, Diaz-Mediavilla J, Hernandez B, Garcia-Frade J, Carrera D, Leon A, Hernandez M, Abellan PF, Bergua JM, San Miguel J, Blade J, Programa para el Estudio y la Terapeutica de las Hemopatias Malignas y Grupo Espanol de Mieloma (PETHEMA/GEM). A prospective PETHEMA study of tandem autologous transplantation versus autograft followed by reduced-intensity conditioning allogeneic transplantation in newly diagnosed multiple myeloma. Blood. 2008;112:3591-3. 27. Krishnan A, Pasquini MC, Logan B, Stadtmauer EA, Vesole DH, Alyea E,3rd, Antin JH, Comenzo R, Goodman S, Hari P, Laport G, Qazilbash MH, Rowley S, Sahebi F, Somlo G, Vogl DT, Weisdorf D, Ewell M, Wu J, Geller NL, Horowitz MM, Giralt S, Maloney DG, Blood Marrow Transplant Clinical Trials Network (BMT CTN). Autologous haemopoietic stem-cell transplantation followed by allogeneic or autologous haemopoietic stem-cell transplantation in patients with multiple myeloma (BMT CTN 0102): a phase 3 biological assignment trial. Lancet Oncol. 2011;12:1195-203. 28. Bjorkstrand B, Iacobelli S, Hegenbart U, Gruber A, Greinix H, Volin L, Narni F, Musto P, Beksac M, Bosi A, Milone G, Corradini P, Goldschmidt H, de Witte T, Morris C, Niederwieser D, Gahrton G. Tandem autologous/reduced-intensity conditioning allogeneic stem-cell transplantation versus autologous transplantation in myeloma: longterm follow-up. J Clin Oncol. 2011;29:3016-22. 29. Gahrton G, Iacobelli S, Bjorkstrand B, Hegenbart U, Gruber A, Greinix H, Volin L, Narni F, Carella AM, Beksac M, Bosi A, Milone G, Corradini P, Schonland S, Friberg K,
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van Biezen A, Goldschmidt H, de Witte T, Morris C, Niederwieser D, Garderet L, Kroger N, EBMT Chronic Malignancies Working Party Plasma Cell Disorders Subcommittee. Autologous/reduced-intensity allogeneic stem cell transplantation vs autologous transplantation in multiple myeloma: long-term results of the EBMT-NMAM2000 study. Blood. 2013;121:5055-63. 30. Donato ML, Siegel DS, Vesole DH, McKiernan P, Nyirenda T, Pecora AL, Baker M, Goldberg SL, Mato A, Goy A, Rowley SD. The graft-versus-myeloma effect: chronic graft-versus-host disease but not acute graft-versus-host disease prolongs survival in patients with multiple myeloma receiving allogeneic transplantation. Biol Blood Marrow Transplant. 2014;20:1211-6. 31. Mir MA, Kapoor P, Kumar S, Pandey S, Dispenzieri A, Lacy MQ, Dingli D, Hogan W, Buadi F, Hayman S, Gandhi M, Gertz MA. Trends and outcomes in allogeneic hematopoietic stem cell transplant for multiple myeloma at mayo clinic. Clin Lymphoma Myeloma Leuk. 2015;15:349,357.e2. 32. Rosinol L, Jimenez R, Rovira M, Martinez C, Fernandez-Aviles F, Marin P, SuarezLledo M, Gutierrez-Garcia G, Fernandez de Larrea C, Carreras E, Urbano-Ispizua A, Blade J. Allogeneic hematopoietic SCT in multiple myeloma: long-term results from a single institution. Bone Marrow Transplant. 2015;50:658-62. 33. Kumar SK, Rajkumar SV. The current status of minimal residual disease assessment in myeloma. Leukemia. 2014;28:239-40. 34. Martinez-Sanchez P, Montejano L, Sarasquete ME, Garcia-Sanz R, FernandezRedondo E, Ayala R, Montalban MA, Martinez R, Garcia Larana J, Alegre A, Hernandez B, Lahuerta JJ, Martinez-Lopez J. Evaluation of minimal residual disease in multiple myeloma patients by fluorescent-polymerase chain reaction: the prognostic impact of achieving molecular response. Br J Haematol. 2008;142:766-74. 35. Rawstron AC, Child JA, de Tute RM, Davies FE, Gregory WM, Bell SE, Szubert AJ, Navarro-Coy N, Drayson MT, Feyler S, Ross FM, Cook G, Jackson GH, Morgan GJ, Owen RG. Minimal residual disease assessed by multiparameter flow cytometry in multiple myeloma: impact on outcome in the Medical Research Council Myeloma IX Study. J Clin Oncol. 2013;31:2540-7. 36. Corradini P, Cavo M, Lokhorst H, Martinelli G, Terragna C, Majolino I, Valagussa P, Boccadoro M, Samson D, Bacigalupo A, Russell N, Montefusco V, Voena C, Gahrton G, Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Molecular remission after myeloablative allogeneic stem cell transplantation predicts a better relapse-free survival in patients with multiple myeloma. Blood. 2003;102:1927-9. 37. Galimberti S, Benedetti E, Morabito F, Papineschi F, Callea V, Fazzi R, Stelitano C, Andreazzoli F, Guerrini F, Ciabatti E, Martino M, Nobile F, Iacopino P, Petrini M. Prognostic role of minimal residual disease in multiple myeloma patients after nonmyeloablative allogeneic transplantation. Leuk Res. 2005;29:961-6. 38. Mateos MV, Oriol A, Martinez-Lopez J, Gutierrez N, Teruel AI, de Paz R, GarciaLarana J, Bengoechea E, Martin A, Mediavilla JD, Palomera L, de Arriba F, Gonzalez Y, Hernandez JM, Sureda A, Bello JL, Bargay J, Penalver FJ, Ribera JM, Martin-Mateos ML, Garcia-Sanz R, Cibeira MT, Ramos ML, Vidriales MB, Paiva B, Montalban MA, Lahuerta JJ, Blade J, Miguel JF. Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: a randomised trial. Lancet Oncol. 2010;11:934-41. 39. Lokhorst HM, Wu K, Verdonck LF, Laterveer LL, van de Donk NW, van Oers MH, Cornelissen JJ, Schattenberg AV. The occurrence of graft-versus-host disease is the
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major predictive factor for response to donor lymphocyte infusions in multiple myeloma. Blood. 2004;103:4362-4. 40. Passera R, Pollichieni S, Brunello L, Patriarca F, Bonifazi F, Montefusco V, Falda M, Montanari M, Guidi S, Giaccone L, Mordini N, Carella AM, Bavaro P, Milone G, Benedetti F, Ciceri F, Scime R, Benedetti E, Castagna L, Festuccia M, Rambaldi A, Bacigalupo A, Corradini P, Bosi A, Boccadoro M, Bandini G, Fanin R, Bruno B. Allogeneic hematopoietic cell transplantation from unrelated donors in multiple myeloma: study from the Italian Bone Marrow Donor Registry. Biol Blood Marrow Transplant. 2013;19:940-8. 41. Auner HW, Szydlo R, van Biezen A, Iacobelli S, Gahrton G, Milpied N, Volin L, Janssen J, Nguyen Quoc S, Michallet M, Schoemans H, El Cheikh J, Petersen E, Guilhot F, Schonland S, Ahlberg L, Morris C, Garderet L, de Witte T, Kroger N, Plasma Cell Dyscrasia Sub-committee of the Chronic Malignancies Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Reduced intensityconditioned allogeneic stem cell transplantation for multiple myeloma relapsing or progressing after autologous transplantation: a study by the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant. 2013;48:1395-400. 42. El-Cheikh J, Devillier R, Crocchiolo R, Furst S, Calmels B, Faucher C, Stoppa AM, Granata A, Castagna L, Ladaique P, Lemarie C, Bouabdallah R, Zandotti C, Merlin M, Berger P, Chabannon C, Blaise D. Impact of pretransplant donor and recipient cytomegalovirus serostatus on outcome for multiple myeloma patients undergoing reduced intensity conditioning allogeneic stem cell transplantation. Mediterr J Hematol Infect Dis. 2013;5:e2013026.
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49 (64) 28 (36)
27 (35) 21 (27) 28 (36) 1 (2) 90 (80-100) 1 (0-3) 76 (98.7%) 77 (100%)
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Median age at transplant, years (range) Median time from diagnosis to transplant, months (range) Gender -Male -Female International Staging System -I -II -III -Missing 1 KPS (median, range) 2 HCT-CI (median, range) Prior Auto transplant Graft source(Peripheral Blood) 3 Cytogenetics/FISH -Standard risk -High Risk GVHD prophylaxis -Methotrexate/Cyclosporine -Methotrexate/Tacrolimus
Total, N=77 (%) 53 (23-69) 12 (7-81)
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Characteristics
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Table 1. Baseline characteristics
50 27
15 (19.4) 62 (80.5)
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Disease Status at Transplant 4 -sCR, CR 17 (22) 5 -VGPR 6(7.7) 6 -PR 47 (62) -Stable or Progressive disease 7 (6) Refractory to Novel agents Bortezomib 2(2.5) 7 Double 5(6.4) Donor type -HLA identical sibling 69 (90) -Matched Unrelated donor (8/8 allele level match) 8 (10) Type of transplant -Myeloablative 11 (14) -Non-myeloablative/Reduced intensity 66 (86) Maintenance therapies post allogeneic-HCT -Lenalidomide 22(29) -Bortezomib 3(4) Conditioning regimen -Low dose TBI (2Gy) 45 (59) -Cyclophosphamide/Fludarabine 7 (9) -Cyclophosphamide/TBI 4 (5) -Fludarabine/Melphalan 11 (14) -Fludarabine/TBI 6 (8) -Others* 4 (5) * Melphalan=1, Fludarabine/Busulfan=1, 5 Fluorouracil, Mitomycin,Etoposide and Cisplatin=2 1-Karnosky performance score 2- Hematopoietic cell transplant co-morbidity index
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3-High risk: del 13 or hypodiploidy on conventional cytogenetics, chromosome 1 q abnormality, t(4:14), t(14:16) or del 17p on fluorescence in situ hybridization (FISH) or conventional cytogenetics 4-sCR: stringent complete response, CR: complete response, 5- VGPR: very good partial response 6-PR: partial response
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7- Refractory to Bortezomib and Lenalidomide treatment
Table 2. Univariate analysis of factors affecting OS. Variable
Hazard ratio
Age (years)
1.065
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ISS stage at diagnosis I II
p-value
(1.014,1.119)
0.012 0.91
1.00
-
-
1.161
(0.484,2.783)
0.73
0.978
(0.436,2.19)
0.95
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III
95% CI
Response status at transplant
1.00
-
-
1.74
(0.70,4.31)
0.23
Stable disease
6.51
(2.05,20.6)
0.001
Months from auto to allo-HCT
1.03
(1.002,1.063)
0.033
PR
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CR/sCR/VGPR
0.004
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CMV reactivation No
1.00
-
-
Yes
3.47
(1.5,7.9)
0.003
No
1.00
-
Yes
2.30
(1.12,4.71)
No
1.00
-
Yes
1.03
(0.47,2.23)
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Acute GVHD(II-IV) -
Chronic GVHD
0.02
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-
Table 3. Multivariate analysis of factors affecting OS Hazard ratio
Age (years)
1.05
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Variable
Response status at transplant
0.04
1.52
(0.606,3.83)
0.37
(1.33,14.1)
0.006
1.00
-
-
3.2
(1.38,7.6)
0.002
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Yes
0.04
-
4.33
No
(1.001,1.113)
-
PR
CMV reactivation
p-value
1.00 CR/sCR/VGPR
Stable disease
95% CI
Table 4. MRD and morphological remission at day +100 N=46 (59.7%)
0.94
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32(41.5%)
MRD positive and CR/sCR
14(18.1%)
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MRD negative and CR/sCR
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Fig 1: PFS a. Overall; b. by transplant reason (planned auto-allo vs. salvage following relapse) c. by year of transplant (before 2000 vs. 2000 or later) and d. by number of lines of therapy in salvage allo-HCT.
Fig2: OS a. Overall; b. by transplant reason (planned auto-allo vs. salvage following relapse) c. by year of transplant (before 2000 vs. 2000 or later) and d. by number of lines of therapy in salvage allo-HCT.
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Figure 3a and 3b Progression free and overall survival by disease risk (FISH/Cytogenetics)
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Figure 3a and 3b Progression free and overall survival by disease risk (MRD status)
S2152-2650(16)30013-1
DOI:
10.1016/j.clml.2016.03.001
Reference:
CLML 768
To appear in:
Clinical Lymphoma, Myeloma and Leukemia
Received Date: 8 January 2016 Revised Date:
26 February 2016
Accepted Date: 21 March 2016
Please cite this article as: Dhakal B, D’Souza A, Martens M, Kapke J, Harrington A, Pasquini M, Saber W, Drobyski WR, Zhang MJ, Hamadani M, Hari PN, Allogeneic hematopoietic cell transplantation in multiple myeloma: impact of disease risk and post allograft minimal residual disease on survival, Clinical Lymphoma, Myeloma and Leukemia (2016), doi: 10.1016/j.clml.2016.03.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Allogeneic hematopoietic cell transplantation in multiple myeloma: impact of disease risk and post allograft minimal residual disease on survival Binod Dhakal, Anita D’Souza, Michael Martens, Jonathan Kapke, Alexandra Harrington,
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Marcelo Pasquini, Wael Saber, William R. Drobyski, Mei Jie Zhang, Mehdi Hamadani,
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Parameswaran N Hari
1. Division of Hematology/Oncology; Medical College of Wisconsin
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2. Division of Biostatistics; Medical College of Wisconsin
3. Department of Medicine; Medical College of Wisconsin
4. Department of Pathology; Medical College of Wisconsin
Corresponding author:
Professor of Medicine
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Parameswaran N Hari, M.D
Medical College of Wisconsin
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Milwaukee, WI 53226 Phone: (414) 805-4600
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Fax: (414)-805-6815
Email: [email protected]
Financial Disclosure and Propriety Statement: Nothing to disclose Running title: Allogeneic transplantation in multiple myeloma Key Words: Allogeneic stem cell transplantation, Multiple myeloma, Risk status and minimal residual disease
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Abstract: Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative
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option for multiple myeloma (MM). We analyzed our experience of allo-HCT in MM and examined outcomes in 77 consecutive MM patients receiving allo-HCT from matched
sibling (n=69) or unrelated donors (n=8). The primary objectives were to assess overall
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survival (OS), progression free survival, (PFS), and non-relapse mortality (NRM) in these patients. Sixty-six patients received non-myeloablative/reduced intensity conditioning
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regimens while 11 received myeloablative regimens. Median follow up of survivors was 50 months (range 2.3-129.3). Twenty-seven (35.1%) had high-risk cytogenetics at diagnosis (t (4:14), 17p deletion, chromosome 1 abnormality, or t (14:16)). All of patients except one had prior auto transplant. On multivariate analysis, older age (HR 1.055, 95% CI 1.001, 1.11; p=0.04) less than complete remission (CR) at allo-HCT (HR 4.3,
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95% CI 1.3, 14.1; p=0.006), and CMV reactivation (HR 3.2, 95% CI 1.38, 7.6, p=0.002) were associated with higher mortality risk. Less than complete remission (CR) at alloHCT was also associated with higher risk for NRM (HR 5.8, 95% CI 1.3, 26.3, p=0.02).
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There was no difference in OS or PFS between high risk and standard risk cytogenetics. No difference in OS and PFS was seen in those who had morphological complete
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response regardless of the minimal residual disease (MRD) status. Allotransplant benefited younger patients and those in CR at the time of transplant. The adverse effect of high-risk cytogenetics may be overcome by the allo-HCT. Micro abstract:
Allogeneic hematopoietic cell transplantation(allo-HCT) is a potentially curative for multiple myeloma. The results from randomized controlled trials, however, have shown conflicting outcomes. We retrospectively analyzed all multiple myeloma patients who underwent allo-HCT at our institution from 2002-2013. Our data suggests that allo-HCT
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can provide long term disease control in young patients and those with high-risk cytogenetics.
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Introduction: Outcomes for patients with multiple myeloma (MM) have improved in the past
decade with the incorporation of novel agents in therapeutic armamentarium, adoption of post autologous hematopoietic cell transplantation (auto-HCT)
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maintenance/consolidation strategies and with general advances in supportive care 1. Despite these advances, nearly all MM patients relapse and eventually develop
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refractory disease. The available options for relapsed patients include bortezomib, lenalidomide retreatment and newer drugs that include carfilzomib, pomalidomide, panabinostat and monoclonal antibodies 2,3. Allogeneic hematopoietic cell transplantation (allo-HCT); a potentially curative option in MM, has several advantages including a tumor-free graft, and the potential graft-versus-myeloma effect mediated by
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the alloreactive donor immune cells 4,5. However, owing to a high non-relapse mortality (NRM) associated with allo-HCT, a clear survival benefit with this modality compared to non-allo HCT approaches remains to be proven 6-8. Development of newer preparative
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regimens as well as improvements in supportive care has led to a decline in NRM from historical rates of 40-50% to 10-15% in recent years 9,10. The role of allo-HCT in the era
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of novel agents is not clearly defined however the approaches are not mutually exclusive 11-14
. Patients with high risk MM by cytogenetic criteria tend to run an aggressive course
despite novel agents15. Whether allo-HCT can improve prognosis of high risk MM is not clear 1. In addition while achieving a minimal residual disease (MRD) negative state in MM has been shown to be a strong favorable prognostic factor 16,for the outcomes of patients achieving a MRD negative remission after allo-HCT is also not known.
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We report here the utility of allo-HCT in a cohort of MM patients and evaluate the impact of allo-HCT on high-risk cytogenetics status. We also evaluate the impact of
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depth for HCT remission and MRD state post allo-HCT on the outcomes.
Materials and Methods: Patient population:
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All adult myeloma patients undergoing allo-HCT for MM from either a matched
sibling donor (MRD) or an unrelated donor (MUD) between 2002-2013 were included in
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the study. The Institutional Review Board at the Medical College of Wisconsin approved this study.
Preparative regimens and GVHD prophylaxis:
Patients received either a myeloablative or a non-myeloablative /reduced intensity conditioning regimens as defined previously 17. Regimen selection was based
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on the physician preference and available clinical trials. All patients received methotrexate and tacrolimus-based acute GVHD prophylaxis after 8/2004 and cyclosporine based prophylaxis before that. Patients received standard anti-microbial
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jiroveci.
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prophylaxis with ciprofloxacin, acyclovir, azoles and prophylaxis for Pneumocystis
Definitions of outcomes: Response, disease progression and relapse were defined according to the
International Myeloma Working Group uniform response criteria 18. For progression-free survival (PFS), a patient was considered a treatment failure at the time of progression/relapse or death from any cause. Death from any cause other than relapse was defined as NRM. Patients alive without evidence of disease relapse or progression were censored at last follow up. Overall survival (OS) was defined as the interval from
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the date of transplantation to the date of death. Surviving patients were censored at last follow up. Acute graft-versus-host disease (aGVHD) 19 and chronic graft-versus-host disease (cGVHD) 20 diagnosis and staging were based as described previously.
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Neutrophil engraftment was defined as first of 3 successive days with absolute neutrophil count >0.5 x 109/L after post-transplantation nadir. Platelet engraftment was
considered to have occurred in the first of three consecutive days with platelet count 20
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x 109/L or higher, in the absence of platelet transfusion for 7 consecutive days. High-risk MM was defined as having high risk chromosomal abnormalities: del 13 or hypodiploidy on conventional cytogenetics, chromosome 1 q abnormality (4:14), t(14:16) or del 17p
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on fluorescence in situ hybridization (FISH) or conventional cytogenetics 18,21. CMV reactivation was defined as more than 1000 copies/ml of CMV DNA by quantitative polymerase chain reaction (qPCR) assay. MRD monitoring by flow cytometry:
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Four or 8-color flow cytometry was perfomed on a FACSCalibur or FACSCanto II (March 2009-2013) using the following antibodies attached to fluorochromes: CD10, CD19, CD20, CD38, CD45, CD56, kappa and lambda. Anti-CD 117 and CD200
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antibodies were analyzed in some cases. Plasma cells were identified by cluster analysis as CD38 bright (+) events. Antigen expression was compared to an isotype
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control containing an anti-CD38 antibody. MRD analysis was performed by analyzing 200,000 events with Paint-a-Gate software (Becton Dickinson) and was defined as at last 0.01% plasma cells with either immunophenotypic aberrance or clonal light chain expression. Aberrancy was defined as lack of CD19 or expression of CD20, CD56, CD117 and/or CD200 in plasma cells; clonality was defined as 0.5 ≤ kappa/lamda ≥4.
Statistical Methods:
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The outcomes of interest included NRM, PFS and OS. Univariate analysis of these outcomes consisted of constructing Kaplan Meier curves of OS and PFS and cumulative incidence estimates of NRM. Cox proportional hazards regression was used
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to assess what factor impact these outcomes and the strength of the effects. For multivariate analysis, a Cox regression model of each outcome was
constructed using stepwise selection of potential risk factors including age, sex,
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International Staging System (ISS), response status at the time of allo-HCT, time from
auto-HCT to allo-HCT, CMV re-activation and aGVHD and cGVHD status. A significance
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level of 0.05 was used as the criterion for inclusion in the final model. Due to sample size limitations, interactions between predictors in the final models were not tested. All analysis was performed in SAS 9.4(SAS institute, Cary, NC). Results: Baseline characteristics
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Seventy-seven patients underwent allo-HCT for MM at our institution between 2002-2013. All except one patient had prior auto-HCT. Twenty-six patients received planned tandem allo-HCT after an auto-HCT. Out of 26 patients undergoing a planned
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tandem auto-allo HCT, 10 patients received planned auto-allo off trial due to high-risk cytogenetics and the remaining were part of BMT CTN 0102. The remaining patients
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received allo-HCT as salvage after auto-HCT relapse. Patient, disease and transplant characteristics are in Table 1. The median age of at transplant was 53 years (range 2369). At the time of allo-HCT, 30% (n= 23) of the patients were in complete remission and majority 62% (n=47) had at least a partial response. Majority had matched sibling donors (90%, n=69). The majority received non-myeloablative/reduced intensity conditioning regimens (86%, n=67). The median follow up of survivors was 50 months (range, 2.3129.3). Twenty-two patients received lenalidomide and three patients received bortezomib as maintenance therapy post allo-HCT.
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Engraftment: The median time to neutrophil engraftment was 13 days (range, 5-13) and 11
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days (range, 6-11) for myeloablative and reduced intensity conditioning regimens respectively. The median time to platelet engraftment was 17 days (range, 5-27) and 13 days (range, 9-15) for myeloablative and reduced intensity conditioning regimens. At day
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CI 91.5-100) of the patients engrafted their platelets.
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100, 97.3% (95% CI 93.7-100) of the patients engrafted their platelets and 95.9% (95%
GVHD:
Grade 2 aGVHD was seen in 14(18%), while grade 3 and grade 4 aGVHD was seen in 5(6.5%) and 3(4%) respectively. Chronic GVHD was seen in 29(37%) of the patients. The cumulative incidence of aGVHD was 23.1% (95% CI 15.4-34.7) at day 100
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and 28.3% (95% CI 19.9-40.4) at 1 year. The cumulative incidence of cGVHD was 28.8 % (95% CI 20.2-41) at 1 year and 33.4% (24.2-46.1) at 3 years.
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Non-relapse mortality:
There were 18 deaths (23.4%) from non-relapse causes overall and these
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etiologies included GVHD (n=5), infections (n=6), cardio or pulmonary failure (n=4) and other causes (n=3). Cumulative incidence of NRM at 1 year was 13% (95% CI 7.3-23.2). On multivariate analysis, lack of CR status at allo-HCT (HR, 5.8 95% CI 1.3-26.2, P=0.021) was associated with higher risk of NRM.
Response/Progression: At day +100 post-transplant evaluation, 14 achieved stringent complete response (sCR), 39 patients were in CR, 5 patients had very good partial response (VGPR), 15
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patients had partial response (PR) and 4 had relapse/progression of the disease. At a median follow up of 50 months, 27(35.1%) had disease progression. The cumulative incidence of disease relapse at day 100 was 2.6% (95% CI, 0.6-10.2) and at 1 year was
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14.4 % (95% CI 8.3-24.9). Progression-free survival:
The PFS at 1 year 72.6% (95% CI, 61.1-81.2) and at 3 year was 47% (95% CI
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34.5-58.2) (Fig 1a). There was no difference in the PFS in patients who had planned tandem allo-HCT vs. those who had salvage allo-HCT (Fig 1b). There was trend for
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improved PFS in patients who had allo-HCT after 2008; however did not reach statistical significance (Fig1c). Number of lines of prior therapies (≤2 prior therapies vs. >2 prior therapies) in patients undergoing salvage allo-HCT did not affect the PFS (Fig 1d). On multivariate analysis, age, stage of disease, time from auto-HCT to allo-HCT and development of GVHD did not have any significant effect on PFS. In our study 8 patients
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received donor lymphocyte infusion (DLI) for progression/relapse, out of which 5 responded i.e. a response rate of 62.5%. The median duration of response to DLI was 8
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months (range, 1-36).
Overall survival:
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The OS at 1 year was 83% (95% CI 72.5-89.8) and at 3 years was 63.8% (95% CI 51-74.2) (Fig 2a). Patients who had planned tandem allo-HCT and those who had salvage allo-HCT had similar OS in our study (Fig 2b). There was no difference in OS in patients who had allo-HCT after 2008(Fig 2c). No difference was seen in OS of patients undergoing salvage allo-HCT when stratified on number of lines of prior therapies (≤2 prior therapies vs. >2 prior therapies) (Fig2d). On multivariate analysis, age (HR 1.05,95% CI 1.001-1.13,p=0.04), lack of CR status at allo-HCT (HR 4.3, 95% CI 1.3-
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7.6,p=0.006) and CMV reactivation (HR 3.2, 95% CI 1.3-7.6,p=0.002) were significantly associated with worse OS (Table 3).
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Risk status: Twenty-seven patients had high-risk disease by FISH or cytogenetics. Fig 3a and 3b shows both the PFS and OS by risk status in these patients. There was no difference
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in high-risk vs. standard risk patients in either PFS (3 year 39% vs. 55%, p= 0.62) or OS (3 year 50% vs. 67%, p=010) respectively. Among the high-risk patients, 5 patients
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(6.4%) were dual-refractory (i.e. refractory to lenalidomide and bortezomib) and 2 patients were refractory to bortezomib only. Of those 5 patients, 3 achieved MRD negative state at day 100 and morphologic CR. These patients were still alive at the time of follow up. The remaining 2 patients had positive MRD at day 100 and died due to nonrelapse causes.
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Minimal residual disease status
Minimal residual disease status at day 100 was available in 46 patients. Of those 46 patients, 32 patients were MRD negative at day 100. Of these, 20 were in CR and 12
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were in sCR. Fourteen patients were MRD positive; 12 were in CR and 2 in sCR at day +100. There was no difference in both OS and PFS by MRD status in those with
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morphological CR/sCR at day 100(Fig4a and 4b). The 3 year PFS and OS for MRD negative vs. positive patients were 63.2% vs. 38.4%(p=0.45) and 78.7% vs. 59.6% (p=0.35)respectively.
Discussion: Our data suggest that allo-HCT in MM can provide sustained long term remissions in patients with high-risk disease or those who have relapsed after auto-HCT. Importantly, there was no difference in the survival between high-risk and standard risk
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cytogenetic risk groups suggesting that this modality may overcome the status conferred by high-risk FISH abnormalities. CMV reactivation was associated with worse overall survival.
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Allogeneic hematopoietic stem cell transplant preceded by classic myeloablative conditioning therapy was explored for MM in the late 1980s through the mid-1990s22-24. A most consistent finding with the use of myeloablative conditioning was high NRM of 40-
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60% leading to alternative approach of non-myeloablative/reduced intensity conditioning (NST/RIC) regimens. Randomized trials have attempted to evaluate tandem AutoHCTalloHCT approach vs. tandem auto-HCT in the upfront transplant setting using non25,26
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myeloablative preparative regimens
. The results of the study showed lower NRM
(10-15%) than the myeloablative conditioning, however survival results were discordant. The BMTCTN 0102, one of the largest myeloma transplant trials conducted in the US showed no difference in the primary end point of 3-year PFS (46% in the tandem auto27
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HCT group vs. 43% in the auto-alloHCT)
. In contrast, the study from the European
Blood and Marrow Transplant network showed that with a median follow up of 8 years, the PFS and OS for the tandem auto-alloHCT was superior to the tandem auto-HCT 28,29
.The difference in outcomes in these
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group with NRM of 13% in the allo-HCT arm
studies could partly be explained by the variability in conditioning regimens used, patient
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selection, MM risk profile etc. In our study, the cumulative incidence of NRM was 13% at 1 year; the 5-year PFS and OS was 38% and 58.6% respectively. These outcomes are similar to and even superior to some other published single institution studies30-32. Given the lack of consistent survival benefit, in both newly diagnosed and relapsed MM, use of allo-HCT in MM should ideally be restricted to well-designed clinical trials. However, in patients with high-risk MM by cytogenetic criteria, long-term prognosis is poor and role of early allo-HCT as part of their initial therapy program or in first chemotherapy-sensitive relapse warrants prospective investigation. The recently launched BMT CTN trial 1302 is
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evaluating the role of early allo-HCT in high risk MM patients followed by maintenance with MLN9708. High-risk cytogenetics are associated with worse outcomes after auto-HCT. The
previously published study
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impact of high- risk cytogenetics on the outcomes disappeared after allo-HCT in 30
. Our study also supports these findings, as both the OS
and PFS in the high-risk groups were similar as the standard risk groups. These findings
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add to the literature that the negative clinical and molecular prognostic factors may be overcome by allo-HCT in MM. The ongoing BMT CTN 1302 assessing the role of allo-
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HCT in high risk MM followed by maintenance with new proteasome inhibitor (ixazomib) may shed more light in this area in the prospective setting.
The role of MRD negativity in multiple myeloma is currently under investigation 33
. Some reports suggest that MRD negativity may translate to improved PFS and OS
34,35
. MRD has also been investigated as a tool to predict relapse free survival after
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alloHCT36. Galimberti et al reported that for patients post alloHCT, persistent PCR (polymerase chain reaction) negativity was associated with a cumulative risk of relapse at five years of 0%, while those with mixed Allele-specific oligonucleotide Polymerase
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chain reaction (ASO-PCR) results had a relapse rate of 33% and those who never achieved ASO-PCR negativity relapsed at a rate of 100%37. Our study did not show any
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survival difference in CR/sCR patients who achieved negative MRD by flow cytomtery at day 100 versus those who were MRD positive; however this could be due to the small sample size of patients with MRD testing in CR/sCR after allo-HCT in our study. Donor lymphocyte infusions are able to induce a clinically meaningful GVM effect
in some patients relapsing after allo-HCT in MM
38
. In a series of 54 patients with MM,
DLI yielded overall and complete response rates of 52 and 17 percent, and acute and chronic GVHD in 57 and 47 percent, respectively
39
.The response to DLI was 62.5% in
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our series. Allogeneic hematopoeitic stem cell transplant thus remains a platform for additional immune based strategies at relapse or to preempt relapse. The Italian Bone Marrow registry data of 196 patients with MM receiving an
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unrelated donor transplant showed a significant improvement in OS for patients with chronic graft versus host disease (cGVHD)(HR,.55)40 suggesting the graft vs MM effect(GVM). In another single institution study, development of cGVHD was associated 30
.
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with favorable overall and progression free survival further elucidating the GVM effect
However, our study did not show any significant effect of cGVHD on survival presumably
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because of low cGVHD rates. Development of acute GVHD in our study was associated with worse survival in univariate analysis but had no significance in multivariate analysis. Donor and recipient CMV seronegative status has been suggested as a predictor of better OS, PFS and NRM41. Other studies have reported higher rates of CMV reactivation but no effect on the post transplantation outcomes
42
. In our study, CMV
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reactivation was consistently associated with worse overall survival underscoring the need for close monitoring and aggressive preemptive treatment. The strength of the study is the relatively large sample of allo-HCT in the era of
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novel therapeutics. Our study also has its limitations owing to its retrospective nature. There is significant heterogeneity in the study groups (planned tandem vs. salvage
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group), the various induction regimens used over the course of years and also the variability in the conditioning regimens. In conclusion, our study demonstrates that young MM patients with high risk
disease may benefit from allo-HCT. Consideration should be given early in the disease course. Close monitoring of CMV and aggressive pre-emptive treatments should be adopted given the worse outcomes with CMV reactivation. Donor lymphocyte infusion can be a salvage option in these patients relapsing after allo-HCT. While our study
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suggests allo-HCT can mitigate high risk MM, ultimately larger prospective studies are still needed to establish the role of allo-HCT particularly in this setting. Clinical practice points:
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1. Multiple myeloma remains an incurable disease despite the development of novel agents, maintenance/consolidation after autologous stem cell transplant and overall improvement in supportive care.
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2.The outcome of patients with high-risk cytogenetics is even dismal with median overall survival of 10-12 months with therapy.
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3. Allogeneic stem cell transplantation is a potentially curative option for this disease. 4. There was no difference in high-risk vs. standard risk patients in either PFS (3 year 39% vs. 55%, p= 0.62) or OS (3 year 50% vs. 67%, p=010) respectively. 5. On multivariate analysis, age (HR 1.05,95% CI 1.001-1.13,p=0.04), lack of CR status at allo-HCT (HR 4.3, 95% CI 1.3-7.6,p=0.006) and CMV reactivation (HR 3.2, 95% CI
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1.3-7.6,p=0.002) were significantly associated with worse OS.
6. Young MM patients with high risk disease may benefit from allo-HCT.
References:
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van Biezen A, Goldschmidt H, de Witte T, Morris C, Niederwieser D, Garderet L, Kroger N, EBMT Chronic Malignancies Working Party Plasma Cell Disorders Subcommittee. Autologous/reduced-intensity allogeneic stem cell transplantation vs autologous transplantation in multiple myeloma: long-term results of the EBMT-NMAM2000 study. Blood. 2013;121:5055-63. 30. Donato ML, Siegel DS, Vesole DH, McKiernan P, Nyirenda T, Pecora AL, Baker M, Goldberg SL, Mato A, Goy A, Rowley SD. The graft-versus-myeloma effect: chronic graft-versus-host disease but not acute graft-versus-host disease prolongs survival in patients with multiple myeloma receiving allogeneic transplantation. Biol Blood Marrow Transplant. 2014;20:1211-6. 31. Mir MA, Kapoor P, Kumar S, Pandey S, Dispenzieri A, Lacy MQ, Dingli D, Hogan W, Buadi F, Hayman S, Gandhi M, Gertz MA. Trends and outcomes in allogeneic hematopoietic stem cell transplant for multiple myeloma at mayo clinic. Clin Lymphoma Myeloma Leuk. 2015;15:349,357.e2. 32. Rosinol L, Jimenez R, Rovira M, Martinez C, Fernandez-Aviles F, Marin P, SuarezLledo M, Gutierrez-Garcia G, Fernandez de Larrea C, Carreras E, Urbano-Ispizua A, Blade J. Allogeneic hematopoietic SCT in multiple myeloma: long-term results from a single institution. Bone Marrow Transplant. 2015;50:658-62. 33. Kumar SK, Rajkumar SV. The current status of minimal residual disease assessment in myeloma. Leukemia. 2014;28:239-40. 34. Martinez-Sanchez P, Montejano L, Sarasquete ME, Garcia-Sanz R, FernandezRedondo E, Ayala R, Montalban MA, Martinez R, Garcia Larana J, Alegre A, Hernandez B, Lahuerta JJ, Martinez-Lopez J. Evaluation of minimal residual disease in multiple myeloma patients by fluorescent-polymerase chain reaction: the prognostic impact of achieving molecular response. Br J Haematol. 2008;142:766-74. 35. Rawstron AC, Child JA, de Tute RM, Davies FE, Gregory WM, Bell SE, Szubert AJ, Navarro-Coy N, Drayson MT, Feyler S, Ross FM, Cook G, Jackson GH, Morgan GJ, Owen RG. Minimal residual disease assessed by multiparameter flow cytometry in multiple myeloma: impact on outcome in the Medical Research Council Myeloma IX Study. J Clin Oncol. 2013;31:2540-7. 36. Corradini P, Cavo M, Lokhorst H, Martinelli G, Terragna C, Majolino I, Valagussa P, Boccadoro M, Samson D, Bacigalupo A, Russell N, Montefusco V, Voena C, Gahrton G, Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Molecular remission after myeloablative allogeneic stem cell transplantation predicts a better relapse-free survival in patients with multiple myeloma. Blood. 2003;102:1927-9. 37. Galimberti S, Benedetti E, Morabito F, Papineschi F, Callea V, Fazzi R, Stelitano C, Andreazzoli F, Guerrini F, Ciabatti E, Martino M, Nobile F, Iacopino P, Petrini M. Prognostic role of minimal residual disease in multiple myeloma patients after nonmyeloablative allogeneic transplantation. Leuk Res. 2005;29:961-6. 38. Mateos MV, Oriol A, Martinez-Lopez J, Gutierrez N, Teruel AI, de Paz R, GarciaLarana J, Bengoechea E, Martin A, Mediavilla JD, Palomera L, de Arriba F, Gonzalez Y, Hernandez JM, Sureda A, Bello JL, Bargay J, Penalver FJ, Ribera JM, Martin-Mateos ML, Garcia-Sanz R, Cibeira MT, Ramos ML, Vidriales MB, Paiva B, Montalban MA, Lahuerta JJ, Blade J, Miguel JF. Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: a randomised trial. Lancet Oncol. 2010;11:934-41. 39. Lokhorst HM, Wu K, Verdonck LF, Laterveer LL, van de Donk NW, van Oers MH, Cornelissen JJ, Schattenberg AV. The occurrence of graft-versus-host disease is the
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major predictive factor for response to donor lymphocyte infusions in multiple myeloma. Blood. 2004;103:4362-4. 40. Passera R, Pollichieni S, Brunello L, Patriarca F, Bonifazi F, Montefusco V, Falda M, Montanari M, Guidi S, Giaccone L, Mordini N, Carella AM, Bavaro P, Milone G, Benedetti F, Ciceri F, Scime R, Benedetti E, Castagna L, Festuccia M, Rambaldi A, Bacigalupo A, Corradini P, Bosi A, Boccadoro M, Bandini G, Fanin R, Bruno B. Allogeneic hematopoietic cell transplantation from unrelated donors in multiple myeloma: study from the Italian Bone Marrow Donor Registry. Biol Blood Marrow Transplant. 2013;19:940-8. 41. Auner HW, Szydlo R, van Biezen A, Iacobelli S, Gahrton G, Milpied N, Volin L, Janssen J, Nguyen Quoc S, Michallet M, Schoemans H, El Cheikh J, Petersen E, Guilhot F, Schonland S, Ahlberg L, Morris C, Garderet L, de Witte T, Kroger N, Plasma Cell Dyscrasia Sub-committee of the Chronic Malignancies Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Reduced intensityconditioned allogeneic stem cell transplantation for multiple myeloma relapsing or progressing after autologous transplantation: a study by the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant. 2013;48:1395-400. 42. El-Cheikh J, Devillier R, Crocchiolo R, Furst S, Calmels B, Faucher C, Stoppa AM, Granata A, Castagna L, Ladaique P, Lemarie C, Bouabdallah R, Zandotti C, Merlin M, Berger P, Chabannon C, Blaise D. Impact of pretransplant donor and recipient cytomegalovirus serostatus on outcome for multiple myeloma patients undergoing reduced intensity conditioning allogeneic stem cell transplantation. Mediterr J Hematol Infect Dis. 2013;5:e2013026.
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49 (64) 28 (36)
27 (35) 21 (27) 28 (36) 1 (2) 90 (80-100) 1 (0-3) 76 (98.7%) 77 (100%)
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Median age at transplant, years (range) Median time from diagnosis to transplant, months (range) Gender -Male -Female International Staging System -I -II -III -Missing 1 KPS (median, range) 2 HCT-CI (median, range) Prior Auto transplant Graft source(Peripheral Blood) 3 Cytogenetics/FISH -Standard risk -High Risk GVHD prophylaxis -Methotrexate/Cyclosporine -Methotrexate/Tacrolimus
Total, N=77 (%) 53 (23-69) 12 (7-81)
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Characteristics
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Table 1. Baseline characteristics
50 27
15 (19.4) 62 (80.5)
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Disease Status at Transplant 4 -sCR, CR 17 (22) 5 -VGPR 6(7.7) 6 -PR 47 (62) -Stable or Progressive disease 7 (6) Refractory to Novel agents Bortezomib 2(2.5) 7 Double 5(6.4) Donor type -HLA identical sibling 69 (90) -Matched Unrelated donor (8/8 allele level match) 8 (10) Type of transplant -Myeloablative 11 (14) -Non-myeloablative/Reduced intensity 66 (86) Maintenance therapies post allogeneic-HCT -Lenalidomide 22(29) -Bortezomib 3(4) Conditioning regimen -Low dose TBI (2Gy) 45 (59) -Cyclophosphamide/Fludarabine 7 (9) -Cyclophosphamide/TBI 4 (5) -Fludarabine/Melphalan 11 (14) -Fludarabine/TBI 6 (8) -Others* 4 (5) * Melphalan=1, Fludarabine/Busulfan=1, 5 Fluorouracil, Mitomycin,Etoposide and Cisplatin=2 1-Karnosky performance score 2- Hematopoietic cell transplant co-morbidity index
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3-High risk: del 13 or hypodiploidy on conventional cytogenetics, chromosome 1 q abnormality, t(4:14), t(14:16) or del 17p on fluorescence in situ hybridization (FISH) or conventional cytogenetics 4-sCR: stringent complete response, CR: complete response, 5- VGPR: very good partial response 6-PR: partial response
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7- Refractory to Bortezomib and Lenalidomide treatment
Table 2. Univariate analysis of factors affecting OS. Variable
Hazard ratio
Age (years)
1.065
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ISS stage at diagnosis I II
p-value
(1.014,1.119)
0.012 0.91
1.00
-
-
1.161
(0.484,2.783)
0.73
0.978
(0.436,2.19)
0.95
EP
III
95% CI
Response status at transplant
1.00
-
-
1.74
(0.70,4.31)
0.23
Stable disease
6.51
(2.05,20.6)
0.001
Months from auto to allo-HCT
1.03
(1.002,1.063)
0.033
PR
AC C
CR/sCR/VGPR
0.004
ACCEPTED MANUSCRIPT
CMV reactivation No
1.00
-
-
Yes
3.47
(1.5,7.9)
0.003
No
1.00
-
Yes
2.30
(1.12,4.71)
No
1.00
-
Yes
1.03
(0.47,2.23)
RI PT
Acute GVHD(II-IV) -
Chronic GVHD
0.02
M AN U
SC
-
Table 3. Multivariate analysis of factors affecting OS Hazard ratio
Age (years)
1.05
TE D
Variable
Response status at transplant
0.04
1.52
(0.606,3.83)
0.37
(1.33,14.1)
0.006
1.00
-
-
3.2
(1.38,7.6)
0.002
EP
AC C
Yes
0.04
-
4.33
No
(1.001,1.113)
-
PR
CMV reactivation
p-value
1.00 CR/sCR/VGPR
Stable disease
95% CI
Table 4. MRD and morphological remission at day +100 N=46 (59.7%)
0.94
ACCEPTED MANUSCRIPT
32(41.5%)
MRD positive and CR/sCR
14(18.1%)
AC C
EP
TE D
M AN U
SC
RI PT
MRD negative and CR/sCR
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
Fig 1: PFS a. Overall; b. by transplant reason (planned auto-allo vs. salvage following relapse) c. by year of transplant (before 2000 vs. 2000 or later) and d. by number of lines of therapy in salvage allo-HCT.
Fig2: OS a. Overall; b. by transplant reason (planned auto-allo vs. salvage following relapse) c. by year of transplant (before 2000 vs. 2000 or later) and d. by number of lines of therapy in salvage allo-HCT.
RI PT
ACCEPTED MANUSCRIPT
M AN U
SC
Figure 3a and 3b Progression free and overall survival by disease risk (FISH/Cytogenetics)
AC C
EP
TE D
Figure 3a and 3b Progression free and overall survival by disease risk (MRD status)